In the Name of God the Compassionate the Merciful

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Archives of Iranian Medicine, Volume 15, Number 4, April 2012 iii Table of Contents

Table of Contents

194 • Editorial Esophageal Cancer Incidence Trends in Northeastern Iran: Compar- ing Rates Over 36 Years H. Khademi, F. Kamangar 194 196 • Original Articles Cancer Incidence in Golestan Province: Report of an Ongoing Popu- lation-based Cancer Registry in Iran, 2004–2008 G. Roshandel, A. Sadjadi, M. Aarabi, A. Keshtkar, S. M. Sedaghat, S. M. Nouraie, S. Semnani, R. Malekzadeh 196

Trends in Change of Mental Health Status in the Population of Teh- ran between 1998 and 2007 A. A. Noorbala, S. A. Bagheri Yazdi, M. Hafezi 201

Prevalence of Psychiatric Disorders in the General Population of Kashan, Iran A. Ahmadvand, Z. Sepehrmanesh, F. S. Ghoreishi, S. Afshinmajd 205

Suicide Epidemiology and Characteristics among Young Iranians at Poison Ward, Loghman-Hakim Hospital (1997–2007) A. Pajoumand, H. Talaie, A. Mahdavinejad, S. Birang, M. Zarei, F. F. Mehregan, B. Mostafazadeh 210

Xerostomia after Radiotherapy and its Effect on Quality of Life in Head and Neck Cancer Patients S. Kakoei, A. A. Haghdoost, M. Rad, S. Mohammadalizadeh, N. Pour- damghan, M. Nakhaei, M. Bahador 214

Impact of Exploration of Sensory Branches of Saphenous Nerve in Anterior Cruciate Ligament Reconstructive Surgery F. Mirzatolooei, K. Pisoodeh 219

Which Information Resources are used by General Practitioners for Updating Knowledge Regarding Diabetes? O. Tabatabaei-Malazy, S. Nedjat, R. Majdzadeh 223

Congenital Anomalies in Infants Conceived by Assisted Reproductive Techniques R. Mozafari Kermani, L. Nedaeifard, M. R. Nateghi, A. Shahzadeh Fazeli, E. Ahmadi, M. A. Osia, E. Jafarzadehpour, S. Nouri 228

Chromosomal Abnormality in Patients with Secondary Amenorrhea A. Safai, M. Vasei, A. Attaranzadeh, F. Azad, N. Tabibi 232

Augmentation Rhinoplasty with Combined use of Medpor Graft and Irradiated Homograft Rib Cartilage in Saddle Nose Deformity E. Razmpa, B. Saedi, F. Mahbobi 235

iv Archives of Iranian Medicine, Volume 15, Number 4, April 2012 Table of Contents

239 • Review Article Pathogenesis and Glycemic Management of Type 2 Diabetes Mellitus: A Physiological Approach F. Ismail-Beigi 239 247 • Brief Report Liver Involvement in Melamine-associated Nephrolithiasis P. Hu, J. Wang, M. Zhang, B. Hu, L. Lu, C. R. Zhang, P. F. Du 247 249 • Case Reports Two Novel Familial Balanced Translocations t(8;11)(p23;q21) and t(6;16)(q26;p12) Implicated in Recurrent Spontaneous Abortion F. Keify, N. Zhiyan, F. Mirzaei, S. Tootian, S. Ghazaey, M. R. Abbaszadegan 249

Bilateral Psoas Abscess: Atypical Presentation of Spinal Tu- berculosis V. Goni, B. R. Thapa, S. Vyas, N. R. Gopinathan, S. Rajan Mano- haran, V. Krishnan 253 257 • Photoclinic Z. Khorgami, T. Anbara, A. Mohammadnejad, H. Mahmoodza- deh 257 259 • History of Contemporary Medicine in Iran Impact of Quality Mentorship on Achievements of Shiraz Medical School in the 1970s and the Role of Professor Fara- marz Ismail-Beigi M. H. Azizi, S. Nasseri-Moghaddam 259 263 • Excerpts from Persian Medical Literature 265 • Commented Summary from Current Med- ical Literature “Serum Pepsinogen II as a Good Marker for Mass Screening and Eradication of H. pylori Infection in Populations at risk for Gastric Cancer” S. Massarrat, A. Sheykholeslami 265

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 v Esophageal Cancer Incidence Trends in Northeastern Iran

Editorial Esophageal Cancer Incidence Trends in Northeastern Iran: Comparing Rates Over 36 Years

See the pages 196-200

Cite the article as: Khademi H, Kamangar F. Esophageal Cancer Incidence Trends in Northeastern Iran: Comparing Rates Over 36 Years. Arch Iran Med. 2012; 15(4): 194 – 195.

n this issue of the Journal, Roshandel and colleagues present We believe that the reductions are real. Although Mahbouhi the results of a population-based cancer registry in Golestan and Kmet’s case diagnoses were mostly based on clinical and/ I Province, in northeastern Iran.1 The authors should be or radiologic features, rather than microscopic verification,2 clini- praised for establishing a population-based cancer registry with cal features of EC – i.e., progressive dysphagia in older patients high standards in Iran, where there is relatively scant reliable in- followed by emaciation and death – make it easily distinguish- formation from comprehensive registries, thus adding to our cur- able from most other malignant or non-malignant conditions. One rent knowledge of cancer epidemiology in Iran and the Middle- exception, however, is gastric cardia adenocarcinoma, which has East. In a matter of a few years, these investigators were able to similar clinical presentations. Results from recent studies show improve the methods of cancer registry from retrospective to pro- that this cancer is rather common in Golestan Province, suggest- spective registry, substantially increase the proportion of cases ing some of the EC cases diagnosed in the 1970s might have been that are verified microscopically, and reduce the number of cases gastric cardia cancers; though this cannot explain the observed that are classified solely based on death certificates. differences between now and then. The sum of the ASRs for fe- What makes the results of this cancer registry of even more in- male esophageal and gastric (both cardia and noncardia) cancers terest is that Golestan Province has long been known to have ex- shown in Table 3 of Roshandel is 31.5 / 105 (19.1 for EC and 12.4 ceptionally high rates of esophageal cancer (EC). Based on anec- for gastric cancer). This number is lower than the rates observed dotal reports of such high rates, Janiz Kmet from the International in the region with the lowest incidence in the 1970s (38.7 / 105) Agency for Research on Cancer (IARC) and Ezzatollah Mahbou- and far lower than those seen in the region with the highest inci- bi from the Institute of Public Health Research (IPHR) of Tehran dence (195 / 105). The real difference is perhaps much more, as University established a cancer registry in Golestan Province – only half the gastric cancers in this area are cardia cancers, and it then the eastern part of Mazandaran Province -- and neighboring is unlikely that all of them would have been misclassified as EC, areas from 1968 to 1971, the results of which were published in considering that in the 1970s gastric cancer itself was the second 1973.2 This cancer registry, the first of its kind in Iran, showed highest reported cancer in the area. Similar, but not quite as strik- very high EC incidence rates, with annual age-standardized rates ing reductions, have been seen in men too. Also, one has to note (ASRs) up to 165 per 100,000 in men and 195 per 100,000 in that the1970s rates were adjusted to the World Population in 1960, women, in certain parts of the Golestan Province (Table 4 in whereas Roshandel’s rates were adjusted to the standard World Roshandel’s study). Rates were high in other parts of the Province Population in 2000.1 Given that in 1960 World Population was too, though not as high. These findings led to the establishment younger, if Roshandel et al. were to adjust their rates to 1960, they and completion of several etiologic and early detection studies in would have been even lower. the 1970s. These studies were terminated in 1979, but in the late So what is the cause of such a decline? One could only make 1990s and early 2000s a new international collaboration resumed educated guesses, as reliable information on the etiology of EC investigations into the etiology of EC in the Golestan Province in Golestan Province is relatively scant. Genetic risk factors are (reviewed in Kamangar et al3, and Islami et al4). These new col- not suspect, as gene pool, at least at the nucleotide level, takes laborations have thus far led to the completion of a case-control millions of years to change. No major immigration or emigra- study and an ongoing cohort study.3,5 The results of the cancer tion has happened in this area in the past 40 years. So what about registry by Roshandel et al. complement the results of the case- environmental factors? Approximately 90% of the EC cases in control and cohort studies and help in more accurate diagnosis of this area are esophageal squamous cell carcinomas (ESCCs)6 but cases in the cohort. Furthermore, they allow us to compare rates in Golestan – unlike that seen in the United States and Europe -- of various cancers, including EC rates between now and those cigarette smoking and alcohol consumption are not major causes found by Mahbouhi and Kmet 36 years earlier. of ESCC.7–9 Early publications in the 1970s, mostly based on eco- Roshandel’s results suggest that EC rates are still high in Goles- logical studies,9 suggested a host of factors as potential risk fac- tan. However, compared to 36 years ago, ASRs of EC in this tors for ESCC in this area. However, future case-control studies Province have decreased between 57% and 82%, respectively. examined only a number of these factors and provided support to Facing such dramatic reductions, two questions come to mind. only a few of them – i.e., low socioeconomic status,7,10 low intake First, are the reductions real? Or are they due to other explana- of fruit and vegetables,9,11 opium use,8,9,12 and drinking very hot tions, such as overestimation of the rates in 1970s? Second, if the tea9,13 – to be risk factors. The putative risk effects of low intake declines are real, what could be the possible cause? of vitamins and/or essential metals and minerals, such as zinc,14,15

194 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 H. Khademi, F. Kamangar and also wheat seed contamination4,9 by carcinogens, fungi, or References unknown foreign seeds are still open questions. None of the suggested risk factors were very strong, and none has yet been shown 1. Roshandel G, Sadjadi A, Arabi M, Keshtkar A, Sedaghat M, Nouraei to be a risk factor for ESCC in a prospective study. But if we as- M, et al. Cancer Incidence in Golestan: report of an Ongoing Popula- tion-based Cancer Registry in Iran, 2004–2008. Arch Iran Med. 2012; sume that these are causal, one might be able to suggest why rates 15: 196 – 200. have reduced. 2. Mahboubi E, Kmet J, Cook PJ, Day NE, Ghadirian P, Salmasizadeh Socioeconomic status of the society overall has improved dra- S. Oesophageal cancer studies in the Caspian Littoral of Iran: the Cas- matically over the past few decades. As discussed elsewhere,10 pian cancer registry. Br J Cancer. 1973; 28: 197 – 214. 3. Kamangar F, Malekzadeh R, Dawsey SM, Saidi F. Esophageal cancer there has been substantial improvement in access to education, in Northeastern Iran: a review. Arch Iran Med. 2007; 10: 70 – 82. electricity, safe drinking water, telephone communications and 4. Islami F, Kamangar F, Nasrollahzadeh D, Moller H, Boffetta P, roads. For example, the number of people aged 7 to 29 years in Malekzadeh R. Oesophageal cancer in Golestan Province, a high- incidence area in northern Iran - a review. Eur J Cancer. 2009; 45: the study area who had no formal education decreased from 75% 3156 – 3165. in 1966 to 7% in 1996, and the percentage of households with ac- 5. Pourshams A, Khademi H, Malekshah AF, Islami F, Nouraei M, Sad- cess to electricity increased from 11% in 1966 to 95% in 1996. As jadi AR, et al. Cohort Profile: the Golestan Cohort Study--a prospec- a result of improvement in the roads and availability of refrigera- tive study of oesophageal cancer in northern Iran. Int J Epidemiol. 2010; 39: 52 – 59. tors, access to fresh fruit and vegetables has increased. Addition- 6. Islami F, Kamangar F, Aghcheli K, Fahimi S, Semnani S, Taghavi N, ally, introduction of industrialized farming to the area has resulted et al. Epidemiologic features of upper gastrointestinal tract cancers in in significant improvements in both storage and winnowing of Northeastern Iran. Br J Cancer. 2004; 90: 1402 – 1406. wheat seed, thus decreasing the possibility of contamination to 7. Cook-Mozaffari PJ, Azordegan F, Day NE, Ressicaud A, Sabai C, Ar- amesh B. Oesophageal cancer studies in the Caspian Littoral of Iran: the lowest achievable levels. results of a case-control study. Br J Cancer. 1979; 39: 293 – 309. Opium use has also declined. A study of 1590 rural individuals 8. Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, in the 1970s showed that the prevalence of opium use in areas Abnet CC, et al. Opium, tobacco, and alcohol use in relation to oe- with high or very high risk for EC was 54% in men over 50 years sophageal squamous cell carcinoma in a high-risk area of Iran. Br J 12 Cancer. 2008; 98: 1857 – 1863. of age and 30% in women in that age range. Recent data from 9. Esophageal cancer studies in the Caspian littoral of Iran: results of Golestan Cohort Study (unpublished), however, show that the population studies--a prodrome. Joint Iran-International Agency for prevalence of opium use in rural men and women over 50 years Research on Cancer Study Group. J Natl Cancer Inst. 1977; 59: 1127 of age is 32% and 12%, respectively. Perhaps such a substantial – 1138. 10. Islami F, Kamangar F, Nasrollahzadeh D, Aghcheli K, Sotoudeh M, decrease can partly explain reduced rates. Abedi-Ardekani B, et al. Socio-economic status and oesophageal can- These factors, alone or interacting with each other, might have cer: results from a population-based case-control study in a high-risk resulted in reduced risks. In addition, it has been suggested that area. Int J Epidemiol. 2009; 38: 978 – 988. 11. Islami F, Malekshah AF, Kimiagar M, Pourshams A, Wakefield J, Go- a very strong risk factor, yet unidentified, may exist in Golestan glani G, et al. Patterns of food and nutrient consumption in northern 3 Province that has led to the extremely high rates of EC. If such Iran, a high-risk area for esophageal cancer. Nutr cancer. 2009; 61: factor exists, though yet entirely speculative, its prevalence may 475 – 483. be on the decline because of the substantial changes in the envi- 12. Ghadirian P, Stein GF, Gorodetzky C, Roberfroid MB, Mahon GA, Bartsch H, et al. Oesophageal cancer studies in the Caspian littoral of ronment observed over the past few decades. Iran: some residual results, including opium use as a risk factor. Int J Declining rate of EC in Golestan, due to any reason, is good Cancer. 1985; 35: 593 – 597. news. Establishing an excellent registry in Golestan, which helps 13. Islami F, Pourshams A, Nasrollahzadeh D, Kamangar F, Fahimi S, health authorities as well as ongoing studies, is also good news. Shakeri R, et al. Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study. BMJ. We look forward to future reports from this registry, hoping that 2009; 338: b929. even further declines would be reported. In the meantime, further 14. Abnet CC, Lai B, Qiao YL, Vogt S, Luo XM, Taylor PR, et al. Zinc epidemiological studies are needed to increase our knowledge of concentration in esophageal biopsy specimens measured by x-ray the causes of EC in this region. fluorescence and esophageal cancer risk. J Natl Cancer Inst. 2005; 97: 301 – 306. 15. Kmet J, Mahboubi E. Esophageal cancer in the Caspian littoral of Hooman Khademi MD1,2, Farin Kamangar MD•1,3 Iran: initial studies. Science. 1972; 175: 846 – 853. 1Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran, 2International Agency for Research on Cancer, Lyon, France. 3Department of Public Health Analysis, School of Community Health and Policy, Morgan State University, Baltimore, MD, USA. E-mail: [email protected]

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 195 Cancer Incidence in Golestan Province

Original Article Cancer Incidence in Golestan Province: Report of an Ongoing Population-based Cancer Registry in Iran between 2004 and 2008

Gholamreza Roshandel MD1,2, Alireza Sadjadi MD1,3, Mohsen Aarabi PhD2, Abbasali Keshtkar PhD4, Seyed Mehdi Sedaghat MD5, Seyed Mehdi Nouraie PhD1, Shahryar Semnani MD•2, Reza Malekzadeh MD1

See the pages: 194-195

Abstract Background: Golestan Province, at the western end of the Asian esophageal cancer (EC) belt in northeastern Iran, was reported to have one of the highest worldwide rates of EC in the 1970s. We have previously shown a declining incidence of EC in Golestan during the last decades. This study reports additional new results from the Golestan Population-based Cancer Registry (GPCR). Methods: The GPCR collected data from newly diagnosed (incident) cancer cases from all 68 public and private diagnostic and therapeutic centers in Golestan Province. CanReg-4 software was used for data entry and analysis based on the guidelines of the International Agency for Research on Cancer (IARC). Age-standardized incidence rates (ASR) of cancers were calculated using the 2000 world standard population. Results: From 2004 through 2008, 9007 new cancer cases were reported to the GPCR. The mean (SD) age was 55.5 (18.6) years, and 54% were diagnosed in men. The ASRs of all cancers were 175.3 and 141.1 per 100,000 person-years for males and females, respectively. Cancers of the stomach (ASR:30.7), esophagus (24.3), and lung (15.4) were the most common cancers in males. In females, breast cancer (ASR:26.9) was followed by malignancies of the esophagus (19.1) and stomach (12.4). The diagnosis of cancer was based on histopathological reports in 71% and on death certificate only in 9% of cases. Conclusions: The EC incidence rate continues to decline in Golestan, while the incidence rates of stomach, colorectal, and breast cancers continue to increase.

Keywords: Cancer registry, esophageal cancer, Golestan, Iran

Cite the article as: Roshandel G, Sadjadi A, Aarabi M, Keshtkar A, Sedaghat SM, Nouraie SM, Semnani S, Malekzadeh R. Cancer Incidence in Golestan Province: Report of an Ongoing Population-based Cancer Registry in Iran, 2004–2008. Arch Iran Med. 2012; 15(4): 196 – 200.

Introduction Turkmen plain and neighboring hills6 and includes Turkmen (35%) and Fars (65%) ethnic groups. Historically, the incidence n Iran it is mandatory to report all confirmed or suspicious of EC was found to be very high in this region.7 Mahboubi et al. cancer diagnoses to the Iranian Ministry of Health (IMOH).1 in 1973 reported exceptionally high age-adjusted incidence rates I Iranian health authorities have maintained a pathology- (up to 165.5/100,000 in men and 195.3/100,000 in women) for based cancer registry since 1986.2 The first report of this registry, EC in this region.6 which includes at maximum 80% of the new cancer cases, was The Golestan Population-based Cancer Registry (GPCR) began published recently.3 The Digestive Diseases Research Center in 2001. The first report from this registry was a retrospective can- (DDRC) of Tehran University of Medical Sciences (TUMS) has cer surveillance for 1996 to 2000, published in 2006. This study established population-based cancer registries in two northern showed a declining incidence of EC and an increasing incidence provinces of Iran, Ardabil, and Golestan, in collaboration with the of gastric, colorectal, and breast cancers in this region compared International Agency for Research on Cancer (IARC), the Center to the data published from this area in the 1970s.8 GPCR is now for Disease Control at IMOH and local medical universities.4 run by the Golestan Research Center of Gastroenterology and Golestan Province is located at the southeastern corner of the Cas- Hepatology (GRCGH) of Golestan University of Medical Sci- pian Sea (northeast Iran), at the western end of the Asian esopha- ences (GOUMS), under the supervision of DDRC/TUMS. Since geal cancer (EC) belt.5 It is located in the steppe grasslands of the January 2006, all data in the GPCR was collected prospectively, and the GPCR has been a member of the International Association Author’s affiliations: 1Digestive Diseases Research Center (DDRC), Tehran Uni- versity of Medical Sciences (TUMS), Tehran, Iran. 2Golestan Research Center of of Cancer Registries (IACR) since 2007. In this report, we pres- Gastroenterology and Hepatology (GRCGH), Golestan University of Medical Sci- ent cancer incidence data collected by the GPCR over the 5-year ences (GOUMS), Gorgan, Iran. 3Department of Epidemiology, University Medical period from 2004 through 2008. Center Groningen, University of Groningen, Groningen, The Netherlands, 4Endocri- nology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran. 5Department of Health, Golestan University of Medical Sciences Materials and Methods (GOUMS), Gorgan, Iran. •Corresponding author and reprints: Shahryar Semnani MD, Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sci- GPCR collected information on newly diagnosed (incident) can- ences, 3rd floor, Shahid Nabavi Clinic, th4 Azar Alley, 5th Azar St., Gorgan, Iran. cer cases from all public and private diagnostic and therapeutic Tel: +98-171-234-0835, Fax: +98-171-236-9210, E-mail: [email protected]. Accepted for publication: 14 September 2011 centers in Golestan Province, including hospitals, pathology/labo-

196 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 G. Roshandel, A. Sadjadi, M. Aarabi, et al.

Figure 1. Population pyramid of Golestan Province, 2006. Figure 2. Previous* (1970s) and current divisions of Golestan Province, Iran (*Refer- (Source: Health Department of Golestan University of Medi- ence 6). cal Sciences) ratory centers, imaging centers and some specialist physicians’ truncated (34–65 years) ASR (TASR) of EC.13 P-values of less private offices from 2004 through 2008. We also obtained infor- than 0.05 were considered statistically significant. mation from medical centers and regional registries in the neigh- The protocol was approved by the Ethics Committee of GOUMS boring provinces, particularly Khorasan Razavi, Mazandaran, and and the DDRC Institutional Review Board. Confidentiality mea- Tehran, to minimize loss of data for Golestan residents who were sures were used to ensure the preservation of anonymity of the diagnosed in other provinces. Data was collected both actively cancer cases, the best quality of registry data, and the best possible and passively by well-trained registry staff that regularly visited usage of the data.9,14 all centers and collected information on cancer cases. GPCR also regularly received information on cancer-related deaths from the Results death registry at the health department of GOUMS and matched this data against the file of registered cancer patients to identify During the 5-year period from 2004 through 2008, 9007 new additional unreported cases, which were classified as death cer- cancer cases were reported to GPCR from 68 healthcare centers tificate only (DCO) cases. across the province, the provincial death registry, and medical GPCR registered only primary cancers; secondary tumors re- centers and cancer registries in neighboring provinces. More than sulting from the invasion or metastasis of primary cancers were half, 4862 (54%), of the cases were male (male to female ratio = excluded from this report. Malignant tumors of all organs were 1.2; P = 0.001). Of all 9007 cases, 69% were confirmed by histo- registered based on IARC standards.9 pathological and 2% were confirmed by cytological examinations. 10% of data collection forms were checked and compared with The other methods of diagnosis were DCO in 9%, clinical in 10%, the original documents in the source centers to verify the accu- and para-clinical (e.g., imaging studies or surgical reports) in 10% racy and completeness of the abstraction process. The results of of cases. The overall ASRs for all cancers were 175.3 (95% CI: this checking process were acceptable in the majority of centers. 166.5–184.5) and 141.1 (95% CI: 133.2–149.5) per 100,000 per- The third edition of the International Classification of Diseases son-years in males and females, respectively. Male patients were for Oncology (ICD-O-III) was used to code the anatomical site generally older than female patients, with median (inter-quartile and histology of the tumors.10 IARC multiple primary rules11 were range) ages of 62 (48-73) and 53 (41-66) years, respectively (P used for patients with malignant tumors of more than one site. = 0.001). Cases reported to GPCR were initially checked for duplications Microscopic verification (MV) was done in 71% of all cancer before entry into the database.12 This duplication check included cases. The MV%s of the five most common cancers in males and comparisons of the reported last name, first name, age, father’s females are shown in Table 1. Table 2 shows several indices of name, topography of tumor, place of residence, and year of diag- data quality for GPCR data collected between 2004 and 2008. The nosis. The Persian version of CanReg4 software was used for data MV% increased from 60% in 2004 to 75% in 2008, with a con- entry, and the data was checked with the IARC check program.12 comitant decline in the DCO% from 23% in 2004 to 5% in 2008. Incidence rates were age-adjusted to the 2000 world standard The proportion of cases with an unknown primary site decreased population in 18 age categories of 5 years each (0–4, 5–9..., from 6% in 2004 to 2% in 2008. There were no cases with an 85+), and expressed per 100,000 population. Information about unknown method of diagnosis or an unknown age or sex in the the Golestan population in 2006 was obtained from the provin- GPCR between 2004 and 2008. cial census done by the Health Department of GOUMS. Figure Table 3 shows the case numbers, crude rates and ASRs of the 1 shows the population pyramid of Golestan in 2006. We used ten most common cancers in each sex. Stomach and esophageal Segi’s method to calculate the age-standardized incidence rates malignancies were the most common cancers in males, while (ASRs) per 100,000 person-years for all cancers as well as the

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 197 Cancer Incidence in Golestan Province

Table 1. Proportion of cases with microscopic verification (MV%) for the five most common cancers in males and females of Golestan Province, Iran (2004–2008). Sex Location MV% Male Stomach 68 Esophagus 73 Trachea, bronchus, lung 29 Hematopoietics 98 Colorectal 74 Female Breast 75 Esophagus 73 Stomach 64 Hematopoietic 100 Colorectal 73

Table 2. Trend of data quality indices in Golestan Population-based Cancer Registry (GPCR), 2004–2008. 2004 2005 2006 2007 2008 Total population 1592989 1614376 1640200 1668561 1693165 Number of cancer cases 1513 1709 1851 1937 1997 ASR of all cancers-male 156 177 187 172 174 ASR of all cancers -female 118 130 149 151 150 Microscopic verification (%) 60 70 71 74 75 Death certificate only (%) 23 11 8 6 5 Unknown primary site (%) 6 2 1 2 2 Unknown method of diagnosis (%) 0 0 0 0 0 Unknown age (%) 0 0 0 0 0 Unknown sex (%) 0 0 0 0 0 ASR: Age standardized incidence rates (per 100000 person-years).

Table 3. Case numbers, crude incidence rates and age-standardized incidence rates (ASR) per 100,000 persons-years of the top ten cancers in Golestan Province, Iran (2004–2008). Male Female Organ Number of cases Crude rate ASR Organ Number of cases Crude rate ASR Stomach 793 19.17 30.7 Breast 886 21.80 26.9 Esophagus 622 15.04 24.3 Esophagus 478 11.76 19.1 Lung 405 9.79 15.4 Stomach 325 8.00 12.4 Colorectal 345 8.34 12.4 Colorectal 266 6.54 9.5 Leukemia 338 8.17 10.5 Leukemia 238 5.86 7.4 Skin 324 7.83 12.6 Skin 207 5.09 8.2 Prostate 267 6.46 10.1 Ovary 187 4.60 5.7 Lymphoma 263 6.36 7.6 Nervous system 165 4.06 5.3 Nervous system 242 5.85 7.2 Lymphoma 161 3.96 4.7 Bladder 222 5.37 8.7 Lung 160 3.94 5.9 Total: All sites 4862 117.55 175.3 Total: All sites 4145 101.97 141.1 All sites, except skin 4561 110.27 163.8 All sites except skin 3953 97.25 133.6 breast and esophageal cancers were the most common tumors in 2). The proportions of cases with microscopic verification in- females. creased from 60% to 75% and the cases diagnosed only by death Table 4 shows the ASRs and TASRs (34–65 years) of EC in certificate decreased from 23% to 5% during this time, and from the different regions of Golestan Province (Figure 2) reported in 2006 on, all data has been collected prospectively. Indices of data 1968–1971 and in the current Cancer Registry data. The incidence quality are now within acceptable ranges according to IARC stan- rate of EC was higher in Gonbad and Kalaleh districts, located in dards,11 which suggests that the GPCR is now a qualified popula- the eastern area of the province, than in the other districts at both tion-based cancer registry by these standards. time points, both in males and in females. Between 1968–1971 The incidence of cancers was higher in males than in females, and 2004–2008, the district- and gender-specific EC ASRs de- which is in agreement with the results of most other cancer regis- clined 57%–82%. tries.3,11,15 The mean age for cancer cases in our study (55.5 years) was similar to other reports from Iran.15,16 Discussion According to this study, the ASRs of cancer in Golestan Prov- ince were 175.3 for males and 141.1 for females, which were The Golestan Population-based Cancer Registry showed im- similar to the findings of another population-based cancer registry provement in several quality measures during 2004–2008 (Table in Iran.17 A recent pathology-based National Cancer Registry from

198 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 G. Roshandel, A. Sadjadi, M. Aarabi, et al.

Table 4. Age standardized incidence rates (ASR) and truncated (34–65 years) ASR (TASR) for esophageal cancer (EC) in different regions of Golestan Province, Iran in 1968-1971 and 2004–2008.

Previous study† GPCR* 1968–1971 2004–2008 Male Female Male Female

ASR TASR ASR TASR ASR TASR ASR TASR

Region A¶ 53.8 104.1 38.7 92.7 14.9 34.4 12.7 30.9

Region B¶ 83.7 173.7 76.9 185.4 18.1 72.1 13.6 39.4

Region C¶ 81.3 151.6 59.6 128.1 21.5 68.5 23.3 70.9

Region D¶ 96.6 217.7 137.7 334.9 37.5 126.4 27.3 84.8

Region E¶ 165.5 515.6 195.3 480.7 70.7 193.7 42.6 140.4 * Golestan Population-based Cancer Registry † Reference 6 ¶ Refer to Figure 2

IMOH, on the other hand, has underestimated the incidence of as socioeconomic status, drinking hot tea, opium consumption, cancer in Golestan (reporting ASRs of cancers for Golestan as low poor oral health, and drinking non-piped water, are probably more as 61 in males and 54 in females)3 and other parts of the country. important in the etiology of EC in Golestan.22–25 One major rea- This is most likely due to the different methodologies of the two son for declining EC rates in this area is the overall improvement registries: the only data source for the IMOH registry is pathology in socioeconomic status, including higher incomes, availability reports, and all data is collected passively, which are well-known of electricity, access to safe drinking water, natural gas for heat- shortcomings of this type of registry. Therefore, it is highly rec- ing and cooking, television, telephone communication and public ommended that national cancer incidence and mortality rates be transport in 98% of the urban areas and 92% of the rural areas in estimated based on population-based cancer registries with active today’s Golestan.26,27 case ascertainment, as they were estimated in the past.18 Table 4 compares the current incidence rates of EC in the differ- Stomach and esophageal cancers were the most common can- ent regions of Golestan Province (Figure 2) with the rates reported cers in Golestan males during this time period. These results are during the 1970s.6 Despite the striking 57% - 82% drop in ASRs, similar to reports from some other Asian countries.19 The most the geographical distribution of EC in the present study was simi- frequent female cancers in Golestan Province were breast and lar to that of the previous report.6 For example, the incidence rate esophagus, similar to the findings in East Azarbaijan Province.20 of EC was considerably higher in Gonbad and Kalaleh (regions Babaei et al. also reported breast cancer to be the most common fe- 6a and 6b in the previous report) in both the current and previ- male cancer in Semnan Province, although this site was followed ous studies.6 Thus, despite its overall declining trend, EC remains in frequency by cancers of the uterus and ovary.16 In contrast, in a major health problem in this part of Golestan Province, which Yemen, another country in the region, the most frequent cancers needs further investigation to determine unknown risk factors. In in males were leukemia and lymphoma, and the most common addition, implementation of an EC control program may be ben- malignancies in females were breast cancer and leukemia.21 As eficial in this area. incidence rates and common causes of cancers show considerable In conclusion, GPCR is now a qualified population-based Can- variation between countries and even between different regions cer Registry based on IARC standards, and a major asset for plan- of the same country, cancer control programs need to be planned ning cancer prevention strategies in this province. It may also with population-specific priorities. be considered a good model for establishing population-based We found an increasing trend in the incidence of cancer in both Cancer Registries in other provinces of Iran and in other Middle males and females between 2004 and 2006 (Table 2). The most Eastern countries. Similar to our previous report,8 we have found likely explanation for this trend is that the cancer cases in 2004 that the EC incidence rate continues to decline in Golestan, while and 2005 were registered retrospectively, and underestimation is the rates of stomach, colorectal, and breast cancers continue to an important limitation of retrospective data collection. The pro- increase. spective phase of the GPCR was started since 2006, and our results show no significant change in cancer incidence rates from 2006 to 2008. Acknowledgments We found a decreasing trend in EC rates and increasing trends in the incidence of colorectal, breast and lung cancers and leuke- The authors are deeply grateful to Dr. Sanford M. Dawsey from mia when compared to previous reports from this area.6,8 These NCI for reviewing the manuscript and his valuable comments. We changing rates may be partly due to the adoption of a western would also like to thank Mrs. Honeyehsadat Mirkarimi, Mr. Ab- type lifestyle in Golestan during the last 20 years. The decreasing bas Moghaddami, Mrs. Seyedzinab Hasheminasab, Mr. Reza Mo- trend of EC, which has been reported previously,8 was confirmed hammadi, GPCR staff, pathologists, physicians, and other health in this study. Recent epidemiological studies in the Turkmen plain professionals in Golestan Province in addition to the staff at the of Iran by our group have shown that alcohol and tobacco are not cancer office of IMOH for their valuable assistance. This work the main risk factors for EC in this area.22 Other risk factors, such was supported by GRCGH/GOUMS and DDRC/TUMS.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 199 Cancer Incidence in Golestan Province

References 16. Babaei M, Mousavi S, Malek M, Tosi G, Masoumeh Z, Danaei N, et al. Cancer occurrence in Semnan Province, Iran: results of a population-based cancer registry. Asian Pac J Cancer Prev. 2005; 6: 159 1. Islamic Parliament of Iran. Mandatory Registration of Cancer; 2010. – 164. Available from: URL: http://lawoffice.mohme.gov.ir/laws/dedicated_ 17. Babaei M, Jaafarzadeh H, Sadjadi AR, Samadi F, Yazdanbod A, Fal- law/laws_all.jsp?from=s&id=1&id2=148 (Accessed 7.12.2010) lah M, et al. Cancer incidence and mortality in Ardabil: report of an 2. Cancer Office of the Iranian Ministry of Health.National Cancer Reg- ongoing Population-Based Cancer Registry in Iran, 2004–2006. Iran istry Report 2000–2001. Tehran: Iranian Ministry of Health; 2002. J Public Health. 2009; 38: 35 – 45. 3. Mousavi SM, Gouya MM, Ramazani R, Davanlou M, Hajsadeghi N, 18. Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Maleke- Seddighi Z. Cancer incidence and mortality in Iran. Ann Oncol. 2009; zadeh R, Parkin DM. Cancer occurrence in Iran in 2002, an interna- 20: 556 – 563. tional perspective. Asian Pac J Cancer Prev. 2005; 6: 359 – 363. 4. Etemadi A, Sadjadi A, Semnani S, Nouraie SM, Khademi H, Bahadori 19. Moore MA, Eser S, Igisinov N, Igisinov S, Mohagheghi MA, Mousa- M. Cancer registry in Iran: a brief overview. Arch Iran Med. 2008; 11: vi-Jarrahi A, et al. Cancer epidemiology and control in North-Western 577 – 580. and Central Asia-past, present and future. Asian Pac J Cancer Prev. 5. Kamangar F, Malekzadeh R, Dawsey SM, Saidi F. Esophageal cancer 2010; 11: 17 – 32. in Northeastern Iran: a review. Arch Iran Med. 2007; 10: 70 – 82. 20. Somi MH, Farhang S, Mirinezhad SK, Naghashi S, Seif-Farshad M, 6. Mahboubi E, Kmet J, Cook PJ, Day NE, Ghadirian P, Salmasizadeh S. Golzari M. Cancer in East Azerbaijan, Iran: results of a population- Oesophageal cancer studies in the Caspian Littoral of Iran: The Cas- based cancer registry. Asian Pac J Cancer Prev. 2008; 9: 327 – 330. pian Cancer Registry. Br J Cancer. 1973; 28: 197 – 214. 21. Saleem HOB, Bawazir AA, Moore M, Abdulla K. Five years cancer 7. Kmet J, Mahboubi E. Esophageal cancer in the Caspian littoral of incidence in Aden Cancer Registry, Yemen. Asian Pac J Cancer Prev. Iran: initial studies. Science. 1972; 175: 846 – 853. 2010; 11: 507 – 511. 8. Semnani S, Sadjadi A, Fahimi S, Nouraie M, Naeimi M, Kabir J, et 22. Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, al. Declining incidence of esophageal cancer in the Turkmen Plain, Abnet CC, et al. Opium, tobacco, and alcohol use in relation to oe- eastern part of the Caspian Littoral of Iran: a retrospective cancer sur- sophageal squamous cell carcinoma in a high-risk area of Iran. Br J veillance. Cancer Detect Prev. 2006; 30: 14 – 19. Cancer. 2008; 98: 1857 – 1863. 9. Jensen OM. Cancer Registration: Principles and Methods. Lyon: In- 23. Abnet CC, Kamangar F, Islami F, Nasrollahzadeh D, Brennan P, ternational Agency for Research on Cancer; 1991. Aghcheli K, et al. Tooth loss and lack of regular oral hygiene are asso- 10. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, et ciated with higher risk of esophageal squamous cell carcinoma. Can- al. International Classification of Diseases for Oncology. 3rd ed. Ge- cer Epidemiol Biomarkers Prev. 2008; 17: 3062 – 3068. neva: World Health Organization; 2000: 240. 24. Islami F, Kamangar F, Nasrollahzadeh D, Aghcheli K, Sotoudeh M, 11. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et Abedi-Ardekani B, et al. Socio-economic status and oesophageal canal. Cancer Incidence in Five Continents. Vol 9. Lyon: International cer: results from a population-based case-control study in a high-risk Agency for Research on Cancer; 2007. area. Int J Epidemiol. 2009; 38: 978 – 988. 12. Cooke AP, Parkin DM, Ferlay J. CanReg: Computer Software for 25. Islami F, Pourshams A, Nasrollahzadeh D, Kamangar F, Fahimi S, Cancer Registries. 4th ed. Lyon: International Agency for Research on Shakeri R, et al. Tea drinking habits and oesophageal cancer in a high- Cancer; 2001. risk area in northern Iran: population based case-control study. BMJ. 13. Segi M. Cancer Mortality for Selected Sites in 24 Countries (1950– 2009; 338: b929. 57). Sendai: Department of Public Health, Tohoku University of Med- 26. Pourshams A, Khademi H, Malekshah AF, Islami F, Nouraei M, Sad- icine; 1960. jadi AR, et al. Cohort profile: The Golestan Cohort Study--a prospec- 14. Storm H, Brewster DH, Coleman MP, Deapen D, Oshima A, Threlfall tive study of oesophageal cancer in northern Iran. Int J Epidemiol. T, et al. Guidelines for confidentiality and cancer registration. Br J 2010; 39: 52 – 59. Cancer. 2005; 92: 2095 – 2096. 27. Pourshams A, Saadatian-Elahi M, Nouraie M, Malekshah AF, Rakh- 15. Sadjadi A, Malekzadeh R, Derakhshan MH, Sepehr A, Nouraie M, shani N, Salahi R, et al. Golestan cohort study of oesophageal cancer: Sotoudeh M, et al. Cancer occurrence in Ardabil: results of a popu- feasibility and first results.Br J Cancer. 2004; 92: 176 – 181. lation-based Cancer Registry from Iran. Int J Cancer. 2003; 107: 113 – 118.

200 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. A. Noorbala, S. A. Bagheri Yazdi, M. Hafezi

Original Article Trends in Change of Mental Health Status in the Population of Tehran between 1998 and 2007

Ahmad Ali Noorbala MD•1, Seyed Abas Bagheri Yazdi MSc2, Mohsen Hafezi MD1

Abstract Introduction: According to a WHO report, the world will face great changes in the epidemiology of diseases in next three decades. In- fectious and communicable diseases will be replaced by mental disorders at an alarming rate (9), making psychiatric disorders the most common cause of disability and premature death. This study compares trends and changes in the mental health of the residents of Tehran (≥ 15 years old) in 1998 and 2007. Methods: This study was an overview of two cross-sectional, descriptive researches that were performed in 1998 and 2007. The study populations in these two studies were residents of Tehran. Samples were recruited by regular randomized cluster sampling. In both studies, the General Health Questionnaire (GHQ-28) was used to assess mental health. Trained physicians and health experts completed questionnaires, and data were analyzed by SPSS software (Version 18). Results: The results showed that 21.5% of participants in the 1998 survey suffered from mental disorders, of which 27.7% were women and 14.9% were men. In 2007, this figure increased to 34.2% (37.9% in woman and 28.6% in men). The prevalence of mental disorders increased from 1998 until 2007 by about 1.6 fold (1.4 fold for women and 1.9 fold for men). In both studies, the risk of mental disorders increased with increasing age. Anxiety symptoms were more prevalent in both studies compared to somatization, depression, and social dysfunction scales. Discussion: The result shows a dramatic increase of mental disorder prevalence in Tehran from 1998 until 2007. We believe there is a lack of sufficient and qualified facilities for mental health provisions in Tehran. Based on these facts, policymakers and officials have to place greater importance in controlling stressful situations that predispose people to mental disorders, with the intent to improve the mental health of Tehran residents.

Keywords: General Health Questionnaire (28), mental health situation, Tehran, trends of change

Cite the article as: Noorbala AA, BagheriYazdi SA, Hafezi M. Trends in Change of Mental Health Status in the Population of Tehran between 1998 and 2007. Arch Iran Med. 2012; 15(4): 201 – 204.

Introduction the most frequent disorders were anxiety, depression, somato- form, and substance dependence. any countries attempt industrialization and are faced with Mental health surveys in Iran can be divided into two groups, great changes, such as rapid population growth, urban- based on when the survey was undertaken. The first group con- M ization, and immigration. Such changes can increase sisted of surveys between 1963 and 1971, before the Islamic revo- stress and psychosocial problems in communities, and it would lution in Iran. In these surveys, the prevalence of mental disorders not be surprising that over the next decades we could see dramatic was between 11.9% and 18.6%.3–5 The second group consisted of changes in disease epidemiology and the health needs of people. studies performed after the Islamic revolution, which noted the Mental disorders may be the most common cause of disability and prevalence of mental disorders to be between 12.5% and 30.2%.6 premature death. The high prevalence of mental disorders is as- The first comprehensive mental health survey in Iran was per- sociated with chronicity and long-term disability, which renders formed in 1998 as part of a national project named “Health and them a top priority in health policy.1 Disease”. In this study, the prevalence of mental disorders was By considering mental health figures in Iran and other parts of 21% (25.9% in women and 14.9% in men). The prevalence was the world, it is evident that researchers must pay more attention to higher in people who were older than 45, divorced, widowed, this field. According to 2002 WHO estimates, about 500 million married, unemployed, retired, and housewives compared to other people in the world suffer from mental disorders; 50% of them groups. In this study, anxiety and depressive symptoms were more have neuroses, such as anxiety or depression.2 A 2005 review of prevalent than somatization and social dysfunction symptoms.7 27 studies found that 27% of adult Europeans have been affected In another complementary study that assessed the validity and by at least one mental disorder in the past 12 months. In this study, reliability of the General Health Questionnaire (GHQ-28), 879 people (≥ 15 years old) in Tehran were evaluated by trained psy- Authors’ affiliations: 1Psychosomatic Ward Imam Khomeini Hospital, Tehran chiatric residents during clinical interviews according to DSM-IV University of Medical Sciences, Tehran, Iran. 2Ministry of Health and Medical criteria. In this study 21.5% of participants had psychiatric dis- Education of Iran, Tehran, Iran. orders. Major depression and generalized anxiety disorder were •Corresponding author and reprints: Ahmad Ali Noorbala MD, Psychoso- matic Ward Imam Khomeini Hospital, Tehran University of Medical Sciences, the most prevalent psychiatric disorder. Age over 45, being single, Keshavarz Blvd., Tehran. Tel: +98-216-119-2421, Fax: +98-216-693-0330, unemployed, and illiterate were predisposing factors for mental E-mail: [email protected]. disorders. Comparing results of the first national mental health Accepted for publication: 22 October 2011 survey in Iran with the results of this study has indicated that the

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 201 Mental Health Status in the Population of Tehran between 1998 and 2007

Table 1. Comparison of prevalence of mental disorders in terms of demographic variables.

1998 2007 Variable Suspected cases Prevalence Suspected Prevalence rate Sample size (%) Sample size (%) (n) rate (%) cases (n) (%) Gender Male 2523 (45.4) 376 14.9 7705 (39.8) 2206 28.6 Female 3037 (54.6) 820 27.6 11665 (60.2) 4418 37.9 Age (years) 15–24 2379 (36.5) 345 14.5 4723 (24.4) 1379 29.2 25–44 2398 (36.8) 412 17.2 8449 (43.6) 2625 31.1 45–64 1284 (18.7) 303 23.6 4430 (22.9) 1737 39.3 65+ 449 (8.0) 136 30.3 1768 (9.1) 883 49.9 Occupation Employed 4470 (80.4) 728 16.3 14634 (75.5) 4546 31.1 Unemployed 1090 (19.6) 468 42.9 4736 (24.5) 2078 43.9 Marital Status Unmarried 1096 (19.7) 240 14.6 2199 (11.4) 664 30.2 Married 4186 (75.3) 854 20.4 16581 (85.6) 4769 32.6 Divorced or widowed 278 (5.0) 102 36.7 590 (3.0) 184 47.2 Education Illiterate 647 (11.7) 185 28.6 4068 (21.0) 1774 43.6 Elementary 2021 (36.3) 376 25.5 5517 (28.5) 2080 37.7 Diploma 1569 (28.6) 342 21.8 6475 (33.4) 1975 30.5 Above diploma 1323(23.4) 293 14.5 3310 (17.1) 795 24.0 Total 5560 1196 21.5 19370 6624 34.2

Table 2. Estimated logistic regression coefficients and odds ratios.

1998 2007 Variable P-value OR 95% CI P-value OR 95% CI Gender Male — — — — — — Female < 0.004 1.541 1.392–1.688 < 0.001 1.346 1.167–1.525 Age < 0.001 1.208 1.009–1.407 < 0.001 1.447 1.263–1.631 Education Educated — — — — — — Uneducated and less educated < 0.01 1.112 0.915–1.309 < 0.001 1.447 1.263–1.631 Marital Status Unmarried — — — — — — Married 0.139 0.531 0.446–0.616 0.712 0.323 0.140–0.464 Widowed and divorced < 0.001 1.711 1.584–1.840 < 0.001 1.288 1.001–1.575 Occupation Employed — — — — — — Unemployed < 0.001 1.813 1.575–2.052 < 0.001 1.507 1.262–1.754 prevalence of mental disorders in Tehran (21.5%) approximated commonly used in epidemiological surveys of mental disorders. the mean prevalence in Iran (21%).6 This questionnaire has been created by Goldberg in 1972 with the The second national survey on the epidemiology of psychiatric aim of finding psychiatric disorders in people in the community, disorders in Iran was performed in 2001 using the Schizophrenia clinic, and other situations. It is one of the most familiar instru- and Affective Disorder Scale. The prevalence of psychiatric dis- ments for the screening of psychiatric disorders and assessing orders in this study was 17.1% (23.4% in women and 10.8% in mental health and has greatly influenced psychiatric and behav- men). Psychiatric disorders were more prevalent in the 41–55 age ioral science research.8,9 group, divorced, urban, illiterate, housewives, and unemployed Research on community mental health not only improves mental people. In this survey, 10.9% of the study population suffered health care of people at need, but also can guide us in preventing from at least one psychiatric disorder.2 psychiatric disorders. The purpose of this study is to recognize the The General Health Questionnaire (28) is one of the instruments trends of mental health in the population of Tehran. A compari-

202 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. A. Noorbala, S. A. Bagheri Yazdi, M. Hafezi

Table 3. Comparison of mean scores of GHQ-28 in study population of Tehran.

Degree of GHQ-28 results Mean scores Standard deviation t P-value freedom Male 4.11 4.42 1998 2.71 5558 < 0.01 Female 5.69 5.56 Male 5.08 5.90 2007 4.74 19368 < 0.001 Female 6.97 6.43 1998 4.90 4.98 Total 14.1 24928 < 0.0001 2007 6.03 6.16 son of the changes in mental health of the population of Tehran and restricted social participation of women. in 1998 and 2007 based on demographic variables such as age, In both studies, aging was associated with increased prevalence, sex, work status, education, marital status, and number of family so that people over 65 years old had the highest psychiatric dis- members is one of the specific aims of this study. orders.6,10 Retirement, menopause, loneliness, and biological changes were factors that could have contributed to the increased Materials and Methods prevalence in these age groups. Illiterate people had a higher prevalence of psychiatric disorders This is a review of two cross-sectional descriptive surveys. The than other groups in both studies, which was consistent with most first study was done in 1998 as part of “the Health and Disease studies in Iran. We have attributed this higher prevalence to social Project” and the second study was done in 2007 as part of the and cultural restrictions among illiterate people, and their inability “Urban HEART Survey”. The study populations of two studies to use more efficient coping strategies in stressful situations. were consisting of residents of Tehran city. The sampling tech- As with findings of other studies in Iran and the world, the prev- nique was regular cluster randomized. A total of 5,590 people alence of psychiatric disorders was higher in unemployed and participated in the first study and 19,370 people in the second.6,10 retired people. It was possible that lower incomes, the stress of The GHQ-28 was used to assess residents’ mental health con- being jobless, and restricted social interactions were factors that ditions. This questionnaire has four sections: somatic symptoms, increased the rate of psychiatric disorders among jobless people anxiety and sleep problems, social dysfunction, and depression. and housewives compared to the employed. According to many studies, both throughout the world and in Iran, People, who were divorced, widowed, or married had higher this questionnaire has good reliability and validity as a psychiatric rates of psychiatric disorders compared with singles; this was disorder screening tool. The scoring system used in this study was consistent with the findings of other studies in Iran.12,13 The stress a traditional scoring which gives 0 score (responses with no or of divorce, financial problems, life management, and parenting little), and 1 scores (responses with much or very much), with a possibly contributed to the higher prevalence. total score between 0 and 28. 11 The findings of both studies showed that illiterate or less educat- Trained physicians and health experts completed questionnaires ed people had a higher prevalence of psychiatric disorders com- in both studies during a two-month period. Results were analyzed pared with those more educated. Other studies in the world have by SPSS version 13 software. shown that the prevalence of psychiatric disorders in illiterate people is higher, and that being educated is a protective factor for 14,15–17 Results mental disorders. Social and cultural restrictions and their inability to use more efficient coping mechanisms are contribut- Information about the mental health status of people in both ing factors to this difference. The results are consistent with the 7,10,18–20 studies (based on demographic variables) is shown in Table 1. findings of other studies in Iran. Results from logistic regression are presented in Table 2. The In both studies the highest positive response rate was related to higher odds of mental disorders were associated in both studies irritability, anxiety, and sleep problems. The lowest response rate with the following: female sex, divorced and widowed, less edu- was seen with suicidal ideation; these results were also consistent cated, unemployed, and the elderly at 95% CI. with previous findings in Iran. Table 3 shows a comparison of the mean scores of GHQ-28 In Table 2, the mean score of women is higher compared with questionnaires in both study populations. men. This difference has statistical significance and could be related to biological factors as well as lower social participation of Discussion women. The increases happened in prevalence of mental disorders dur- The findings of this study showed that the prevalence of psychi- ing a decade in Tehran city, can be attributed to social, political, atric disorders in Tehran in 1998 was 21.5%, while in 2007 it was financial, and cultural problems that have occurred in Iran and the 34.2%. The results indicated that the prevalence of mental disor- world during this decade. ders increased by 1.6 fold from 1998 until 2007; this increase was The results have shown that the prevalence of mental disorders 1.4 fold for women and 1.9 fold for men (Table 1). In both studies, has considerably increased over a decade in Tehran, and the dif- psychiatric disorders were more prevalent in women than in men. ference between the mean scores of individuals in the two studies This was consistent with previous studies in Iran and other coun- is statistically significant (Table 3). Considering the higher preva- tries. The higher prevalence might have been related to biologi- lence of psychiatric disorders in 2007 compared to 1998, perhaps cal factors, sexual roles, environmental and work-related stresses, policymakers should pay greater attention to mental health pro-

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 203 Mental Health Status in the Population of Tehran between 1998 and 2007 vision in Tehran and other Iranian cities. This can be achieved 9. Goldberg D. The Detection of Psychiatric Illness by Questionnaire. with the help of counseling centers in Tehran city. In our opinion, London: Oxford University Press; 1973. 10. Noorbala AA, BagheriYazdi SA, Asadi Lari M, Vaez Mahdavi MR. attention to employment issues and the provision of recreational Mental health status of fifteen years and older in Tehran- Iran [in Per- and sport facilities could have a positive effect on this unfortunate sian]. Andisheh va Raftar. 2011; 16: 479 – 483. trend. 11. Goldberg DP, and Hillier, VF. A scaled version of general health questionnaire. Psychol Med. 1979; 9: 131 – 145. 12. Palahang H, Nasr M, Baraheni MT, Shah Mohamaddi D. Epidemiol- References ogy of psychiatric disorders in Kashan [in Persian]. Andisheh va Raf- tar. 1994; 4: 19 – 27. 1. Murray CJL, Lopez AD, Mathers CD, Stein C. The Global Burden 13. Yaghoobi N, Nasr M, Shah Mohammadi D. Epidemiology of psychi- of Disease 2000 project: Aims, methods and data sources. Geneva: atric disorders in urban and rural areas of Someesara city in Gilan World Health Organization; 2001. district [in Persian]. Andisheh va Raftar. 1995; 4: 55 – 65. 2. Mohammadi MR, Davidan H, Noorbala AA, Malekafzali H, Bagheri- 14. Hodiamont P, Peer N, Syben N. Epidemiological aspects of psychiat- Yazdi SA, Naghavi, MR, et al. Epidemiology of psychiatric disorders ric disorder in a Dutch health area. Psychol Med. 1987; 17: 495 – 505. in Iran in 2001 [in Persian]. Hakim J. 2003; 6: 64 – 65. 15. Stansfeld SA, Marmot MG. Social class and minor psychiatric dis- 3. Bash KW and Bash-Liechtic J. Studies on the epidemiology of neuro- order in British civil servants: a validated screening survey using the psychiatric disorders among the population of the city of Shiraz. Iran General Health Questionnaire. Psychol Med. 1992; 22: 739 – 749. Social Psychiatry. 1964; 9: 163 – 171. 16. Weissman MM, Mayers JK, Harding PS. Psychiatric disorders in a 4. Bash KW, Bash-Liechtic J. Studies on the epidemiology of neuro- U.S. urban community: 1975–1976. Am J Psychiatry. 1978; 135: 456 psychiatric disorders among the rural population of the province of – 462. Khuzestan. Iran Social Psychiatry. 1969; 4: 137 – 143. 17. Wittchen HU, Jacobi F. Size and burden of mental disorders in Eu- 5. Davidian H, Izedi S, NehaptianV, Motabar M. Preliminary evaluation rope—a critical review and appraisal of 27 studies. Eur Neuropsycho- of psychiatric disorders in Khazar region (Roodsar City) [in Persian]. pharmacol. 2005; 15: 357 – 376. Behdasht Iran J. 1972; 4: 145 – 156. 18. Noorbala AA, BagheriYazdi SA, Mohammad K. Validation of GHQ- 6. Noorbala AA, Mohammad K, BagheriYazdi SA. Epidemiological sur- 28 as a screening tool for psychiatric disorders in Tehran [in Persian]. vey of psychiatric disorders in Tehran [in Persian]. Hakim J. 2001; 2: Hakim J. 2008; 11: 47 – 53. 212 – 223. 19. Omidi A, Tabatabaii A, Sazvar SA, Akkashe G. Epidemiology of psy- 7. Noorbala AA, Mohammad K, BagheriYazdi SA, Yasami MT. Mental chiatric disorders in Natanz [in Persian]. Andisheh va Raftar. 2003; health survey in people 15 years old in Islamic Republic of Iran [in 31: 20 – 25. Persian]. Hakim J. 2002; 5: 1 – 10. 20. Sadegi K, Saberi SM, Osareh M. Epidemiology of psychiatric dis- 8. Fones CS, Kua EH, Ng Tp, Ko SM. Studying the mental health of orders in urban population of Kermanshah [in Persian]. Andisheh va Singapore. Singapore Med J. 1998; 53: 250 – 251. Raftar. 1999; 23: 16 – 25.

204 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Ahmadvand, Z. Sepehrmanesh, F. S. Ghoreishi, et al.

Original Article Prevalence of Psychiatric Disorders in the General Population of Kashan, Iran

Afshin Ahmadvand MD1, Zahra Sepehrmanesh MD•1, Fatemeh Sadat Ghoreishi MD1, Siamak Afshinmajd MD2

Abstract Background: Mental health is one of the most important public health issues because of its major contribution in decreasing the global burden of disease and its important role in assurance, dynamism, and efficacy. The present study evaluates the prevalence of mental disorders in the over 18-year-old population in Kashan, Iran during 2008–2009. Methods: This was a descriptive, cross-sectional study. Subjects were selected via stratified random sampling. The study was conducted in two stages. In the first stage, subjects were evaluated using the General Health Questionnaire. In stage two, two psychiatrists used a DSM-IV checklist to conduct clinical interviews. The collected data were analyzed by SPSS version 16, OR, CI, Chi-square, and Mantel- Heanszel tests. Results: The prevalence of mental disorders in Kashan was 29.2%. In women it was 35.5%, and in men, 21.2%. The most prevalent disorders were mood (9.3%) and anxiety disorders (4.7%). Among the 505 subjects with mental disorders based on clinical interviews, 162 (32.1%) suffered from mood disorders, 129 (25.6%) anxiety disorders, 21 (4.2%) psychotic disorders, 16 (3.4 %) neurologic disorders, 17 (3.4%) dissociative disorders, and 120 (23.7%) had other disorders. In this study, 7.8% of the subjects had more than one mental disorder. In the case of mood disorders, major depression (8.2%) was the most common; as for anxiety disorders, generalized anxiety disorder (7.2%) was the most prevalent. The prevalence was higher in people aged 56–65 (35.8%), widows (35.8%), the illiterate (42.8%), and the unemployed (38.8%). Mental disorder was significantly affected by gender, education, occupation, and marital status. Conclusions: The results show that psychiatric disorders in Kashan are higher than at the time of the previous research in this region (1999). Therefore, prevention programs and treatment of psychiatric disorders in this city are of great priority.

Keywords: Interview, mental disorders, prevalence

Cite the article as: Ahmadvand A, Sepehrmanesh Z, Ghoreishi FS, Afshinmajd S. Prevalence of Psychiatric Disorders in the General Population of Kashan, Iran. Arch Iran Med. 2012; 15(4): 205 – 209.

Introduction teria. These disorders included mood disorders (13.9%), anxiety disorders (13.6%), and alcohol abuse (5.2%).5 Recently the WHO he World Health Organization (WHO) estimates that one has performed a study in twenty-six countries according to DSM of four families worldwide has at least one member suffer- and ICD criteria.6 Preliminary data in fourteen countries showed T ing from a mental disorder and mental disorders will be the that in thirteen out of the fourteen countries, anxiety disorders most global burden of disease by the year 2020.1 These disorders were the most prevalent (2.4% to 18.2% over twelve months). are evaluated based on the degree of deviation from normal be- Mood disorders (0.8%–9.6%), drug abuse (0.1%–6.4%), and im- havior.1 In addition to many problems and limitations, psychiatric pulsive disorders (0.0%–6.8%) were less prevalent.7 problems create prejudice in social and occupational relationships Epidemiologic research on psychiatric disorders in different ar- due to social stigmas. Psychiatric disorders have many effects on eas of Iran declared that the prevalence of psychiatric disorders communities due to creating needs for physical and financial sup- has fluctuated between 11% to 23.8% from 1963 to 2000.8 A report. These patients need social and emotional support in addition view of epidemiologic studies regarding psychiatric disorders in to the expense for their families.2 different countries has shown that the prevalence of these disor- The WHO in 2001 declared that nearly forty-five million people ders were estimated differently because of the variety in sampling suffer from psychiatric disorders worldwide. At least one in four methods, interviews, and classifications in diagnosis. These stud- people experience psychiatric problems during their lifetime.3 ies have shown that the prevalence of these disorders in Iran is not A review study in 2005 showed that 27% of adults in European less than other countries and the WHO reports. The prevalence countries had at least one psychiatric problem over a twelve-month of these disorders in Iran is as follows: 14% in Semnan,9 17% in duration.4 Another descriptive study (2004) in Europe showed Rudsar,10 12.5% in Yazd’s Meibod,11 23.7% in Kashan,12 23.8% that nearly one out of four persons had experienced one psychiat- in Gilan,13 16.6% in Gonabad,14 19.9% in Isfahan,15 and 21.5% ric problem in some period of their life, according to DSM-IV cri- in Tehran.16 According to these data, this study evaluates the mental health Authors’ affiliation: 1Psychiatric Department, Kashan University of Medical of people in Kashan. The results of this study are important for Sciences, Kashan, Iran. 2Department of Neurology, Shahed University of Medi- determining the prevalence and type of mental disorders. cal Sciences, Tehran, Iran. •Corresponding author and reprints: Zahra Sepehrmanesh MD, Psychiatric Department, Akhavan Hospital, Kashan University of Medical Sciences, Kashan, Material and Methods Iran. Tel: +98-361-444-3000, Fax: +98-361-446-0266, E-mail: [email protected] Accepted for publication: 25 July 2011 This descriptive study was conducted on people 18 years and

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 205 Prevalence of Psychiatric Disorders older in Kashan, Iran during 2008–2009. The sample number was software, Chi-square, OR, CI, and the Mantel-Heanszel tests. Be- 1800 persons. Subjects were selected by stratified random sam- fore completing questionnaires, participants gave their informed pling with the use of a randomized number table, from among 39 consents. All information was kept secret. Study approved by health care centers. We provided a list of persons over the age of Ethics Committee of Kashan University of Medical sciences. 18 years based on age and sex, and the proportion of each center ki was specified via ni = × n . Subjects were contacted by telephone Results N and invited to come to their health care centers. For subjects who could not come on time, particularly men and the elderly, we sent A total of 1800 individuals whose demographic characteristics trained clinical psychologists to their homes. Subjects with scores are listed in Table 1 were invited to participate in this study. Ac- above the cut-off point in the GHQ test were referred for clinical cording to GHQ-28, 606 individuals were suspected to have psy- interview by two psychiatrists as based on the DSM-IV check-list. chiatric disorders and referred for clinical interviews. From these, The GHQ-28 questionnaire was designed by Goldberg and 60 did not participate in the interviews and were excluded from Hellier in 1979. This questionnaire screens for mental disorders in the study; 546 had clinical interviews. psychiatry,17 and has four scales: somatization, anxiety, dysfunc- After evaluation of the general health questionnaires, 606 tion, and depression. It is scored according to the Likert manner, (33.7%) of the 1800 participants may have had a psychiatric dis- and its validity and reliability is estimated to be 91%.18 order; 1194 (66.3%) had no problems. In the interview phase, 505 A DSM-IV check-list was used simultaneously by two psychia- (92.7%) of the 606 individuals had psychiatric disorders and 41 trists to agree on the same diagnosis. The Kappa coefficient was (7.3%) had no psychiatric problems (Table 2). 0.87. The clinical interview check-list was provided by Noorbala The most frequent occurrence of mental disorders was in the age and colleagues based on DSM-IV criteria. This structural ques- group 56 to 65, but there was no significant difference between tionnaire includes 149 symptoms of mental disorders such as age and psychiatric disorders (P = 0.542). Psychiatric disorders mood disorder, anxiety, psychotic, psychosomatic, epilepsy, men- were present in 337 (35.5%) women and 168 (21.2%) men. There tal retardation, and organic mental disorders.8 was a significant difference between sex and psychiatric disorders All data were registered and analyzed with SPSS version 16 (P < 0.001, Table 3).

Table 1. Demographic characteristic of participants as number (%) Age n(%) 18–27 292(16.3) 28–37 300(16.6) 38–47 477(26.5) 48–57 497(27.6) 58–66 130(7.3) 66 + 104(5.7) Marital status n(%) Single 193(10.7) Married 1543(85.7) Widow 54(3.0) Divorced 10(0.6) Education n(%) Illiterate 265(13.1) Primary 586(32.6) Secondary 316(17.6) Diploma 416(23.1) Higher diploma 247(13.6) Sex n(%) Female 981(54.5) Male 819(45.5) Occupation n(%) Worker 188(10.4) Student 97(5.4) Retired 303(17.1) Self-employed 148(8.2) Unemployed 222(12.3) Housekeeper 837(46.6) Total 1800(100)

Table 2. Results of GHQ-28 Test & clinical interview as number (%). GHQ-28 Test n(%) Above cut-of-point 606(33.7) Under cut-of- point 1194(66.3) Total 1800(10) Clinical interview** n(%) With disorder 505(92.7) Without disorder 41(7.3) Total 546(100) In this stage 60 people did not refer for clinical interview **

206 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Ahmadvand, Z. Sepehrmanesh, F. S. Ghoreishi, et al.

Table 3. Frequency of psychiatric disorders based on demographic variables. With disorder Without disorder Age Total P-value n(%) n(%) 18–25 82(28.1) 210(71.9) 292 26–40 218(28.8) 534(71.2) 752 41–55 135(28.1) 342(71.9) 477 =0.542 56–65 43(35.8) 77(64) 120 +66 27(27.3) 72(73) 99 Total 505(29.2) 1235(70.8) 1740 Marital status n(%) n(%) Total P-value Single 36 (19.3) 151 (80.7) 187 Married 448 (30.1) 1042 (69.9) 1490 Widow 19 (35.8) 34 (64.2) 53 =0.01 Divorced 2 (20) 8(80) 10 Total 505(29.2) 1235(70.8) 1740 Education n(%) n(%) Total P-value Illiterate 95(42.8) 127(57.2) 223 Primary 202(30.8) 363(64.2) 565 Secondary 78(25.1) 233(74.9) 311 0.001 Diploma 86(21.2) 320(78.8) 406 Higher diploma 44(18.6) 192(81.4) 236 Total 505(29.2) 1235(70.8) 1740 Sex n(%) n(%) Total P-value Female 337 (35.5) 611 (64.5) 948 Male 168 (21.2) 624 (78.8 792 < 0.001 Total 505 (29.2) 1235 (70.8) 1740 Occupation n(%) n(%) Total P-value Worker 39(21.1) 146(79) 185 Student 18(18.9) 77(81) 95 Retired 38(26.8) 104(73) 142 Self-employed 61(20.3) 240(80)) 301 =0.00 Unemployed 83(38.8) 130(61.2)1 213 Housekeeper 266(33.1) 537(67) 803 Total 505(29.2) 1235(7.08) 1740

Table 4. Frequency of psychiatric disorders types based on sex variable.

Mood Anxiety Psychotic Neurological Disorders Dissociative Multiple Other disorders disorders disorders disorders Total P-value Sex disorders disorders disorders n (%) n (%) n (%) n (%) Female 114(33.8) 89(26.5) 9(2.7) 9(2.7) 12(3.5) 28(8.3) 76(22.5) 337 Male 48(28.5) 40(23.8) 12(7.2) 7(4.2) 5(3) 12(7.2) 44(26.1) 16 0.212 Total 162 129 21 16 17 120 40 505

The ratio of psychiatric disorders in women and men was sig- psychiatric disorders according to the clinical interviews, major nificant by used Mantel-Heanszel test and control of marriage depression was present in 41 (8.2%) individuals. In the anxiety status, education, and age variables. In this study, mood disorders disorder group, general anxiety disorder was present in 36 (7.2%), were more frequent in women, however, it was not significant be- and obsessive compulsive disorder was present in 34 (6.8%) in- tween sex and type of psychiatric disorders (P = 0.212, Table 4). dividuals (Table 5). In this study, 465 (92.2%) persons had only Psychiatric disorders were most prevalent among widows one disorder and 40 (7.8%) persons had more than one disorder. (35.8%), while singles had the smallest prevalence (19.3%). This difference was significant P( = 0.01), and with considering other Discussion variables such as age and sex with Mantel Heanszel Test (P = 0.001). The unemployed had a high prevalence of psychiatric dis- The present research was designed to estimate the prevalence of orders, seen in 83 (38.8%) individuals. Persons with an elemen- psychiatric disorders in individuals above 18 years old in Kashan. tary education had the most prevalent psychiatric disorders and According to the results, the prevalence of psychiatric disorders individuals whose education level was above a diploma had the was 29.2%. This rate was higher than other studies.10,12,13,17,19–26. smallest prevalence of psychiatric disorders, which was a signifi- The prevalence of mental disorders in this study was lower than cant (P < 0.001). other cities such as Qazvin (30.2%) and Shahrekord (39.1%).27,28 Overall, the results show the prevalence of psychiatric disorders The results are similar to New Zealand (29.5%) and United States in Kashan is 29.2%. The most prevalent psychiatric disorders studies (29.1%).29,30 were mood (9.3%) and anxiety disorders (4.7%). The prevalence Different results seen in Iran can be due to different methods of psychotic disorders was (1.2%), and neurocognition disorders, and tools for screening, diagnosis, classification, range of age (0.9% for each). Among the 505 individuals who suffered from groups, as well as the experience and proficiency of interviewers

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 207 Prevalence of Psychiatric Disorders

Table 5. Frequency of psychiatric disorders based on psychiatrist diagnosis. Mood Disorders n(%) Major depression 41(8.2) Minor depression 27(5.3) Dysthymia 29(5.7) Bipolar I type 12(2.4) Bipolar II Type 9(1.8) Cyclothymia 18(3.5) Post partum depression 4(0.8) Total 162(32.1) Anxiety disorders n(%) General anxiety disorder 36(7.2) Obsessive compulsive disorder 34(6.8) Agoraphobia disorder 3(0.6) Specific phobia disorder 15(2.8) Social phobia disorder 18(3.6) Post traumatic stress disorder 10(2) Panic disorder 13(2.6) Total 129(25.6) Psychotic disorders n(%) Schizophrenia 11(2.2) Other psychosis 10(2) Total 21(4.2) Neurological disorders n(%) Epilepsy disorder 5(1) Mental retardation disorder 7(1.4) Delirium disorder 4(1) Total 16(3.4) Dissociative disorders n(%) Amnesia 17(3.4) Other disorders 120(23.7) Comorbidity disorders 4.(7.8) Total 505(100) in different studies. These differences can also be attributed to the Mohammadi in Iran, Lehtinen in Finland, and Hosain in Leba- economical, social, cultural, and geographical situations in differ- non22,26,36; whereas the Palahang study in Kashan (1995) showed ent places and time of research. It seems that the lack of proper more prevalence in the 44–55 age group.12 An increased preva- recreation facilities and insufficient information about psychiatric lence of psychiatric disorders with age can be the result of lower disorders can better explain the high prevalence in Kashan. levels of body strength, somatic disorders, menopause in women, In this investigation, mood (9.3%) and anxiety disorders (4.7%) retirement, and the fact that the elderly are more prone to stressful were the most common psychiatric disorders. This study was situations, and somatic and psychiatric disorders. nearly in agreement with studies by Noorbala in Tehran,16 the In this research, the illiterate (42.8%) had the most prevalence Palahang study in Kashan,12 Florez31 and Preville32 in Canada, for psychiatric disorders whereas individuals with a diploma and Simsek in Turkey,33 and Garte in Italy.34 higher academic education (18.6%) had the least prevalence, In the Noorbala study, mood (9.8%) and anxiety (7.4%) disor- which agreed with other studies.12,16,22 Social and cultural limits ders were the most common psychiatric disorders.16 In the Pala- and the inability to use proper mechanism in confrontation with hang study the prevalence of mood disorders and anxiety disor- stress are the causes for the higher prevalence of psychiatric dis- ders were 11.75% and 11.15% respectively.12 Other studies in Iran orders in illiterates. (Khorasan and Hamedan),22,35 Finland,36 New Zealand,29 and Leb- According to this study prevalence of psychiatric disorders in anon37 showed anxiety and mood disorders as the most prevalent women who were housekeepers and unemployed men were more disorders, but the order was different than in our study. than employed men or women, which agreed with other research- Psychiatric disorders were two times more prevalent in women es.8,11,16 (35.5%) than men (21.2%) [OR = 2049. CI = 1/650 2/543]. These The probable reasons for these problems are low income, stress results were in agreement with other researches in Iran,11,14,28,12,38 due to unemployment, limitations in social relationships, and the and in the other areas of world.39,36,40 monotony of life in unemployed individuals and housekeepers. The finding that psychiatric disorders are more common in Another finding in this study was the statistically significant women can be due to more limitations in social activities, biologic relationship between patients’ psychiatric disorders and a family factors, and environmental stresses. Data in this study showed that and personal history of psychiatric disorders. The prevalence of prevalence of psychiatric disorders was higher in widowed, mar- psychiatric disorders in individuals with a personal history of psy- ried, and divorced individuals than in singles. This was in agree- chiatric disorders was six-fold higher than others (OR = 6.99). In ment with other studies in Iran (Kashan, Tehran, Hamedan)12,16,22 individuals with a family history of psychiatric disorders it was and in disagreement with Meyer in German, who noted that psy- three-fold higher than others. This can be described as the conse- chiatric disorders were more prevalent in singles.40 quences of biological factors and the effects of psychiatric disor- The reason for psychiatric disorders being more prevalent in ders in one member of the family on others. widows can be attributed to the fact that the death of a spouse The results of this study suggest that 29.1% of the subjects above is an etiology for stress, and can act as a predisposing factor for 18 need psychiatric health services. This indicates the enhanced psychiatric disorders. responsibility of politicians and decision makers in Kashan to In this study, the prevalence of psychiatric disorders in the age plan for the administration of psychiatric health. Considering the group above 56 was more than others. This is in agreement with high prevalence of mood and anxiety disorders in Kashan, new

208 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Ahmadvand, Z. Sepehrmanesh, F. S. Ghoreishi, et al. consultation centers, psychiatric therapeutic services and support Gonabad, Khorasan. Tehran psychiatric institute, Tehran, Iran; 1998. are necessary. Moreover, housekeepers, the unemployed, illiter- 15. Ghasemi GR, Asadollahi GA, Ahmadzadeh GH, Najmi B, Palahang H. Prevalence of mental disorders in Esfahan City. Res Med Sci. 1996; ates, women, divorced women, and individuals above 56 are at a 4: 190 – 194. higher risk for psychiatric disorders. 16. Noorbala AA, Bagheri yazdi SA. Prevalence of psychiatric disorders The creation of centers similar to health centers is necessary for in Tehran city. Hakim. 1999; 2: 212 – 224. the evaluation and diagnosis of high-risk groups who need referral 17. Noorbala AA, Bagheri Yazdi SA, Yasamy MT, Mohammadi K. A Look at the Mental Health Feature in Iran. First ed. Iran: Moallef: to a specialist (psychiatric or psychologist). Holding educational 2001; 55. classes for improving awareness and changing the negative at- 18. Palahang H, Shah Mohammadi D. Assessment of Reliability and Va- titude towards psychiatric disorders, offering ways to alleviate lidity of GHQ28. Iran: Tehran University of Medical Sciences; 1996. stressful factors and improve the quality of life is also important. 19. Bash KW, Bash-liechti J. Studies on the epidemiology of neuropsy- chiatric disorders among the population of the city of Shiraz, Iran. Soc Psychiatry. 1969; 9: 163 – 171. Limitations 20. Harazi MA, Bagheri Yazdi SA. Epidemiology of Mental Disorders in Ur- ban Areas of Yazd City. Iran: Yazd University of Medical Sciences; 1994. 21. Sadeghi KH, Saberi SM, Osare M. Epidemiology of mental disorders This research has some limitations, such as the non-compliance in the urban population of Kermanshah. Andisheh va Raftar. 2000; of participants in completing questionnaires and referral for diag- (22, 33): 16 – 25. nosis by a psychiatrist. Changing the place of living and lack of 22. Mohammadi M, Bagheri Yazdi SA, Rahgozar M, Mesgar Pour B, availability to subjects was one of limitations. Lotfi A. Epidemiology of psychiatry disorders in Hamedan province in 2001. J Hamedan Univ Med Sci. 2004; 11: 28 – 36. 23. Shen YC, Zhang MY, Hunag YQ, He YL, Liu ZR,Chang H, et al. Twelve Acknowledgments month prevalence, severity, and unmet need for treatment of mental disorders in metropolitan china. Psychol Med. 2006; 36: 257 – 267. 24. Kawakami N, Jakeshima J, Ono Y, Uda H, Hata Y, Nakane Y, et al. Twelve This research was funded by the Kashan University of Medical month prevalence, serverity, and treatment of common mental disorders Sciences. We thank Mrs. Rezvan Saei for her active participation in communities in japan: preliminary finding from the world health Japan in collecting data and completing questionnaires. surrey 2002 – 2003 psychiatry. Clin Neurosci. 2005; 59: 441 – 453. 25. Morosini PL, Coppo P, Reltro F, Pasquini P. Prevalence of mental disorders in Tuscany: a community study: in lari (pisa). Ann Ist Super References Samita. 1992; 28: 547 – 552. 26. Hosain GM, Chatterjee N, Are N, Islam T. Prevalence, pattern, and de- 1. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Measur- terminats of mental disorders in rural Bangladesh. Pub Health. 2007; ing the global burden of disease and risk factors.1990-2001. In: Lopez 121: 18 – 24. AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global 27. Joafshani MA. Prevalence of Neurotic Disorders in Alvand and Gaz- Burden of Disease and Risk Factors. New York: Oxford University vin City [Epidemiology these]. 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Prevalence and predictors Mental Health survey Initiative. 8 march 2011. of mental disorders among women in south eastern turkey. J Publlic 7. Demyttenaere K, Bruffaerts R, Posada-Villa J, Gasquet I, Kovess V, Health. 2008; 30: 487 – 493. Lepine JP, et al. Prevalence, severity, and unmet need for treatment of 34. Garte MG, Carpiniello B, Morosini PL, Rudas N. Prevalence of men- mental disorders in the world health organization world mental health tal disorders in sardina: a community study in an inland mining dis- surveys. JAMA. 2004; 291: 2581 – 2590. trict. Psychol Med J. 1991; 21: 1061 – 1071. 8. Noorbala AA, Bagheri Yazdi SA, Yasamy MT, Mohammadi K. Mental 35. Mohammadi M, Bagheri Yazdi SA, Rahgozar M, Mesgarpour B, Rezayi health survey of the population in Iran. Br J Psychiatry. 2004; 184: 70 – 73. Ansari EA. Epidemiological study of psychiatric disorders in Khorasan 9. Afshari Monfared G, Bagheri Yazdi SA, Bolhari J. Epidemiologiy of province in 2001. 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Archives of Iranian Medicine, Volume 15, Number 4, April 2012 209 Suicide Epidemiology and Characteristics in Iranian youth

Original Article

Suicide Epidemiology and Characteristics among Young Iranians at Poison Ward, Loghman-Hakim Hospital (1997–2007) Abdolkarim Pajoumand MD1, Haleh Talaie MD MPH•1, Arezou Mahdavinejad MD1, Shirin Birang MD3, Mahboubeh Zarei MD2, Fatemeh Fereshteh Mehregan MD4, Babak Mostafazadeh MD1,2

Abstract Background: Suicide is a critical public health problem. In developing countries, the highest suicide rate is found in young adults with remarkable increasing rate. In this study, we have evaluated the epidemiology and characteristics of 8–16-year-old individuals who attempted suicide and were hospitalized in Loghman-Hakim Hospital, Tehran, Iran from 1997 to 2007. Methods: A total of 6414 hospitalized patients, ages 8–16, who attempted suicide and were residents of Loghman-Hakim Hospital were investigated. We performed a retrospective chart review to study the characteristics of cases in a 10-year period by review of psychiatric and medical records. Results: Out of 6414 patients 22.6% were male, 5978 patients were 12–16 years old and the rest were aged 8–12 years. During the 10- year period, suicides showed a rising trend among adults, while in children no significant increase was detected. Communicative disorders were the most common underlying risk factors, particularly in females. One patient out of five cases had psychiatric disorders, of which adjustment disorders were the most predominant. A remarkable peak in suicides was observed in May and July, while winter had the highest suicide rate among seasons. Conclusions: Suicide due to drug overdose is higher in females than males in young population. This increasing trend is a psychiatric concern and should be resolved by improving mental and public health.

Keywords: Poisoning, psychiatry, suicide, youth

Cite the article as: Pajoumand A, Talaie H, Mahdavinejad A, Birang S, Zarei M, Mehregan FF, Mostafazadeh B. Suicide Epidemiology and Characteristics among Young Iranians at Poison Ward, Loghman-Hakim Hospital (1997–2007). Arch Iran Med. 2012; 15(4): 210 – 213.

Introduction young people depends on what other factors are operational in that country.9 Abuse, loss of friends (including boyfriend or girl- uicide is recognized as a major public health problem friend), substance abuse, academic failure, family discord, legal/ S throughout the world.1 There are nearly 900,000 suicides disciplinary problems, school concerns, and mental health con- worldwide each year, including as many as 200,000 ado- ditions such as depression increase the risk for suicide among lescents and young adults. Suicide in children and adolescents is a youths of both sexes.2 Sex differences in suicide attempt rates are national and global phenomenon.2 Lack of scientific knowledge considerable, but the pattern of sex differences is not same be- about suicide attempts in youth is because of the limited research tween countries.7 on this subject in addition to the conclusion of some researchers Self-poisoning is one of the prevalent methods used for attempt- that suicide is beyond children’s capabilities.3,4 Before puberty, the ing suicide. It seems attempted suicide among children is more prevalence of suicide attempts is rare and increases during adoles- common than estimated. Recent studies report that the suicide cence. Because of the growing risk for suicide with increasing rate among children aged 5–14 years is 1–2 deaths per 100,000 age, adolescents are the main target of repeated suicide attempts.5,6 and among youth aged 15–19 years, it is 11 deaths per 100,000.7 A variety of global suicide rates depends on local factors such as This age selection is based on a recommendation by Margaret data collection and reporting methods.7 Suicide rates lower than Thompson (Head of Ontario, Canada Poison Center). According 6.5 per 100,000 have been reported in Latin America and Middle to a study performed in Iran in 1997, poisoning occurred more Eastern Arabic countries. The highest rates have been reported common at ages 2–6 years for children and 21–40 years for adults. from Finland, Latvia, Lithuania, New Zealand, the Russian Feder- The most common route of poisoning was oral intoxication, par- ation, and Slovenia with rates over 30 per 100,000.8 In industrial- ticularly drugs, which has been confirmed by a recent report in ized countries, males commit suicide 4 times as often as females. 2007. Intentional poisoning has been reported 4 times more than The exact place that suicide has in the deaths of adolescents and unintentional cases.10,11 The aim of this study was to describe the epidemiology and char- Authors’ affiliations: 1Toxicological Research Center, Loghman-Hakim Hospi- tal, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2Poison Cen- acteristics of 8–16-year-old individuals who attempted suicide ter, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, (parasuicide) and were hospitalized in Loghman-Hakim Hospital, Tehran, Iran.3 Radiology Ward, Loghman-Hakim Hospital, Shahid Beheshti Tehran, Iran during a 10-year period (1997 to 2007). Male and fe- University of Medical Sciences, Tehran, Iran.4Pediatric Ward, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. male suicide attempts were compared with respect to psychiatric •Corresponding author and reprints: Haleh Talaie MD MPH, Toxicologi- disorders, reason for suicide, seasonality, and educational level. cal Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Parasuicide is an apparent attempt at suicide, commonly called a Medical Sciences, Tehran, Iran. Tel: +98-215-541-8175, Fax: +98-215-540-8847, E-mail: [email protected]. suicidal gesture, in which the aim is not death. Accepted for Publication: 21 September 2011

210 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Pajoumand, H. Talaie, A. Mahdavinejad, et al.

Table 1. Frequency of attempted suicides among 8–16 year olds admitted to Loghman-Hakim Hospital. Female Male Total Age group Number % Number % Number % 8–12 year olds 289 66.3 147 33.7 436 100 12–16 year olds 4674 78.2 1304 21.8 5978 100 Total 4963 77.4 1451 22.6 6414 100

Table 2. Motivations and reasons for attempted suicides among 8–16 year olds admitted to Loghman-Hakim Hospital. Motivations and reasons for suicide attempt Number % Substance abuse 88 7.7 Communicative disorder 666 58.4 Economic problem 18 1.6 Family loss 87 7.6 Sudden changes in mood 53 4.6 Familial history of substance abuse 8 0.7 Parental divorce 15 1.3 Parental discord 21 1.8 Educational issues 41 3.6 Combination of the above reasons 60 5.3 Others 84 7.4 Total 1141 100

Table 3. Month variations of attempted suicides. Age group 8–12 year olds 12–16 year olds Month Female Male Female Male n % n % n % n % January 7 4.8 26 9.3 109 8.4 348 7.5 February 14 9.5 18 6.4 135 10.4 427 9.2 March 17 11.6 11 3.9 119 9.2 435 9.4 April 16 10.9 40 14.3 118 9.1 386 8.3 May 19 12.9 20 7.1 97 7.5 467 10.1 June 13 8.8 19 6.8 99 7.6 439 9.5 July 6 4.1 23 8.2 80 6.2 401 8.6 August 16 10.9 31 11.1 123 9.5 441 9.5 September 12 8.2 20 7.1 101 7.8 345 7.4 October 9 6.1 13 4.6 72 5.6 245 5.3 November 9 6.1 33 11.8 94 7.3 317 6.9 December 9 6.1 26 9.3 148 11.4 388 8.4

Materials and Methods Chi-square test. P-values equal to or less than 0.05 were considered significant. In this cross-sectional retrospective study, 6414 individuals that had attempted suicide were recruited. The study population con- Results sisted of hospitalized patients in the age range of 8 to 16 years old that attempted suicide and were residents in the Poison Center Over a 10-year period (1997–2007), 6414 attempted suicides in of Loghman-Hakim Hospital from1997 to 2007. Loghman-Ha- young people aged 8 to 16 were registered in Loghman-Hakim kim Hospital is a unique poisoning referral center in Tehran, Iran Hospital. Of these, 1451 (22.6%) were male and 4963 (77.4%) that admits patients from all cities in Tehran Province. Annually, female. The following suicide distribution was observed accord- around 20,000 hospitalized patients are observed and treated in ing to age groups and sex: females at 8–12 years old (n = 289; this center. The daily turn-over in this center is 80–100 patients. 66.3%) and females at 12–16 years old (n = 4674; 78.2%). Males We performed a retrospective chart review in this referral cen- were less prevalent in both age groups (Table 1). According to ter to study the seasonality and characteristic of patients who the etiologic reasons of attempted suicides, communicative dis- attempted suicide during a 10-year period. Patients’ sex; age; orders were the most common underlying risk factors followed education level; history of attempted suicide; method of suicide; by substance abuse and family conflict (Table 2). Communicative reasons for suicide such as substance abuse, communicative dis- disorders in females were reported higher than in males. order, economical issues, parental discord, loss and divorce, fam- Evaluation of underlying psychiatric disorders showed that ily history of addiction, educational problems, mood disorder, and about 1 out of 5 cases with attempted suicides had psychiatric psychiatric diagnosis that included depression, adjustment, bipo- disorders, most of whom suffered from adjustment disorders. A lar, anxiety, personality and psychotic disorders; as well as the history of attempted suicide was found in 1 out of 7 cases in our season in which the suicide attempt was made were all extracted study population with no difference in gender. Most were stu- by a review of psychiatric and medical records. Gender differ- dents; less than 1% were illiterate. ences and seasonal distribution of suicides were tested with the There was a remarkable increase in suicides observed both in

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 211 Suicide Epidemiology and Characteristics in Iranian youth

Table 4. Seasonal variations of attempted suicides Season Age Winter Spring Summer Autumn group Number % Number % Number % Number %

8–12 year old males 39 27.1 44 30.6 35 24.3 26 18.1

8–12 year old females 44 20.5 60 27.9 77 35.8 34 15.8

Total8–12 year olds 83 23.1 104 29 112 31.2 60 16.7

12–16 year old males 382 29.4 286 22 308 23.7 322 24.9

12–16 year old females 1304 28 1189 25.6 1189 25.6 971 20.9

Total12–16 year olds 1686 28.3 1475 24.8 1497 25.2 1294 21.7 males and females in May and July, while males had the greatest riod from 1997 to 2007. All cases had attempted suicide by using frequency in December and females in May, when separately ana- therapeutic drugs. According to the studies performed in Logh- lyzed. Suicide frequencies showed the lowest rate for the overall man-Hakim Poison Center, the most important agents of acute data in October (Table 3). The peak of suicides occurred in the poisoning were drugs (69.13%). Sedative-hypnotics followed by summer among 8–12 year olds whereby the highest suicide rate opioids (12.34%) and organophosphates (6.21) were reported to among 12–16 year olds was reported during the winter. Generally, be the most common agents in 2003, which corresponded with over the study period, suicide occurrence was obviously higher our results, while in 1997 benzodiazepines (24.5%) were most during the winter in both males and females (Table 4). frequent, followed by antidepressants (20.5%), and analgesics From 6101 eligible cases, the most important cause of patient (18%).10,11 In China, more than 60% of suicide deaths occurred suicide was drugs (91.7%), followed by pesticides (8.1%), self-in- by pesticides.12 In Sweden, drug poisoning was found as the most fliction (0.1%), and substance abuse (0.2%). In the 8–12-year-old common suicide method in nearly every second woman and every cases, the most common drugs of poisoning were TCA (imipra- fifth man who committed suicide.13,14 mine, amitriptyline; 22%), benzodiazepine (lorazepam, diazepam; A rising trend for suicide attempts was found within the period 18.3%), and anticonvulsive drugs (phenobarbital, carbamazepine; of 1997 to 2007 among adults while no significant change was 14.7%). In 12–16-year-old cases, sedative-hypnotics (33.1%) observed for children. Another report from the USA showed that were the dominant drug type used by patients who attempted sui- during 1992–2001, the suicide rate for individuals aged 10–19 cide by drug poisoning, followed by psychotropics (27.3%), and declined from 6.2 to 4.6 per 100,000.12 The rising rates of youth analgesics (17.6%). The most common pesticides for poisoning suicide have been clearly evident in developed countries such as were organophosphates (63%) followed by carbamates (30%). Australia and New Zealand since the 1970s.15 In 1684 out of 6554 patients with sufficient data for diagnos- It is considerable that contrary to international reports, a higher tic assessment, there were 901 (53.5%) adjustment disorders, incidence of poisoning is shown in females than males in all age 441 (26.2%) mood disorders, 132 (7.8%) personality disorders, groups, at a ratio of 3.5:1.16,17 The increasing rate of acute poison- 37 (2.2%) anxiety disorders, 39 (2.3%) bipolar disorders, 32 ing in females is for their much more communicative disorder. (0.8%) psychotic disorders, and 121 (7.2%) had more than one Drug overdose is more common in females throughout the of the above mentioned disorders. In our study, 536 (14.5%) out world. Ghazinour et al. have studied parasuicide for the period of 3687 patients had a record of a previous suicide attempt. There of 2000–2004 in an overall age range and reported that females were 301 patients (56.2%) who had one previous suicide attempt, outnumbered males in the age category of 10–19 years, but in 46(8.6%) had 2 previous attempts, 35 (6.5%) attempted 3 times, males was contrary after the age of 20 years.18 Mello-Santos et and 23 patients (4.3%) had attempted more than 3 times. In 131 al. from Brazil have reported 3-times more suicide attempts for patients (34.4%) there were no previous suicide attempts. males compared to females during 1998–2000.19 During this 10-year period from 1997 to 2007, suicide attempts Psychological disorders were diagnosed in 20% of our study showed a rising trend among adults while the trend in children population. The high rate of adjustment disorders among cases showed no significant peak. The number of attempted suicides with suicide attempts (54%) agreed with other international stud- showed an increase from 1997 to 1998 with an apparent peak ies that have identified various risk factors for suicide, including while there was a decreasing trend until 2002. In the last 5 years, depression, alcoholism, and schizophrenia.20,21 The frequency the increase in suicide attempts was noted among 12–16-year-old of depressive disorders among females in the present study was children. 24%, which was lower than the 50% among adolescents as reported by Shaffer et al.22 in 1988, and higher than females under Discussion the age of 30 (18%) according to Asgard. Psychiatry interviews were not performed for all of our study population, which might 23 The present findings show that there were 6414 cases of attempt- skew the results. ed suicide admitted to the Poison Center of Loghman-Hakim The proportion of victims with previous suicide attempts in the Hospital with the age range of 8 to 16 years during a 10-year pe- present study was 14%, which was lower than the rate of 80%

212 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Pajoumand, H. Talaie, A. Mahdavinejad, et al. among Swedish females aged 15 to 29 years as reported by As- in adolescence. J Adolesc Health. 1992; 13: 409 – 414. gard in 1990.23 Marttunen et al. studied suicide attempts among 13 7. World Health Organization (WHO). Suicide rates and absolute numbers of suicide by country (2002).Geneva (CH): WHO; 2003. [Cited to 22 year olds and reported that females were more likely to have Mar14]. Available from: URL: http2004://www.who.int/mentalhealth a previous suicide attempt than males, while the present study /prevention/suicide/country-reports/en/index. Html (Accessed: April results have revealed no differences in previous suicide attempts 2007). among genders.24 The inconsistent findings probably reflect dif- 8. Mann JJ, Apter A, Bertolote J, Beautrais A, Currier D, Haas A, et al. Suicide prevention strategies: a systematic review. JAMA. 2005; 294: ferences in subjects’ ages and methodologies between studies. 2064 – 2074. In our study, the greatest suicide frequencies were found in May 9. Brown P. Choosing to die: a growing epidemic among the young. Bull and July, the school examination months. As previously reported, World Health Organ. 2001; 79: 1175 – 1177. school problems might trigger suicide among adolescents.25,26 10. Shadnia S, Esmaily H, Sasanian G, Pajoumand A, Hassanian- Moghaddam H, Abdollahi M. Pattern of acute poisoning in Tehran, These findings suggest the critical role of public awareness about Iran in 2003. Hum Exp Toxicol. 2007; 26: 753 – 756. impact of school problems on youth suicidal behavior.25,27 Ung EK 11. Abdollahi M, Jalali N, Sabzevari O, Hoseini R, Ghanea T. A retro- in 2003 has reported a greater occurrence of suicides among youth spective study of poisoning in Tehran. J Toxicol Clin Toxicol. 1997; 35: 387 – 393. in Singapore during the months of June, October, November, and 12. 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Youth suicide and gender in Australia and New Zealand compared with countries of the western world 1973–1987.Aust NZ J were lower in autumn and winter. They have suggested the prob- Psychiatry. 1992; 26: 609 – 617. able role of increased sociological arguments and higher level of 16. Krug EG, Powell KE, Dahlberg LL. Firearm-related deaths in the social activity in spring and summer. These social tensions lead to United States and 35 other high- and upper-middle-income countries. a seasonal peak in the second quarter of the year.30 Int J Epidemio. 1998; 27: 214 – 221. 17. Bertolote JM, Fleishmann A. Suicide and psychiatric diagnosis: a Suicide rates among young people are high, particularly among world perspective. World Psychiatry. 2002; 1: 181 – 185. females. This accelerated rate needs more attention to youth psy- 18. Ghazinour M, Emami H, Richter J, Abdollahi M, Pazhumand A. Age chosocial issues. 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Aging Mental Health.1997; 1: 107 – 111. The Ethical Committee of Shahid Beheshti University of Medi- 22. Shaffer D, Graland A, Gould M, Fisher P, Trautman P. Preventing cal Sciences approved the study protocol, with code number 10. teenage suicide. A critical review. J Am Acad Child Adolesc Psychia- try. 1988; 27: 675 – 687. 23. Asgard U. Apsychiatric study of suicide among urban Swedish wom- Acknowledgment en. Acta Psychiatr Scand. 1990; 82: 115 – 124. 24. Marttunen M, Henriksson M, Aro H, Heikkinen M, Esimetsa E, Lon- We acknowledge the Poison Center of Toronto, Ontario as well nqvist J. Suicide among female adolescents, characteristics, and com- as Dr. Thompson for her suggestion for this research design. Spe- parison with males in the age group 13 to 22 years. J Am Acad Child Adolesc Psychiatry. 1995; 34: 1297 – 1307. cial thanks to the File Recording Department of Loghman-Hakim 25. Gould MS, Fisher P, Parides M, Flory M, Shaffer D. Psychosocial risk Hospital, Tehran, Iran. factors of child and adolescent completed suicide. Arch Gen Psychia- try. 1996; 53: 1155 – 1162. 26. Hoberman HM, Garfinkel BD. Completed suicide in children and ad- References olescents. J Am Acad Child Adolesc Psychiatry.1988; 27: 689 – 695. 27. Gould MS, Kramer RA. Youth suicide prevention. Suicide Life Threat 1. Chishti P, Stone DH, Corcoran P, Williamson E, Petridou E. Suicide Behav. 2001; 31: 6 – 31. mortality in the European Union. Eur J Public Health. 2003; 13:108 28. Ung EK. Youth suicide and parasuicide in Singapore. Ann Acad Med – 114. Singapore. 2003; 32: 12 – 18. 2. Greydanus DE, Calles J Jr. Suicide in children and adolescents. Prim 29. Shields L, Hunsaker D, Hunsaker J. Adolescent and young adult sui- Care. 2007; 34: 259 – 273. cide: a 10-year retrospective review of Kentucky medical examiner 3. Satcher W. National Strategy for Suicide Prevention: Goals and Ob- cases. J Forensic Sci. 2006; 51: 874 – 879. jectives for Action. Washington, DC: SAMHSA, CDC, NIH, HRSA; 30. Ajdacic-Gross V, Wang J, Bopp M, Eich D, Rossler W, Gutzwiller F. 2001. Are seasonalities in suicide dependent on suicide methods? A reap- 4. Pfeffer CR. Suicide. In: Wiener JM, ed. Textbook of Child and Ado- praisal. Soc Sci Med. 2003; 57: 1173 – 1181. lescent Psychiatry. 2nd ed. Washington, DC: American Psychiatric Press; 1997: 727 – 738. 5. Veles CN, Cohen P. Suicideal behavior and ideation in a community sample of children: maternal and youth report. J Am Acad Child Ado- lesc Psychiatry. 1988; 27: 349 – 356. 6. Jeanneret O. A tentative epidemiologic approach to suicide prevention

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 213 Xerostomia and QoL after Radiotherapy

Original Article Xerostomia after Radiotherapy and its Effect on Quality of Life in Head and Neck Cancer Patients

Shahla Kakoei DMD MS•1, Ali-Akbar Haghdoost MD PhD2, Maryam Rad DMD MS3, Sakineh Mohammadalizadeh MS4, Nasim Pourdamghan MD5, Mahdieh Nakhaei DMD6, Maryam Bahador MD7

Abstract Background: Xerostomia is one of the one complications following radiotherapy that can affect quality of life (QoL). This study aims to assess the severity of xerostomia in patients with head and neck cancers after radiotherapy and its effect on QoL. Methods: In this longitudinal prospective study, the severity of xerostomia and related QoL was assessed in 63 head and neck cancer patients who referred to the Radiotherapy Ward. Patients completed a xerostomia questionnaire (XQ) at the beginning, and 2, 4, and 6 weeks after treatment over a period of 6 months. Additionally, unstimulated saliva was collected using the spitting method at all 4 visits. Results: QoL significantly worsened with increased time P( = 0.0001); meanwhile, the severity of xerostomia increased significantly P( = 0.0001). However, there was no significant change in the amount of saliva at these 4 time points P( = 0.23). Regression analysis showed that with each milliliter decrease in saliva secretion, the QoL score decreased 2.25%. With one score increase in xerostomia, from the QoL mean score there was a 1.65% decrease. Conclusion: The decrease in saliva and xerostomia that resulted from radiotherapy plays an important role in worsening QoL among patients who undergo radiotherapy for head and neck cancers. Although the amount of saliva has a significant association with QoL, the xerostomia score which shows subjects’ general feeling also independently impacts QoL. In future studies, we recommend patient assessments for periods longer than 6 months.

Keywords: Quality of life, radiotherapy, saliva flow, xerostomia

Cite the article as: Kakoei S, Haghdoost AA, Rad M, Mohammadalizadeh S, Pourdamghan N, Nakhaei M, Bahador M. Xerostomia after Radiotherapy and its Effect on Quality of Life in Head and Neck Cancer Patients. Arch Iran Med. 2012; 15(4): 214 – 218.

Introduction xerostomia, to date none are definite or curative. New techniques in radiotherapy can be effective in preventing xerostomia by de- ral cancers are among the most common cancers and 1 of creasing salivary gland exposure.3 the 10 most common causes of death, worldwide.1 Multi- However, despite the tools to evaluate salivary gland function, Ople treatments exist for treating oral cancers that include xerostomia is only a subjective symptom.3 In addition to the treat- surgery, radiotherapy, chemotherapy, and the combination of ment effect of radiotherapy on controlling tumor size and patients’ these 3 methods.2 In radiotherapy, high energetic electromagnetic survival; one must be concerned about short term and long term rays (X- or gamma rays) or particles with high levels of energy are disabilities, and quality of life (QoL). Currently QoL is consid- used to destroy malignant cells. Ionizing rays lead to cellular ered a health concern, whose measurement is essential in health death via preventing DNA synthesis and activity.2 Although cells research.7,9 affected by radiotherapy either die or remain alive, they cease to There are many published studies about the effects of radio- divide.1 therapy on the mouth, of which xerostomia is the most frequent Radiotherapy complications in the oral cavity are important with complaint from patients who receive radiotherapy.3,12,13 Numerous regards to oral diseases. Previous studies have shown that xerosto- studies have researched post-radiation xerostomia in Iran.14,15 Al- mia is the most frequent complication among patients who receive though there is tremendous research in this area, few studies have radiotherapy. The prevalence of xerostomia has been reported to simultaneously explored the associations of QoL, general feeling be from 73.5% to 93%.3–5 Other complications include viscous of subjects about xerostomia, and the amount of saliva during and saliva, salivary gland dysfunction, mucositis, soft tissue necrosis, after radiotherapy. periodontal diseases, tasting disorders, decreased sense of taste, Previous studies have shown that objective signs are not accord- oral discomfort or jaw pain, tooth caries, mucosal pigmentation, ed with subjective symptoms.5 Based on the above explanation, limitations in opening the mouth, viral and fungal infections, and we aim to explore the associations of these three variables (QoL, osteoradionecrosis.1,6–11 Although palliative treatments exist for xerostomia, and saliva quantity) in head and neck radiotherapy Auhtors’ affiliations: ¹Kerman Neuroscience Research Center, Kerman, Iran. cases during and after treatment. The intent of this study is to ²Kerman Physiology Research Center, Kerman, Iran. ³Kerman Oral and Dental evaluate xerostomia and its effect on QoL. Diseases Research Center, Kerman, Iran. 4Razi Nursing School, Kerman, Iran. 5General Practitioner, Kerman, Iran, 6Privaite Practice Clinic, 7Oncology Depart- ment, Shafa Hospital, Kerman, Iran Materials and Methods •Corresponding author and reprints: Shahla Kakoei DMD, Oral Medicine Department, Dental school, Shafa Blvd., Kerman, Iran. Patients and setting Tel:+98-913-140-8974, +98-341-211-9024, E-mail: [email protected]. Accepted for publication: 20 July 2011 In a longitudinal prospective study, 63 patients with head and

214 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 S. Kakoei, A. A. Haghdoost, M. Rad, et al. neck cancers were followed for 6 weeks. The subjects were se- were statistically significant P( < 0.001). Subjects received no in- lected from the only radiotherapy referral center at Shafa Hospi- terventions during those 5 days. tal, Kerman, Iran. In order to collect patients’ saliva, they had to refrain from eat- The proposal of this study was approved under the ethical code ing, drinking, smoking, and brushing teeth 90 minutes prior to of EC/KNRC/87-6 by the Neuroscience Research Center, Ker- sample collection. In order to prevent the circadian pattern of sa- man University of Medical Sciences. liva secretion bias, sample collection was conducted between 10 The sample size was calculated to estimate a Pearson correlation and 12 am. Saliva was collected using the spitting method.17 Each of 0.4 or more with 95% confidence interval between the three patient was asked to rest for a few minutes, close his/her mouth main variables of QoL, amount of saliva and xerostomia score. and not to swallow his saliva. Then the patient was asked to lay The method of our sampling was sequential. Patients older than his head obliquely on a plate, which its weight was already reg- 18 years whose bilateral major salivary glands were exposed to istered on its outer side. After each three minutes, patients spitted radiotherapy at doses of at least 2500–3000 cGy were recruited to their saliva in the plates and such an action was repeated for ten participate.3 Patients were included in this study if they presented minutes. Considering that the normal amount of saliva in healthy with nasopharyngeal, laryngeal, parotid, or hypopharyngeal can- individuals is 0.1 to 0.8 mL/min, the amount less than 0.1 mL/min cers, or any other tumors in the oral cavity. The type of radiation accounted for insufficient saliva.1 was conventional X-ray with a linear energy of 9 mv photons. Some patients who received radiotherapy were also administered Statistical analysis chemotherapy (cisplastin), which was dependent upon pathologic Data were analyzed using SPSS version 11.5; we compared status, particularly in cases of nasopharynx and hypopharynx car- the xerostomia and QoL scores and the amount of saliva in four cinomas. Patients were excluded from the study if they had other measurements by repeated ANOVA. In order to assess the dif- known systemic disorders such as Sjögren syndrome, diabetes, ferences among four measurements, we compared double groups connective tissue diseases (rheumatoid arthritis or systematic lu- using paired t-test with Bonferroni correction. In addition, we as- pus erythematosus), or if they were taking any type of medication sessed the association of these scores with the amount of saliva by that effected saliva secretion. Pearson correlation coefficients and multivariate linear regression models. Assessments Patients were initially interviewed prior to the start of their ra- Results diotherapy; follow up visits were conducted 2, 4, and 6 weeks later. Out of 63 subjects, 43 (77.8%) were male. Their mean ± SD age Having explained the objectives of the study and its methodol- was 45.6 ± 15.6 years. Average received radiation doses was 5398 ogy, eligible subjects were asked to sign a consent form at the first cGy during their radiotherapy. The most frequent carcinoma was visit. In all 4 sessions, subjects were asked to complete a question- of the larynx (31.7%). Demographic information, the diseases, naire related to their xerostomia (XQ) and a QoL questionnaire. In and their treatment characteristic are presented in Table 1. addition, during all 4 visits, the amount of their saliva was mea- There was a significant difference among the xerostomia score sured by collecting unstimulated whole saliva in milliliters per at all 4 time points (P = 0.0001). The xerostomia score in the minute for a total time of ten minutes. first session was significantly lower than the next 3 sessionsP ( Data was collected using XQ and QoL questionnaires. The XQ < 0.001), but the differences among following sessions were not included eight questions evaluated by the Likert scale (1: not at statistically significant. Around 20% of the samples dropped out all; 2: a little; 3: moderately,4 : quite a lot; and 5: very much). during the follow-up period. Hence, according to the XQ, the more the patient had a feeling There was a significant difference among the QoL score in all 4 of xerostomia, the higher the xerostomia score would be, which sessions (P = 0.0001). The score of the first session was signifi- ranged between 8 and 40.16 For QoL, we used the QoL part of the cantly higher than in the next 3 sessions. In addition, the score in XQ published by Dirix et al.3 In that study, 15 questions evaluated the second session was higher than the third session. The mean QoL with the Likert scale, as follows: 5: not at all; 4: a little; 3: salivary flow in the first session was 0.29 mL. Although it was moderately; 2: quite a lot; and 1: very much. The worse the pa- greater than seen at during follow up, the variation was not statis- tient’s QoL was, the lower its score would be. This score ranged tically significant P( = 0.23; Table 2). The percentage of xerosto- between 15 and 75. In addition to these questions, demographic mia (saliva < 0.1 mL/min) was 11% in the first session whereas it information of age, sex, educational and marital status, lesion lo- was 25%, 14%, and 25% in the following sessions, which was not cation, and the type of treatment were gathered. statistically significant P( = 0.13). In order to validate the questionnaires, we used the standard The correlation coefficient between saliva amount and QoL forward-backward translation by two independent translators to score before starting radiotherapy showed a weak negative asso- ensure that the Persian versions of the questionnaires were com- ciation (r = -0.15, P = 0.23), while this association was positive parable with their English versions. in the next 3 sessions (r = 0.30, P = 0.02; r = 0.1, P = 0.46; and r In the next step, the content of the questionnaires were verified = 0.3, P = 0.04, respectively). We observed a strong negative as- based on feedback received from 20 people of varying literacy sociation between QoL and xerostomia scores in all four sessions levels. In addition, the internal consistency of the questionnaire (-0.76, -0.67, -0.66, and -0.56; all values of P < 0.0001). There was computed using Chronbach’s alpha, which ranged between was no relationship between the amount of saliva secreted and 0.67 and 0.92 at four times of data collection. Using re-test with xerostomia in all four session (-0.0002, -0.17, -0.012, and -0.38); a 5-day gap, the intra-class correlation (ICC) in response to xero- this association was significant only in the fourth session P( = stomia and QoL questions were 0.31 and 0.37, respectively; both 0.01; Table 3). The changes in salivary flow, QoL, and XQ-score

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 215 Xerostomia and QoL after Radiotherapy are shown in Figure 1. Discussion In our regression model, we found that each mL/min decrease in the flow of saliva decreased the QoL score by 2.25%. Meanwhile, The results of the present study revealed that the feeling of xe- with a one score increase in xerostomia score, the QoL score rostomia more strongly affected QoL compared to actual salivary decreased by 1.65%. However, in the adjusted model for demo- flow amongst patients undergoing radiotherapy. The amount of graphic variables, only the xerostomia score was significantly as- saliva secreted did not significantly change during therapy while sociated with QoL, which meant that salivary secretion compared patients began to suffer from xerostomia after the start of treat- to xerostomia score, had a weaker direct association with the QoL ment. The later lead to a decrease in QoL during radiotherapy. The score. results also showed that QoL decreased in the first two weeks of None of the demographic variables showed significant associa- radiotherapy, but afterward it was more or less constant. tions with saliva flow and xerostomia in our repeated measure Previous studies have demonstrated that xerostomia, which is ANOVA model. caused by local permanent damage to the salivary glands in the In addition, no significant relationship was seen between the radiation treatment zone, is a common and important complaint dose of received radiotherapy with total xerostomia and QoL amongst patients who undergo head and neck radiotherapy.3,4,18–22 scores (P > 0.1 for all values). In a study conducted in 2006 by Pow et al., the effect of intensity modulated radiotherapy on the severity of xerostomia and QoL was assessed, which revealed that xerostomia was an important problem of patients after 2 months of radiotherapy.4 In the present study, it was revealed that the mean amount of saliva in the first session was more than the next 3 sessions. Such a finding was compatible with a study by Lin et al.17 As with the Dirix et al. and Lin et al. findings, we detected an increase in trend in the feeling of xerostomia during the first 6 weeks of radiotherapy.3,17 We did not find any significant, strong association between the sensation of xerostomia and actual salivary flow. It seems that xerostomia is a subjective feeling and other factors may have more effect than the amount of saliva. This finding was also observed in a study by Viasanathan and Nix.23 Generally, oral problems such as patients’ facial appearance, swallowing, speaking, and a decreased level of activity could affect their oral health-related QoL by influencing psycho-social aspects.7,24–26 In a study conducted by McMilan et al., it was shown that oral health-related QoL in patients who underwent radiotherapy due to nasophayngeal cancer significantly improved over time.26 It seemed that the psychological shock that patients may have at the time of diagnosis and in the beginning of treatment manifest as xerostomia even in the absence of a considerable decrease in saliva amount. In the present study, the score of patients’ QoL significantly decreased during the first 6 weeks after the treatment. Although a decrease in QoL and a simultaneous increase in xerostomia do not confirm a causal association, this issue could be due to initiation of radiotherapy. According to other studies, the effect of xerostomia on oral health and QoL is very important.3,17 We only followed our subjects for 6 weeks; however, the long term trend of QoL might be different. Oates et al. followed their cases for 24 months and showed that QoL improved after the start of treatment.7 However, longer follow ups were conducted and the results showed QoL improved for an extended time after treatment, but xerostomia did not decrease.7,26 Based on the above explanation, we believe the short period of follow up was the main limitation of our study. This was solely due to practical considerations, which have also been mentioned in similar studies.17 In addition, we did not assess other aspects of oral health such as pain and mucositis. We encountered numerous problems in our saliva collections mainly due to the severe health condition of our subjects and their low literacy rates, both Figure 1. Changes in salivary flow, XQ score, and QoL during four inter- of which increased our work and efforts in this study to convince vals. subjects to cooperate accordingly.

216 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 S. Kakoei, A. A. Haghdoost, M. Rad, et al.

Table 1. Demographic characteristics of the patients. Characteristics Number of patients (%) Male 49 (77.8%) sex Female 14 (22.2%) Age (mean ± SD) years 45.6 ± 15.6 Uneducated 11(17.5%) Education Diploma and less 50 (79.3%) University educated 2 (3.2%) Married 58 (92.1%) Married status Single 5 (7.9%) Larynx 20 (31.7%) Oropharynx 17 (26.9%) Brain 11 (17.4%) Sight of lesion Oral cavity 5 (7.9%) Lymphoma 4 (6.3%) Salivary gland cancer 7 (11.1%) Ear 1 (1.5%) RT 8 (12.7%) Treatment Chemotherapy & RT 55 (87.3%) Previous surgery 55 (87.3%)

Table 2. Saliva secretion, XQ-score, and QOL score in four sessions.

Time of Salivary flow XQ score QoL score measurement (mL/min) Mean ± SD Number Mean ± SD Number Mean ± SD Number Before RT 63.45 ± 10.55 62 16.87 ± 7.42 62 0.29 ± 0.2 60 Second week 54.81 ± 9.81 54 21.72 ± 5.94 54 0.23±0.17 54 Fourth week 50.57 ± 8.91 53 23.51 ± 4.60 54 0.24±0.25 54 Sixth week 52.64 ± 6.27 47 23/42 ± 4.6 49 0.17±0.22 43 P-value 0.0001 0.0001 0.23

Table 3. The correlation among salivary flow, XQ score and QoL score in four sessions. Salivary flow XQ Time Evaluation type Correlation coefficient Correlation coefficient QoL -0.15 -0.76* Before treatment XQ -0.0002 — QoL 0.30 -0.67* Second week XQ -0.17 — QoL 0.104 -0.66* Fourth week XQ -0.012 — QoL 0.31* -0.56* Sixth week XQ -0.38* — *P ≤ 0.05

According to the results of our study, it seems that low QoL Radiat Oncol Biol Phys. 2006; 66: 981 – 991. amongst patients after head and neck radiotherapy can present an 5. Liu XK, Zeng ZY, Hong MH, Zhang AL, Cui NJ, Chen FJ. Clini- cal analysis of xerostomia in patients with nasopharyngeal carcinoma association with a sensation of dry mouth. It seems that xerosto- after radiation therapy [in Chinese]. Ai Zheng. 2004; 23: 593 – 596. mia does not have a significant association with QoL and sensa- 6. Brosky ME. The role of saliva in oral health: strategies for prevention tion of dry mouth. and management of xerostomia. J Support Oncol. 2007; 5: 228 – 229. 7. Oates JE, Clark JR, Read J, Reeves N, Gao K, Jackson M, et al. Pro- spective evaluation of quality of life and nutrition before and after References treatment for nasopharyngeal carcinoma. Arch Otolaryngol head Neck Surg. 2007; 133: 533 – 540. 1. Epstein J, Van Der Waal I. Oral cancer. In: Greenberg MS, Glick M, 8. Jham BC, da Silva Freire AR. Oral complications of radiotherapy in Ship JA, eds. Burket’s Oral Medicine. 11thed. Ontario, BC: Decker the head and neck. Braz J Otorhinolaryngol. 2006; 72: 704 – 708. Inc., 2008; 153 – 190. 9. Carl W. Local radiation and systemic chemotherapy: preventing and 2. Neeley M. Oral cancer and principle of radiotherapy. In: Prabhu SR, managing the oral complications. J Am Dent Assoc. 1993; 124: 119 ed. Text book of Oral Medicine. 2nd ed. New Delhi: Jaypee Brothers; – 123. 2005: 187 – 196. 10. Andrews N, Griffiths C. Dental complications of head and neck radio- 3. Dirix P, Nuyts S, Vander Poorten V, Delaere P, Van den Bogaert W. therapy: Part 1. Aust Dent J. 2001; 46: 88 – 94. The influence of xerostomia after radiotherapy on quality of life: re- 11. Devita VT, Samuel JR, Rosenberg SA. Oral complications. In: Berger sults of a questionnaire in head and neck cancer. Support Care Cancer. AM, Kilroy TJ, eds. Cancer. 6th ed. Philadelphia: Lippincott, Williams 2008; 16: 171 – 179. & Wilkins; 2001: 2881. 4. Pow EH, Kwong DL, McMillan AS, Wong MC, Sham JS, Leung LH, 12. Wu Y, Hu WH, Xia YF, Ma J, Liu MZ, Cui NJ. Quality of life of na- et al. Xerostomia and quality of life after intensity-modulated radio- sopharyngeal carcinoma survivors in Mainland China. Qual Life Res. therapy vs. conventional radiotherapy for early-stage nasopharyngeal 2007; 16: 65 – 74. carcinoma: initial report on a randomized controlled clinical trial. Int J 13. Guobis Z, Baseviciene N, Paipaliene P, Sabalys G, Kubilius R. Xero-

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 217 Xerostomia and QoL after Radiotherapy

stomia: clinic, etiology, diagnosis and treatment. Medicina (Kaunas). 19. Guchelaar H, Vermes A, Meerwaldt J. Radiation-induced xerostomia: 2006; 42: 171 – 179. pathophysiology, clinical course and supportive treatment. Support 14. Shahdad SA, Taylor C, Barclay SC, Steen IN, Preshaw PM. A double- Care Cancer. 1997; 5: 281 – 288. blind, crossover study of Biotène Oralbalance and BioXtra systems as 20. Cassolato SF, Turnbull RS. Xerostomia: clinical aspects and treat- salivary substitutes in patients with post-radiotherapy xerostomia. Eur ment. Gerodontology. 2003; 20: 64 – 77. J Cancer Care (Engl). 2005; 14: 319 – 326. 21. Chambers MS, Rosenthal DI, Weber RS. Radiation-induced xerosto- 15. Sahba S, Ghadimi S, Talaeepour A-R, Hadad P, Zolfaghari E. The ef- mia. Head Neck. 2007; 29: 58 – 63. ficacy of Iranian made saliva substitute vs. VA-OraLube in improve- 22. Garg AK, Malo M. Manifestations and treatment of xerostomia and ment of oral health- related quality of life in radiotherapy-induced associated oral effects secondary to head and neck radiation therapy. J xerostomia. J Dent Sch Shahid Beheshti Univ Med Sci. 2009; 3: 136 Am Dent Assoc. 1997; 128: 1128 – 1133. – 145. 23. Visvanathan V, Nix P. Managing the patient presenting with xerosto- 16. Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. mia: a review. Int J Clin Pract. 2010; 64: 404 – 407. Xerostomia and its predictors following parotid-sparing irradiation of 24. Shiboski CH, Hodgson TA, Ship JA, Schiodt M. Management of sali- head and neck cancer. Int J Radiat Oncol Biol Phys. 2001; 50: 695 – vary hypofunction during and after radiotherapy. Oral Surg Oral Med 704. Pathol Oral Radiol Endod. 2007; 103: 1 – 19. 17. Lin SC, Jen YM, Chang YC, Lin CC. Assessment of xerostomia and 25. Hahn TR, Kruskemper G. The impact of radiotherapy on quality of its impact on quality of life in head and neck cancer patients undergo- life –a survey of 1411 patient with oral cancer. Mund Kiefer Gesich- ing radiotherapy, and validation of the Taiwanese version of the xero- tschir. 2007; 11: 99 – 106. stomia questionnaire. J Pain Symptom Manage. 2008; 36: 141 – 148. 26. McMillan AS, Pow EH, Leung WK, Kwong DL, Wong MC. Oral 18. Momm F, Volegova-Neher NJ, Schulte-Mönting J, Guttenberger R. health condition in southern Chinese after radiotherapy for nasopha- Different saliva substitutes for treatment of xerostomia following ra- ryngeal carcinoma: Extent and nature of the problem. Oral Dis. 2003; diotherapy. A prospective crossover study. Strahlenther Onkol. 2005; 9: 196 – 202. 181: 231 – 236.

218 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 F. Mirzatoloeei, K. Pisoodeh

Original Article Impact of Exploration of Sensory Branches of Saphenous Nerve in Anterior Cruciate Ligament Reconstructive Surgery

Fardin Mirzatolooei MD•1, Karim Pisoodeh MD2

Abstract Background: Post-operative sensory disturbances following anterior cruciate ligament (ACL) reconstruction using the quadruple hamstring tendon is a prevalent complication. This study evaluates the impact of exploration and salvage of superficial branches of the saphenous nerve on the incidence of post-operative sensory loss. Methods: In a prospective descriptive study, 98 out of 120 patients with ACL reconstruction operated by the transfix method were followed 2 weeks and 6 months post-surgery. Hamstring tendon autograft was harvested through a 2–3 cm anteromedial oblique incision just over the pes anserinus. Meticulous dissection was done to find and save the superficial sensory branches of the saphenous nerve through the incision. Sensory changes were evaluated by physical examination for light touch; patients were requested to complete a specific diagram to evaluate sensory loss. Results: In 44 patients at least one nerve was located and saved. The rate of hypoesthesia in this group of patients was 20.5%. In 54 patients we were unable to locate the nerve. The rate of hyposthesia in this group was 72%, which was statistically significant (P < 0.005). The overall rate of sensory disturbance in 98 patients was 48.9%. A total of 10 patients developed hyposthesia over the anteromedial part of the Mid-leg. Conclusion: Exploration and salvage of the sensory branches of the saphenous nerve has a tremendous effect on the rate of sensory deficit.

Keywords: Anterior cruciate ligament, hamstring tendons, reconstruction

Cite the article as: Mirzatolooei F, Pisoodeh K. Impact of Exploration of Sensory Branches of Saphenous Nerve in Anterior Cruciate Ligament Reconstructive Surgery. Arch Iran Med. 2012; 15(4): 219 – 222.

Introduction dence of sensory disturbances. We hypothesize that exploration of sensory branches of the saphenous nerve is possible through ith improvements in surgical techniques for anterior cru- the incision for graft removal and exploration of these sensory W ciate ligament (ACL) reconstruction, patients’ expecta- branches could decrease post-operative hyposthesia. This ran- tions regarding surgical outcomes have increased, and domized clinical trial study has been conducted to evaluate our more attention is paid to minor complications. The results and thesis. complications of ACL reconstruction using a hamstring tendon graft have been well described.1–4 Materials and Methods One of the less discussed, yet more common complications of this surgery is damage to the infrapatellar branch of the saphenous A total of 120 patients (118 males and 2 females) underwent nerve (IPSN). This iatrogenic damage occurs during graft remov- ACL reconstruction over an 18 month period (July 2007 to Janu- al and its incidence has been reported to be 50%–77%.5–7 In or- ary 2009). The study protocol was approved by the Ethics Com- der to decrease the incidence of this complication some attempts, mittee of Urmia University of Medical Sciences, Urmia, Iran. The including decreasing the incision size and changing its obliquity study was conducted in accordance with the Declaration of Hel- from vertical to a more horizontal incision have been performed. sinki and registered with the Iranian Registry of Clinical Trials as Oblique rather than vertical incisions for the site of graft harvest- identifier number 5257. All participants received oral and written ing have reduced the incidence of altered sensation, however, the information about the purpose and procedures of the study and problem still remains.8 Concerns about damage to the main trunk provided written informed consents. of the saphenous nerve have emerged.9 The average age of the patients was 29 years (18 to 42 years). There is no study that has determined whether exploration of the The first visit was 2 weeks after surgery. To be included in the infrapatellar branch of the femoral nerve could decrease the inci- study, patients must have completed their 6 month follow up. Indication for surgery was a young active patient with an ACL Authors’ affiliation: 1Department of Orthopedic Surgery, Urmia University of rupture who desired to increase his or her level of activity. All Medical Sciences, Urmia, Iran. 2Orthopedic Ward, Urmia University of Medical surgeries were performed by one surgeon who used the hamstring Sciences, Urmia, Iran. •Corresponding author and reprints: Fardin Mirzatolooei MD, Department of quadruple autograft technique. All patients had no histories of orthopedic surgery, Urmia University of Medical Sciences, Urmia, Iran. previous knee surgeries and revision cases were not included. Pa- Tel: +98-914-143-5104, Email: [email protected]. tients with scar tissue around the knee were also excluded. For all Accepted article for publication: 24 August 2011

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 219 Impact of Exploration of Sensory Nerve in ACL surgery

Figure 1. Sensory branch of the saphenous nerve.

Figure 2. Two distinct patterns of hyposthesia over a) anterolateral and b) anteromedial aspects of the leg.

patients, the cross pin fixation technique (Arthrex Inc., Naples, away from the field when the tibial tunnel was performed. Fol- Florida, USA) was used. lowing tibial and femoral tunnel preparation, the Arthrex femoral guide C-ring was positioned and the tibial tunnel was fashioned Surgical technique through the same skin incision. With a small stab incision made The tourniquet used for all cases was inflated to 300 mmHg through the skin of the proximal lateral femoral condyle, the and deflated in less than 1.5 hours. Arthroscopy was performed transfix pin was advanced into the femur. The quadrupled ham- through the standard anterolateral porta. Meniscal injuries were string graft was then fixed into the tibia using Arthrex bioscrews. treated by partial menisectomy or repair using a totally inside No supplementary fixation device was used on the tibia. Finally, technique for meniscal repair. There were no extra incisions for the skin was closed by nylon sutures without fascia or subcutane- meniscus surgeries. A 3 cm incision was made from the supero- ous approximation. medial to inferolateral on the proximal medial portion of the leg. Post-operatively, at 2 weeks and 6 months, patients returned to The landmark for the incision’s starting point was 3 centimeters the clinic for the study visits. At follow up, patients were requested distal to the junction of the joint line with the anterior border of to complete a questionnaire with a specifically designed diagram. the medial collateral ligament. The obliquity of the incision was In the Diagram 1, the shape of the right and left leg were copied in 45 degrees. After cutting the skin, any superficial nerve in the op- a sheath in both antero-posterior and lateral views. All data were erating field was explored with meticulous dissection (Figure 1). collected by a well-trained nurse who had no relation to the study. This dissection was not extended beyond the boundaries of the Three different color pens were available for patients to mark the surgical field. Using a rubber band, the located nerve was spared areas of altered sensation as follows: i) the red pen depicted severe during surgery. At times when no nerves were located, surgery paresthesia or anesthesia, ii) blue indicated moderate paresthesia, continued as usual after a 5 minute exploratory period. Nerve ex- and iii) green was mild paresthesia. ploration was performed with the naked eye; no loupes or micro- For descriptive purposes we reported the qualitative factors in scope were used by the surgeon. Then, the sartorius fascia was cut terms of rates and the quantitative variables in terms of means. and semitendinosus and gracilis tendons were harvested using an Comparison of means between the groups was performed by the open tendon stripper. Special attention was paid not to damage the Mann-Whitney rank sum test. The Chi square and Fisher’s exact explored nerves during graft harvest. The nerves also were kept tests were used to compare differences in proportions. Signifi-

220 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 F. Mirzatoloeei, K. Pisoodeh

Diagram 1. Rate of sensory loss in patients with and without explored nerves. cance was set at 0.05. Geographical distribution of the sensory superficial sensory branches of the saphenous nerve significantly disturbance was described. reduced post-operative sensory loss after ACL reconstruction with the hamstring tendon graft. Approximately 80% of those pa- Results tients whose sensory nerves could be explored had normal sensation post-operatively. The question may be raised as to the loca- All patients were visited at 2 weeks post-surgery and 98 patients tion of the nerves that we could not find. They were present but (82%) completed their 6 month follow up. Twenty-two patients we were unable to locate them because of anatomical variation missed their further follow ups. In 18, the superficial nerve could in their distribution. In fact, our aim in conducting this study was be explored of which 17 had normal sensation. The average inci- not to locate these nerves but to save them if they were in the way sion size was 32 mm. There was no premature graft failure or of the dissection with the intent to see if any change occurred on infection. In 44 out of 98 patients at least 1 superficial sensory the rate of post-operative sensory disturbance. Further anatomi- branch was found and kept intact until the end of surgery. A total cal studies are needed to clarify the exact distribution and land- of 35 out of these 44 patients (79.5%) had normal sensation at marks of saphenous nerve branches. Previous studies have shown the end of 6 months. In the remaining 54 patients no nerves were a much higher incidence of sensory loss with a similar technique located after a 5 minute attempt at nerve exploration or the located but without nerve exploration. Other studies report a rate of post- nerves (2 cases) ruptured during surgery. In this group, 39 patients operative hyposthesia at between 30% to 60%.11–13 Figueroa eval- had some degree of sensory disturbance (72%). Totally, 48 out of uated 22 knees with ACL reconstruction using the electrophysi- 98 patients (48.9%) had sensory deficit (Figure 2). The Chi square ological method and found a 77% rate of nerve injury.7 In one test showed that the difference between the proportion of sensory study, a change in the direction of the incision from vertical to disturbance in both groups (located nerve vs. no nerve) was sig- oblique reduced the incidence of post-operative hyposthesia from nificant P( < 0.0001). 39.7% to 14.9%.14 We should mention that despite the significant The sensory deficit was in the range of mild paresthesia to com- decrease in the incidence of sensory disturbances in our patients plete anesthesia. According to the diagrams, post-operative sen- in whom the nerve could be found, the overall rate of sensory sory changes occurred in two areas (Figure 2). In 38 patients it loss was 48.9%. This high rate of hyposthesia was partially af- was over the superior and anterolateral aspect of the leg. This area fected by the number of patients who had hyposthesia over the of sensory deficit was approximately 2–3 cm distal and lateral to skin of the distal and medial sides of the leg. This model of sen- the incision and was circular in configuration. In 10 patients it sory disturbance could not be the result of damage to the IPSN but was on the anteromedial and distal part of the leg, and was oval in instead to saphenous nerve main trunk. This injury may occur dur- shape. The colors used by the patients to demonstrate the severity ing tendon stripping with the use of various tendon strippers. The of hyposthesia were mainly blue and green in the first pattern and saphenous nerve is the longest branch of the femoral nerve.10 It’s red in the second pattern. anterior branches innervate the anteromedial aspect of the leg and Three patients recovered from sensory damage between the 2 tibial crest. The posterior half of the calf is innervated by posterior follow-ups of 2 weeks and 6 months. All of these patients had branches of this nerve and the most distal branches innervate the mild sensory deficits at the first follow up, which were been repre- medial aspect of the foot. In the literature, damage to the IPSN has sented by blue and green marks. All were in the proximal-antero- been introduced as a major cause of sensory loss after hamstring lateral part of the leg. tendon graft harvesting surgeries.11–15 The anatomical position of the IPSN has been studied in many cadaver dissections.16,17,18 In Discussion 98.5% of cases it is located between the distal pole of the patella and tibial tubercle. This is not the location for hamstring graft Findings of this study revealed that exploration and salvage of harvesting incisions. In fact, the concept of injury to the IPSN in

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 221 Impact of Exploration of Sensory Nerve in ACL surgery arthroscopic ACL surgeries comes from the era when the patellar 3. Jarvela T, Moisala AS, Sihvonen R, Jarvela S, Kannus P, Jarvinen M. tendon graft was the dominant choice for graft selection and the Double-bundle anterior cruciate ligament reconstruction using hamstring autografts and bioabsorbable interference screw fixation: Pro- IPSN was vulnerable to injury during graft removal. In our study, spective, randomized, clinical study with 2-year results. Am J Sports none of the patients complained of hyposthesia lateral to the pa- Med. 2008; 36: 290 – 297. tellar tendon. Instead, the hyposthesias were over the proximal- 4. Xu Y, Ao YF, Yu JK, An H, Liu XP. Compare the clinical results of anterolateral part of the leg. Sensory branches of the saphenous double-bundle with single-bundle anterior cruciate ligament reconstruction. Zhonghua Wai Ke Za Zhi. 2008; 46: 274 – 276. nerve other than IPSN should be responsible for the sensory loss 5. Sgaglione NA, Warren RF, Wickiewicz TL, Gold DA, Panariello RA. at this area. We were unable to find a sensory nerve branch with Primary repair with semitendinosus tendon augmentation of acute an- a specific name in illustrated textbooks or the literature to relate terior cruciate ligament injuries. Am J Sports Med. 1990; 18: 64 – 73. the existed hyposthesia over the proximal-anterolateral part of the 6. Aglietti P, Giron F, Buzzi R, Biddau F, Sasso F. Anterior cruciate ligament reconstruction: bone–patellar tendon–bone compared with leg. For this reason we considered the explored sensory branches double semitendinosus and gracilis tendon grafts. A prospective, ran- of the surgical field as IPSN. domized clinical trial. J Bone Joint Surg. 2004; 86: 2143 – 2155. Another finding in our study was the skin sensory loss over the 7. Figueroa D, Calvo R, Vaisman A, Campero M, Moraga C. Injury to the infrapatellar branch of the saphenous nerve in ACL reconstruction sartorial branch of the saphenous nerve innervations zone, which with the hamstrings technique: clinical and electrophysiological study. occurred in a subset of patients. Ten patients (9.8%) developed The Knee. 2008; 15: 360 – 363. hyposthesia in the medial aspect of their legs just right to the tibial 8. Portland GH, Martin D, Keene G, Menz T. Injury to the infrapatel- crest. This is not a new finding as it has been reported previously lar branch of the saphenous nerve in anterior cruciate ligament recon- 7,9 struction: comparison of horizontal versus vertical harvest site inci- by other authors. As it may be expected, the rate of this com- sions. Arthroscopy. 2005; 21: 281 – 285. plication did not change by our nerve exploration, strengthening 9. Jameson S, Emmerson K. Altered sensation over the lower leg fol- the assumption that it was developed during tendon stripping. The lowing hamstring anterior cruciate ligament reconstruction with trans- saphenous nerve is closely intimated with the gracilis tendon and verse femoral fixation.The Knee. 2007; 14: 314 – 320. 10. Pendergrass TL, Moor JH. Saphenous neuropathy following medial may be injured during gracilis tendon harvesting. Another loca- knee trauma. J Orthop Sports Phys Ther. 2004; 34: 328 – 334. tion where this nerve could be injured is where the side pin exits 11. Kartus J, Movin T, Karlsson J. Donor-site morbidity and anterior knee the bone and pierces the skin. Further studies are needed to clarify problems after anterior cruciate ligament reconstruction using auto- the exact pathophysiology of this complication. grafts. Arthroscopy. 2001; 17: 971 – 978. 12. Ejerhed L, Kartus J, Sernert N, Köhler K, Karlsson J. Patellar tendon Preserving the sensory branches of the saphenous nerve during or semitendinosus tendon autografts for anterior cruciate ligament re- hamstring graft harvesting could decrease the rate of post-opera- construction? A prospective randomized study with a two-year follow- tive sensory disturbances. Despite the relatively constant incision up. Am J Sports Med. 2003; 31: 19 – 25. mode sensory branches were not located in all cases, which repre- 13. Wagner M, Kääb MJ, Schallock J, Haas NP, Weiler A. Hamstring tendon versus patellar tendon anterior cruciate ligament reconstruction sented the variation in anatomical distribution of these branches. using biodegradable interference fit fixation: a prospective matched- We have recommended performing an oblique incision with me- group analysis. Am J Sports Med. 2005; 33: 1327 – 1336. ticulous dissection to locate and preserve any sensory branches at 14. Papasteriou SG, Voulgaropoulos H, Mikalef P, Ziogas E, Pappis G, Giannakopoulos I. Injuries to the infrapatellar branch(es) of the sa- the surgical field. Despite the efforts for decreasing the incidence pheneous nerve in anterior cruciate ligament reconstruction with four- of sensory damage by this method, injury to the main trunk of the strand hamstring tendon autograft: Vertical versus horizontal incision saphenous nerve occurs during graft stripping. for harvest. Knee Surg Sport Traumatol Arthrosc. 2006; 14: 789 – 793. 15. Maeda A, Shino K, Horibe S, Nakata K, Buccafusca G. Anterior cruciate ligament reconstruction with multistranded autogenous semitendi- References nosus tendon. Am J Sports Med. 1996; 24: 504 – 509. 16. Sanders B, Rolf R, McClelland W, Xerogeane J. Prevalence of saphe- 1. Shelbourne KD, Gray T. Minimum 10-year results after anterior cru- nous nerve injury after autogenous hamstring harvest: an anatomic and ciate ligament reconstruction: How the loss of normal knee motion clinical study of sartorial branch. Arthroscopy. 2007; 23: 956 – 963. compounds other factors related to the development of osteoarthritis 17. Kartus J, Ejerhed L, Eriksson BI. The localization of the infrapatellar after surgery. Am J Sports Med. 2009; 37: 471 – 480. nerves in the anterior knee region with special emphasis on central 2. Rue JP, Lewise PB, Parameswaran AD, Bach BR. Single-bundle an- third patellar tendon harvest: a dissection study on cadaver and ampu- terior cruciate ligament reconstruction: technique overview and com- tated specimens. Arthroscopy.1999; 15: 577 – 586. prehensive review of results. J Bone Joint Surg [Am]. 2008; 90: 67 18. Ebraheim NA, Mekhail AO. The infrapatellar branch of the saphenous – 74. nerve: An anatomic study. J Orthop Trauma. 1997; 11: 195 – 199.

222 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 O. Tabatabaei-Malazy, S. Nedjat, R. Majdzadeh

Original Article

Which Information Resources are used by General Practitio- ners for Updating Knowledge Regarding Diabetes?

Ozra Tabatabaei-Malazy MD MPH1, 2, Saharnaz Nedjat MD PhD 2,3, Reza Majdzadeh PhD•2,3

Abstract Background: Little is known about the degree of utilization of information resources on diabetes by general practitioners (GPs) and its impact on their clinical behavior in developing countries. Such information is vital if GPs’ diabetes knowledge is to be improved. Methods: This cross-sectional study recruited 319 GPs in the summer of 2008. Questions were about the updates on diabetes knowledge in the previous two years, utilization of information resources (domestic and foreign journals, congresses, the Internet, reference books, mass media, and peers), attitude toward the importance of each resource, and impact of each resource on clinical behavior. Results: A total of 62% of GPs had used information resources for improving their knowledge on diabetes in the previous two years. Domestic journals accounted for the highest utilization (30%) and the highest importance score (83 points from 100); with the importance score not being affected by sex, years elapsed after graduation, and numbers of diabetic visits. Clinical behavior was not influenced by the information resources listed; whereas knowledge upgrade, irrespective of the sources utilized, had a significantly positive correlation with clinical behavior. Conclusion: Domestic journals constituted the main information resource utilized by the GPs; this resource, however, in tandem with the other information resources on diabetes exerted no significant impact on the GPs’ clinical behavior. In contrast to the developed countries, clinical guidelines do not have any place as a source of information and or practice. Indubitably, the improvement of diabetes knowledge transfer requires serious interventions to improve information resources as well as the structure of scientific gatherings and collaborations.

Keywords: Behavior of general practitioners, information resources, knowledge translationas

Cite the article as: Tabatabaei-Malazy O, Nedjat S, Majdzadeh R. Which Information Resources are used by General Practitioners for Updating Knowledge Regard- ing Diabetes? Arch Iran Med. 2012; 15(4): 223 – 227.

Introduction change in the clinical behavior of health-care providers, but we should first determine which of these methods are given preferen- esearch in the field of knowledge translation and innova- tiality by each particular audience. R tion at large underlines a deep incongruence between In most societies, general practitioners (GPs) represent a high knowledge production and its application.1,2 The domain proportion of health knowledge consumers as they are by and of health is no exception as is evident by the gap between new large the first line of treatment for patients.8 Medical information knowledge and its utilization in chronic diseases, in particular dia- resources vary from country to country due to a whole host of rea- betes.3 Indeed, for all the advances in the treatment of diabetes in sons, the most prominent of which is perhaps accessibility. There- the past three decades, the treatment outcome of this medical con- fore, decision-makers should be furnished with information on the dition in developed and developing countries is still far from opti- most utilized resources with the highest impact on diabetes care mal,4 with approximately only one third of patients achieving ac- by GPs if they are to design appropriate intervention measures for ceptable levels of blood sugar control.3 A variety of reasons such furthering knowledge transfer in this important group. as non-adherence of patients to treatment protocols and inappro- The main objective of this study was to seek the most effective priate treatment prescribed by physicians have been suggested as information resources on the clinical behavior of GPs in the field the causes of failure to achieve treatment goals.5 of diabetes at Iran as an example of developing countries in the Iran is also faced with this disparity between knowledge produc- Middle East. tion and knowledge use or, in other words, between what is known and what is actually practiced.6,7 Enhancing knowledge utilization Materials and Methods necessitates novel approaches to forge a link between research and practice.2 There are currently several methods for effecting a Study population This cross-sectional study was conducted in the summer of Authors’ affiliations: 1Endocrinology and Metabolism Research Center (EMRC), Tehran University of Medical Sciences, Tehran, Iran. 2School of Public 2008. In this study, we recruited 319 GPs who had a minimum of Health, Tehran University of Medical Sciences, Tehran, Iran. 3Knowledge Utili- two years’ clinical experience. GPs employed in centers that di- zation Research Center (KURC), Tehran University of Medical Sciences, Tehran, rectly dealt with diabetics, such as specialized clinics or diabetes Iran. •Corresponding author and reprints: Reza Majdzadeh PhD, Knowledge Utili- clinics affiliated with research centers, as well GPs who worked zation Research Center (KURC), Tehran University of Medical Sciences, Tehran, in clinics where diabetes was less likely to be encountered (i.e., Iran. #12, East Nosrat Ave., North Kargar, Tehran University of Medical Sci- clinics affiliated with the Blood Transfusion Organization) were ences, Tehran 141786, Iran. Tel: +98-216-649-5859, Fax: +98-216-649-5859, E-mail: [email protected]. excluded from the present study. Accepted for publication: 24 August 2011 The study was conducted in two stages: a pre-test stage, where

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 223 Information Resources for General Practitioners

Table 1. Comparison of background variables according to “updating diabetes knowledge during last two years” in general practitioners.

Variables Updating during last two years P-value Positive Negative

Female n (%) 122 (61.6) 71 (58.7) Gender 0.64 Male n (%) 76 (38.4) 50 (41.3) Elapsed years after graduation (mean ± SE) 10.3±0.5 10.0±0.6 0.72 Number of monthly diabetic visits (mean ± SE) 25.7±2.2 24.9±3.2 0.83

Table 2. Utilization of information resources and relationship between independent variables. Years elapsed after Number of monthly diabetic Information resources Utilization Male/female graduation visits Percentage Odds Ratio† (P-value) (95% CI) (95% CI) 29.8 0.97 (0.89) 1.01 (0.71) 0.99 (0.83) Domestic journals (24.8–35.1) (0.59–1.58) (0.97–1.04) (0.99–1.01) 26.3 1.06 (0.83) 0.98 (0.22) 1.00 (0.72) Reference books (21.6–31.5) (0.64–1.76) (0.94–1.01) (0.99–1.01) (0.75) 0.99 ٭(0.05) 1.04 (0.12) 1.60 16.6 Congresses (12.7–21.2) (0.88–2.89) (1.00–1.07) (0.99–1.01) 14.1 0.82 (0.56) 0.99 (0.79) 0.99 (0.45) Internet (10.5–18.4) (0.43–1.59) (0.95–1.04) (0.98–1.01) 7.8 0.85 (0.71) 1.01 (0.59) 1.00 (0.36) Mass media (5.1–11.3) (0.36–1.99) (0.96–1.07) (0.99–1.02) (0.77) 1.00 ٭(0.05) 1.05 (0.10) 2.29 5.3 International journals (3.3–8.4) (0.85–6.18) (1.00–1.11) (0.99–1.02) 5.0 1.20 (0.72) 0.99 (0.75) 1.01 (0.41) Peers (2.9–8.0) (0.44–3.32) (0.92–1.07) (0.99–1.02) † Because there was no statistically significant relationship between the variables in the adjusted analysis, only crude results are presented.

Table 3. Attitudes of general practitioners toward the importance of different information resources for updating diabetes knowledge and its determinant factors. Years elapsed after Number of monthly Information resources Importance† Male/female graduation diabetic visits Linear regression coefficient (P-value) Mean ±SD (95% CI) -1.34 (0.64) -0.14 (0.48) 0.001 (0.98) Domestic journals 83.15 ± 25.24 (-7.03–4.36) (-0.53–0.25) (-0.09–0.09) 1.82 (0.57) 0.41 (0.06) 0.04 (0.45) Congresses 79.34 ± 28.11 (-4.55–8.19) (-0.02–0.84) (-0.06–0.13) (0.27) 0.06 ٭(0.05) -0.50 (0.37) 3.39 Peers 70.77 ± 32.90 (-4.03–10.80) (-1.00–0.00) (-0.05–0.18) 3.66 (0.35) -0.51 (0.06) -0.03 (0.66) Internet 69.57 ± 34.28 (-4.08–11.41) (-1.03–0.02) (-0.14–0.09) 5.88 (0.13) -0.12 (0.64) 0.00(0.99) International journals 58.36 ± 33.77 (-1.73–13.49) (-0.64–0.40) (-0.12–0.12) ٭٭(0.001) 0.23- (0.61) 0.16- ٭٭(0.003) -13.60 Mass media 51.88 ± 39.95 (-22.49– -4.71) (-0.78–0.46) (-0.36– -0.09) (0.41) 0.07 (0.33) 0.35 ٭(0.05) 10.37 Reference books 48.34 ± 46.58 (-0.15– -20.88) (-0.37–1.07) (-0.09–0.23) .P≤0.01 was considered statistically significant ٭٭.P≤0.05 was considered statistically significant ٭ .Possible minimum and maximum score, range: 0 to 100 †

20 experts helped revising the questionnaire; and a re-test stage, resource in knowledge transfer, and the impact of the information where we assessed the intra-cluster correlation (ICC) by utilizing resources on clinical behavior. the questionnaire to interview 10 GPs. The ICC was 0.63–0.86. Given the important role that patient education plays in the con- Three research assistants were initially trained and sent to a trol of diabetes and its complications,8 this factor was considered general refresher course for GPs, where their performance was to be a positive clinical behavior alongside diabetes medication. subjected to imperceptible monitoring by two of the course par- Accordingly, the provision and non-provision of at least two edu- ticipants. Before the study commencement, the research assistants cational recommendations to patients for better control of hyper- fully explained the objectives and methods of the study to the par- glycemia were selected as the criterion for suitability and unsuit- ticipants. Participants completed the questionnaire, which includ- ability of clinical behavior. Although this variable was selected to ed information about demographics, utilization of information show the patient care of health-care providers, who may spend resources (domestic or foreign journals, congresses, the Internet, more time on their patients, it was a surrogate measure for “ap- reference books, mass media, and peers) on diabetes in the previ- propriate clinical behavior”. ous two years, attitude toward the importance of each information

224 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 O. Tabatabaei-Malazy, S. Nedjat, R. Majdzadeh

Table 4. Factors affecting general practitioners’ clinical behaviors on diabetic patients care.

Clinical behavior Crude Adjusted Variable analysis Odds Ratio Appropriate Inappropriate P-value P-value (95% CI) Female n (%) 163 (59.9) 30 (63.8) Gender 0.75 — — Male n (%) 109 (40.1) 17 (36.2) Yes n (%) 181 (66.5) 17 (36.2) 3.72 Updating diabetes knowledge <0.0001 <0.0001 No n (%) 91 (33.5) 30 (63.8) (1.93–7.19)

Years elapsed after graduation (mean ± SE) 10.18 ± 0.43 10.11 ± 1.13 0.95 — —

Number of monthly diabetic visits (mean ± SE) 24.97 ± 1.90 27.83 ± 5.38 0.57 — —

Table 5. Information resources affecting general practitioners’ clinical behaviors on diabetic patients care.

Clinical behavior Crude analysis Information resources Utilization Appropriate P-value† Inappropriate n (%) n (%) Yes 87 (32) 8 (17) Domestic journals 0.04 No 185 (68) 39 (83) Reference books Yes 78 (28.7) 6 (7.1) 0.02 No 194 (71.3) 41 (87.2) Congresses Yes 49 (18) 4 (8.5) 0.14 No 223 (82) 43 (91.5) Internet Yes 41 (15.1) 4 (8.5) 0.36 No 231 (84.9) 43 (91.5) Yes 23 (8.5) 2 (4.3) Mass media 0.55 No 249 (91.5) 45 (95.7) Yes 17 (6.3) 0 (0) International journals 0.15 No 255 (93.8) 47 (100) Yes 15 (5.5) 1 (6.3) Peers 0.48 No 257 (94.5) 46 (97.9) †Because there was no statistically significant relationship between the variables in the adjusted analysis, only crude results are presented.

Data analysis study. Thus, 319 (91.4%) GPs responded to our questions. Linear and logistic regression was performed for analysis. Uti- lization or non-utilization of information resources as the predic- Characteristics of the study population tor (dependent) variable and sex, time lapse after graduation, and The study population comprised 193 (60.5%) women and 126 number of diabetic visits per month as the independent variables (39.5 %) men. The mean age of the participants was 38 years were entered in the logistic regression (Enter Model). [standard deviation (SD) = 7.7] with a range of 27 – 82 years. The importance of each single information resource on diabetes The time lapse after graduation was between 2 and 55 years with was assessed on a numerical scale of 1 to 5, with a score of 5 a mean number of 10 years (SD = 7). The number of diabetic denoting “very important” and 1 signifying “unimportant”. The patients visited per month was between 1 and 200 persons, with a final score of each information resource was subsequently calcu- mean of 25 persons/month (SD = 32). lated and analyzed as the predictor variable of “importance score” alongside the other independent variables in the linear regression Updating diabetes knowledge (Enter Model). Regardless of information resource Finally, the effect of the individual variables and utilization of There were 62% of participants who sought to update their diabetes each single medical information resource on the GPs’ clinical be- knowledge during the previous two years. Table 1 depicts the results havior was evaluated via the logistic regression analysis. of the analysis of the variables relating to “updating diabetes knowledge”; there was no significant relationship between the variables. Ethical consideration The proposal of this research was submitted to the process of Utilization of information resources Research Project Evaluation at Tehran University of Medical Sci- Table 2 illustrates the results of the analysis of “utilization of ences and included the approval of the university Ethics Commit- information resources” as the dependent variable and the effect tee. Verbal consent was obtained from the participants. of the independent factors, which was conducted to be used in the crude and adjusted analyses. From information resources listed, Results domestic medical journals (30%), reference books (26%), and congresses (17%) were the most popular sources. From a total of 349 GPs who were initially invited to participate Crude analysis showed that with each elapsed year from gradu- in the present study, 319 persons met the inclusion criteria and ation, increased utilization of the congresses (1.04 times) and in- consented. There were 25 persons who did not meet the inclusion ternational journals (1.05 times) did not significantly impact the criteria and 5 persons who did not consent to be enrolled into the adjusted analysis.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 225 Information Resources for General Practitioners

Importance of information resources ion leaders are capable of effecting a positive change in behavior The assessment of the GPs’ attitudes toward the importance of as opposed to the mass media, which can only supply fresh in- each information resource in Table 3 revealed that domestic medi- formation.16 The criteria for identifying opinion leaders has been cal journals scored the highest at 83.1 (SD = 25.2), followed by assessed in the Iranian health care delivery system and they were congresses at 79.3 (SD = 28.1) and peers at 70.8 (SD = 32.9). almost identical to Western countries.17 As a result, in addition The crude analysis was indicative of the effect of the independent to promoting such human resources, it is essential that efforts be factors on some information resources, while the adjusted linear made to facilitate physical and practical access to these resources regression demonstrated no such effect. and to publicize these unofficial resources alongside official -re sources (journals) through congresses and seminars.18 It seemed Factors influencing clinical behavior that a lack of recourse to human resources on the part of the GPs As self-reported by the GPs, 85.3% fulfilled the criterion for ap- in our study stemmed from unfamiliarity or insufficient access. propriate clinical behavior in diabetes care, i.e., providing patients Our GPs awarded the highest scores in terms of the importance with at least two educational recommendations for improving of medical information resources on diabetes to domestic journals control of hyperglycemia. The results of the impact of the vari- (83 points), congresses (79 points), and peers (71 points). In this ables and utilization of information resources on Iranian GPs’ scoring, an increase in the time lapse after graduation resulted in clinical behavior on diabetic patients care are shown respectively a significant decrease of 0.50 in the GPs’ attitude toward utiliza- in Tables 4 and 5. Of all factors, only “updating diabetes knowl- tion of peers as an information resource. The importance score of edge” had an increasing impact (3.72; P < 0.001) on clinical be- the mass media had a significant decrease of 13.60 in men and havior in the adjusted analysis. also a significant drop of 0.23 per one-diabetic patient increase in the total of monthly diabetic visits. By contrast, the importance Discussion score of reference books had a significant rise of 10.37 in men. In addition, none of the independent variables exerted a significant In the present study, 62% of the GPs reported having updated influence on the importance score of any information resource on their diabetes knowledge in the two previous years. We did not diabetes in the adjusted analysis. Previous studies have shown that investigate the barriers to knowledge utilization; be that as it may, in conjunction with the foregoing factors, values and attitudes can the fact that 38% of our study population had failed to bring their impact knowledge utilization rates.19,20 knowledge of diabetes and its complications up to date at least in Table 4 shows that around 85% of study subjects reported that the two-year period leading up the commencement of our study they have made recommendations to their patients. This finding might have been the result of a lack of an appropriate milieu con- does not agree with the results of a study on the quality of diabetes ducive to up-to-the-minute learning. management in Iran between the years 2005 and 2007.21 The said Domestic journals, followed by reference books and congresses study has evaluated the quality of diabetes management in 2,456 comprised the most widely used medical information resources diabetics in all 25 Iranian provinces and found that only 22% of on diabetes amongst our study population. Logistic regression them had received appropriate diabetes education. As this variable analysis has demonstrated that the probability of the utilization of was self-reported in the present study, the majority of GPs claimed these resources was not correlated with the independent variables. that they had offered educational recommendations to their dia- The accessibility of domestic journals and the fact that the utiliza- betic patients in combination with medication. The validity of this tion of these resources does not require much time or special skills variable to reflect reality of clinical practice has limitations. The seems to have contributed to their favorability. ‘percentage of the diabetic patients’ and especially ‘ratio of new Given the priority accorded to domestic medical journals by our diabetic patients over follow up patients’ could be considered as study population, drawing upon these information resources for complementary variables for better assessment of the appropriate- knowledge transfer amongst this group of professionals seems to ness of clinical practice. Since the purpose of the present study be a viable option. A review study of cross-sectional and obser- was comparison of the different sources of knowledge on the GPs vational articles published during the years 1978 – 1992 regard- behaviors, we considered the feasibility of data gathering and se- ing the utilization of medical information resources by physicians lected the present variable (giving educational recommendation). in the U.S. and Canada9 has reported the most utilized medical This should be considered as a surrogate measurement, although information resources to be journals and books (the equivalent), it is of value for the analytical objectives of the present study, it followed by peers.9 is just a proxy of giving appropriate care to the patients and not An evaluation of 100 GPs in the urban areas of Pakistan showed appropriate to be used for a description of the appropriateness of that although most of them (62%) were not in line with the stan- the clinical practice. dard criteria for diabetes diagnosis, a mere 37% sought to improve None of the personal variables or information resources with the their diabetes knowledge. In that study, medical journals (44%), exception of “update their diabetes knowledge” exerted a significant congresses (27%), and the Internet (21%) formed the bulk of the influence on the GPs’ behavior in the present study. These findings medical information resources utilized by the GPs. highlight the need for the provision of other information resources Peers had the lowest percentage (5%) amongst the medical in- such as standard clinical practice guidelines, although there is no formation resources exploited by our GPs. That is in stark contrast guarantee that sufficient attention will be paid to clinical guidelines.22 to previous studies contending that unofficial channels like peers It should be noted that the present study predated the publication of are one of the ways to update knowledge and influence clinical the clinical diabetes guideline, so “Clinical Guideline” was not on behavior.10–13 Opinion leaders, a concept first introduced by Hiss the options of local information resource. Earnest efforts have been et al.,14 are believed to have the greatest standing amongst peers underway recently to formulate national clinical guidelines based on in knowledge upgrade.15 According to these investigators; opin- “Appraisal of Guidelines for Research and Evaluation” (AGREE) in

226 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 O. Tabatabaei-Malazy, S. Nedjat, R. Majdzadeh the field of diabetes and its complications in Iran entitled “National/ – 180. Regional Diabetic Foot Guideline” has been published in print23 and 11. Kannouse DH, Kallich JD, Kahan JP. Dissemination of effectiveness and outcomes research. Health Policy. 1995; 34: 167 – 192. electronic formats (http://emri.tums.ac.ir). 12. Grimshaw JM, Eccles MP, Walker AE, Thomas RE. Changing physi- An evaluation of 43 published diabetes guidelines between 1980 cian’s behavior: What works? and thoughts on getting more things to and 2000 has shown that these guidelines failed to meet the meth- work. J Contin Educ Health Prof. 2002; 22: 237 – 243. odological standards of formulating clinical guidelines.24 There is 13. Geertsma RH, Parker RC, Whitbourne SK. How physicians view the process of change in their practice behavior. J Med Educ. 1982; 57: ample evidence that the traditional approach to the enhancement 752 – 761. of knowledge, with is merely facilitating access and introducing 14. Hiss RG, Macdonald R, Davis WK. Identification of physician edu- new information resources, leaves too much to be desired.25,26 cational influential’s (EI’s) in small community hospitals. Res Med It is deserving of note that for all the foregoing measures, knowl- Educ. 1978; 17: 283 – 288. 15. Stross JK. The educationally influential physician. J Contin Educ edge derived from research could still fail to reach its audience Health Prof. 1996; 16: 167 – 172. and that necessitates structures 27–29 or individuals to forge a link 16. Orr G. Diffusion of Innovations, by Everett Rogers (1995). 18 March between researchers and policy makers with a view to conveying 2003. Available from: URL: http://www.stanford.edu/class/symb- 30–32 sys205/Diffusion%20of%20Innovations.htm (Accessed April 12, the research message. 2011) Given the importance of studying as a significant factor in updat- 17. Shokoohi M, Nedjat S, Golestan B, Soltani A, Majdzadeh R. Can cri- ing diabetes knowledge of the GPs in our study on the one hand teria for identifying educational influentials in developed countries be and the non-correlation between the available information re- applied to other countries? A study in Iran. J Contin Educ Health Prof. 2011; 31: 95 – 102. sources and clinical behavior of the GPs on the other, it seems that 18. Verhoeven A, Boerma E, Meyboom-de Jong B. Use of information these information resources are devoid of the requisite quality for sources by family physicians: A literature survey. Bull Med Libr As- updating diabetes knowledge. We would, therefore, recommend soc. 1995; 83: 85 – 90. that in conjunction with a mass distribution of resources such as 19. Ehrenfeld M, Eckerling S. Perceptions and attitudes of registered nurses to research: a comparison with a previous study. J Adv Nurs. clinical guidelines, earnest interventions be made in order to alter 1991; 16: 224 – 232. GPs’ attitude toward available information resources and to im- 20. Denis JL, Lehoux P, Hivon M, Champagne F. Creating a new articu- prove the quality of the knowledge presented in these resources. lation between research and practice through policy? The views and To that end, simultaneous use of several well-structured infor- experiences of researchers and practitioners. J Health Serv Res Policy. 2003; 8 (suppl 2): 44 – 50. mation resources and introduction of these resources through ex- 21. Amini M, Goya MM, Delavari A, Mahdavi A, Tabatabaei A, Haghighi isting channels can also be advantageous. S. Quality of diabetes management in Iran 2005-2007. J Med Counc Islam Repub Iran. 2009; 26: 20 – 29. 22. Sica G, Harker-Murray P, Montori VM, Smith SA. Adherence of pub- Acknowledgments lished diabetes mellitus practice guidelines to methodologic standards of guideline development. Endocrinol Metab Clin N Am. 2002; 31: This study was a Master of Public Health thesis in the School of 819 – 828. Public Health and funded jointly by this School and the Endocri- 23. Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences. In: Arzaghi SM, Tabatabaei-Malazy O, eds. nology and Metabolism Research Center of Tehran University of National Regional Diabetes Guideline/Diabetic Foot. 1st ed. Tehran, Medical Sciences. Iran: Vista; 2009. 24. David DA, Taylor-Vaisey A. Translating guidelines into practice: a systematic review of theoretic concepts, practical experience and re- References search evidence in the adaptation of clinical practice guidelines. Can Med Ass. 1997; 157: 408 – 416. 1. Lomas J. Words without action? The production, dissemination, and 25. Grol R, Grimshaw J. From best evidence to best practice: Effective impact of consensus recommendations. Annu Rev Public Health. implementation of change in patients’ care. The Lancet. 2003, 362: 1991; 12: 41 – 65. 1225 – 1230. 2. Utterback JM. Innovation in industry and the diffusion of technology. 26. Benjamin EM, Schneider MS, Hinchey KT. Implementing practice Science. 1974; 183: 620 – 626. guidelines for diabetes care using problem-based learning. Diabetes 3. Nobel J. Bridging the knowledge — action gap in diabetes: Informa- Care. 1992, 22: 1672 – 1678. tion technologies, physician incentives and consumer incentives con- 27. Thompson GN, Estabrooks CA, Degner LN. Clarifying the concepts verge. Chronic Illness. 2006; 2: 59 – 69. in knowledge transfer: a literature review. J Adv Nurs. 2006; 53: 691 4. Murugesan N, Shobana R, Snehalatha C. Immediate impact of a dia- – 701. betes training programme for primary care physicians—An endeavour 28. Choi- Bernard CK. Understanding the basic principles of knowledge for national capacity building for diabetes management in India. Diab translation. J Epidemiol Community Health. 2005; 59: 93. Res Clin Pract. 2009; 83: 140 – 1445. 29. Majdzadeh R, Nedjat S, Denis JL, Yazdizadeh B, Gholami J. Linking 5. Goldstein BJ, Gomis R, Lee HK , Leiter LA. The global partnership research to action in Iran: two decades after integration of the Health for effective diabetes management, type 2 diabetes treat early, treat- Ministry and the medical universities. Public Health. 2010; 124: 404 ment intensively. Int J Diab Clin Pract. 2007; 61: 16 – 21. – 411. 6. Nedjat S, Majdzadeh R, Gholami J, Nedjat S, Maleki K, Qorbani M, 30. Larijani B, Delavari A, Damari B, Vosoogh Moghadam A, Majdzadeh et al. Knowledge transfer in Tehran University of Medical Sciences: R. Health policy making system in Islamic Republic of Iran: Review an academic example of a developing country. Implement Sci. 2008; an experience. IJPH. 2009; 38 (suppl 1): 1 – 3. 26: 39. 31. Larijani B, Majdzadeh R, Delavari AR, Rajabi F, Khatibzadeh S, 7. Majdzadeh R, Nedjat S, Fotouhi A, Malekafzali H. Iran’s approach Esmailzadeh H, et al. Iran’s health innovation and science develop- to knowledge translation. Iranian J Pub Health. 2009; 38 (suppl 1): ment plan by 2025. IJPH. 2009; 38 (auppl 1): 15 – 18. 58 – 62. 32. Majdzadeh R, Sadighi J, Nedjat S, Mahani SA, Gholami J. Design 8. Expert Committee on the Diagnosis and Classification of Diabetes of a knowledge translation model in Tehran University of Medical Mellitus. American Diabetes Association: Clinical practice recom- Sciences for research utilization. J Contin Educ Health Prof. 2008; mendations 2002. Diabetes Care. 2002; 25 (auppl 1): S1 – S147. 28: 270 – 277. 9. Haug J. Physicians’ preferences for information sources: a meta-analytic study. Bull Med Libr Assoc. 1997; 85: 223 – 232. 10. Weinberg AD, Ullian L, Richard WD, Cooper P. Informal advice and information seeking between physician. J Med Educ. 1981; 56: 174

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 227 Congenital Anomaly in ART Infants

Original Article

Congenital Anomalies in Infants Conceived by Assisted Re- productive Techniques

Ramin Mozafari Kermani MD•1, Leila Nedaeifard MD1, Mohammad Reza Nateghi MD1, Abolhassan Shahzadeh Fazeli MD2, Ebrahim Ahmadi MSc1, Mohammad Ali Osia MD3, Ebrahim Jafarzadehpour MD4, Soudabeh Nouri Bs1

Abstract Background: Many studies show that congenital defects in infants conceived by assisted reproductive techniques (ART) are more than infants of normal conception (NC). The aim of this study is to determine the frequency of congenital anomalies in ART infants from Royan Institute and to compare congenital anomalies between two ART techniques. Methods: In a cross-sectional descriptive study, 400 ART infants from Royan Institute who resided in Tehran were selected by non- random, consecutive sampling. Infants were examined twice (until 9 months of age) by a pediatrician. Infants’ congenital anomalies were described by each body system or organ and type of ART. Data were analyzed by SPSS version 16 and Fisher’s exact test. Results: The frequency of different organ involvement in the two examinations were: 40 (10%) skin, 25 (6.2%) urogenital system, 21 (5.2%) gastrointestinal tract, 13 (3.2%) visual, and 8 (2%) cardiovascular system. Major congenital defects in infants conceived by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) were hypospadiasis, inguinal hernia, patent ductus arteriosus plus ventricular septal defect (PDA + VSD), developmental dysplasia of the hip, lacrimal duct stenosis during the first year of life, hydronephrosis and urinary reflux over grade III, undescending testis, ureteropelvic junction stenosis, and torticoli. Conclusions: Two-thirds of ART infants had no defects. A total of 7% of IVF and ICSI infants had one of the major abovementioned congenital anomalies. This rate was higher than NC infants (2%–3%). There was no difference between the ICSI and IVF group.

Keywords: Assisted reproductive techniques, congenital anomalies, infants, intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF)

Cite the article as: Mozafari Kermani R, Nedaeifard L, Nateghi MR, Shahzadeh Fazeli A, Ahmadi E, Osia MA, Jafarzadehpour E, Nouri S. Congenital Anomalies in Infants Conceived by Assisted Reproductive Techniques. Arch Iran Med. 2012; 15(4): 228 – 231.

Introduction is due to the careful, continuous examination of these infants in comparison with normal infants. Some anomalies such as small any studies have been performed concerning infants con- umbilical hernias and pigmented skin spots or ear tags, which may ceived by assisted reproductive techniques (ART). In the not be reported in normal infants, are reported in ART infants.2 M general population, 3% of surviving neonates have one Many centers that follow up ART infants report a higher inci- major congenital anomaly at birth. Some anomalies are detected dence of hypospadiasis and undescended testes in these infants.3 during childhood or adolescence. The major cause of congenital One of the major biases is careful sonography of these infants dur- anomalies are genetic factors which cause 50% of spontaneous ing pregnancy. In 1990, one center in the United States reported a abortions during the first trimester of pregnancy and 5% of neona- high incidence of periventricular cysts in the brain, hydronephro- tal deaths.1 Some factors probably increase the incidence of con- sis and unilateral agenesis of the kidneys in these infants, which genital anomalies in ART infants. For example, natural selection could not be detected by physical examination.4 which occurs in normal conception (NC) pregnancies does not In many countries only birth time anomalies are recorded, how- occur in ART fertilization. Changes of hormonal status in the lab ever many anomalies such as pyloric stenosis appear later.2 during the process of mitosis or myosis may cause chromosomal Another reason for increased reporting of more anomalies in anaploidy. Chemical compounds may also induce point mutations ART infants is the precise reporting of these anomalies in the during artificial conception. aborted ART fetus or neonate in comparison to the normal popula- Although in European countries congenital anomalies of ART tion. We could not compare ART infants with normally conceived infants are recorded and followed, they could not be compared infants.5 with the incidence of anomaly in the normal population. The rea- The only comparable group with ART infants are those parents son for higher incidence of congenital anomalies in ART infants became fertile by other techniques, such as ovulation induction. However there are few studies about these infants. Authors’ affiliations: 1Child Health and Development Research Department, The other confounding factors are the higher age of these cou- Tehran Medical Sciences, Branch of Academic Center for Education, Culture ples. In older mothers (27–28 years old) who request ART,6 the and Research (ACECR), Tehran, Iran. 2Department of Genetics, Royan Institute 7,8 9,10 for Reproductive Biomedicine, ACECR, Tehran, Iran. 3Oral disease Department, probability of abortion or aneuploidy increases and Men- Shahed University, Tehran, Iran. 4Optometry Department, Tehran University of delian mutation incidences increase in ART infants of older fa- Medical Sciences, Tehran, Iran. thers.10–12 •Corresponding author and reprints: Ramin Mozafari Kermani MD, Child Health and Development Research Center, Tehran, Iran. P.O. Box: 1555837611, Many studies have reported more congenital anomalies in the Telefax: +98-218-851-7180, E-mail: [email protected]. ART methods, particularly in vitro fertilization (IVF) infants, in Accepted for publication: 13 July 2011 comparison to natural conception (NC) infants, which is related

228 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 R. Mozafari Kermani, L. Nedaeifard, M. R. Nateghi, et al.

Table 1. Prevalence of organ and system anomalies in ART infants.

ART method IVF ICSI ART Systems or Organs Number Percentage Number Percentage Number Percentage Normal 52 67.5 215 66.5 267 66.7 Skin 6 7.8 34 10.5 40 10 Urogenital 6 7.8 19 5.9 25 6.2 Gastrointestinal 3 3.9 18 5.5 21 5.2 Visual 1 1.3 12 3.7 13 3.25 Cardiovascular 3 2.6 5 1.5 8 2 Limbs-bones 2 2.6 6 1.8 8 2 Endocrine 3 3.9 3 0.9 6 1.5 Otolaryngeal — — 5 1.5 5 1.2 Blood and lymphatic 1 1.3 3 0.9 4 1 Nervous — — 3 0.9 3 0.75 Abnormal (total) 25 32.5 108 33.4 133 33.3 Total 77 19.2 323 80.8 400 100

Table 2. Prevalence of major anomalies in ART infants. ART method IVF ICSI ART Disease Number Percentage Number Percentage Number Percentage Inguinal hernia 1 13. 4 1.2 5 1.2 Undescended testis 0 0 2 0.6 2 05. UPJ stenosis 0 0 1 0.3 1 0.2 Hypospadiasis 1 1. 3 4 1.2 5 1.2 Hydronephrosis 2 2.6 1 0.3 3 0.7 and reflux Severe PDA + VSD 2 2.6 1 0.3 3 0.7 Lacrimal duct stenosis 1 1.3 3 0.9 4 1 DDH 2 2.6 2 0.6 4 1 Torticoli 0 0 1 0.3 1 0.2 Total anomalies 9 11.7 19 5.9 28 7 Total 77 19.2 323 80.8 400 100

Table 3. Prevalence of congenital anomalies in IVF and ICSI infants in different countries. Country Congenital anomaly in IVF infants (%) Congenital anomaly in IVF infants (%) Iran 5.9 11.7 Belgium50 4.2 4.5 Australia48 8.6 9 Sweden46 8.6 8.1 Norway51 3.1 3 to multi-fetal pregnancy and prematurity.13–18 infants were classified by body organs or limb involvement and In more invasive methods, particularly intracytoplasmic sperm divided into 10 groups by ICD-10 (International Classification of injection (ICSI) in which sperm does not pass its natural way Disease) classification. If the anomaly was not exactly diagnosed and natural selection deletion does not occur (in an oligospermic by physical exam, sonography, radiography or echocardiography man), more chromosomal anomalies have been seen. Other inter- were used. ventions also used in IVF are the gonadotropin stimulator, oocyte Data were analyzed by SPSS version 16 and Fisher’s exact test. aspiration, and culture media, which probably increases the incidence of congenital anomalies.19,20 Results In Iran many infants are conceived by ART, however there are no Iranian studies about congenital anomalies. The aim of this A total of 208 (52%) boys and 192 (48%) girls were exam- study is the determination of congenital anomalies and distribu- ined. The prevalence of congenital anomalies according to organ tion rate of organ and system defects of these anomalies in a com- or system involvement and ART method are shown in Table 1. parison of infants conceived by different ART methods. Skin anomalies were: 3 (0.75%) hemangioma, 19 (4.7%) umbilical hernia, 7 (1.7%) eczema, 4 (1%) skin hyperpigmentation, 2 Materials and Methods (0.5%) semian line, and 5 (1.2%) inguinal hernia. Anomalies seen in the urogenital system were: 1 (0.2%) microlitiasis, 7 (1.7%) In a cross-sectional descriptive study, 400 ART infants from hydrocele of the testis, 5 (1.2%) labia adhesion, 1 (0.2%) micro- Royan Institute who were residents of Tehran were examined penis, 2 (0.5%) undescended testes, 1 (0.2%) ureteropelvic junc- during 22 month in the Child Health and Development Research tion (UPJ) stenosis, 5 (1.2%) hypospadias, 3 (0.7%) renal reflux Center. This study was approved by the Ethics Committee of the and hydronephrosis. Gastrointestinal anomalies were: 1 (0.2%) Academic Center for Education, Culture and Research (ACECR) constipation, 11 (2.75%) gastro-esophageal reflux, 5 (1.2%) pro- and Royan Institute. longed icter, and 4 (1%) thrush. This was a non-random, consecutive sampling due to the lim- In the cardiovascular system there were 8 (2%) patent ductus ited number of available infants which did not allow us to sample arteriosus ± ventricular septal defect (PDA + VSD); visual anom- randomly. Infants were examined twice, at birth to 6 months and alies were: 4 (1%) stenosis of the lacrimal duct, 3 (0.75%) con- from 6 to 9 months by a pediatrician. Congenital anomalies of junctivitis, and 6 (1.5%) strabismus. Orthopedics were: 4 (1%)

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 229 Congenital Anomaly in ART Infants developmental dysplasia of the hip (DDH), 1 (0.2%) torticoli, 1 the prevalence of sensory hearing loss in NC (0.5–1 in 1000 (0.2%) spina bifida, and 2 (0.5%) pes varus. infants). The otolaryngeal system anomalies were 3 (0.7%) lingual frenu- Regarding nervous system defects, there were 3 (0.7%) CP in- lum, 1 (0.2%) hearing loss, and 1 (0.2%) ear deformity. In the fants conceived by ICSI which was higher than the prevalence blood and lymphatic system there were 1 (0.2%) anemia, 1 (0.2%) in the general population (0.2%).31 In other studies, the preva- lymphadenitis, and 2 (0.5%) G6 PD. Nervous system anomalies lence of CP in ART infants was 4 times,24 1.6 times,32 and 1.8 included 3 (0.7%) infants with cerebral palsy (CP), and finally the times33 more than NC infants. In 5 studies, no significant differ- endocrine system anomalies were: 3 (0.7%) hypothyroidism and ences were noted between ART and NC infants in nervous system 3 (0.7%) rickets. anomalies.25,26,34–36 In all studies, the most common reason for CP According to ICD-10, hypospadiasis, inguinal hernia, severe in these infants was prematurity and low birth weight.36,37 There PDA + VSD, stenosis of the lacrimal duct until age one year, was no significant difference in the prevalence of CP in ICSI and urethral reflux more than grade III and hydronephrosis, unde- IVF infants in our study (P = 1). scended testis (until one year of age), UPJ stenosis, torticoli, and Congenital hypothyroidism was (0.7%) in our study and 0.1% in DDH, which requires surgery are all considered major anomalies. Tehran’s neonate population.38 There were no differences between Anomalies in Table 2 are classified according to major anomalies the two groups of ART infants (P = 1). and ART technique. In general, one-third of ART infants had either one minor or major anomaly and 7% had one of the major congenital anomalies, Discussion which was higher when compared with the general population (2%–3%).1,39 This prevalence was similar to a study in Finland The major problem in classification of congenital anomalies is (5.5%–6.6%)40,41 and higher than the prevalence of major con- the definition of a major anomaly. In this study all anomalies that genital anomalies in the Netherlands (2.3%, 3.7%),42,43 England required surgery, until one year of age or a disturbed function of (4.8%),44 Australia (4.3%),45 and Sweden (5%).46 the organs have been considered major congenital anomalies. In comparison with other studies, Germany (8.6%)47 and Austra- Of ART infants who were examined twice, one-third had con- lia (8.9%),48,49 had lower prevalences. genital anomalies. IVF infants had higher numbers of congenital In our study the percent of major congenital anomalies among heart diseases, DDH and hydronephrosis with renal reflux (Table ICSI (5.9%) and IVF (11.7%) infants was not significantly differ- 2). ent between the two groups (P = 0.08). A higher prevalence of congenital anomalies were seen in the In 4 studies on IVF and ICSI infants in other countries, there skin (10%), urogenital (6.2%), gastrointestinal (5.2%), visual were no reported significant differences between the two groups (3.2%), and cardiovascular systems (2%). regarding major congenital anomalies (Table 3). However, the prevalence of inguinal hernia was 1.2%, which In our country, after more than one decade of infants born via was lower than term (3%–5%) or preterm (9%–11%) NC in- ART, there were no studies on congenital anomalies and the com- fants.21 There were no significant differences in the prevalence of parison to NC infants. The results of two examinations of ART inguinal hernias in both groups (P = 1). infants until 9 months of age showed that two-thirds were normal, The prevalence of major anomalies in the urogenital system in 7% had one major anomaly, which was 3 times more than the gen- IVF infants was 7.8%, whereas for ICSI infants it was 5.9%. In eral population and there was no significant difference between the another study the prevalence of major anomaly of urogenital ICSI and IVF infants. system were 3.9% and 2.5% ( in IVF and ICSI infants, respec- Financial support: This study was financially supported by the tively) which was not significant P( = 0.45) with each other and Academic Center for Education, Culture and Research (ACECR). other studies (3% in IVF and 5% in ICSI).22 Date of draft: September 2007 – July 2009 Gastrointestinal anomalies were seen in 5.2% of infants; all of Place of origin: Child Health and Development Research Cen- which were classified as minor anomalies, the higher rate seen in ter, Tehran, Iran. ICSI infants compared to the IVF group. Major anomalies of the cardiovascular system were seen in Acknowledgment 0.7% of infants, which was similar to the general population (0.8%).23 However, it was not significantly different between the This study was financially supported by the Academic Center two groups (P = 0.09). for Education, Culture and Research (ACECR) and the authors A total of 3.2% of infants had visual anomalies, which was high- express their gratitude to Mrs. Afsane Azari and Miss Sharareh er in the ICSI group (P = 0.57). In one study, this was reported Dadashloo for their cooperation. There is no conflict of interest as 0.9%–4.2% in IVF infants24; other studies reported no differ- in this article. ences between ART infants and the control group.22,25–28 In the general population,1.6% of infants needed lacrimal duct stenosis surgery,29 which was 1% in our study. References There were 2% of infants who had either limb or bone anomalies, which was not different between the ICSI and IVF infants (P 1. 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Obstetric outcome among women comes in single tons and twins after assisted conception: A systematic with unexplained infertility after IVF: a matched case-control study. review of controlled studies. Br Med J. 2004; 328: 261 – 265. Hum Reprod. 2002; 17: 1755 – 1761. 16. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes 42. Koudstaal J, Braat DD, Bruinse HW, Naaktgeboren N, Vermeiden JP, in singletons following in vitro fertilization: a meta-analysis. Obstet Visser GH. Obstetric outcome of singleton pregnancies after IVF: a Gynecol. 2004; 103: 551 – 563. matched control study in four Dutch university hospitals. Hum Rep- 17. Wennerholm UB, Bergh C. Outcome of IVF pregnancies. Fetal Ma- rod. 2000; 15: 1819 – 1825. tern Med Rev. 2004; 15: 27 – 57. 43. Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP, Wil- 18. Mcdonald SD, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes lemsen WN, Visser GH. Obstetric outcome of with pregnancies after of singleton pregnancies achieved by in vitro fertilization: a systematic in-vitro fertilization: a matched control study in four Dutch university review and meta-analysis. J Obstet Gynecol Can. 2005; 27: 449 – 459. hospitals. Hum Reprod. 2000; 15: 935 – 940. 19. de Breakeleer M, Dao TN. Cytogenetic studies in male infertility: a 44. Sutcliffe AG, Taylor B, Saunders K, Thornton S, Lieberman BA, review. Hum Reprod. 1991; 6: 245 – 250. Grudzinskas JG. Outcome in the second year of life after in vitro fertil- 20. Aittomaki K, Bergh C, Hazekamp J, Nygren KG, Selbing A, Soder- ization by intracytoplasmic sperm injection: a UK case control study. storom-Anttila V, et al. Genetics and assisted reproduction technology. Lancet.2001; 357: 2080 – 2084. Acta Obstet Gynecol Scand. 2005; 84: 463 – 473. 45. Wang JX, Norman RJ, Kristiansson P. The effect of various infertil- 21. Behrman RE, Kligman RM, Jensin HB. 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Nelson Textbook of Pediatrics.17th ed. Vol. II; part 28. USA: Saunders; 2004: 2127 –

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 231 Chromosomal Abnormality in SA

Original Article Chromosomal Abnormality in Patients with Secondary Amenorrhea

Akbar Safai MD1, Mohammad Vasei MD2, Armin Attaranzadeh MD•1, Fariborz Azad DVM1, Narjes Tabibi MS1

Abstract Background: Secondary amenorrhea is a condition in which there is cessation of menses after at least one menstruation. It is a symptom of different diseases, such as hormonal disturbances which range from pituitary to ovarian origin, as well as chromosomal abnormalities. Knowledge of the distinct cause of secondary amenorrhea is of tremendous benefit for the management and monitoring of patients. In this study, we determine the chromosomal abnormalities in patients with secondary amenorrhea in Southwest Iran. Methods: We selected 94 patients with secondary amenorrhea who referred to our Cytogenetic Ward from 2004 until 2009. For karyotyping, peripheral blood lymphocyte cultures were set up by conventional technique. Results: In this study, 5.3% (n=5) of patients with secondary amenorrhea presented with chromosomal abnormalities, of which all con- tained an X element. The chromosomal abnormalities were: i) 45, X (n=1); ii) 47, XXX (n=1); iii) 45, X [13]/ 45, Xi(X)q[17] (n=1); iv) 45, X[12]/46,X,+mar[12] (n=1); and v) 46,X,del(Xq)(q23q28) (n=1). Conclusion: Our study revealed that some causes of secondary amenorrhea could be due to chromosomal abnormalities. Therefore, cytogenetic studies should be important tests in the evaluation of patients with secondary amenorrhea.

Keywords: Chromosomal abnormality, cytogenetic study, karyotyping, secondary amenorrhea

Cite the article as: Safai A, Vasei M, Attaranzadeh A, Azad F, Tabibi N. Chromosomal Abnormality in Patients with Secondary Amenorrhea. Arch Iran Med. 2012; 15(4): 232 – 234.

Introduction Materials and Methods

menorrhea is classified as either primary or secondary. Pri- In a cross-sectional study, all women with secondary amenor- mary amenorrhea is defined as the lack of onset of men- rhea who referred to the Cytogenetic Ward of the Department of Astruation by age 14–16 according to developmental sta- Pathology, Shiraz University of Medical Science, Shiraz, Iran tus.1,2 Secondary amenorrhea is a condition demonstrated by the from 2004 to 2009 were selected. Secondary amenorrhea was de- absence of menstruation for six months or 3 previous cycle inter- fined as the absence of menstruation after at least one menstrua- vals in a female who has had at least one previous menstruation. tion that occurred prior to their complaint.2 Clinical and laboratory Among the general population, amenorrhea is detected in 2%–5% data were obtained from hospital records or the referring physi- of all females of childbearing age.1 There are many causes for cian. Family history was reviewed during genetic counseling and secondary amenorrhea, of which hormonal disorders are the main family members were tracked back three generations. Secondary cause.2 Hormonal disorders include hypothalamic-pituitary dis- sexual characteristics and hormonal conditions were recorded. Se- turbances, polycystic ovary, resistant ovary syndrome, and prema- rum luteinizing hormone (LH) and follicle stimulating hormone ture ovarian failure. Understanding the distinct cause of secondary (FSH) concentration data were retrospectively analyzed from hos- amenorrhea is of tremendous assistance in management and mon- pital records. If serum LH and FSH levels were checked several itoring these patients. Genetic or chromosomal abnormalities are times, the maximal value was used in the analysis. Blood samples one of the most important causes of secondary amenorrhea, and were obtained with heparin syringes and lymphocytes were cul- may be either a single gene disorder, chromosomal abnormality or tured in RPMI 1640 basal media and 10% fetal calf serum (Gibco, multifactorial.1,2 Chromosomal abnormalities are divided into nu- Invitrogen, USA) and treated with 0.1 µg/ml colcemide (Gibco, merical, structural, and mosaicism.1 In some studies from various Invitrogen, USA) after a 72 hour incubation period. Subsequently, parts of the world, numerical or structural chromosomal abnor- metaphase chromosomes were spread and stained using standard malities have been reported at levels ranging from 3.8% to 44%.1– G-banding techniques. 11 Such a wide variation is likely due to varied selection criteria of In every patient, at least 15 metaphase chromosomal complexes patients in different studies. were examined and if mosaicism was suspected, further meta- In this study, we evaluated cytogenetic findings in patients diag- phases were examined. nosed with secondary amenorrhea who resided in Southwest Iran. Results Authors’ affiliations:1 Pathology Ward, Shiraz Medical University, Shiraz, Iran, 2Tehran Medical University, Tehran, Iran. A total of 94 women with secondary amenorrhea referred to this •Corresponding author and reprints: Armin Attaranzadeh MD, Pathology center for karyotype analysis from other genetic clinics, gyne- Ward, Shiraz Medical University, Setad sq., Shiraz. Tel: +98-511-228-8813, Fax: +98-511-228-8812, E-mail: [email protected]. cological practitioners, and other services. Patients’ ages ranged Accepted for publication: 22 June 2011 from 16 to 41 years with a mean of 26.5 years. They had men-

232 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 A. Safai, M. Vasei, A. Attaranzadeh, et al. struation one time prior to their diagnosis and the delay in men- ally is caused by cortical or hypothalamic disorders with an endo- struation ranged from 6 months to 7 years. crine abnormality or ovarian dysfunction. Normal karyotype was present in 89 women (94.7%); 5 cases Chromosomal abnormality is a rare, but important cause of (5.3%) had at least one chromosomal abnormality, as shown be- secondary amenorrhea that can be detected by cytogenetic analy- low: sis. The prevalence of chromosomal abnormalities in secondary i) 45, X (n=1); ii) 47, XXX (n=1); iii) 45, X [13]/ 45, Xi(X)q[17] amenorrhea varies from 3.8% to 44% in different parts of the (n=1); iv) 45, X[12]/46,X,+mar[12] (n=1); and v) 46,X,del(Xq) world. (q23q28) (n=1). Wong et al.2 evaluated 312 patients and compared their results A total of 47 individuals (50%) had high levels of LH (23–90 with other studies (Table 1). According to this study, the preva- mIU/mL; mean: 63 mIU/mL) and FSH (28–134 mIU/mL; mean: lence of chromosomal abnormalities was 9.9%, whereas in other 74 mIU/mL). In patients with chromosomal abnormalities, there studies it varied from 3.8% to 44%. There is no specific cause were abnormal levels of LH (mean: 72 mIU/mL) and FSH (mean: for this wide variation of results among different ethnic groups, 88 mIU/mL) in 4 cases (80%). but may be due to different selection criteria as well as different In 33 women, there was a history of hormone therapy, from population genetics throughout the world. One selection criteria is which 29 responded to treatment and 4 were unresponsive. No the genetic study in patients with increased gonadotrophin levels.4 family history was present in the patients. None of patients with In our study, the frequency of chromosomal abnormalities was chromosomal abnormalities had histories of hormone therapy. 5.3% which is comparable to other studies (Table 1). Chromo- somal abnormality may be numerical or structural. In a previous study, numerical anomaly and their mosaicism have been shown to be the most common causes of chromosomal abnormalities, with a numerical to structural ratio of 22:9.2 In our study, 2 cases (40%) had numerical anomalies 47,XXX and 45,X; 2 (40%) had mosaicism [45,X/46X,+mar and 45,X/46,Xi(Xq)]; and 1 case (10%) had a structural anomaly 46,X,del(Xq)(q23 q28). Premature ovarian failure may be secondary to X chromosome deletion or translocation. POF1 and POF2 genes located at Xq, are the genes essential for normal ovarian function.2,12 In our results, all patients had X chromosome abnormalities, of which 4 (80%) had total or partial deletions of the X chromosome. In secondary amenorrhea, the frequencies of chromosomal abnormalities were 45,X (40%–50%); X mosaicism (25%–36%); X structural (8%); and 46,XY female (16%).1,11 Autosomal abnormalities are rare. van Niekerk showed one case of X/autosome translocation5 and Jyothy reported one case of 46,XY,13p+ in secondary amenorrhea patients.3 In this study, we Figure 1. Chromosomal abnormality in one patient with 45, X[13]/45,Xi(X) did not find any similar abnormalities. q[17] karyotype. A comparison of primary and secondary amenorrhea in our region showed a higher prevalence of chromosomal abnormali- Discussion ties in primary amenorrhea (20%) than in secondary amenorrhea (5.3%).13 Our results for secondary amenorrhea cytogenetic ab- Secondary amenorrhea is one of the important reasons for pa- normalities were much less than other studies of primary amenor- tient referral to an endocrine or gynecologic clinic. Karyotype ex- rhea, in which the frequency ranged between 24.5–27.3.5,8 amination is a useful tool in cytogenetic laboratories. In secondary Currently, chromosome analysis is not limited to research, but is amenorrhea, a history of pregnancy does not exclude cytogenetic increasingly studied in many clinical disorders. Many indications abnormalities and after exclusion of non-genetic cases, patients exist for karyotyping, of which one is amenorrhea (primary or should receive genetic counseling.2 Secondary amenorrhea usu- secondary). In secondary amenorrhea, patients with high gonado-

Table 1. Number and frequencies of secondary amenorrhea among different ethnic populations. Hong South Population US Chile Germany Iran Turkey Shanghai India Kong Africa Cases 30 47 15 94 9 18 339 312 103 46,XX 26 32 10 89 8 10 324 281 99 Abnormal 4 15 5 5 1 8 15 31 4 karyotype (13%) (32%) (33%) (5.3%) (11%) (44%) (4.4%) (9.9%) (3.8%) 45,X — 5 — 1 — — — 5 — Mosaic 45,X — — — 2 — — — 11 — 46,Xi — — — — — — — 1 — 47,XXX — — — 1 — — — 3 — 46,X/delX — — — 1 — — — 6 — Others — — — — — — — 5 — Devi and Castilo Opitz Temocin van This study Lin and Yu9 Jyothy3 Wong2 Benn7 et al.10 et al.11 et al.8 Nierkerk5

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 233 Chromosomal Abnormality in SA tropin levels that are idiopathic who present with clinical signs of Genet. 2002; 2: 55 – 59. Turner Syndrome are advised to undergo karyotyping for evalua- 4. Brovik CL. Cytogenetic studies on primary and secondary amenorrhea. Brazil J Genetic. 1984; 7: 129 – 36. tion and monitoring. Karyotype studies in secondary amenorrhea 5. van Niekerk WA. Chromosomes and gynecologist. Am J Obstet Gyne- show a significant prevalence of chromosomal anomalies, thus col. 1978; 130: 862 – 75. early cytogenetic investigation is necessary to guide further treat- 6. Lakhal B, Braham R, Berguigua R, Bouali N, Zauali M, Chaieb M, et ment. Our observations have revealed the necessity for cytoge- al. Cytogenetic analysis of premature ovarian failure using karyotyping and interphase fluorescencein situ hybridization (FISH) in a group netic examination in all women of reproductive age who present of 1000 patients. Clin Genet. 2010; 78: 181 – 85. with symptoms of secondary amenorrhea. We also recommend 7. Devi A, Benn PA. X-chromosome abnormalities in women with pre- fluorescent in situ hybridization (FISH) for patients with second- mature ovarian failure. J Reprod Med. 1999; 44: 321 – 324. ary amenorrhea because in routine cytogenetic studies, low levels 8. Temocin K, Vardar MA, Suleymanova D. Results of cytogenetic investigation in adolescent patients with primary or secondary amenor- of mosaicism cannot be ruled out. rhea. J Pediatr Adolesc Gynecol. 1997; 10: 86 – 88. To better evaluate and determine cytogenetic abnormalities in 9. Lin J, Yu C. Hypergonadotropic secondary amenorrhea: Clinical anal- both primary and secondary amenorrhea, a larger geographical ysis of 126 cases. Zhonghua Fu Chan Ke Za Zhi. 1996; 31: 278 – 282. 10. Castillo S, Lopez F, Tobella L, Salazar S, Daher V. The cytogenet- study in Iran is recommended. ics of premature ovarian failure. Rev Child Obstet Gynecol. 1992; 57: 341 – 345. References 11. Opitz O, Zoll B, Hansmann I, Hinney B. Cytogenetic investigation of 103 patients with primary or secondary amenorrhea. Hum Genet. 1983; 65: 46 – 47. 1. Rajangam S, Nanjappa L. Cytogenetic studies in amenorrhea. Saudi 12. Therman E, Susman B. The similarity of phenotypic effects caused by Med J. 2007; 28: 187 – 192. Xp and Xq deletions in the human female: A hypothesis. Hum Genet. 2. Wong MSF, Lam STS. Cytogenetic analysis of patients with primary 1990; 85: 175 – 183. and secondary amenorrhea in Hong Kong: Retrospective study. Hong 13. Safaei A, Vasei M, Ayatollahi H. Cytogenetic analysis of patient with Kong Med J. 2005; 11: 267 – 272. primary amenorrhea in southwest of Iran. Iran J Pathol. 2010; 5: 121 3. Jyothy A, Kumar KSD, Swama M, Raja Sekhar M, Uma Devi B, – 125. Reddy PP. Cytogenetic investigation in 1843 referral cases of disor- dered sexual development from Andhra Pradesh, India. JHG J of Hum

234 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 E. Razmpa, B. Saedi, F. Mahbobi

Original Article Augmentation Rhinoplasty with Combined use of Medpor Graft and Irradiated Homograft Rib Cartilage in Saddle Nose Deformity

Ebrahim Razmpa MD1, Babak Saedi MD•1, Farshid Mahbobi MD1

Abstract Background: We used the irradiated homograft rib cartilage as an augmentation tip support and Medpore alloplast for reconstruction of the dorsum in patients with saddle nose deformities. Thereafter, the safety and efficiency of this method was evaluated to determine if this can be a safe and efficient technique for patients with saddle nose deformities. Methods: A total of 32 patients who suffered from saddle nose deformities due to past trauma or aggressive rhinoplasty underwent reconstruction using the Medpor prosthesis for dorsum reconstruction and irradiated rib cartilage as acolumellar strut during the same technique. After at least one year follow up, patients’ satisfaction and their aesthetic indexes were evaluated and compared with preoperative results. Results: More than 84% of patients were satisfied from the results of the surgery and only one patient had a complication of the infection which resulted in removal of the prosthesis. There were statistically significant differences between most of the pre- and postoperative aesthetic indexes. Conclusion: Despite the superiority of autogenous material in nose reconstruction, lack of such materials in revision rhinoplasty cases present challenges to surgeons. This study proposes the safety and efficiency of the Medpor alloplast for reconstruction of the dorsum and irradiated rib cartilage for the tip, at least for a short period of time.

Keywords: Alloplast, irradiated cartilage, Medpor, rhinoplasty, saddle nose

Cite the article as: Razmpa E, Saedi B, Mahbobi F. Augmentation Rhinoplasty with Combined use of Medpor Graft and Irradiated Homograft Rib Cartilage in Saddle Nose Deformity. Arch Iran Med. 2012; 15(4): 235 – 238.

Introduction polyethylene (Medpor) has these characteristics.2, 5,8–16 Therefore, Medpor can be a good option for augmentation of the dorsum. asal plastic surgery is accepted as a complicated and effi- However, in special urgent cases and the need to re-establish tip cient aesthetic surgery. Although the most prevailing use support, homografts are superior.3,4,13 Among the diverse choices Nof this type of surgery is for cosmetic purposes, its other of materials, an irradiated homograft rib can be a good alternative common use is for reconstructive reasons. Occasionally some pa- because it can be easily shaped and replaced with the patients’ tients, particularly traumatic cases, encounter many impediments own tissues, in addition to its non-immunogenic character and among which tissue deficiency is the hardest hindrance to over- lower extrusion rate in the tip area.1,13,14 come.1 Over time, many researchers have attempted to use differ- We used irradiated homograft rib cartilage as augmentation of ent materials as a substitute for missing parts. the tip support and Medpor alloplast for reconstruction of the dor- It has been demonstrated that autologous materials are superior sum. We assessed the outcome and safety of this method in recon- to exogenous materials, however, lack of reliable tissue resources struction of saddle nose deformity. in most saddle nose deformities on the one hand, the morbidity of graft removal from distant sites, and time consuming nature Materials and Methods of the procedure on the other hand, leads to attempts at different methods of substitution.1-7 Study subjects The typical deformities of the saddle nose consist of inadequate We enrolled 32 patients who suffered from saddle nose deformi- dorsal height, decreased tip supports, and projection. Consequent- ties due to past trauma or unsuccessful rhinoplasty. These patients ly, an augmentation procedure with dorsal graft and columellar underwent reconstruction by the same technique between May strut graft as complementary parts of the routine septorhinoplasty 2007 and January 2009 in an otolaryngology section of a tertiary is required. referral center (Imam Khomeini Hospital complex). The consecu- There are two broad groups of graft materials: allografts and tively enrolled patients had no histories of any systemic diseases homografts. Apart from the types of material, the ideal material (e.g., diabetes, immune deficiency, or rheumatologic diseases), should be biocompatible, stable to re-absorption and resistant to hypersensitivity to Medpor, or substances used for preparation of infection. Among allografts, it is claimed that porous high-density the irradiated rib cartilage. Authors’ affiliation: 1Otolaryngology Department, Tehran University of Medi- cal Sciences, Tehran, Iran. Ethics approval •Corresponding author and reprints: Babak Saedi MD, Otolaryngology Re- The protocol of this study was approved by the Institutional Re- search Center, Imam Khomeini Medical Center, Bagherkhan St., Chamran High- way, Tehran 141973141, Iran. view Board of the Tehran University of Medical Science. Detailed Fax: +98-216-658-1628, E-mail: [email protected] information about the study was given to the participants and a Accepted for publication: 13 July 2011 written informed consent was obtained from each one. All aspects

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 235 Augmentation Rhinoplasty in Saddle Nose

Table 1.Comparison between preoperative and postoperative aesthetic analyses. Preoperative Postoperative Difference Evaluated index P-value Mean ± SD Mean ± SD Mean ± SD Dorsum depression 6.25 ± 1.1 1.78 ± 0.79 4.47 ± 1.19 < 0.001* Nasofrontal angle 139.3 ± 7.1 138.6 ± 5.4 0.75 ± 4.6 <0 .361 Nasolabial angle 92.4 ± 9.3 98.8 ± 8 6.44 ± 5.5 < 0.001* Projection 56.1 ± 6.2 59.8 ± 3.3 2.7 ± 4.4 0.001*

Table 2. Comparison between preoperative and postoperative aesthetic analysis according to ideal values. Evaluated index Index status Preoperative Postoperative P-value Appropriate 0 19(59.9%) Dorsum status <0.001* Non-appropriate 32(100%) 13(40.6%) Appropriate 7(21.9%) 10(31.2%) Nasofrontal angle 0.391 Non-appropriate 25(78.1%) 22(68.8%) Appropriate 14(43.3%) 12(37.5%) Nasolabial angle 0.611 Non-appropriate 18(56.3%) 20(62.5%) Appropriate 13(40.6%) 5 (15.6%) Projection 0.026* Non-appropriate 19(59.4%) 27(84.4%)

of the study were conducted according to the Declaration of Hel- in-groove. The graft was attached to the nasal spine with 4-0 ny- sinki. All materials used in this study were proven to be safe and lon sutures, which were removed after 6 weeks. approved by the FDA. The Medpor prosthesis was specially designed for the dorsum by the manufacturer. Its size was defined according to the volume Procedures and materials of the defect and also its shape was altered during surgery. We used an endonasal rhinoplasty approach. However, in severely deviated noses, severely over-or under-projected noses, Tests and assessment and cases of severe problems of the tip, an open approach with In addition to demographic information, the type of proce- a similar technique was used. All procedures were performed by dure, its characteristics, and duration of nasal plastic surgery one of the senior authors under general anesthesia. The Medpor for all patients were documented. Surgical details such as open implants (Medpor surgical implants, Porex Surgical Inc., College or closed approach, septoplasty, hump removal, osteotomy, or Park, GA) were shaped with a #10 scalpel blade when necessary tip plasty was collected for all procedures. The nasal obstruc- and it replaced in a pocket which can be create deep to the nasal tion and patients’ satisfaction were evaluated according to the dorsum periosteum. The height of the prosthesis was adapted ac- Visual Analogue Scale (VAS) as 0 (worst status) and 10 (best cording to the ideal dorsal height. No packing was used during status) during the pre- and postoperative periods. Patients com- surgeries, but an Aquaplast splint was positioned on the dorsum, pleted a five-choice questionnaire that detailed a more accu- which was removed after one week. Afterwards, tape was posi- rate scaling of their satisfaction: 1 (completely unsatisfied), 2 tioned over the nose and it was evaluated for the location of the (partially unsatisfied), 3 (partially satisfied), 4 (satisfied), and 5 prosthesis. Antibiotic prophylaxis (Cephalexin 500 mg, qid × 5 (completely satisfied). days) was administered to all patients and acetaminophen (325 Additionally, pre- and postoperative digital standard photo- mg, qid) was used as the sole analgesic. Subsequently, patients’ graphs were taken to compare and re-evaluate the nasal tip pro- nasal splints were removed after 7 days postoperatively and tap- jection, rotation and status of the dorsum with the preoperative ings were continued for 4 weeks thereafter. values and views. Photographs were taken with a Canon Power The irradiated rib cartilages were adopted obtained from cadav- Shot S5 digital camera and a Canon X12 Zoom lens to ensure eric rib cartilage whose donors were screened for HIV, HBsAg, proper and uniform photographic size. We used the same position and other infections. Rib cartilages were exposed to gamma ray for patients and photographer, according to the Frankfort hori- radiation at doses of 30,000 to 60,000 Gy for the sterilization zontal line at a fixed distance of 1 m. The facial section between process. Consequently, the processed ribs were preserved in an- the horizontal planes running above the eyebrows and below the tibiotic solution before application. The columellar strut was con- mentum was copied from the postoperative photograph. The tip structed from pieces of processed rib cartilage. Its initial dimen- projection, rotation, and dorsum status were measured as follows. sions were 2 to 3 cm long, 2 to 3 mm wide, and 1 to 2 mm thick, such that it could be trimmed as a graft of different dimensions. It Nasal tip projection was placed into a pocket dissected with a curved Stevens scissor We used Byrd’s method for evaluating tip projection by drawing between the medial crura. The strut was loaded in the intercrural a line from the alar-cheek junction to the tip of the nose. If the up- space, with slight force. The cephalic portion of the strut was at- per lip projection was normal, a verticalline was drawn adjacent tached to the midportion of the medial crura with two 4-0 nylon to the most projecting part of the upper lip. To achieve adequate mattress sutures. The caudal edge of the strut was allowed to lie tip projection, at least 50% of the horizontal line had to lie anterior freely between the medial crura in a way that resembled a tongue- to the vertical line. If 60% of the line lay anterior to it, the tip was

236 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 E. Razmpa, B. Saedi, F. Mahbobi considered over projected and needed to be reduced. If 50% of the tip was anterior to the vertical line, it indicated a short nose with inadequate projection that needed augmentation. By utilizing Byrd’s method, we considered normal projection to be in the range of 55 ± 5%.

Nasal tip rotation Adobe Photoshop 7.0 software (Adobe Systems Inc., San Jose, CA, USA) was used to measure the nasolabial angle between two lines drawn parallel to the upper lip and columella. Rotation in the range of 90–95° for men and 95–110° for women was considered Figure 1. Postoperative patient satisfaction results. normal. One postoperative infection resulted from trauma, which was Dorsum status managed by removal of the prosthesis. After six months, another The dorsum status was measured by calculating the amount of surgery was performed and the patient’s prosthesis was replaced. maximal bulging or deepening over the dorsum with reference to Prosthesis displacement in the cephalic portion occurred in 2 pa- a tangent line from Nasion (deepest point of nasal bone to) to tip tients during the early postoperative period. Both patients recov- defining point. ered after taping for 2 weeks. All measurements were performed by Adobe Photoshop 7 soft- Figure 2 shows the preoperative pictures and postoperative re- ware, which provided an accurate analysis of the same facial sec- sults of 2 patients. tions in the postoperative photographs.

Statistical analysis Data were analyzed using SPSS 11.5 for Windows (SPSS Inc., Chicago, IL, USA). We used the Chi square test to evaluate pre- and postoperative ratios in each group and ANOVA test to compare average data in three groups. The values were evaluated using descriptive statistical methods (mean ± SD) and results were expressed at a significance level ofP < 0.05.

Results

During the study period, we enrolled 32 patients with a mean age of 30.5 ± 7 years (range: 18–45), of which 10 (31.2%) were female and 22 (68.8%) were male. There were 23 (71.9%) patients who had trauma histories, 5 (15.6%) had previous rhinoplasty, and the remaining 4 (12.5%) patients had congenital deformities. The method of surgery was the closed approach in 25 (78%) and open approach in 7 (21.9%) cases. In addition, 30 (93.8%) patients needed septoplasty. The mean duration of surgery was 95 Figure 2. Pre- and postoperative views of two patients. ± 25 minutes. The mean follow up period was 25.2 ± 4.9 months. Preoperatively, the mean patient VAS for nasal obstruction was Discussion 4.9 ± 2.6 and 1.9 ± 0.8 in the postoperative period, however, was not significant. Saddle nose deformity as an outcome of past trauma is a difficult Table 1 shows the comparison of pre- and postoperative aes- case to manage. There have been numerous proposed methods thetic indexes. with which to overcome this difficulty. Most are based on using patient’s own tissues, but regarding the lack of adequate tissues Paired sample t-test materials in complicated cases as well as donor site morbidity, These indexes were also evaluated according to their ideal val- the idea of using biocompatible synthetic materials has been pro- ues, as summarized in Table 2. posed. Among different types of biocompatible materials, Med- por is an interesting option for alloplasts5,13–15 and irradiated rib Chi-square test cartilage is a feasible homograft. Therefore, we have intended to As previously mentioned, the patient satisfaction rate was report- compare the results of their co-utilization in a reconstructive pro- ed through two methods. Firstly, results were analyzed according cedure for saddle nose deformity. to VAS (8.8 ± 1.9). Secondly, patients completed questionnaires, The final outcome of this research gave acceptable results with which indicated no patient dissatisfaction with the surgical out- minor complications. The stability and preparation simplicity of come (Figure 1). There was no significant difference between the the porous high-density polyethylene allows for satisfactory re- open and closed approach with regards to patient satisfaction and sults for reconstruction of the dorsum. However, there are par- other evaluated variables. ticular forms of the Medpor prosthesis for augmentation of the nasal tip, of which the final feature is not natural; in particular, its

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 237 Augmentation Rhinoplasty in Saddle Nose unusual tip recoil causes some difficulties for patients.13,14,17 of the Medpor alloplast for reconstruction of the dorsum and ir- Previously, different materials such as ivory, gold, and paraffin radiated rib cartilage for the tip, over a short time. have been used to replace lost nasal tissues; however, all failed to achieve satisfactory results. Among these, Gor-Tex materials have References had varying degrees of success with specialspecific drawbacks.3,16 Unlike other materials, Medpor has numerous advantages over 1. Sykes JM, Patel KG. Use of Medpor implants in rhinoplasty other materials such as less extrusion, lack of surrounding cap- surgery. Operative Techniques in Otolaryngology Head and Neck Surgery. 2008; 19: 273 – 277. sule formation, and stability, which provide better reconstruction 2. Godin M, Della Torre T. The use of expanded polytetrafluoroethylene results. In addition, growth of soft tissue over and into the pros- (e-PTFE) implants in rhinoplasty. Operative Techniques in thesis can cause reduced migration and infection rate of the pros- Otolaryngology. 2008; 19: 285 – 289. thesis.1–3,5,12–16 3. Conrad K, Gillman G. A 6-year experience with the use of expanded polytetrafluoroethylene in rhinoplasty. Plast Reconstr Surg. 1998; As with a study by Romo who had to remove the Medpor im- 101: 1675 – 1683. plants from his infected cases,16 our attempts at conservative man- 4. Turegun M, Acarturk TO, Ozturk S, Sengezer M. Aesthetic and agement of the infected cases failed, which resulted in removal functional restoration using dorsal saddle shaped Medpor implant of the implant. Although having considered the low rate of these in secondary rhinoplasty. Ann Plast Surg. 2008; 60: 600 – 603. 5. Brenner MJ, Hilger PA. Grafting in rhinoplasty. Facial Plast Surg phenomena, Medpor can be satisfactorily used in these compli- Clin North Am. 2009; 17: 91 – 113. cated cases. 6. Romo T , Kwak ES. Nasal grafts and implants in revision Because of the high rate of prosthesis rejection in the tip,14 we rhinoplasty. Facial Plast Surg Clin North Am. 2006; 14: 373 – 387. 7. Berghaus A, Stelter K. Alloplastic materials in rhinoplasty. Current used irradiated rib cartilage for tip augmentation as the columel- Opinion in Otolaryngology a Head and Neck Surgery. 2006; 14: 18 lar strut in the routine technique. Therefore, during the follow 270 – 277. up periods there were no complications with its use. Our study 8. Cenzi R, Farina A, Zuccarino L, Carinci F. Clinical outcome of 285 had good projection results, which were compatible with other Medpor grafts used for craniofacial reconstruction. J Craniofac 1,7,13,14 Surg. 2005; 16: 526 – 530. reports. 9. Öztürk S, Sengezer M, Coskun Ü, Zor F. An unusual complication Although we used Medpor conservatively, Kim et al. have re- of a Medpor implant in nasal reconstruction: a case report. Aesthetic ported the successful use of this type of graft as a spreader graft.19 Plast Surg. 2002; 26: 419 – 422. Therefore, in the future, surgeons most probably can safely use it 10. Shi RJ, Jiang CY, Wu QW. Rhinoplasty with Medpor surgical implant material. Chinese J Otorhinolaryngol Skull Base Surg. in other parts of the nose. 2006; 6: 203 – 204. Park et al., among others, compared the long-term effects of 11. Romo T, Sclafani AP, Sabini P. Use of porous high-density Medpor usage in nasal plastic surgery with other procedures in polyethylene in revision rhinoplasty and in the platyrrhine nose. different parts of the body and had acceptable results. However, Aesth Plast Surg. 1998; 22: 211 – 221. 12. Niechajev I. Porous polyethylene implants for nasal reconstruction: none of the authors claimed that the usual graft materials can be clinical and histologic studies. Aesth Plast Surg. 1999; 23: 395 – spared forgotten in routine nasal plastic surgeries and superseded 402. by synthetic materials.20 13. Maas C, Monhian N, Shah S. Implants in rhinoplasty. Facial Plast The primary measurement tool in this study, Photoshop 7 soft- Surg. 1998; 13: 279 – 290. 14. Sajjadian A, Naghshineh N, Rubinstein R. Current status of grafts ware, is an efficient tool for precise and objective measurement of and implants in rhinoplasty: Part II. Homologous grafts and rhinoplasty indexes.18 This can be one of the major distinctions of allogenic implants. Plast Reconstr Surg. 2010; 125: 99e – 109e. this study, which has shown favorable results. The significant dif- 15. Peled Z, Warren A, Johnston P. The use of alloplastic materials in rhinoplasty surgery: a meta-analysis. Plast Reconstr Surg. 2008; ferences in evaluated aesthetic indexes and their change towards 121: 85 – 92. ideal values can lead to a better understanding of the outcome 16. Romo T, Choe KS, Sclafani AP. Secondary cleft-lip rhinoplasty measurement of this type of analysis. utilizing porous high-density polyethylene. Facial Plast Surg. Our follow up period (25.2 ± 4.9 months) seems to be adequate 2003; 19: 369 – 377. 17. Nolst Trenité GJ, Gilbert J. Considerations in ethnic rhinoplasty. for preliminary reports, however, longer follow up is needed to Facial Plast Surg. 2003; 19: 239 – 246. evaluate major concerns with Medpor, extrusion, and irradiated 18. Sadeghi M, Saedi B,Sazegar AA. The role of columellar struts to rib cartilage, its re-absorption.15 Our results cannot disclaim the gain and maintain tip projection and rotation: a randomized blinded use of other graft materials, such as concha or rib cartilage, and trial. Am J Rhinol Allergy. 2009; 23: 223 – 229. 19. Kim YH, Kim BJ, Jang TY. Use of porous high-density polyethylene the calvarias graft as good material sources for augmentation rhi- (Medpor) for spreader or extended septal graft in rhinoplasty: noplasty. aesthetics, functional outcomes, and long-term complications. Ann Correction of a saddle nose is a challenging procedure. Despite Plast Surg. 2011; 67: 464 – 468. the superiority of autogenous materials in nose reconstruction, 20. Park JY, Kim SG, Baik SM, Kim SY. Comparison of genioplasty using Medpor and osteotomy. Oral Surg Oral Med Oral Pathol lack of safe materials in revision rhinoplasty cases present chal- Oral Radiol Endodontics. 2002; 109: e26 – e30. lenges to surgeons. This study proposes the safety and efficiency

238 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 F. Ismail-Beigi

Review Article Pathogenesis and Glycemic Management of Type 2 Diabetes Mellitus: A Physiological Approach

Faramarz Ismail-Beigi MD PhD•1

Abstract Type 2 diabetes (T2DM) is an incompletely understood chronic, progressive multifactorial disease with insulin resistance and decreased β-cell function playing dominant roles in its genesis. The worldwide incidence of the disease is rapidly increasing to pandemic proportions. The increase in incidence of T2DM is attributable to changes in lifestyle, diet and obesity, but other causes remain to be defined. The disease is a major cause of early mortality due to atherosclerosis and cardiovascular disease (CVD), and is the leading cause of blindness, leg amputations, and chronic renal disease. Hyperglycemia inT2DM becomes manifest once insulin secretion is no longer adequate for the metabolic demands of the individual. The approach to glycemic management of the disease is increasingly based on understanding the underlying pathophysiology. Efforts to maintain and preserve β-cell function during the earlier phases of the disease may have important implications in prevention of subsequent complications of T2DM. Finally, the approach to glycemic management of the disease should be individualized by considering the psycho-socio-economic condition of each patient, and glycemic targets should reflect presence of comorbid conditions, age of the patient, the stage of their disease in terms of duration, presence of macro- and micro-vascular complications, and propensity for severe hypoglycemia.

Keywords: β-cell number, disposition index, glycemic target range, insulin resistance

Cite the article as: Ismail-Beigi F. Pathogenesis and Glycemic Management of Type 2 Diabetes Mellitus: A physiological Approach. Arch Iran Med. 2012; 15(4): 239 – 246.

Introduction Pathophysiology and natural history of T2DM T2DM is a chronic, progressive metabolic disease defined by glance at the Centers for Disease Control and Prevention the presence of hyperglycemia. The disease is incompletely un- website (http://www.cdc.gov/media/pressrel/2010/r101022. derstood and represents a complex metabolic condition. It is char- Ahtml) stating that the number of persons in the United States acterized by hyperglycemia, insulin resistance, decreased β-cell with type 2 diabetes mellitus (T2DM) will double or triple by numbers and maximal secretory function, increased glucagon se- 2050, or at the diabetes map of the world by International Diabe- cretion and hepatic glucose production, hypertension, abnormali- tes Federation (http://www.diabetesatlas.org/) convincingly ties in adipocyte and lipid metabolism, decreased incretin effect, shows the unfortunate and pandemic nature of T2DM. The in- rapid gastric emptying, increased appetite, obesity, systemic increase in incidence of T2DM is attributable to changes in lifestyle, flammation, elevated cytokines, hypercoagulation, and endothe- diet and obesity, but other causes such as the roles of pollutants lial cell dysfunction.6–9 and environmental toxins remain to be further defined.1 In a sur- Underlying the abnormal glucose homeostasis in T2DM is re- vey of the 10 leading risk factors for death among countries strat- sistance to some actions of insulin (importantly stimulation of ified according to their income levels, high blood glucose and glucose transport and suppression of hepatic glucose release), overweight or obesity ranked 3rd and 5th, respectively, and high inadequate secretion of insulin to match metabolic needs, and blood glucose ranked 5th or 6th in low-, middle-, and high-income increased production of glucose by the liver. A schematic of the countries, repsectively.2 T2DM is the leading cause of blindness, natural history of T2DM is depicted in Figure 1A. Insulin resis- non-traumatic lower limb amputation, and chronic kidney disease tance (the inverse of insulin-sensitivity) is commonly increased requiring dialysis or renal replacement. In addition, the major in the “pre-diabetes” phase, but normal glucose levels are main- cause of early mortality in patients with T2DM is attributable to tained as long as β-cells can secrete higher amounts of insulin.10 progressive atherosclerosis and cardiovascular disease (CVD).3,4 However, although during the pre-diabetes phase insulin secretion T2DM is a major contributor to the very large rise in the rate of is stimulated, the levels are less than what is needed; this reflects non-communicable diseases affecting developed as well as devel- decreases in responsiveness of β-cells to glucose and in maximal oping nations.5 The current and future burden of T2DM on health β-cell secretory capacity. There is also decreased responsiveness status, life span of individuals, and personal and societal cost can- of the liver to insulin (to suppress glucose production by gluco- not be over-stated. neogenesis and glucose release by glycogenolysis), and increased resistance of muscle to insulin (to stimulate glucose uptake); the Author’s affiliation:1 Departments of Medicine and Biochemistry, Case Western resistance to actions of insulin in peripheral tissues, including Reserve University, Cleveland, Ohio 44106-4951. adipocytes, reflect post-receptor defects in the insulin-signaling •Corresponding author and reprint: Faramarz Ismail-Beigi MD PhD, Depart- ments of Medicine and Biochemistry, Case Western Reserve University, Cleve- pathway. land, Ohio 44106-4951, Tel: (216)368-6122, E-mail: [email protected]. Of clinical significance is the decrease in the number of β-cells Accepted for publication: 21 December 2011 in islets of patients with T2DM (Figure 1B), and a decrease in

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 239 Glycemic Control in T2DM

Natural History of Type 2 Diabetes 3

350 Post-meal glucose Pre Diabetes Diabetes Obese 300 Postmeal Glucose (IFG, IGT) 250 Lean Fasting glucose 200 2 150 100 Glucose (mg/dL)Glucose 50 cell Volume (%) Volume cell - 250 β 1 200 Insulin resistance 150 100

50 Maximal β- Insulin level Relative cell functional capacity 00 0 Relative amount(%) Relative --15 --10 -5 0 55 10 15 20 25 30 NGT NGT IFG T2DM Years

Adapted from: Kendall DM, et al. Am J FigureMed, 2009;122:S37 1A. -50. Figure 1B.

300

250 10 9 8

7 200 6 5 4 D (relative units)(relative 150 3 C 2 E A B Acute InsulinSecretion Acute 1 0 100 0 5 10 AIR AIR (µU/mL) Insulin Sensitivity Index 50 (relative units)

0 NGT IGT DIA

Figure 1C. Figure 1D.

Figure 1. Natural history of T2DM: central role of β-cell function. A) An idealized drawing of the natural history of T2DM. Adapted from Kendall DM, et al.10 The vertical dotted line at year 0 depicts the time of diagnosis. Top: Post-meal glucose rises before time 0 (Pre-diabetes), and both post-meal and fasting glucose rise over time after diagnosis (Diabetes). Bottom: Insulin resistance rises and may remain relatively constant over time, whereas the high insulin levels prior to diagnosis (which is not adequate for the level of pre- and post-prandial glycemia) slowly fall with progression of the disease. β-cell function (maximal secretory capacity) deteriorates over time and is ~50% of normal (or less) at diagnosis. B) Relative β-cell volume. Data are from Butler et al.11 β-cell volume (as an indicator of β-cell mass) is increased in obese individuals with normal glucose tolerance (NGT), perhaps as an adaptation to greater insulin requirement; mean ± SE. Obese individuals with impaired fasting glucose (IFG) have a decrease in β-cell volume, which is further decreased in T2DM. C) β-cell function in T2DM. Redrawn from Weyer et al.13 The acute insulin response to a bolus of intravenous glucose is from a longitudinal study of a cohort of Pima Indians who developed T2DM over time (NGT = normal glucose tolerance; IGT = impaired glucose tolerance; DIA = T2DM). In comparison with Panel B, β-cell function is decreased more than relative β-cell volume. D) Insulin secretion as a function of insulin sensitivity. The solid line (also identified as the disposition index) depicts the values derived from a population of normal individuals. Of note, the parameters vary several-fold on either axis. Inheritance appears to play a dominant role in the degree of insulin secretion and insulin sensitivity, while differences in body fat content also have an important role in the variability in insulin sensitivity. In addition to the distribution shown in populations, adaptive changes can also occur in individuals. For example, a person at point A who develops an increase in insulin sensitivity (perhaps due to exercise and loss of fat mass) and moves to point B, or a person who develops a decrease in insulin sensitivity and moves to point C can maintain euglycemia as long as they remain on the normal distribution curve. However, normal persons with low insulin sensitivity and high insulin secretion may be limited in their adaptive response, and a further decrease in their sensitivity to insulin (as seen during the last trimester of a normal pregnancy, following gain in body fat, or use of excessive glu- cocorticoids) if not matched by an increase in insulin secretion may lead to hyperglycemia. Finally, a person at point D who develops a decrease in insulin sensitivity plus a decrease in insulin secretion (and moves to point E) is prone to T2DM or has developed the disease (dotted line). maximal insulin secretory capacity per β-cell.11,12 Examination of The β-cell failure, which is also age-related, is mediated by a com- Figure 1B based on autopsy results, and taking into account that bination of genetic factors, exposure to elevated levels of glucose means ± SE are shown, one can readily see that there is tremen- and free fatty acids in blood (gluco- and lipo-toxicity, respective- dous variation in the number of β-cells among normal individuals. ly), possibly deposition of amyloid fibrils in islets, and increased Of note, relative β-cell volume varies greatly (5 to 7-fold) among demand to secret more insulin in response to ambient hypergly- normal individuals and in each of the categories shown in the fig- cemia. It is noteworthy that the bulk of the currently described ure; the large variation in relative β-cell volume is most likely an genetic abnormalities associated with T2DM are related to β-cell inherited trait that may be modified by intrauterine milieu during function.16,17 The critical role of β-cell failure in the development gestation.11,12 One can also see that there are increased numbers of of T2DM has significant implications in the management of the β-cells in obese persons (perhaps an adaptive response), and there disease. are decreasing numbers of β-cells in individuals with pre-diabetes Examination of Figure 1D is also of great interest. The figure and T2DM. Based on longitudinal studies on Pima Indians,13 in shows the relationship between insulin secretion and insulin sen- addition to other studies,14 there is at least a 50% loss of maximal sitivity in normal euglycemic individuals. Critical to our under- β-cell function at the time of diagnosis of T2DM6,15 (Figure 1C). standing is the fact that there is great variation in insulin secretion

240 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 F. Ismail-Beigi as well as in insulin sensitivity among normal individuals. The is essential.31,32 Moreover, given the multiple abnormalities that underlying causes for this vast variation are unclear; most of the underlie the hyperglycemia of T2DM, simultaneous control of the variation is not explained by adiposity and probably reflects ge- different pathways might be advantageous. netic or epigenetic factors. Although the figure depicts the relationship among different normal individuals, each person has the Considerations for setting glycemic targets ability of moving left or right on the x-axis (insulin sensitivity). An important first step in glycemic management is setting an ap- For example, a person who gains weight may have a decrease propriate glycemic target for each individual patient with T2DM. in his or her insulin sensitivity, but will continue to have normal The current guidelines specify general A1C targets of < 7.0% or < blood glucose levels as long as insulin secretion increases. Hence, 6.5%.18,33 However, the critical role of patient-specific psychologi- T2DM represents a condition where insulin secretion is much less cal, social, and economic conditions and the patient’s capacity for than what is needed, given the degree of insulin resistance in the self-management in choosing an appropriate glycemic target can- individual. not be overemphasized.34 Issues to be considered include safety of the recommended strategy, especially in those with a higher Diagnosis and evaluation risk for severe hypoglycemia. More intensive treatment usually The diagnosis of T2DM, as currently outlined by the Ameri- means use of a higher number and dosages of medications result- can Diabetes Association (ADA), is based on an A1C ≥ 6.5%, ing in increasing adverse effects and cost. The psychological and or fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L), or cognitive status of the patient constitutes important determinants 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral of whether the treatment plan will be successful.34,35 Hence, evalu- glucose tolerance test, or the presence of classical symptoms of ation of the psychological state and a mini-mental exam are use- hyperglycemia and a random plasma glucose ≥ 200 mg/dL.18 Di- ful. The financial cost of the prescribed treatment plan needs to be agnostic measures recommended by the American Association of considered. Finally, the ultimate goal of enhancing the patient’s Clinical Endocrinologists (AACE) considers an A1C ≥ 6.5% to be quality of life must not be forgotten, and glycemic targets should an optional criterion.19 be adapted to changes in the patient’s health and living conditions. Patients with newly-recognized T2DM often have had a slow The presence of other severe comorbid conditions that are de- progression of the disease for a few to many years prior to diagno- bilitating and could interfere with implementation of the manage- sis. Evaluation of patients with T2DM should include past history ment strategy should be targeted to higher A1C levels (Table 1). of CVD, and family history of T2DM and CVD. Blood pressure Here the goal is prevention of large glycosuria, water and electro- (BP), BMI, physical activity, diet, comorbidities, renal function, lyte loss, infections, and development of non-ketotic hyperosmo- presence of microalbuminuria, retinopathy, or neuropathy, serum lar coma. In general, the higher the age of the patient and the lon- cholesterol LDL, HDL, and TG, and smoking status should be ger the duration of the disease, the more significantly established evaluated. is the atherosclerotic process and microvascular derangements, which portend less benefit from intensive glycemic treatment. In- The goal of glycemic control tensive treatment of glycemia in patients with T2DM, especially The overall aim of glycemic management is to prevent long- with insulin or sulfonylureas, can result in episodes of severe hy- term macrovascular and microvascular complications of T2DM poglycemia. Older patients with low cognitive function are prone while avoiding (or at least greatly minimizing) episodes of se- to develop severe hypoglycemia, and dementia has been reported vere hypoglycemia (defined as episodes requiring third-party with episodes of severe hypoglycemia.36,37 Severe hypoglycemia assistance), and enabling a good quality of life. Evidence from in patients with T2DM and CVD may lead to myocardial isch- large randomized trials both in type 1 diabetes and newly-recog- emia, and may increase the risk of myocardial infarction, cardiac nized20–22 or established T2DM23–27 show that control of glycemia arrhythmias, or sudden death.38,39 The intensity of glucose control delays onset and slows progression of microvascular complica- should be immediately relaxed by an average of ~45–60 mg/dL tions of diabetes, including nephropathy, retinopathy, and neu- (~1.5% to 2.0% HbA1C)40 for at least several weeks following ropathy. On the other hand, recent trials that have been conducted a severe hypoglycemic episode. Further relaxation of glycemic in older patients with established T2DM and a history of CVD goals for more prolonged periods should be considered follow- or one or more risk factors for CVD have found no reduction in ing 2 or more episodes. The glycemia target in patients with “hy- total mortality or CVD-related mortality from intensive lowering poglycemia unawareness” should be markedly relaxed for a very of glucose to normal or near-normal glycemic levels compared prolonged period, awaiting the potential reversal of the condition. to standard glycemic control. They also reported higher rates of Figure 2 summarizes the influence of clinical features on selec- severe hypoglycemia and weight gain with intensive treatment. tion of an A1C target for a specific patient from a spectrum of 24,25,28,29 However, long-term follow-up of patients with newly- A1C goals.34 In general, the evidence suggests that in younger diagnosed T2DM whose hyperglycemia had previously been patients with recently-recognized T2DM and little (or no) com- treated intensively resulted in reduced CVD events.30 Clearly, the plications, near-normal glycemic targets aimed at prevention of benefits derived from intensive glycemic control must be weighed complications over many years of life can be suggested. In con- against risks for each individual patient. trast, in older individuals with established T2DM and evidence While this article is specifically focused on glycemic manage- of CVD (or multiple CVD risk factors), somewhat higher targets ment of T2DM, it is critical to appreciate that T2DM is a complex may be more appropriate. metabolic condition, and that glycemic control is only one facet The glycemic goal for each patient should be individualized and of the proper management of T2DM. Hence, a multifactorial ap- take into consideration their psycho-socio-economic condition proach aimed at control of all known risk factors for development and a spectrum of A1C values rather than a set A1C number.34 of CVD and microvascular disease as well as life-style changes Individualization of the target range according to the presence of

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 241 Glycemic Control in T2DM

Figure 2. Suggested glycemic treatment goals in patients with T2DM.§ The figure depicts glycemic goals and treatment intensities with increasing severity or magnitude of clinical parameters, as well as with increasing limitations in the psycho-socio-economic context. The increasing height of the triangles reflects increases in the considered parameter. The positions of the triangles in the figure are not meant to represent their relative importance in setting glycemic targets. § While there is a strong positive correlation between HbA1C and mean blood glucose levels in populations, there is also significant individual variation as well as variation in populations (for a variety of medical, non-medical, and unknown reasons) both between glucose levels at a given HbA1C and HbA1C values at a given average blood glucose level.38 The figure is adapted from Ismail-Beigi et al.34 severe comorbid conditions, age of the patient, the stage of their a few to several months. disease both in terms of duration and presence of macro- and micro-vascular complications, and propensity for severe hypogly- Medical approaches cemia should be considered (Figure 2).34 Different classes of pharmaceutical agents available for glycemic management of T2DM, the expected reductions in A1C, their General glycemic treatment considerations mechanism of action, effects, and their potential advantages and Ideal strategies for effective long-term glycemic control place disadvantages are listed in Table 2.47–61 The list has greatly ex- the patient at the center of the decision-making process. Time de- panded in the past two decades. Because the various medications voted to education and dialogue is required to achieve goals. The are listed in multiple publications and reviews, they will only be important roles that nurses, nutritionists, certified diabetes educa- briefly reviewed here.62–64 Insulin and its analogs, used either tors, and other staff play in this process cannot be overempha- singly or in combination with other medications, continue to be sized. A balanced diet rich in fiber, with control of total calories the strongest agent in reducing glycemia. However, insulin use is and free carbohydrates should be advocated.32,41 Exercise has an also associated with a high risk for severe hypoglycemia. In early independent and additive effect to a proper diet and weight loss to mid-stages of T2DM, addition of bedtime long-acting insulin program on glycemic control.42–44 Smoking cessation should be (starting with 10–15 units and titrating up by 2–3 units every 4–7 emphasized. Much success, at lower cost and greater satisfaction, days) can reduce A1C by 1.5%–2.0%, or more. 47,50,65–67 Use of has been reported with the use of telecommunication and comput- short-acting and long-acting analogs is more popular than human er-based data transfer systems.45,46 regular insulin or NPH, but very strong evidence in their favor is The rapidity of reaching the glycemic target range needs consid- lacking. Metformin is the cornerstone of treatment of T2DM; it is eration. Although there are no set rules, several parameters appear generally well tolerated, has few side effects, and rarely causes se- important, including the fact that the disease is chronic and that vere hypoglycemia.18,33,53 Sulfonylurias constitute a popular class adaptive changes to the hyperglycemic state have taken place; the of oral medications; their efficacy becomes limited over years, level of hyperglycemia, the capabilities and wishes of the patient and their use, especially in patients with compromised renal func- based on knowledge and understanding, the degree of acceptance tion, is associated with severe hypoglycemia. Glinides have a for frequent self glucose-monitoring, and their ability to prevent short duration of action (hours) and are most effective when used severe hypoglycemic events constitute other important consider- pre-prandially. GLP-1 agonists (given by injection) and oral DPP- ations. It is often prudent to achieve the A1C target in stages over 4 inhibitors are newer insulin-providing agents; they are unique in

242 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 F. Ismail-Beigi

Table 1. Patient-specific clinical features considered in defining glycemic targets. 1) Severe comorbid conditions 2) Age 3) Duration of T2DM 4) Presence of CVD 5) Presence of microvascular complications 6) History of severe hypoglycemia

Table 2. Pharmacological agents for treatment of type 2 diabetes. Expected reduction Advantages (A) Class Agents Mechanism Effects in A1C Disadvantages (D) (%)

Insulin-providing

Short-acting: Human insulin, Activate ↑ glucose disposal Aspart, Humalog, Glulisine (A) Effective in all patients; large effect. 1.0–2.5 insulin ↓ gluconeogenesis Insulin Long-acting: NPH, Glargine, (D) Severe hypoglycemia; injection; cost, receptors ↓ lipolysis, proteolysis, and Detemir weight gain. ketogenesis Mixed insulin preparations

↑ insulin secretion, mostly Glyburide, Glipizide, 1.0–2.0 Close K (A) Oral agents; not expensive. Sulfonylurea ATP in response to an increase Glimepiride channels (D) Severe hypoglycemia; durability. in plasma glucose

↑ insulin secretion, mostly (A) Oral agents; not expensive; short 0.5–1.0 Close K in response to an increase Glinide Repaglinide, Nateglinide ATP duration of action; hepatic clearance. channels in plasma glucose, short (D) Efficacy; severe hypoglycemia. duration of action

↑ insulin secretion (A) Rare severe hypoglycemia; weight loss. Activate ↓ glucagon secretion (D) Injections; cost; nausea and vomiting; GLP-1 agonist Exenetide, Liraglutide 0.5–1.5 GLP-1 ↑ satiety, delays gastric ? pancreatitis; ? c-cell tumors of thyroid; ? receptors emptying long-term safety.

Sitagliptin, Saxagliptin, Inhibit DPP-4 ↑ endogenous GLP-1, (A) Oral agents; rare severe hypoglycemia. DPP-4 inhibitor Vildagliptin, others being 0.5–0.8 enzyme ↑ insulin secretion, (D) Less efficacy; cost; ? pancreatitis; ? developed ↓ glucagon secretion long-term safety.

Insulin - nsitizing

(A) Oral agent; rare hypoglycemia; well- Activate ↓ hepatic glucose Biguanide Metformin 1.0–2.0 tolerated; safe; inexpensive; durability. AMPK production (D) GI intolerance.

Activate (A) Oral agent, ? reduced CVD. PPAR-γ ↑ insulin sensitivity in (D) Side effects including edema, heart Thiazolidinedione Pioglitazone 0.5–1.4 nuclear muscle and liver failure, weight gain, fractures; ? bladder receptors cancer

Other

Activate ↓ glucagon secretion Amylin analogue Pramlintide 0.5–1.0 amylin (A) Weight loss. ↑ satiety, delays gastric receptor (D) Injection; nausea and vomiting; cost. emptying

Inhibit α-glucosidase Acarbose, Miglitol 0.5–0.9 α-glucosidase (A) Oral agents. ↓ carbohydrate absorption inhibitor in the small (D) Gas production. intestine

Bile acid Bind bile Colesevelam ~0.5 Not known (A) Lowers cholesterol. sequestrant acids (D) GI tolerance; efficacy; cost.

Activate D2- Alters hypothalamic control D2-dopamine (A) Oral agent; long-acting available Boromocriptine (rapid release) ~0.5 dopaminergic of insulin sensitivity in agonist (D) efficacy; some GI side effects; cost receptors peripheral tissues

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 243 Glycemic Control in T2DM their suppression of glucagon secretion. Control of appetite with ment of the disease should be individualized by considering the weight loss of a few to several kilograms can be associated with psycho-socio-economic condition of each patient, and glycemic the use of GLP-1 agonists. The long-term safety of these newer targets should reflect presence of severe comorbid conditions,age agents is under study. Pioglitazone acts to increase insulin sen- of the patient, the stage of their disease both in terms of duration sitivity; untoward side effects include weight gain, edema, heart and presence of macro- and micro-vascular complications, and failure, and risk of fractures, especially in women.60 Additional propensity for severe hypoglycemia. less frequently used agents are listed under “Other” in Table 2. Given the multiple pathogenic mechanisms of T2DM, use of References multiple agents with complementary modes of action to control glycemia, and if possible, preserve β-cell function before it reach- 1. Hardoon SL, Morris RW, Thomas MC, Wannamethee SG, Lennon LT, es critically low levels can be considered; however, convincing Whincup PH. Is the recent rise in type 2 diabetes incidence from 1984 68,69 to 2007 explained by the trend in increasing BMI? Diabetes Care. evidence for beneficial effects of this approach is lacking. The 2010; 33: 1494 – 1496. recommended choice of combination of agents depends on the 2. Narayan KMV, Ali MK, Koplan JP. Global noncommunicable disease stage of the disease and the degree of β-cell dysfunction. Effec- – where world meet. N Engl J Med. 2010; 363: 1196 – 1198. tive combinations include metformin plus long-acting insulin at 3. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in bedtime, and metformin plus a DPP-4 inhibitor, a GLP-1 agonist, nondiabetic subjects with and without prior myocardial infarction. N a glinide, or pioglitazone. Metformin plus a sulfonylurea is a less Engl J Med. 1998; 339: 229 – 234. desirable, but commonly used combination. Long-acting insulin 4. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting plus a glinide can also be considered. Insulin is often added much blood glucose concentration, and risk of vascular disease: a collab- 47,53,67 orative meta-analysis of 102 prospective studies. Lancet. 2010; 375: later than medically indicated. 2215 – 2222. 5. Beaglehole R, Bonita R, Alleyne G, Horton R, Li L, Lincoln P, et al. Surgical approaches for glycemic control Lancet NCD Action Group. UN High-Level Meeting on Non-Com- municable Diseases: Addressing four questions. Lancet. 2011; 378: Bariatric surgery, and the resultant large weight loss, has prov- 449 – 455. en to be a highly effective mode of treatment for T2DM in very 6. DeFronzo R. From the triumvirate to the ominous octet: a new para- obese individuals.70,71 Different gastric bypass and gastric limiting digm for the treatment of type diabetes mellitus. Diabetes. 2009; 58: procedures differ in their efficacy for treatment of diabetes, and 773 – 795. 7. Boden G, Chen X, Stein TP. Gluconeogenesis in moderately and the mechanisms underlying their effect on glucose homeostasis is severely hyperglycemic patients with type 2 diabetes mellitus. Am J under investigation. In general, procedures that greatly limit the Physiol. 2001; 280: E23 – E30. absorptive surface are the most efficacious but also have the high- 8. Færch K, Vaag A, Holst JJ, Hansen T, Jørgensen, T, Borch-Johnson est rates of complications.71 The potential long-term untoward ef- K. Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glyce- fects of these procedures are being determined. mia and impaired glucose tolerance: the Inter99 Study. Diabetes Care. 2009; 32: 439 – 444. Unknowns and areas to be explored 9. Lorenzo C, Wagenknecht L, D’Agostino R, Rewers M, Karter A, The underlying cause(s) of accelerated CVD in T2DM, and the Haffner S. Insulin resistance, β-cell dysfunction, and conversion to type 2 diabetes in a multiethnic population. Diabetes Care. 2010; 33: role of glycemic control in this process remain to be fully deter- 67 – 72. mined. A better understanding of the genetic and environmental 10. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of factors underlying the large variation in insulin resistance and incretin-based therapy: therapeutic potential, patient selection, and β-cell number and function in normal persons is critical to strate- clinical use. Am J Med. 2009; 122: S37 – S50. 11. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. gies to prevent and more effectively treat T2DM. Given the mil- β-cell deficit and increased β-cell apoptosis in humans with type 2 lions of people who will be newly-diagnosed with T2DM in the diabetes. Diabetes. 2003; 52: 102 – 110. next two decades, it is critical that evidence favoring treatment 12. Rahier J, Guiot Y, Goebbels RM, Sempiux C, Henquin JC. Pancreatic 69 β-cell mass in European subjects with type 2 diabetes. Diabetes Obes modalities that help preserve β-cell function be generated. While Metab 2008; 10 (suppl 4): 32 – 42. there is general agreement on the first-line use of metformin, evi- 13. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of dence is lacking to inform the superiority of the additional agents insulin secretory dysfunction and insulin resistance in the pathogen- to be employed in conjunction with metformin. More information esis of type 2 diabetes mellitus. J Clin Invest. 1999; 104: 787 – 794. 14. U.K. Prospective Diabetes Study Group. U.K. prospective diabetes is necessary on setting of appropriate glycemic targets and how study 16. Overview of 6 years’ therapy of type II diabetes: a progres- best to individualize therapy. Finally, assessment of long-term sive disease. Diabetes. 1995; 44: 1249 – 1258. safety of GLP1 agonists and DPP-4 inhibitors should be provided. 15. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia. 2001; 44: 929 – 945. Conclusion 16. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. T2DM is an incompletely understood multifactorial disease with Meta-analysis of genome-wide association data and large-scale repli- insulin resistance and decreased β-cell function playing dominant cation identifies additional susceptibility loci for type 2 diabetes. Nat roles in its genesis. Hyperglycemia in T2DM becomes manifest Genet. 2008; 40: 638 – 645. 17. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch once insulin secretion by β-cells is no longer adequate for the RP, et al. Twelve type 2 diabetes susceptibility loci identified through metabolic demands. The approach to glycemic management of large-scale association analysis. Nat Genet. 2010; 42: 579 – 589. the disease is evolving and increasingly based on understanding 18. American Diabetes Association. Standards of Medical Care in Diabe- the underlying pathophysiological disturbances. Efforts to main- tes—2011. Diabetes Care. 2011; 34: S11 – S61. 19. American Association of Clinical Endocrinologists Board of Di- tain and preserve β-cell function during the earlier phases of the rectors, American College of Endocrinologists Board of Trustees. disease may have implications in prevention of subsequent com- AACE/ACE statement on the use of hemoglobin A1C for the diagnosis plications of T2DM. 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Mezuk B, Eaton WW, Albrecgt S, Golden SH. Depression and type fect of antihyperglycemic agents added to metformin and a sulfonyl- 2 diabetes over the lifespan: a metaanalysis. Diabetes Care. 2008; 31: urea on glycemic control and weight gain in type 2 diabetes: a network 2383 – 2390. meta-analysis. Ann Intern Med. 2011; 154: 672 – 679. 36. Bonds DE, Miller ME, Bergenstal R, Buse JB, Byington RP, Cutler J, 60. Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of et al. The relationship between severe hypoglycemia and mortality in thiazolidinediones: systematic review and meta-analysis of observa- type 2 diabetes: The ACCORD Study. BMJ. Epub 2010. tional studies. BMJ. 2011; 342: d1309. 37. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hy- 61. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan poglycemic episodes and risk of dementia in older patients with type 2 AY, et al. Use of twice-daily exenatide in Basal insulin-treated pa- diabetes mellitus. 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65. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatter- 68. Leahy JL, Hirsch IB, Peterson KA, Schneider D. Targeting β-cell jee R, et al. Comparative effectiveness and safety of medications for function early in the course of therapy for type 2 diabetes mellitus. J type 2 diabetes: An update including new drugs and 2-drug combina- Clin Endocrinol Metab. 2010; 95: 4206 – 4216. tions. Ann Intern Med. 2011; 154: 602 – 613. 69. Nyalakonda K, Sharma T, Ismail-Beigi F. Preservation of beta cell 66. Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander P. A function in type 2 diabetes. Endocr Practice. 2010: 16: 1038 – 1055. stepwise approach to insulin therapy in patients with type 2 diabetes 70. Sjostrom L, Lindroos AK, Peitonene M, Torgerson J, Bouchard C, mellitus and basal insulin treatment failure. Endocr Pract. 2011; 17: Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 395 – 403. 10 years after bariatric surgery. N Eng J Med 2004; 351: 2683 – 2693. 67. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, et al. 71. Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, Comparison of bedtime insulin regimens in patients with type 2 dia- et al. Weight and type 2 diabetes after bariatric surgery: systematic betes mellitus: a randomized, controlled trial. Ann Intern Med. 1999; review and meta-analysis. Am J Med. 2009; 122: 248 – 256. 30: 389 – 396.

246 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 P. Hu, J. Wang, M. Zhang, et al.

Brief Report Liver Involvement in Melamine-associated Nephrolithiasis

Peng Hu MD•1, Jing Wang MD1, Min Zhang MD1, Bo Hu MD1, Ling Lu MD1, Chuan-Rong Zhang MD1, Peng-Fei Du MD1

Abstract It is currently believed that melamine ingestion can lead to insoluble crystals in an animal’s urinary system with subsequent physical obstruction or bladder carcinoma. However, whether melamine can cause injury of other tissues and organs in humans is yet unknown. In this study, we encountered 3 affected children with liver lesions, 2 males and 1 female, and detailed their clinical characterizations. Their ages were respectively 2, 6, and 10 months. Among the 3 patients with liver lesions, only 1 exhibited symptoms of gradual progressive jaundice, abdominal distention, hepatic intumesce, and bilirubin abnormality; the other 2 were asymptomatic. The mechanism associated with liver lesion may, at least in part, be due to physical deposition and blockage of the biliary tract system. Disturbance of the acid-base equilibrium may be another reason that accelerates stone formation in human tissues.

Keywords: Alanine aminotransferase, child, liver lesion, melamine, nephrolithiasis, ultrasonography

Cite the article as: Hu P, Wang J, Zhang M, Hu B, Lu L, Zhang CR, Du PF. Liver Involvement in Melamine-associated Nephrolithiasis. Arch Iran Med. 2012; 15(4):247 – 248.

+ + - - Introduction electrolytes (K , Na , Cl , and HCO3 ) were determined. Anion + + - - gap (AG) was calculated as AG = (Na + K )-(Cl + HCO3 ). Uri- ince the outbreak of the “Melamine Milk Crisis” in Sep- nary and hepatic ultrasonography was performed in all 3 chil- tember 2008, many clinical and experimental investiga- dren. Since most melamine-associated nephrolithiasis were small S tions have revealed some common aspects of childhood or sand-like, and none of our patients were in serious condition, urinary stones induced by melamine tainted formula.1 We have simple conservative managements were adopted, that included previously described the correlation between stone formation and fluid infusion, urine alkalinization, increased water intake, and exposure history in 49 children with melamine-associated nephro- increased urination. lithiasis, and found that the size of melamine-induced stones was dependent on the melamine content of the formula ingested, but Results not on the duration of exposure.2 However, whether melamine can cause injury of other tissues and organs in humans is yet un- There were 3 children, 2 males and 1 female, diagnosed with known.3 Here, we retrospectively review the clinical data of these liver lesions (ALT > 40U/L, and/or AST > 40U/L, and/or GGT > patients and encounter 3 affected children with liver lesions. 50U/L). Their ages were 2, 6, and 10 months. None suffered from any of the following infections: TORCH, HAV, HBV, HCV, EBV, Materials and Methods HIV, and SY. In addition, other common or uncommon diseases, such as biliary atresia, progressive familial intrahepatic cholesta- A total of 49 children who suffered from melamine-associated sis, metabolic liver disease, and idiopathic neonatal hepatitis nephrolithiasis were recruited into our study from September to were ruled out. The other 46 patients who had no liver involve- December 2008. All patients ranged in age from 1 to 96 months, ment ranged in age from 1 to 96 months, with a mean of 23 ± 7.8 with a mean of 25 months. There were 32 males and 17 females. months. There were 30 males and 16 females. The median age at History of exposure to contaminated formula (formula brand, diagnosis was significantly earlier in children with liver lesions melamine content, duration of consumption, use of formula alone, (P < 0.05), while the male/female ratio was identical in the two or in combination with breast milk) was documented. The content groups (P > 0.05). of melamine was estimated according to the report by the General Most affected children were asymptomatic (15 cases; 30.6%). Administration of Quality Supervision, Inspection, and Quaran- Three main clinical presentations, including unexplained crying tine of China (GAQSIQC).4 Urinalysis, renal function [blood urea when urinating (9 cases) was seen in 18.4%, oliguria (8 cases) nitrogen (BUN), creatinine (Cr), and uric acid (UA)], liver sta- in 16.3%, and abdominal pain (6 cases) was noted in 12.2% of tus [alanine aminotransferase (ALT), aspartate aminotransferase melamine-associated nephrolithiasis. Among 3 patients with liver (AST), total bilirubin, (TBIL), direct bilirubin (DBIL), indirect lesions, only 1 exhibited gradual progressive jaundice, abdominal bilirubin (IBIL), and γ-glutamyltransferase (GGT)], and serum distention, hepatic intumesce, and bilirubin abnormality; the other 2 were asymptomatic. Authors‘ affiliation: 1Department of Pediatrics, The First Affiliated Hospital of The clinical data of the 2 groups in this study are shown in Table Anhui Medical University, Hefei 230022, Anhui Province, China. 1. Higher ALT, AST, TBIL, DBIL, IBIL, and GGT were present in •Corresponding author and reprints: Peng Hu MD, Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, patients with liver lesions when compared to those without liver in- Hefei, 230022, Anhui Province, China. E-mail: [email protected]. volvement (P < 0.05), whereas for the duration of consumption and Accepted for publication: 2 November 2011 the diameter of nephrolithiasis, the opposite was found (P < 0.05).

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 247 Liver Lesions Associated with Melamine Exposure

Table 1. The clinical data of patients. Patients with liver lesions Patients without liver involvement Parameter P-value (n = 3) (n = 46) Melamine content (mg/kg) 1331.3 ± 1207.3 1295.3 ± 967.1 NS Duration of consumption (m) 5.7 ± 4.5 19.5 ± 6.3 <0.0001 Urine pH 5.8 ± 0.3 6.3 ± 0.6 NS BUN (μmol/L) 3.3 ± 0.6 4.7 ± 1.2 NS Cr (μmol/L) 14.3 ± 3.8 12.7 ± 8.9 NS UA (μmol/L) 221.0 ± 82.3 254.9 ± 74.8 NS ALT (U/L) 119.3 ± 72.5 25.2 ± 8.7 <0.0001 AST (U/L) 107.3 ± 50.2 35.6 ± 9.5 <0.0001 TBIL (μmol/L) 57.3 ± 90.6 4.7 ± 1.7 <0.0001 DBIL (μmol/L) 39.0 ± 63.2 2.9 ± 1.1 <0.0001 IBIL (μmol/L) 18.0 ± 27.5 1.3 ± 0.2 <0.0001 GGT (U/L) 58.7 ± 68.7 15.7 ± 2.3 <0.0001 K+ (mmol/L) 5.0 ± 0 4.5 ± 0.4 NS Na+ (mmol/L) 141.3 ± 4.9 139.5 ± 2.3 NS Cl- (mmol/L) 105.0 ± 5.2 103.4 ± 2.4 NS - HCO3 (mmol/L) 18.7 ± 0.6 19.4 ± 2.4 NS AG (mmol/L) 22.7 ± 0.6 21.2 ± 2.4 NS Diameter of nephrolithiasis (mm) 2.7 ± 2.2 6.5 ± 3.9 <0.0001 NS = not significant.

Discussion Conflict of interest statement The authors declare that they have no conflict of interest related Former research has mentioned liver involvement in melamine- to the contents of this manuscript. associated nephrolithiasis. In a report by Guan et al.,3 serum ALT levels were normal in all but 2 children, similar to our results, both Acknowledgments of who were also under 1 year of age. In addition, according to a report by Zhang et al.,5 5 children with urinary stones induced We are grateful to Professor Yuan Han Qin, Pediatrics Department, by melamine-tainted formula had liver abnormalities, which in- The First Affiliated Hospital of Guangxi Medical University for help- cluded hepatomegaly, elevated AST, and gallstones. These find- ful comments on this manuscript. We also sincerely thank the partici- ings were compatible with the observations from animal model pating children and their families for making this study possible. studies. In Chinese feeding studies where Roman laying hens were administrated melamine at 8.6~140.9 mg/kg for 34 days, References concentrations of melamine in the kidney were 1.3~21.7 mg/kg and in the liver concentrations reached 0.5~6.9 mg/kg.6 In our 1. Ding J. Childhood urinary stones induced by melamine-tainted for- study, the concentrations of ALT and AST in all 3 patients were mula: How much we know, how much we don’t know. Kidney Int. 2009; 75: 780 – 782. elevated to some extent. However, only 1 patient exhibited the 2. Hu P, Lu L, Hu B, Zhang CR. The size of melamine-induced stones significant manifestations of liver lesions, with gradually progres- is dependent on the melamine content of the formula fed, but not on sive jaundice, abdominal distention, hepatic intumesce, and bili- duration of exposure. Pediatr Nephrol. 2010; 25: 565 – 566. rubin abnormality. The mechanism associated with liver lesions is 3. Guan N, Fan Q, Ding J, Zhao Y, Lu J, Ai Y, et al. Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J unclear, but may, at least in part, be due to physical deposition and Med. 2009; 360: 1067 – 1074. blockage of the biliary tract system. Significantly elevated levels 4. Hu P, Wang J, Hu B, Lu L, Zhang M. Common features of melamine- of DBIL and GGT indicate the existence of obstruction. Distur- associated urinary stones: a summary of available information based bance of the acid-base equilibrium, such as higher AG and lower on biochemical and ultrasonographic evidence. J Trop Pediatr. 2011. [Epub ahead of print]. PMID: 21602229. urine pH, may be another reason that accelerates stone formation 5. Zhang L, Wu LL, Wang YP, Liu AM, Zou CC, Zhao ZY. Melamine- in human tissues.7 contaminated milk products induced urinary tract calculi in children. Because many children with identified stones were asymptom- World J Pediatr. 2009; 5: 31 – 35. atic, and liver status was not a part of routine screening, it was 6. Bai X, Bai F, Zhang K, Lv X, Qin Y, Li Y, et al. Tissue deposition and residue depletion in laying hens exposed to melamine-contaminated likely that there were many more cases with liver lesions not diets. J Agric Food Chem. 2010; 58: 5414 – 5420. brought to the attention of medical authorities. Also, many chil- 7. Wen JG, Li ZZ, Zhang H, Wang Y, Zhang RF, Yang L, et al. Melamine dren had small biliary tract stones undetectable by standard meth- related bilateral renal calculi in 50 children: Single center experience ods, which could have led to a possible underreporting of affected in clinical diagnosis and treatment. J Urol. 2010; 183: 1533 – 1537. 8. Gossner CM, Schlundt J, Ben Embarek P, Hird S, Lo-Fo-Wong D, 8 children. Therefore, liver involvement in melamine-associated Beltran JJ, et al. The melamine incident: Implications for international nephrolithiasis should be noted in future studies. food and feed safety. Environ Health Perspect. 2009; 117: 1803 – 1808.

248 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 Keify F, Zhiyan N, Mirzaei F, et al.

Case Report Two Novel Familial Balanced Translocations t(8;11)(p23;q21) and t(6;16)(q26;p12) Implicated in Recurrent Spontaneous Abortion

Fatemeh Keify MS1, Narges Zhiyan MD1,3, Farzaneh Mirzaei MS1, Semiramis Tootian MS1, Saeedeh Ghazaey MS1, Mohammad R. Abbaszadegan MT (ASCP) PhD1,2

Abstract Reciprocal translocations represent one of the most common structural rearrangements observed in humans. Estimates of the population frequency range from 1/673 to 1/1000. We have described two novel balanced translocations in two unrelated families who experienced Recurrent Spontaneous Abortions (RSA) following their separate non-consanguineous marriages. Initial cytogenetic studies were performed on cultured blood cells. High resolution GTG-banding analysis using cytovision software performed on their chromosomes revealed a novel balanced translocation t(8;11)(p23;q21) in a brother (45 years) and his sister (27 years) in one family. The second novel balanced translocation t(6;16)(q26;p12) was observed in a consanguineous couple with 4 RSA. These two families have an increased risk of having children with unbalanced karyotypes or RSA, because of incorrect chromosomal segregation during meiosis.

Keywords: Balanced translocation, karyotyping, t(8;11), t(6;16)

Cite the article as: Keify F, Zhiyan N, Mirzaei F, Tootian S, Ghazaey S, Abbaszadegan MR. Two Novel Familial Balanced Translocations t(8;11)(p23;q21) and t(6;16)(q26;p12) Implicated in Recurrent Spontaneous Abortion. Arch Iran Med. 2012; 15(4): 249 – 252.

Introduction Alternative segregation patterns for a reciprocal translocation results in unbalanced gametes, producing gametes with partial ecombinations in homologous chromosomes normally oc- trisomies and monosomies. Other segregation products may also cur during meiosis, with the exchange of various chromo- form, resulting in trisomies and monosomies or tetrasomies and R somal fragments producing different alleles with each nor- nullisomies. Studies using the sperm obtained from balanced mal chromosomal translocation. Reciprocal translocations are reciprocal translocation carriers have shown that approximately frequent structural rearrangements observed in humans where two equal numbers of alternate and adjacent segregants are generally different chromosomes exchange segments. Studies show that formed, and these two groups represent the most common types population frequency rates are between 1/673 to 1/1000.1,2 Indi- of segregant. The remaining segregants are infrequent. Corre- viduals with balanced reciprocal translocations are clinically nor- sponding data are not available for female carriers. Unlike studies mal; however, they have an increased risk of having progeny with on spermatocytes, it is difficult to obtain large numbers of oocytes unbalanced karyotypes with interference in the meiotic segrega- to analyze these translocations. However, female translocation tion of their abnormal chromosomes. carriers are capable of producing the same types of unbalanced All 23 sets of homologous chromosomes couple to form 23 segregants that have been reported in male carriers.3,4 paired linear structures or bivalents during normal meiotic pro- In this report ,two novel balanced translocations in two unrelated phase. These structures later separate and divide into different families were described .A balanced translocation involving chro- daughter cells. Reciprocal translocation results in 21 rather than mosomes 8 and 11 occurred in a family with a brother and a sister 23 bivalents in a cell. The reciprocal translocation and their nor- who experienced recurrent spontaneous abortions (RSA) follow- mal homologs form two other derivative chromosomes, a single ing their separate non-consanguineous marriages .The distal short pairing structure called a quadrivalent. Multiple ways of chromo- arm of chromosome 8 was replaced with the long arm on chro- somal segregation exist within a quadrivalent. Most of the gam- mosome 11 (p23;q21). The second novel balanced translocation etes that contain these chromosomal segregations have unbal- t(16;6)(q26;p12) was observed in a non-consanguineous couple anced translocations. Theoretically, normal chromosome comple- with four RSA. ments are present in 50% of the resulting gametes and the other 50% are carriers of balanced translocation. Case Report Authors’ affiliations: 1Pardis Clinical and Genetics Laboratory, Mashhad, Iran. 2Division of Human Genetics, Immunology Research Center, Avicenna Research Two families with different balanced translocations were exam- Institute, MUMS, Mashhad, Iran. 3Razavi’s Social Welfare Organization, Mash- ined. The first family was a 45-year-old man and his 27-year-old had, Iran. •Corresponding author and reprints: Mohammad R. Abbaszadegan MT sister who referred to Pardis Clinical and Genetics Laboratory, (ASCP) PhD, Division of Human Genetics, Bu-Ali Research Institute, Mashhad Mashhad, Iran, during July 2010 with four RSA for the sister and University of Medical Sciences, Mashhad 9196773117, Iran. five RSA for the brother’s spouse. The phenotypes of both pa- Tel: +98-511-711-2343, Fax: +98-511-711-2343, E-mail: [email protected] tients were examined. The brother and his wife who were in a Accepted for publication: 2 December 2011 non-consanguineous marriage resulted in 8 pregnancies: 2 RSA,

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 249 Novel Familial Balanced Translocations in Recurrent Spontaneous Abortion

Figure 1. Karotyping of family with balanced translocation 8;11. 46,XY or XX,t(8;11)(p23;q21).

Figure 2. Family pedigree with balanced translocation 8;11 (p23;q21).

1 normal 17-year-old boy, 3 RSA, and 2 deceased children (one somes 8;11[46,XX,t(8;11)(p23;q21)] as her brother (Figure 1). boy and one girl who died before the age of one). The normal Other laboratory findings such as complete blood count (CBC), boy inherited a normal chromosome 8 and 11 from his mother TORCH, and hormones were normal. This family’s pedigree with and balanced translocation 8 and 11 from his father. Therefore, balanced translocation is shown in Figure 2. his karyotype is similar to his father. The deceased children had The second family consisted of a 34-year-old man and his wife, developmental delays and hypotonia. There was no clear diag- aged 26 years. This couple whose marriage was consanguineous nosis for the deceased children. Both parents had normal phe- had four abortions, however, the phenotype of the man and his notypes and hormonal tests. Other non-genetic reasons for RSA wife were normal. Karyotype analysis was performed for both. were ruled out. Karyotyping was performed using cultured blood Metaphase spreads were studied on the basis of GTG technique cells and high resolution banding followed by Cytovision soft- at high resolution banding, which revealed 46 chromosomes. ware analysis on the chromosomes. The karyotyping result for However, both had a balance translocation between the long arm his wife was normal, however, the brother had a balance translo- of chromosome 6 and short arm of chromosome 16 as follows: cation between chromosomes 8;11 [46,XY,t(8;11)(p23;q21)]. In [46,XY or XX,t(6;16)(q26;p12)] (Figure 3). The pedigree of this this family, the 27-year-old sister had four RSA. Her karyotype family is shown in Figure 4. analysis showed the same balance translocation between chromo- All four individuals from both pedigrees that carry the bal-

250 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 Keify F, Zhiyan N, Mirzaei F, et al.

Figure 3. Karotyping of family with balanced translocation 6;16. 46,XX or XY,t(6;16)(q26;p12).

Figure 4. Family pedigree with balanced translocation 6;16 (q26;p12).

anced reciprocal translocations are themselves clinically normal. tions and have normal phenotypes can transfer unbalanced trans- The gametes obtained from their parents do not have any dupli- locations to their fetuses, causing either RSAs or other congenital cated or deleted fragments in chromosomes 8 and 11, or 6 and abnormalities such as developmental delays and/or hypotonia. 16. Therefore, they are balanced translocation carriers, similar to Different studies have shown that the risk of having a live born their fathers or mothers. Additionally, both families went through child with an unbalanced karyotype is 2%–10%, however, most extensive genetic counseling and prenatal diagnosis (PND) was are aborted.3,4 Reciprocal translocations can be inherited or oc- strongly recommended. There is a 50% chance of an unbalanced cur as new or de novo mutations. The risk for having de novo translocation being inherited in each future generation of these balanced translocations is greater than rearrangements inherited families. An increased risk of having children with unbalanced from a normal parent and has been reported to be approximately karyotypes secondary to meiotic malsegregation of their translo- 6%–9%.2 In this family, only 50% of the resulting gametes would cation also exists in future generations. carry a normal chromosome complement or would be balanced translocation carriers similar to the father or mother. The other Discussion 50% of the resulting gametes are including two variations. One of the variants has been ascertained to the birth of a clinically ab- The family members who carry these novel balanced transloca- normal fetus with the derivative chromosome 8, but not the com-

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 251 Novel Familial Balanced Translocations in Recurrent Spontaneous Abortion plementary abnormal chromosome 11. These variations include References an abnormal fetus with monosomic chromosome 11 long arm material and trisomic chromosome 8 short arm materials. Other 1. Van Dyke LL, Weiss L, Roberson JR, Babu VR. The frequency and variants have an abnormal fetus that has the derivative chromo- mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age. Hum. Genet. some 11, but not complementary abnormal chromosome 8. These 1983; 35: 301 – 308. fetuses are monosomic for the short arm of chromosome 8 and 2. Warburton D. De novo balanced chromosome rearrangements and trisomic for the long arm of chromosome 11. In both cases, the extra marker chromosomes identified at prenatal diagnosis: clinical fetus is aborted. significance and distribution of breakpoints. Med Genet. 1991; 49: 995 – 1013. Therefore, for individuals with balanced translocation, PND is 3. Escudero T, Lee M, Sandalinas M, Munne S. Female gamete segre- recommended. Fluorescent in situ hybridization (FISH) may be gation in two carriers of translocations involving 2q and 14q. Prenat used to detect chromosomal abnormalities in preimplantation ge- Diagn. 2000; 20: 235 – 237. 5 4. Munne S, Bahce M, Schimmel T, Sadowy S, Cohen J. Case report: netic diagnosis (PGD) or PND. Chromatid exchange and predivision of chromatids as other sources The primary aim of PGD is to reduce recurrent spontaneous of abnormal oocytes detected by preimplantation genetic diagnosis of abortions and to increase the pregnancy success rate in infertile translocations. Prenat Diagn. 1998; 18: 1450 – 1458. couples. Therefore, PGD has been offered to carriers of transloca- 5. Van Assche E, Staessen C, Vegetti W, Bonduelle M, Vandervorst M, 6 Van Steirteghem A, et al. Preimplantation genetic diagnosis and sperm tions for PND and pregnancy termination of abnormal fetuses. analysis by fluorescence in-situ hybridization for the most common These two novel translocations are the first report for these reciprocal translocation t(11;22). Mol Hum Rep. 1999. 5: 682 – 690. breakpoint rearrangements between chromosome 8;11 and 6;16. 6. Braude P, Pickering S, Flinter F, Mackie Ogilvic C. Preimplantation Although in 2000, Fert-Ferrer et al. have described unbalanced genetic diagnosis. Natu Rev Genet. 2002; 3: 941 – 955. 7. Fert-Ferrer1 S, Guichet A, Tantau1 J, Delezoide1 AL, Ozilou1 C, translocation t(8;11), however, the breakpoints are different. The Romana1 SP, et al. Subtle familial unbalanced translocation t(8;11) new translocation is t(8;11)(p23.2;p15.5). These researchers have (p23.2;p15.5) in two fetuses with Beckwith-Wiedemann features. analyzed two fetuses and shown that they carried the same un- Prenat Diagn. 2000; 20: 511 – 515. balanced translocation with monosomy for chromosome 8 and trisomy for chromosome 11. The phenotypes of the fetuses were similar to Beckwith-Wiedemann syndrome (BWS).7

252 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 V. Goni, B. R. Thapa, S. Vyas, et al.

Case Report Bilateral Psoas Abscess: Atypical Presentation of Spinal Tu- berculosis

Vijay Goni MS1, Babu Ram Thapa MD1, Sameer Vyas MD1, Nirmal Raj Gopinathan MS•1, Sakthivel Rajan Manoharan MS1, Vibhu Krishnan MS1

Abstract Three patients who came to the surgical outpatient department of ‘Postgraduate Institute of Medical Education and Research’, Chandi- garh, India with features suggestive of acute abdomen are presented. On thorough evaluation, they had bilateral psoas abscess and on detailed investigations, tuberculosis was found to be the etiological factor. They were treated conservatively with good follow-up results. Psoas abscess may be clinically difficult to diagnose because of its rarity, insidious onset of the disease, and non-specific clinical presentation which can cause diagnostic delays resulting in high morbidity. Early diagnosis and appropriate management remains a challenge for clinicians. All three patients presented here have recovered following detailed investigation and appropriate management. The diagnosis of spinal tuberculosis should be considered in patients with vertebral osteomyelitis, psoas abscess, and appropriate risk factors such as a history of previous exposure in both developed and developing countries, as tuberculosis is re-emerging as an important etiological factor in spinal pathologies.

Keywords: Acute abdomen, atypical presentation, iliopsoas abscess, spinal tuberculosis

Cite the article as: Goni V, Thapa BR, Vyas S, Gopinathan NR, Rajan Manoharan S, Krishnan V. Bilateral Psoas Abscess: Atypical Presentation of Spinal Tuber- culosis. Arch Iran Med. 2012; 15(4): 253 – 256.

Introduction moglobin was 7.2 gram/dL, white blood cell count 14,200 with predominant neutrophils, and an erythrocyte sedimentation rate escribed by Pott in 1779, tuberculosis of the spine is a com- (ESR) of 120 mm at 1 hour. Mantoux test was positive. Urinalysis mon entity encountered by orthopedic surgeons in tropical ruled out the presence of a urinary tract infection. She was nega- Dcountries. Being so uncommon in other parts of world and tive for HIV 1 and 2. Chest X-ray was normal and an ultrasonog- with varied clinical presentations, spinal tuberculosis may pose raphy pf abdomen was performed. The Ultrasonogram picked up diagnostic challenges and therapeutic dilemmas. It leads to signif- a hypoechoic collection with many internal echoes in both psoas icant morbidity and mortality in the young productive age group. muscles. She was started on broad spectrum empirical antibiotics Although psoas abscess due to spinal tuberculosis has been de- for pyogenic psoas abscess. A lumbosacral radiograph revealed scribed, bilateral psoas abscess with varied presentation is rare, erosive changes in the fifth lumbar vertebra. An orthopedic sur- and it is considered worthwhile to present our experiences with geon was called for consultation and the patient underwent, a con- three such cases treated in our hospital. trast enhanced CT scan, of abdomen and pelvis and MRI of the lumbosacral spine (Figures 1 and 2). Case 1 Contrast enhanced CT reported irregular lytic destruction of the The patient was a 12-year-old female admitted to the emergency fifth lumbar vertebra along with a large pre- and para-spinal col- surgical outpatient department of ‘Postgraduate Institute of Medi- lection that extended from the fourth lumbar vertebra to the third cal Education and Research’, Chandigarh, India with complaints sacral vertebra. There was also a 10.4 × 4.2 cm septated enhanc- of abdominal pain, vomiting, fever, and malaise. She was appar- ing lesion located in the left anterior perinephric space between ently healthy 3 months prior to admission, when she began to the iliac and psoas muscles. Similarly, a 5.6 × 4.4 cm collection complain of intermittent back pain for which she was treated with was located on the right side. Ultrasound-guided pigtail catheter analgesics by a local doctor. Her symptoms subsided. For the past drainage was performed on the left side and around 40 mL of pu- 3 weeks she had intermittent fever and had missed school due to rulent material was removed. The catheter was kept for 4 days abdominal pain. She was admitted as a case of acute abdomen and and the total pus drained was about 70 mL. Aspirate was positive evaluated. The patient had tenderness in both iliac fossa, along for acid-fast bacilli and also polymerase chain reaction for Myco- with an ill-defined palpable mass in the left iliac fossa. She also bacterium tuberculosis. The patient was started on a middle path had tenderness in the lower lumbar region. The patient weighed regimen with bed rest and antitubercular drugs that included iso- 24 kilograms, was anemic, and febrile with stable vitals. Her he- niazid, rifampicin, and pyrazinamide. Acid-fast bacilli culture was also positive by 47 days. By 6 weeks she showed improvement Authors’ affiliation:1 Postgraduate Institute of Medical Education and Research, in general condition and was mobilized with a brace from month Chandigarh, India. 3. At the end of 8 months follow-up the patient had significantly •Corresponding author and reprints: Nirmal Raj Gopinathan MS, Dip. SI- improved, both symptomatically and functionally. Her ESR and COT, Department of Orthopedics and Traumatology Postgraduate Institute of Medical Education and Research, Chandigarh, India. Tel: +91-991-420-9740, CRP readings were normalized by then. E-mail: [email protected]

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 253 Atypical Presentation of Spinal Tuberculosis

Figure 2. Coronal image showing signal intensities in both psoases indicating bilateral psoas abscess in case 1.

Figure 1. MRI image showing destruction of L5-S1 end plates and large prevertebral collection in case 1.

Figure 3.T2-weighted image of case 2. Coronal image depicting bilateral Figure 4. T1-weighted image of case 2. Coronal image showing bilateral psoas abscess. psoas abscess.

Case 2 The material was negative for bacteria and acid-fast bacilli on Case 2 was a 23-year-old male who presented to the Surgical staining. He underwent CT-guided biopsy of the involved verte- outpatient Department of ʻʻPostgraduate Institute of Medical Edu- brae, which revealed caseous necrosis and granuloma formation. cation and Researchˮ, Chandigarh, India with backache and vague Based on these findings he was started on anti-tuberculous treat- abdominal pain for the previous 8 months. There was evening rise ment with a 4 drug regimen that included isoniazid, rifampicin, of temperature for the past 2 months and significant weight loss ethambutol, and pyrazinamide along with bed rest. Acid-fast cul- of about 6 kilograms. Night pain was present and the patient had ture was positive at the end of 6 weeks. The patient developed contact a cousin brother who was under treatment for pulmonary hepatotoxicity and was put on modified a regimen of ethambu- tuberculosis. General examination revealed anemia and cachexia. tol, ciprofloxacin, and streptomycin. He was mobilized with a The patient had diffused lower abdominal tenderness and guard- brace from the third month. At the 10 month follow-up he had ing. There was tenderness with paraspinal spasm in the dorsolum- improved significantly. Duration of therapy was prolonged for a bar region. His hemoglobin was 6.2 gram/dL. Neutrophils and year due to the modified regimen and stopped once CRP levels lymphocytes were elevated in the differential count. ESR at one normalized. hour was 80 mm. Chest X-ray showed no abnormality. An ultrasound examination of abdomen revealed a hypoechoic collection Case 3 with many internal echoes in both psoas muscles and radiography A 40-year-old male presented with abdominal pain that radiated revealed reduction in the D12 and L1 disc spaces along with end to his back along with intermittent fever for the past three weeks. plate changes. The patient was empirically treated for pyogenic He was admitted and subjected to routine hemogram, chest X- psoas abscess with ceftriaxone, vancomycin, and metronidazole. ray, ultrasound of the abdomen and pelvis, urine analysis, and CT scan and MRI (Figures 3 and 4) were performed which re- an upright radiography of the abdomen. Ulrasound examination vealed a 5.2 × 3.2 cm collection in the right psoas and 2.4 × 1.8 showed bilateral psoas masses. Radiography showed destruction cm collection on the left side with destruction of the D12 and L1 of the L2-L3 endplates and reduction in the disc space. He had vertebrae. Ultrasound-guided pig tail catheter drainage was per- increased neutrophils and elevated ESR (140 mm at 1 hour). Em- formed on the right side and 20 mL of pus was removed. Cath- pirical antibiotics were started and he underwent CT and MRI eter was removed after 2 days as there was no further discharge. (Figures 5 and 6). Imaging studies were positive for 2 × 2 cm

254 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 V. Goni, B. R. Thapa, S. Vyas, et al.

Figure 5. T1-weighted image of case 3.

Figure 6.T2-weighted image of case 3. and 3 × 2 cm masses in the right and left psoas muscles. Ultas- cause of psoas abscess in developing countries can be Mycobac- ound-guided pigtail catheter was introduced on the left side and terium tuberculosis, spread by hematogenous or direct extension a 5 mL purulent discharge was removed. Aspirate was negative from lumbar spinal vertebral osteomyelitis.3,4 Psoas abscess may for bacterial and acid-fast bacilli stains. Meanwhile, CT-guided be clinically difficult to diagnose because of its rarity, insidious biopsy was performed which confirmed tuberculosis. Acid-fast onset, and non-specific clinical presentation which can cause di- culture was positive at 6 weeks. The patient was started on a 4 agnostic delays resulting in high morbidity. Early diagnosis and drug antituberculous regimen and had significant improvement appropriate management remain a challenge for clinicians. All 3 over a period of 6 months. Duration of therapy was extended for patients in this case series presented with acute abdomen. 9 months. At 3-years follow up, the patient has remained well The classical triad of fever and limitation of hip joint move- except for occasional backache. ments, other than back pain may be present in only 35% of patients with psoas abscess.5 Fever, weight loss, and constitutional Discussion symptoms are encountered in less than 40% of cases.6 Progressive local back pain for weeks to months with or without associated Tuberculosis is a known factor contributing to morbid spinal muscle spasm and rigidity should prompt the clinician to suspect conditions in both developed and developing countries. Vertebral a spinal cause for the abscess. In general, laboratory testing is non- tuberculosis is the most common form of skeletal tuberculosis, specific. ESR and C-reactive protein are generally elevated and which constitutes about 50% of all cases of tuberculosis of the may be useful in following the disease course.7 Plain radiographs bones and joints. However, its association with bilateral psoas may reveal underlying discitis or vertebral osteomyelitis in chron- abscess presenting as an acute abdomen is not common. Psoas ic lesions but may not be of much help in differentiating pyogenic abscess may be classified as primary or secondary depending on or tuberculous etiology. the presence or absence of the underlying disease. The peculiar Abdominal ultrasound may pick up hypoechoic lesions sugges- anatomy of the psoas muscle and its fascia puts it in direct com- tive of psoas abscess in 60% of patients but may not be able to munication with the mediastinum and thigh. Since the muscle lies identify an underlying etiology.8 MRI appears to have 90% sensi- in proximity to viscera such as the sigmoid, appendix, jejunum, tivity and 80% specificity for diagnosing psoas abscess. The gold ureters, kidneys, pancreas, spine, and iliac lymph nodes, any un- standard imaging modality is intravenous contrast enhanced spiral derlying disease in these organs can result in secondary psoas ab- CT.8,9 However, MRI is better than CT at imaging the spinal canal scess.1 Staphylococcus aureus (88%) is considered to be the most and provides a more complete evaluation of the spinal pathology. common cause of primary psoas abscess followed by streptococci Ultimately, definit diagnosis is achieved with drainage and analy- and Escherichia coli. The etiology of primary psoas abscess is sis of pus or histopathological examination of specimens obtained unclear, but lymphatic and hematogenous spread of an infectious by CT-guided biopsy.8 All our patients had ultrasound-guided process from an occult source in the body, often associated with drainage and analysis of the abscess fluid. Only patient number 1 immunosupression has been implicated.1 had acid-fast bacilli on staining, however all 3 had acid-fast bacilli Ricci et al. have noted that the most common cause of second- grown on culture. ary psoas abscess was Crohn’s disease.2 However, an important Histopathological examination of CT-guided biopsy specimens of patients 2 and 3 showed caseous necrosis and granuloma forma-

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 255 Atypical Presentation of Spinal Tuberculosis tion suggestive of tuberculosis. All patients were started on broad spectrum intravenous antibiotics that covered Staphylococcus au- Author’s contribution section reus and once tuberculosis was confirmed, they were treated by Prof. Dr. B. R. Thapa was the one under whom our paediatric the middle path regimen classically described by Tuli, et al.10 As patient was admitted and Dr. Nirmal Raj, Dr. Sakthivel Rajan, described by Tuli, the middle path regimen encompasses the treat- and Dr. Vibhu Krishnan were the surgeons who managed these ment method where aggressive surgical therapy is not performed cases in the Outpatient Department and wards; all were treated in all patients. The patients are managed with rest, modern antitu- under eminent guidance of the spine surgeon, Dr. Vijay Goni. Dr. berculous medicines, and spinal braces. Surgical treatment is per- Sameer Vyas was the interventional radiologist who helped us in formed only in selected patients.10 Aspiration of abscesses have drainage as well as collection of material for analysis. been performed for diagnostic purposes and not for therapy as we consider that the appropriate antituberculous treatment would be References able to cause subsidence of abscesses without the need for surgical drainage. Surgical drainage is contemplated once there is a 1. Mallick I, Thoufeeq M, Rajendran T. Iliopsoas abscesses. Postgrad neurological deficit. Adjuvant surgery should be considered for Med. 2004, 80: 459 – 462. 2. Ricci MA, Rose FB, Meyer KK. Pyogenic psoas abscess: worldwide patients with disease progression on therapy (medical treatment variations in etiology. World J Surg. 1986; 10: 834 – 843. failure) or those who have spinal cord compression, neurological 3. Maron R, Levine D, Dobbs TE, Geisler WM. Two cases of Pott’s deficit or spinal instability. disease associated with bilateral psoas abscesses: case report. Spine. The diagnosis of spinal tuberculosis should be considered in 2006; 31: 561 – 564. 4. Elevli M, Çivilibal M, Duru NS, Şengül H, Çölbay G, Erdoğan Y. Two patients with vertebral osteomyelitis, psoas abscess, and appro- children with spinal tuberculosis associated with psoas abscess. Çocuk priate risk factors. In both developed and developing countries it Enf Derg. 2010; 4: 110 – 113. is re-emerging as an important etiological factor in spinal mostly 5. Vaz AP, Gomes J, Esteves J, Carvalho A, Duarte R. A rare cause of due to immunosuppression of different etiologies. Unilateral pre- lower abdominal and pelvic mass, primary tuberculous psoas abscess: a case report. Cases J. 2009; 2: 182. sentation is more common and bilateral psoas abscess has been 6. Nussbaum ES, Rockswold GL, Bergman TA, Erickson DL, Seljeskog reported rarely in the literature. EL. Spinal tuberculosis: a diagnostic and management challenge. J Neurosurg. 1995; 83: 243 – 247. 7. Janssens JP, De Haller R. Spinal tuberculosis in a developed country: a Patient consent section review of 26 cases with special emphasis on abscesses and neurologic Written informed consent was obtained from the patients for complications. Clin Orthop. 1990; 257: 67 – 75. publication of this case series and accompanying images. A copy 8. Lee YT, Lee CM, Su SC, Liu CP, Wang TE. Psoas abscess: a ten-year of the written consent has been submitted to the journal. review. J Microbiol Immunol Infect. 1999; 32: 40 – 46. 9. Tomich EB, Della-Giustina D. Bilateral psoas abscess in the emergency department: a case report. West J Emerg Med. 2009; 10: 288 – 291. Competing interests section 10. Tuli SM. Results of treatment of spinal tuberculosis by “middle-path” The author(s) declare that they have no competing interest. regime. J Bone Joint Surg Br. 1975; 57: 13 – 23.

256 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 Z. Khorgami, T. Anbara, A. Mohammadnejad, et al.

Photoclinic

Figure 1. Generalized pigmentation (A) Head and neck; (B) closed view.

Figure 2. Microscopic view of abdominal skin which shows hyperkeratosis, mild focal papillomatosis, moderate irregular acanthosis, and hyperpigmentation of the basal layer of the epidermis (H&E, Left: 40×, right: 100×).

Cite the article as: Khorgami Z, Anbara T, Mohammadnejad A, Mahmoodzadeh H. Photoclinic. Arch Iran Med. 2012; 15(4): 257 – 258.

A 54-year-old man with sudden onset of rapid progressive gen- showed chronic gastritis, crypt abscess formations, and hypertro- eralized skin hyperpigmentation (Figure 1) referred to the Gas- phy. troenterology Department of Shariati Hospital, Tehran, Iran in Laboratory findings included: hypernatremia, hypokalemia, and August 2009. He had been assessed for Addison’s disease in the elevated serum cortisol (28.3 mcg/dL, NL: 5–26 mcg/dL). Other Endocrinology Department 3 months prior because of generalized biochemical parameters were within normal ranges. Abdominal hyperpigmentation and malaise, but discharged with no certain and pelvic CT scan revealed a distended stomach with irregularity diagnosis. Later, the patient developed diet intolerance with nau- in the pyloric region and fundus of the stomach. Therefore, the sea and vomiting, which resulted in a loss of over 14 Kg during patient was referred to the Surgical Department for exploratory 6 months. He underwent upper gastrointestinal tract endoscopy, laparotomy, which revealed advanced gastric cancer with gastric which revealed decreased distensibility of the stomach with dif- outlet obstruction, and multiple small liver and peritoneal metas- fused antral mucosal edema. Multiple biopsies were taken, which tases. Biopsy and gastrojejunostomy anastomosis was performed. Histopathological evaluation of the stomach, liver, and peritoneal Zhamak Khorgami MD•1, Taha Anbara MD1, Atefeh Mohammadnejad MD1, biopsies showed moderately differentiated mucinous type adeno- Habibollah Mahmoodzadeh MD2 Authors’ affiliations:1 Shariati Hospital, Tehran University of Medical Sciences, carcinoma. Pathologic evaluation of the abdominal skin biopsy 2Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran. showed hyperkeratosis, papillomatosis, and hyperpigmentation of •Corresponding author and reprints: Zhamak Khorgami MD, Surgery Depart- the basal layer (Figure 2). ment of Shariati Hospital, North Kargar Ave., Tehran, Iran. Tel: +98-218-490-2450, Fax: +98-218-863-3039 E-mail: [email protected]. What is your diagnosis? Accepted for publication: 27 July 2011 See the next page for diagnosis.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 257 Photoclinic

Photoclinic Diagnosis: Generalized Acanthosis Nigricans

Acanthosis nigricans (AN) lesions are focal symmetric, velvety currence or metastases of the primary neoplasm. Thus, complete hyperkeratotic discoloratic plaques that develop usually on skin treatment of AN is often unsatisfactory.5 folds, particularly the axilla, flexures, nipple, navel, and anogen- Overall, more attention should be paid to AN, especially the ital region.1,2 Benign types of AN may run in families with no generalized form, in order to consider underlying malignancies evidence of endocrinological disturbances or internal malignancy, before they become widespread. but can be associated with endocrine problems such as Addison’s disease. It has also been reported in obese, dark-skinned people, References and those known for insulin resistance and diabetes.3 Sudden and/or late onset, and extensive rapid marked thicken- 1. Matono S, Fujita H, Tanaka T, Tanaka Y, Sueyoshi S, Tsubuku T. ing with mucous membrane, nail, hair, palms, and involvement of Malignant acanthosis nigricans with esophageal cancer. Esophagus. 2009; 6: 127 – 131. the soles are important differentiating pointers in malignant AN, 2. Kamińska-Winciorek G, Brzezińska-Wcisło L, Lis-Święty A, Krauze which almost always indicate the presence of internal malignan- E. Paraneoplastic type of acanthosis nigricans in patient with hepato- cy.4 AN occurrence in adults is closely related with internal ma- cellular carcinoma. Adv Med Sci. 2007; 52: 254 – 256. lignancy, most often gastrointestinal and respiratory tract cancers, 3. Matsuoka L, Wortsman J, Gavin J, Goldman J. Spectrum of endocrine 5 abnormalities associated with acanthosis nigricans. Am J Med. 1987; which are common in many countries. Generalized AN (GAN) 83: 719 – 725. is a rare paraneoplastic syndrome, which has been reported in pa- 4. Schwartz R. Acanthosis nigricans. J Am Acad Dermatol. 1994; 31: tients with advanced and inoperable cancers, such as gastric or 1 – 19. cervix uteri carcinoma. There is a belief that growth stimulating 5. Weismann K. Skin disorders as markers of internal disease. Paraneo- 6,7 plastic dermatoses. Ugeskr Laeger. 2000; 162: 6834 – 6839. factors derived from tumor cells are probable causes of GAN. 6. Andreev V, Boyanov L, Tsankov N. Generalized acanthosis nigricans. However, this sign is non-specific and usually develops too late Dermatologica. 1981; 163: 19 – 24. for any curative procedures.8 7. Mikhail G, Fachnie D, Drukker B, Farah R, Allen H. Generalized malignant acanthosis nigricans. Arch Dermatol. 1979; 115: 201 – 202. Treatment of AN is difficult because it needs management of 8. Mori S. Useful cutaneous markers of internal malignancy in the early the underlying neoplasm. Skin lesions may improve by surgical stage [in Japanese]. Gan To Kagaku Ryoho. 1988; 15: 1564 – 1568. excision of the tumor, but may also worsen subsequently with re-

258 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 M. H. Azizi, S. Nasseri-Moghaddam

History of Contemporary Medicine in Iran

Impact of Quality Mentorship on Achievements of Shiraz Medi- cal School in the 1970s and the Role of Professor Faramarz Ismail-Beigi

Mohammad Hossein Azizi MD•1, Siavosh Nasseri-Moghaddam MD2

Professor Faramarz Ismail-Beigi

Abstract Almost four decades ago, an eminent physician, outstanding mentor and scholar, Professor Faramarz Ismail-Beigi (b. 1941) was appointed Chair of the Department of Internal Medicine at Shiraz Medical School. Soon, this proved to be the beginning of a golden era in medical education at that center. Professor Ismail-Beigi invited outstanding teachers and physicians to collaborate with him. Their efforts during the next decade laid a strong and unique foundation for medical education based on quality mentorship and role-modeling. In this paper, we briefly highlight the importance of mentorship in medicine and medical education, followed by a glance at the academic life and career of Professor Ismail-Beigi and his role as a prominent mentor at the Shiraz School of Medicine.

Keywords: Iran, mentorship, school of medicine

Cite the article as: Azizi MH, Nasseri-Moghaddam S. Impact of Quality Mentorship on Achievements of Shiraz Medical School in the 1970s and the Role of Profes- sor Faramarz Ismail-Beigi. Arch Iran Med. 2012; 15(4): 259 – 262.

Introduction to advise Telemachus to go after his father, she disguised herself as Mentor. Therefore, Mentor is considered as a ‘father figure’ ver the past four decades, we have witnessed substantial who sponsors, guides and develops a younger person. Since the changes in medicine and medical education. This has oc- early 18th century, the term ‘mentor’ has been used to delineate O curred because of technological and scientific advance- such a person. The mentor is thus a wise advisor1 and a trusted ments, availability of abundant information in different disciplines counselor or guide to a younger person, i.e., the ‘mentee’.2 of medicine, mechanisms of learning, and the way these changes Training qualified, skilled, humane physicians who are life-long are viewed. Despite these, the central role of quality mentors and self-learners is the ultimate goal of any medical school. To do this, teachers has remained the same in training highly qualified gradu- quality mentorship is a pivotal requirement. However, it seems ates. that as much as it is needed, it is a shortcoming of many medical In Greek mythology, Mentor was the name of a friend of Odys- schools worldwide, including Iran. This is due to the fact that a seus. When Odysseus was leaving for the Trojan War, he assigned mentor is not just a skilled physician, but a multi-faceted person Mentor and his foster-brother Eumaeus to be in charge of his son, who is willing and capable of encouraging and providing practical Telemachus. Mentor served Telemachus as a loyal, trustworthy, plans for personal dilemmas of the mentee. and wise advisor. When Athena, the goddess of wisdom, wanted Quality mentors of medicine are role models in their daily practice. They not only teach mentees up-to-date scientific concepts Authors’ affiliations: 1Academy of Medical Sciences of the I.R. of Iran, Tehran, and fundamental professional skills, but also the art of medicine Iran. 2Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. and medical ethics codes. Therefore, there are considerable differ- •Corresponding author and reprints: Mohammad-Hossein Azizi MD, Acad- ences between a medical teacher who merely is capable of trans- emy of Medical Sciences of the I.R. of Iran, Tehran, Iran. ferring scientific data to students and a mentor who teaches men- Tel: +98-212-293-9869, E-mail: [email protected] Accepted for publication: 15 February 2012 tees medical knowledge, professional skills, and medical ethics.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 259 Professor F. Ismail-Beigi in Shiraz Medical School

The mentor is viewed by mentees as “an influential senior spon- was appointed as the Chief of Medicine at the former Pahlavi Uni- sor or supporter”.3 versity in Shiraz. Under his leadership, substantial propagation of The importance of quality mentorship in medicine has recently modern academic medicine occurred in Shiraz. Besides being the gained more attention. For instance, according to Nakanjako and Chief of Medicine, he served at other positions which greatly en- colleagues the fundamental component of medical education is hanced the development of medical education in Shiraz. His other high quality mentoring which plays a major role in career accom- academic appointments included: plishment of mentees.4 In addition, mentorship has a profound impact on professional development of mentees as well as their • Director of the Bio-Medical Research Unit and Institute of future career selection.5 A positive correlation has been found Nuclear Medicine, 1972 – 1981. between mentoring, research skills, and efficiency of mentees.6 • Member of the former Pahlavi University Research Council, Quality mentorship in medicine affects various aspects of medical 1972 – 1976. students’ training. According to Tobin: “The physician-researcher • Member of the Central Committee of Iranian Board of Internal as mentor has at least seven roles to fulfill: teacher, sponsor, advi- Medicine, 1973 – 1978. sor, agent, role model, coach, and confidante.”7 Superior teachers • Member of the Central Committee for Medical Education at the always consider teaching and learning as a two-way communi- Iranian Ministry of Science and Higher Education, 1973 – 1975. cation process and know the circumstances which affect learn- • Member of the Central Research Committee at the Iranian ing.8 The mentorship process is successful when it is dynamic, in Ministry of Science and Higher Education, 1975 – 1978. which the so-called ‘supermentor’, a team of mentors or multiple mentors continuously support mentees.9

Shiraz Medical School and the role of Professor Ismail-Beigi as a role model and mentor

The establishment of Shiraz School of Medicine The roots of Shiraz School of Medicine in southern Iran date to 1946 when the Medical Auxiliary Training School (Amouzesh- gah-e Alee Behdari-e Shiraz) was founded. A graduate of the American University of Beirut, Dr. Zabih Ghorban (1903–2006) was appointed Associate Professor of Medicine and Dean of the newly found school. At that time, Saadi Hospital (later Shaheed Faghihi Hospital) in Shiraz was the only clinical training center for medical students. It had five clinical wards, which included an Internal Medicine Department with 32 beds, headed by Dr. Abol-Hassan Dehghan, who also was a graduate of the Ameri- can University of Beirut and specialized in tropical diseases in A view of Shiraz School of Medicine in the 1970s. London, UK. Dr. Dehghan served as Associate Professor of Medicine at Shiraz Medical Auxiliary Training School in 1946.10 Professor Ismail-Beigi as a mentor The Shiraz School of Medicine was officially founded 6 years later in 1952.11 It was a medical school with special features. Ac- Dr. Ismail-Beigi was not only a successful physician and it was cording to Professor Khosrow Nasr, the former Dean of Shiraz not only his positions which helped medical education in Shiraz School of Medicine, there were six major pillars that shaped the to develop, but his unique personal characteristics as a role-model School of Medicine in Shiraz. They included: selection of English and his endless enthusiasm in teaching and developing others as its institutional language, establishment of a modern and well- made him an outstanding figure. His colleagues viewed him as equipped hospital (Nemazee Hospital), bylaws, full-time faculty a dedicated physician, a generous mentor, consummate clinician, members, the attractiveness of Shiraz and bright students willing and a trusted friend of mentees. Professor Asghar Rastegar, a to accept change.12 friend and colleague of Professor Ismail-Beigi who himself served The school flourished in the 1970s when Professor Faramarz as Professor of Internal Medicine at Shiraz Medical School during Ismail-Beigi and his colleagues joined the Department of Internal the same period stats: “Two individuals, Khosrow Nasr and Fara- Medicine. marz Ismail-Beigi, however, stand out among all for their unique Faramarz Ismail-Beigi was born in Tehran on December 28, role in making the Department of Medicine in Shiraz into the finest 1941 in a highly-educated family. His father, Dr. Zia-o-din Ismail- clinical department in Iran and probably the Middle East. Khos- Beigi Shirazi was a Professor of Physics. Faramarz graduated row Nasr stands out for his creativity, vision, sense of optimism, from Hadaf High School in Tehran, Iran and continued his educa- and his ability to bring disparate groups together to achieve goals tion at Berea College in Kentucky, USA where he received his critical to the institution. Faramarz Ismail-Beigi stands out for his Bachelor of Art degree in 1962. He enrolled at Johns Hopkins commitment to excellence, his confidence in the ability of Shiraz School of Medicine and graduated in 1966. Dr. Ismail-Beigi con- students and residents, and his uncompromising stand for highest tinued his residency in internal medicine and did a post-doctoral level of professionalism. He embodied the essence of an academic fellowship in biophysics and internal medicine at the University physician, an outstanding teacher, true scholar as well as a dedi- of California at Berkley where he received his PhD and board of cated clinician. For a young faculty such as me he had created an Internal Medicine in 1972. He returned to Iran in the same and organizational structure to maximize our contributions. This was

260 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 M. H. Azizi, S. Nasseri-Moghaddam and is rare in Iran where the commitment to one’s own success of- also instrumental in helping me in my career. I remember after ten supersedes the commitment to the success of others as well as graduating from medical school, after the summer break, I was the institution one serves. During the past 40 years, I have had the trying to decide on a further specialization. At that time, the De- privilege of working with many outstanding leaders in academic partment of Internal Medicine was considered to be the most dif- medicine in the US. I still consider Khosrow Nasr and Faramarz ficult to get into and Dr. Ismail Beigi was seen as a “hard task Ismail-Beigi as among the top individuals I have worked with in master”! I made an appointment and with much trepidation went my professional life.” 13 to see him. I have always remembered that interview; he made me understand that I could become whatever I put my passion into. He was tremendously supportive and always encouraged me even when I had difficulty coping after the death of my father. I still have the letter of appreciation he wrote to me acknowledging my efforts in teaching the undergraduates. It was always exciting and stimulating working in that department. They put so much effort, despite all the shortcomings, to train excellent doctors”.13 Dr. A. M. Rostami, a former resident of internal medicine at Shiraz Medical School and current Professor and Chair of the Department of Neurology at Thomas Jefferson University quotes him as follows: “Dr. Ismail-Beigi’s teaching style was legendary. Even in areas outside the focus of his clinical or research training, he was able to give an in-depth view of the subject and invited the audience to read about it in the references that he provided. Sometimes we would ask him a question that we thought he would Professors Ismail-Beigi and Asghar Rastegar (Courtesy of Dr. Raees-Ja- have difficulty answering! After about a 30-second pause, during lali, nephrologist, Shiraz). which we were sure that we had got him, he would give the most This view is shared by others who know him as well. Dr. Farokh sophisticated answer in a logical and coherent manner and would Saidi, Professor of Surgery and former Dean of Shiraz Medical put us to shame! Based on their own experiences at Hopkins and School described Dr. Ismail-Beigi as follows:“He devoted all his Pennsylvania, Dr. Ismail-Beigi and Dr. Rastegar started a new efforts, while in Shiraz, to guiding and educating his younger medicine residency program at Shiraz. According to their plan, compatriots”.13 they asked the top Shiraz Medical School graduates who wanted Dr. Reza Malekzadeh, ex-chancellor of Shiraz University who is to do a residency in medicine or related areas abroad to stay on currently in charge of a leading research institute in Tehran and a as residents in the new program. After 2–3 years, they could re- pioneer of such establishments in Iran, has received his M.D. and ceive further training in medicine and their subspecialty of choice postgraduate medical training in Shiraz when Dr. Ismail-Beigi in top medical schools in the United States and Europe. It was used to be chair of the department of internal medicine there. He stipulated that the students would return to Shiraz and contribute quotes Dr. Ismail-Beigi and his team as follows: “In the 1970s, to the depth and breadth of the department of medicine and its Professor Ismail-Beigi and his colleagues (i.e., Professor Asghar subspecialties. At this juncture, Dr. Ismail-Beigi must be proud Rastegar, Professor Khosrow Nasr, Professor Yeganehdoost, and of his great academic achievements, service to his patients and Professor Mansour Haghshenas just to name a few) dedicated education of several generations of medical students, residents as themselves to train physicians whose major common feature was well as clinical and research trainees, in Iran and abroad. We, his longing for the art and science of medicine. Their tireless efforts former trainees, salute him for his teaching, mentorship, leader- was translated to development of an outstanding department ship skills and his dedication that revolutionized the teaching and practice of medicine at Shiraz University School of Medicine and of internal medicine who allured the best characters and made 13 responsible, capable and caring physicians of them, who in by extension to the entire Fatherland.” addition to providing excellent care to their patients, were able Being described as such and alike by colleagues, administrators, and willing to continue and develop the tradition, which had been and students means a lot. Not every professional can achieve this. founded with so much love. Many of these graduates managed During his years of activity at Shiraz Medical School, in addition to contribute effectively to the progress of various disciplines of to being a reliable mentor, dedicated teacher, and caring physi- medicine and medical education in Iran over the next several cian, he managed to hire outstanding internists at his department, decades, not only during the calm eras, but also during the high all of whom shared a common character: dedication to excel- tide of the imposed Iran-Iraq war. The key to this success was that lence in whatever they did. This was the essence of the foundation these mentors did all what they said, and even more, and were that Dr. Ismail-Beigi and his colleagues built successfully which highly appreciated as excellent role-models”.13 trained many outstanding and influential teacher-physicians in During his years of service at Shiraz Medical School, numerous successive generations, at a time when none of the founders were students had the privilege of being trained by him and all viewed there to supervise. him as a dedicated role-model. Dr. Jila Dana-Haeri, a former resident of Dr. Ismail-Beigi and a practicing internist, remembers her Publications and scientific interests mentor as follows: “Dr. Ismail-Biegi together with Dr. Rastegar created the best medical center in the country and one of the best In addition to the instrumental educational activities, between in the region. Dr. Ismail-Beigi was passionate about his work as 1970 and 2011, Professor Ismail-Beigi has been rather active in a teacher and as a physician he cared about his patients. He was basic and clinical research. This has led to the publication of 62

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 261 Professor F. Ismail-Beigi in Shiraz Medical School clinical papers and 111 articles in basic science in peer-reviewed Professor Ismail-Beigi as well as proving his C.V. We also would journals. His main interest is ‘diabetes mellitus’. (See his review like to extend our gratitude to professors and graduates of Shiraz article on “Pathogenesis and glycemic management of type 2 School of Medicine who share their valuable memories for this diabetes mellitus: a physiological approach” in this issue of the manuscript. Journal, pp: 239 – 246). Professor Ismail-Beigi is currently a full- time professor of medicine at Case Western Reserve University in References Cleveland, Ohio, USA where he serves as the Chief of the Depart- ment of Clinical and Molecular Endocrinology. 1. Rustgi A K, Hecht GA. Mentorship in academic medicine. Gastroen- terology. 2011; 141: 789 – 792. 2. Mentor. Available from: URL: http://www.merriam-webster.com/dictionary/mentor (Accessed 22.12.2011) 3. Mentor. Available from: URL: http://dictionary.reference.com/ browse/mentor (Accessed 22.12.2011) 4. Nakanjako D, Byakika-Kibwika P, Kintu K, Aizire J, Nakwagala F, Luzige S, et al. Mentorship needs at academic institutions in resource- limited settings: a survey at Makerere University College of Health Sciences. BMC Med Educ. 2011; 11: 53. Available from: URL: http:// www.biomedcentral.com/1472-6920/11/53 (Accessed 22.12.2011) 5. Kadivar H. The importance of mentorship for success in family medicine. Ann Fam Med. 2010; 8: 374 – 375. 6. Chew LD. Watanabe JM, Buchwald D, Lessler DS. Junior faculty’s perspectives on mentoring. Acad Med.2003; 78: 652. 7. Tobin M J. Mentoring, seven roles and some specifics. Am J Respir Crit Care Med. 2004; 170: 114 – 117. 8. Cox K R, Ewan CE. The Medical Teacher. Second ed. New York: Churchill Livingstone; 1988: 23. 9. Mentors and Mentees. Georgetown University Medical Center, Office of Faculty and Academic Affairs. Available from: URL: http://gumc. georgetown.edu/evp/facultyaffairs/documents/GUMC Mentoring Guidebook.pdf (Accessed 27.12.2011) Figure 3. Nemazee Hospital, Shiraz, 1974. Professor Ismail-Beigi, Pro- 10. Azizi MH. A brief history of the establishment of Shiraz Medical fessor Borhanmanesh and former residents of internal medicine. Stand- Auxiliary Training School: The forerunner of Faculty of Medicine at ing from left to right: Dr. Moslemi, Dr. Rajaei, Dr. Sodifi, Dr. Fakhaar, Dr. Shiraz University. Arch Iran Med. 2006; 9: 295 – 298. Moghtader, Professor Ismail-Beigi, Dr. Gabriel, Professor Borhanmanesh, 11. Hedayati J. The History of Contemporary Medicine in Iran [in Per- Dr. Hoshmand, Dr. Keshmiri. Sitting: Dr. Mehraban, Dr. Rezvani, Dr. Rafat, sian]. Tehran: Iran University of Medical Sciences and Health Ser- Dr. Badri. (Courtesy of Dr. Rahim Keshmiri, Internist, Shiraz) vices; 2002: 203. 12. Nasr K. Shiraz University School of Medicine: its foundation and de- Acknowledgment velopment. Arch Iran Med. 2009; 12: 87 – 92. 13. Azizi MH. A Collection of Essays on the History of Shiraz Medical School; In the Honor of Professor Faramarz Ismail-Beigi. Tehran: The authors wish to thank Professor Ismail-Beigi for being MirMah Publication; 2012. In press.

262 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 Excerpts from Persian Medical Literature

Excerpts from Persian Medical Literature

Association between Primary Dysmenorrhea and Preterm Delivery There is scant information about the mechanism and biochemical pathway of preterm delivery. Since some drugs that have been used to treat preterm labor are also useful for the treatment of primary dysmenorrhea. This study has attempted to evaluate the association between primary dysmenorrhea and preterm delivery. If the association is statistically significant, primary dysmenorrhea should be regarded as a risk factor for preterm delivery. We performed a case-control study and enrolled 160 women with idiopathic preterm delivery as the case group and 160 women with term delivery as controls. This study was undertaken in women who referred to the Obstetric Clinic of Imam Reza Hospital, Mash- had, Iran during 2008. Both groups were healthy, singleton and had no obstetric problems. Demographic information, and histories of primary dysmenorrhea and previous preterm labor were recorded in a questionnaire. Statistical data were analyzed by the t-test, chi square, Mann-Whitney, and logistic regression tests by using SPSS software version 15. There was a greater history of primary dysmenorrhea in women with preterm labor, which was significant when compared with the control group. Gravid women with a history of primary dysmenorrhea had a 3.5-fold increased risk of preterm delivery compared to women with no history of primary dysmenorrhea (P = 0.005). In subgroup analysis, gravid women with a history of severe primary dysmenorrhea had a 5.5-fold increased risk of spontaneous preterm delivery (P = 0.000), while gravid women with moderate primary dysmenorrhea had a 2.6-fold increased risk of spontaneous preterm delivery (P = 0.001). Primary dysmenorrhea is associated with an increased risk of spontaneous preterm delivery. A common pathophysiologic pathway may exist between these two disorders.

Source: Akhlagh F, Esmaili H, Mahmoodi F. The Iranian Journal of Obstetrics, Gynecology and Infertility. 2011; 14(5): 1 – 8.

Metabolic Disorders in Women with Previous Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) is a common complication of pregnancy associated with fetal and maternal adverse outcomes. These women are at higher risk for development of type 2 diabetes mellitus (T2DM), metabolic and cardiovascular diseases. Various results have been presented on the long term consequences of GDM. We have aimed to compare the incidence of these metabolic disorders between women with previous GDM and those with no history of GDM. Three groups of non-diabetic women, aged 15–45 years who participated in the first phase of the Tehran Lipid and Glucose Study (TLGS) were selected according to the following: 1) women with previous GDM, 2) women with histories of previous still births or macrosomia and no history of GDM, and 3) normal age-BMI matched controls. Women were followed for an average of 9 years for the development of T2DM, hypertension and dislipidemia. The cumulative incidence of T2DM in the GDM group was 3-fold higher than the control group. Incidence rates of T2DM were not significantly different between women in the MC-ST group and their controls; however, serum concentrations of fasting blood sugar (FBS) were significantly differed between these two groups. There was no significant difference in the cumulative incidence of hypertension and dislipidemia between the case and control groups. Women with previous GDM are at an increased risk of developing T2DM later in life. It seems that GDM screening in pregnancy could identify women at risk of metabolic disease.

Source: Ramezani Tehrani F, Hashemi S, Hasheminia M, Azizi F. Iranian Journal of Endocrinology and Metabolism. 2011: 13 (4): 339 – 345.

A Study of Arsenic in Drinking Water in East Azerbaijan Province, Iran Consumption of water contaminated with arsenic can cause various adverse health effects. The Iranian standard for arsenic in drinking water is 50 µg/L, while World Health Organization (WHO) has recommended a maximum level of 10 µg/L of arsenic in drinking water. As some drinking water sources are contaminated with arsenic in Hashtrood, East Azerbaijan Province, Iran (a neighborhood of Charoymagh) and since arsenic detection is not currently included in routine monitoring of drinking water, this study has aimed to trace detectable amounts of arsenic in drinking water sources of the Charoymagh district, East Azerbaijan Province. Water supply, sanitation status, and presence of arsenic were studied in the Charoymagh district and residential villages. Water sampling and field work was carried out by environmental health experts. The EZ Arsenic Test kit was used for testing arsenic levels in the water samples. Out of 210 villages, arsenic was detected in the drinking water of 41 villages (19.52%). In 8 villages, the level of arsenic in the drinking water was higher than the allowable Iranian standard of 50 µg/L. In 33 villages, the arsenic concentration was 10 µg/L ≤ <50 µg/L. A total number of 7290 individuals (22.06%) were exposed to higher than recommended WHO levels of arsenic in their drinking water. It is concluded that Charoymagh district is an area that contains arsenic in some of the drinking water sources. It is necessary to replace water sources that have high levels of arsenic with safe drinking water in those villages.

Source: Hosseinpour Feizi MA, Mosaferi M, Dastgiri S, Kusha A. Medical Journal of Tabriz University of Medical Sciences and Health Services. 2011; 33 (2): 25 – 31.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 263 Excerpts from Persian Medical Literature An Assessment on Frequency of Accidents and Related Factors in Professional Drivers of Heavy Vehicles

Based on a World Health Organization (WHO) report, 1.3 million deaths per year worldwide are the results of traffic accidents. It is expected that any number of injuries and deaths that result from traffic accidents would rise by 65% (injuries) and 80% (deaths) until the year 2020. According to data from WHO, Iran has one of the highest mortality rates from traffic accidents in the world. The aim of this study is to assess traffic accident rates and related factors among professional drivers of heavy vehicles. This study is a cross-sectional, descriptive analytic survey. A total of 1136 professional, heavy vehicle drivers who presented to one of the driver’s periodic examination centers in the city of Yazd were included in this study. Required data that included a history of traffic accidents, age, driving experience, and weekly work hours were collected through a questionnaire. The rate of reported accidents in one year was 7.7%. The findings showed a significant relationship between factors such as age, body mass index, work hours, shift work and traffic accidents (P < 0.05%). Second job, chronic illnesses, and driving experience had no significant relationship with traffic accidentsP ( > 0.05%). Even after adjustment of the study variables by regression analysis, there was a significant relationship between weekly work hours, body mass index, age over 60 and under 29 years and traffic accidents P( < 0.05%). Because of the increased risk of traffic accidents related to age over 60 years, it seems that a decrease in professional drivers’ work hours after this age may reduce traffic accidents. In addition, advice and supervision on the reduction of drivers’ weekly work hours could lead to decreased numbers of traffic accidents.

Source: Seyyedmehdi SM, Dehghan F, Salari S, Hedayati Mashkale M, Attarchi M. Scientific Journal of Forensic Medicine Islamic Republic of Iran. 2010; 16 (3): 187 – 94.

264 Archives of Iranian Medicine, Volume 15, Number 4, April 2012 S. Massarrat

Commented Summary from Current Medical Literature “Serum Pepsinogen II as a Good Marker for Mass Screening and Eradication of H. pylori Infection in Populations at risk for Gastric Cancer”

Cite the article as: Massarrat S, Sheykholeslami A. “Serum Pepsinogen II as a Good Marker for Mass Screening and Eradication of H. pylori Infection in Popula- tions at risk for Gastric Cancer”. Arch Iran Med. 2012; 15(4): 265 – 266.

Summary: Serum pepsinogen II (sPGII) is underutilized and fective biomarker for the diagnosis of gastritis.7 In this large study, considered an inconspicuous biomarker in clinical practice. We serum pepsinogen II levels were measured in more than 2000 refocused on this neglected but novel biomarker and conducted patients in relation to morphological findings of gastric mucosa. the present study, aiming to elucidate the normal level of sPGII in This study confirmed both our early report8 and that of Kiyohira et healthy Chinese patients and to investigate the clinical utility of al.9 where high serum pepsinogen II levels were good biomarkers sPGII for gastric disease screening. of gastritis. In 2008–2009, a total of 2022 participants from northern China Thus, we would like to comment on this thoroughly performed were selected and enrolled in the study. sPGII and Helicobacter study, based upon our earlier and ongoing investigations: pylori (H. pylori)–immunoglobulin G were measured with ELI- • Unfortunately, the classification of gastritis is not performed SA. according to the up-to-date Sydney report. Only one biopsy was sPGII showed a normal value of 6.6 microg/L in a total of 466 taken from the corpus and two from the antrum. The authors have patients with endoscopically- and histologically-normal stom- not considered the severity, extent, and predominance of gastritis achs. A small sex difference was observed: the average value of in the antrum or corpus or the presence of multifocal pangastritis, sPGII was 7 microg/L and 6 microg/L in males and females, re- grade of precancerous conditions and their localizations in this spectively (P < 0.001). In the differentiation between healthy and large study. diseased (endoscopically-diseased stomach or gastritis/atrophic • As there were a large number of patients, a very small differ- gastritis in endoscopic biopsies) stomach mucosae, the best sP- ence could be found in the levels of pepsinogen II in males and GII cut-off value was 8.25 microg/L (sensitivity 70.6%, specific- females, which seems to be of no clinical importance. Howev- ity 70.8%). In screening the H. pylori seropositivity, the optimum er, other factors such as BMI, physical activity or exercise, and cut-off sPGII value was 10.25 microg/L (sensitivity 71.6%, speci- particularly the fasting state of the subjects before taking blood ficity 70.1%). samples must be considered in a comparison between both sexes. We demonstrated that the mean values of sPGII in a healthy Chi- Sham feeding and meal intake have an important effect on the nese population are 7 microg/L and 6 microg/L for males and fe- level of total serum pepsin activity (pepsinogen I and II together) males, respectively. sPGII significantly increases in diseased and and pepsinogen I.10 Smoking habits differ between males and fe- H. pylori-infected stomach, and the best sPGII cut-off value is males; there is higher gastric acid secretion in smokers than non- 8.25 microg/L in the differentiation between patients with healthy smokers.11 and diseased stomach mucosae. Furthermore, Chinese patients • We found a serum pepsinogen II level of 6.6 ± 2.8 µg/mL in 51 with sPGII greater than 10.25 microg/L are at greater risk of vari- subjects with completely normal mucosa in the antrum and cor- ous H. pylori-related gastropathies, and are therefore prior candi- pus, which approximated the same level mentioned in the Chinese dates for gastro-protection therapy. paper, with 8.25 µg/mL as the cut-off value for the differentiation between the subjects with gastritis and those with normal mucosa. Source: He CY, Sun LP, Gong YH, Xu Q, Dong NN, Yuan Y. J • He et al. did not find any difference in serum pepsinogen II lev- Gastroenterol Hepatol. 2011; 26: 1039 – 1046. els in subjects with superficial gastritis and those with dysplasia and gastric cancer. Such patients usually have a very advanced Comments: It has been over three decades since the measure- atrophic gastritis with severe inflammation and intestinal meta- ment of serum pepsinogens have been introduced after their puri- plasia in the upper stomach. If the authors had had taken mul- fication from gastric mucosa for the diagnosis of certain advanced tiple biopsy specimens from the corpus, as in our study where we gastric diseases,1–4 particularly in Japan for those at risk for gastric obtained 3 specimens, they would have verified higher levels of cancer.5,6 Despite this widespread determination of pepsinogen I serum pepsinogen II in subjects with advanced disorders in the and II, attention was paid only to low serum levels of pepsinogen corpus. I and the low ratio of pepsinogen I to pepsinogen II for the diagno- • As serum levels of pepsinogen II decrease more than pepsin- sis of corpus atrophy. The relationship between pepsinogen II and ogen I, a few weeks after H. pylori eradication (about 50% vs. H. pylori-induced morphological changes of the gastric mucosa 30%),12–18 thus it would be a suitable marker to determine suc- were ignored. cessful H. pylori eradication. This would mean that with the In a recent Chinese publication by He et al., according to the measurement of serum pepsinogen II levels, not only would H. results of one study on a large number of patients, the authors pylori-induced gastritis be screened in the population, but its suc- claimed that the determination of serum pepsinogen II levels has cessful eradication can be verified by its remarkable decrease in been completely neglected in the last decades as an important, ef- comparison with values prior to eradication.

Archives of Iranian Medicine, Volume 15, Number 4, April 2012 265 Commented Summary from Current Medical Literature

While the measurement of pepsinogen I detects those with ad- diseased and normal stomachs. J Gastroenterol Hepatol. 2011; 26: vanced corpus gastritis who are at risk for gastric cancer develop- 1039 – 1046. 8. Haj-Sheykholeslami A, Rakhshani N, Amirzargar A, Rafiee R, Sha- ment (which, according to many studies, does not regress signifi- hidi SM, Nikbin B, et al. Serum pepsinogen I, pepsinogen II, and gas- cantly after H. pylori eradication), high levels of pepsinogen II trin 17 in relatives of gastric cancer patients: comparative study with are a good parameter of H. pylori-induced gastritis. It is a suitable type and severity of gastritis. Clin Gastroenterol Hepatol. 2008; 6: marker for the mass eradication of H. pylori, which would prevent 174 – 179. 9. Kiyohira K, Yoshihara M, Ito M, Haruma K, Tanaka S, Chayama K. the development of atrophic gastritis and precancerous conditions Serum pepsinogen concentration as a marker of Helicobacter pylori in areas at high risk of gastric cancer. Additionally, its decline after infection and the histologic grade of gastritis; evaluation of gastric eradication indicates treatment success. mucosa by serum pepsinogen levels. Br J Cancer. 1996; 73: 819 – 824. 10. Schumann KM, Massarrat S. Changes in total pepsin activity and pep- Author: Sadegh Massarrat MD, Arghavan Sheykholeslami MD, sinogen I in human sera under stimulation and inhibition of gastric Digestive Diseases Research Center, Shariati Hospital, Tehran acid secretion. Hepatogastroenterology. 1991; 38 (suppl 1): 33 – 36. University of Medical Sciences, Tehran, Iran. E-mail: massarrat@ 11. Massarrat S, Enschai F, Pittner PM. Increased gastric secretory capacity in smokers without gastrointestinal lesions. Gut. 1986; 27: 433 ams.ac.ir – 439. 12. Hunter FM, Correa P, Fontham E, Ruiz B, Sobhan M, Samloff IM. Se- rum pepsinogens as markers of response to therapy for Helicobacter pylori gastritis. Dig Dis Sci. 1993; 38: 2081 – 2086. References 13. Wagner S, Haruma K, Gladziwa U, Soudah B, Gebel M, Bleck J, et al. Helicobacter pylori infection and serum pepsinogen A, pepsinogen 1. Kushner I, Rapp W, Burtin P. Electrophoretic and immunochemical C, and gastrin in gastritis and peptic ulcer: significance of inflamma- demonstration of the existence of four human pepsinogens. J Clin In- tion and effect of bacterial eradication. Am J Gastroenterol. 1994; 89: vest. 1964; 43: 1983 – 1993. 1211 – 1218. 2. Matzku S, Rapp W. Purification of human gastric protease by im- 14. Furuta T, Kaneko E, Baba S, Arai H, Futami H. Percentage changes in munnoadsorbents: pepsinogen II group. Biochem Biophys Acta. 1976; serum pepsinogens are useful as indices of eradication of Helicobacter 446: 30 – 40. pylori. Am J Gastroenterol. 1997; 92: 84 – 88. 3. Samloff IM, Liebman WM. Cellular localization of the group II pep- 15. Bermejo F, Boixeda D, Gisbert JP, Sanz JM, Defarges V, Alvarez Ca- sinogens in human stomach and duodenum by immunofluorescence. latayud G, et al. Basal concentrations of gastrin and pepsinogen I and Gastroenterology. 1973; 65: 36 – 42. II in gastric ulcer: influence of Helicobacter pylori infection and use- 4. Samloff IM, Varis K, Ihamaki T, Siurala M, Rotter JI. Relationships fulness in the control of the eradication. Gastroenterol Hepatol. 2001; among serum pepsinogen I, serum pepsinogen II, and gastric mucosal 24: 56 – 62. histology. A study in relatives of patients with pernicious anemia. Gas- 16. Gisbert JP, Boixeda D, Al-Mostafa A, Vila T, de Rafael L, Alvarez troenterology. 1982; 83: 204 – 209. Baleriola I, et al. Basal and stimulated gastrin and pepsinogen levels 5. Miki K, Ichinose M, Shimizu A, Huang SC, Oka H, Furihata C, et al. after eradication of Helicobacter pylori: a 1-year follow-up study. Eur Serum pepsinogens as a screening test of extensive chronic gastritis. J Gastroenterol Hepatol. 1999; 11: 189 – 200. Gastroenterol Jpn. 1987; 22: 133 – 141. 17. Maconi G, Lazzaroni M, Sangaletti O, Bargiggia S, Vago L, Bianchi 6. Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, et al. Porro G. Effect of Helicobacter pylori eradication on gastric histology, Asia Pacific Working Group on Gastric Cancer. Screening for gastric serum gastrin and pepsinogen I levels, and gastric emptying in patients cancer in Asia: current evidence and practice. Lancet Oncol. 2008; 9: with gastric ulcer. Am J Gastroenterol. 1997; 92: 1844 – 1848. 279 – 287. 18. Plebani M, Basso D, Scrigner M, Toma A, Di Mario F, Dal Bò N, et al. 7. He CY, Sun LP, Gong YH, Xu Q, Dong NN, Yuan Y. Serum pep- Serum pepsinogen C: a useful marker of Helicobacter pylori eradica- sinogen II: a neglected but useful biomarker to differentiate between tion? J Clin Lab Anal. 1996; 10: 1 – 5.

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