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Home , Chelation, Dimercaptosuccinic acid, Penicillamine

Elmer Press Case Report J Med Cases. 2014;5(4):187-193

Lead Intoxication Treated With D-

Yuka Iijimaa, Nobuhiro Akuzawaa, c, Takashi Hatoria, Kunihiko Imaia, Yonosuke Kitaharaa, Masahiko Kurabayashib

musculoskeletal pain, gastrointestinal complaints, headache, Abstract fatigue and hematological abnormalities [3]. Chronic intoxication may cause irreversible end-organ damage in the A 36-year-old man was admitted to our hospital with abdominal nervous system, endocrine glands, kidneys, joints and bones pain, nausea, weight loss and malaise. He had worked as a painter [3]. for 2 months. Laboratory testing showed anemia, dysfunction A diagnosis of lead intoxication is often overlooked be- and elevated blood lead concentration. After administration of oral cause the blood lead concentration does not reflect body lead D-penicillamine, his urinary lead increased significantly. stores [2]. Increased urinary lead excretion after - His abdominal pain resolved after 5 days. His clinical course was ethylenediaminetetraacetic acid (Ca-EDTA) administration otherwise uneventful. His anemia and liver dysfunction resolved after 2 months. His blood lead concentration remained normal for indicates high body lead stores [2]. Chelating agents such as a year after discharge without recurrence of plumbism. Physicians Ca-EDTA, D-penicillamine, (BAL) or succimer should be aware of the clinical features of plumbism because early (meso-2,3-, DMSA) can be used to diagnosis is difficult. treat lead intoxication [3, 4]. Here, we present a male patient who developed lead in- Keywords: Abdominal pain; Anemia; D-penicillamine; Lead in- toxication after working as a painter for 2 months. His main toxication complaints were loss of appetite, constipation and nausea. The main cause of his lead intoxication was probably inha- lation of lead particles while stripping anti-rust compounds

including Pb3O4 from a bridge. His symptoms rapidly im- Introduction proved after with D-penicillamine. This report focuses on the important symptoms for diagnosis of High lead concentrations can affect a wide range of biologi- lead intoxication and reviews previously reported cases, in- cal functions leading to gastrointestinal dysfunction, anemia, cluding discussion of the difficulty of early diagnosis. neurological dysfunction, hypertension and damage [1]. Inhalation or ingestion of lead particles results in lead intoxication. Inhalation of lead fumes or dust may cause Case Report lead intoxication in workers doing painting, paint removal or construction [1-3]. The symptoms of acute intoxication may A 36-year-old man was admitted to our hospital because of be subtle and non-specific, and patients may present with increasing fatigue, constipation and nausea. He had been a clerical worker until 3 months before admission, but the bankruptcy of his company had forced him to change jobs. Manuscript accepted for publication February 11, 2014 He had therefore started work as a painter 2 months before admission. His main duties were paint stripping and re- aDepartment of Internal , Social Insurance Gunma Chuo painting of a bridge. He wore a helmet, goggles, dust res- General Hospital, 1-7-13 Koun-cho, Maebashi, Gunma 371-0025, pirator, protective clothing and leather gloves. He started to Japan bDepartment of Medicine and Biological Science, Gunma University develop intermittent abdominal pain after 3 weeks and was Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, prescribed scopolamine butylbromide tablets at another hos- Gunma 371-8511, Japan pital, but his pain did not resolve. His body weight decreased cCorresponding author: Nobuhiro Akuzawa, Social Insurance Gunma from 55 kg to 48 kg over 8 weeks and he complained of per- Chuo General Hospital, 1-7-13 Koun-cho, Maebashi, Gunma sistent malaise, nausea and loss of appetite, and was admit- 371-0025, Japan. Email: [email protected] ted to our hospital for a detailed assessment. He had no re- doi: http://dx.doi.org/10.14740/jmc1698w markable past history or family history. He was a nonsmoker

Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org 187 188 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Iijima et al J Med Cases. 2014;5(4):187-193

Figure 1. (A) Abdominal X-ray on admission showed retention of feces suggesting constipation. There were no other abnormalities despite severe abdominal pain. (B) Blood smear on admission showed basophilic stippling in erythrocytes, leading to a suspicion of lead intoxication (original magnification × 400).

and did not drink . He was taking only mosapride and His urinary lead excretion measured from pooled sam- lansoprazole, which had been prescribed at another hospital. ples rose from 0.9 mg/day on day 2 to 5.1 mg/day on day 3, Physical examination on admission revealed that his and decreased thereafter (Fig. 2). The δ- height was 165 cm, weight was 48 kg, temperature was 37.3 (δ-ALA) concentration in spot urine samples peaked on day °C and heart rate was 78 beats/min. He was hypertensive, 2 and then gradually decreased. His abdominal pain resolved with a blood pressure of 155/84 mmHg. He had moderate by day 5, and he was able to tolerate a normal diet by day conjunctival pallor, gray pigmentation of the gingiva and 10. His constipation improved over the same period. From hyperactive bowel sounds, but no abdominal tenderness. day 7, his urinary lead excretion measured from pooled Neurological examination showed no abnormalities. Elec- urine samples stayed less than 0.5 mg/day, and his δ-ALA trocardiography and chest X-ray were normal, and abdomi- concentration in spot urine samples stayed below 15 mg/L. nal X-ray showed increased intestinal gas and constipation We therefore stopped on day 8. Although (Fig. 1A). Routine laboratory testing on admission showed his anemia and associated symptoms such as shortness of normocytic normochromic anemia, mild liver dysfunction, breath on effort persisted, he was discharged from hospital hyponatremia and a high blood urea nitrogen level (Table on day 14, because his concentration was gradu- 1). His serum and haptoglobin levels were normal. His ally improving. He was moved to the sales department of unsaturated iron binding capacity was low despite a high se- his company, where there was no possibility of further ex- rum ferritin level, suggesting abnormal iron utilization. He posure to lead. His blood lead concentration was 26.3 µg/dL had normal serum levels of vitamin B12 (486 pg/mL, normal at 1 month after discharge and 15.9 µg/dL at 2 months. His range: 180 - 914 pg/mL) and folic acid (5.4 ng/mL, normal δ-ALA concentration in spot urine samples also normalized range: 2.4 - 9.7 ng/mL). His blood smear showed basophilic to 2.1 mg/L after 2 months. His hemoglobin concentration stippling (Fig. 1B) and a high reticulocyte count (4.1%). His increased to 10.0 g/dL after 1 month, and returned to normal urinary hippuric acid, methylhippuric acid and 2,5-hexane- (14.5 g/dL) after 2 months. His serum ferritin level decreased dione levels were not elevated. We measured his blood lead, to 212.3 ng/mL after 1 month and normalized to 69.6 ng/ chromium and cadmium concentrations because his history mL after 2 months, and his liver dysfunction resolved after suggested possible inhalation or ingestion of stripped paint 2 months. The basophilic stippling in his blood smear also dust including these heavy . His blood chromium con- resolved after 2 months. He was well at his 1-year follow-up centration was < 2 µg/dL and cadmium concentration was < assessment, with no recurrence of plumbism. 1 µg/dL, but his blood lead concentration was high (111 µg/ dL, normal range: < 20 µg/dL). The diagnosis of lead intoxication was confirmed with a Discussion positive lead chelation test. We initially intended to adminis- ter Ca-EDTA as a first-line chelating agent, but it would have The most common clinical picture of plumbism is of chronic taken about a week to obtain this. Instead, we administered lead intoxication, often due to occupational exposure over a 1 g/day of D-penicillamine orally for a week from day 2. prolonged period [5]. The blood lead concentration reflects

187 188 Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org Lead Intoxication J Med Cases. 2014;5(4):187-193

Table 1. Laboratory Findings on Admission

Hematology Red blood cells* 268 × 104/mm3 Hemoglobin* 8.1 g/dL Hematocrit* 23.7% MCV 88.4 fL MCH 30.2 pg White blood cells 6,900/mm3 Platelets 28.5 × 104/mm3 Biochemistry Total 7.2 g/dL Albumin 5.0 g/dL AST 32 IU/L ALT* 74 IU/L LDH 196 IU/L ALP 217 IU/L g-GTP 38 IU/L Total bilirubin* 2.4 mg/dL Direct bilirubin 0.2 mg/dL Choline esterase 238 IU/L CPK 120 IU/L Amylase 106 IU/L Total cholesterol 158 mg/dL Blood urea nitrogen* 26.6 mg/dL Creatinine 0.74 mg/dL Uric acid 3.5 mg/dL Sodium* 134 mEq/L Potassium 4.5 mEq/L Chloride 101 mEq/L Glucose 108 mg/dL Iron 157 mg/dL UIBC* 74 mg/dL Ferritin* 341 ng/mL Haptoglobin 121 mg/dL

*These values are outside the normal ranges. MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin; AST: aspartate aminotransferase; ALT: alanine aminotrans- ferase; LDH: lactate dehydrogenase; ALP: alkaline phosphatase; γ-GTP: gamma-glutam- yltranspeptidase; CPK: creatine phosphokinase; UIBC: unsaturated iron binding capacity. lead distribution in the red blood cells and plasma and may bones [6]. The blood lead concentration may therefore not be be useful for the diagnosis of plumbism, but lead is also dis- an accurate reflection of previous lead absorption if the expo- tributed in the soft tissues and bones [6]. The active pool sure is not continuous and ongoing. Moreover, many patients is distributed in the blood and soft tissues and the storage who presented with severe had lower blood pool is in the bones [6]. The half-life of lead is 35 days in lead concentrations (< 40 µg/dL) [7], suggesting a need for the blood, 40 days in the soft tissues and 20 - 30 years in the other indicators for early-stage diagnosis of plumbism. Lead

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Figure 2. Daily urinary lead excretion (rectangles) and δ-aminolevulinic acid (δ-ALA) concentration in spot urine samples (triangles). The δ-ALA concentration peaked on day 2. Lead excretion increased significantly after ad- ministration of D-penicillamine, peaking on day 3. Both parameters gradually decreased after the peak.

is an electropositive with a high affinity for sulfhy- in lead poisoning is 25 - 35 mg/kg/day in divided doses for dryl groups, and inhibits 5-aminolevulinic acid dehydratase 3 weeks, with a gap of 7 days between courses [13]. Two or and ferrochelatase [8]. A high urinary δ-ALA concentration three courses of D-penicillamine are often needed to reduce or blood protoporphyrin level may therefore be useful the blood lead concentration to an acceptable level [13, 14]. for diagnosing lead intoxication, especially in patients with Fortunately, our patient did not develop any complications an acceptable blood lead concentration despite symptoms of related to D-penicillamine therapy, and there was no re- lead intoxication. Furthermore, re-elevation of the urinary elevation of his urinary δ-ALA concentration or blood lead δ-ALA level due to tissue redistribution of lead can indicate concentration after 7 days of chelation therapy. This suggests the need for additional administration of chelating agents that a single course of oral D-penicillamine can provide suf- [9]. Measurement of the total urinary lead excretion the day ficient chelation of lead in patients with relatively low body after Ca-EDTA infusion (30 mg/kg, up to 2 g) is the most di- lead levels. rect method of estimating the total body lead burden, and this A previous review of adult cases of inorganic lead intox- test is positive if a 24-h urine collection after chelation con- ication reported 31 cases due to occupational exposure [15]. tains more than 2.89 µmol (0.6 mg) [3]. In the present case, Of these, 29% had no complaints, and the most common we administered D-penicillamine instead of Ca-EDTA and symptom in the remainder was abdominal pain, followed the 24-h urinary lead excretion peaked at 5.1 mg/day. Until by fatigue and arthralgia. All six patients who presented recently, Ca-EDTA and BAL were the main drugs used for with acute-onset symptoms had abdominal pain. Moreover, the treatment of lead intoxication in adults [10]. Both these loss of appetite and weakness are more common in patients drugs are not effective when taken orally, and should be ad- with plumbism than in healthy adults [14]. We searched the ministered intravenously [10]. Ca-EDTA is also reported to PubMed database from 2000 to 2013, and found 10 report- remove substantial amounts of zinc, an essential metal, from ed patients with acute-onset symptoms of lead intoxication the body [11]. More recently, succimer (DMSA), a water- (Table 2) [5, 8, 16-20]. Six of these 10 patients had occupa- soluble analogue of BAL that can be administered orally, tional lead exposure, and nine underwent chelation therapy. has been used for the treatment of heavy metal poisoning The period of lead exposure was reported in only three cases. including lead, and [12]. D-penicillamine Although most of the patients had symptoms such as abdom- is another chelating agent that can be taken orally, but is not inal pain, malaise, headache, nausea and constipation, they as effective as EDTA or BAL, and is associated with serious did not seek treatment from a hospital or their local doctor adverse events including nephrotic syndrome, severe bleed- while they could still tolerate the symptoms, leading to de- ing and [10]. The results of a recent study suggest lays in diagnosis and treatment [17]. In five patients (cases that the optimal regimen for D-penicillamine administration 5, 6, 8, 9 and 10), abdominal pain led to consultation with a

189 190 Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org Lead Intoxication J Med Cases. 2014;5(4):187-193

Table 2. Reported Adult Patients with Acute-Onset Symptoms of Lead Intoxication

Blood Age, sex, Exposure Illness Hb (g/ Chelation Case Author Symptoms lead level occupation period period dL) therapy (µg/dL)

1 Ziegler [14] 16, F, Unknown 6 months Abdominal pain, 91.9 9.2 EDTA unknown weight loss

2 Bennett [8] 40, M, painter Unknown 6 weeks Abdominal pain, 87.1 9.4 EDTA malaise, arthralgia, DMSA mental impairment

3 Bennett [8] 51, M, Unknown 4 weeks Headache, 84.2 13.2 EDTA decorator nausea, dizziness, DMSA constipation, hand weakness

4 Bennett [8] 22, M, painter Unknown 2 weeks Abdominal pain, 85.2 9.7 EDTA malaise, nausea, DMSA headache

5 Ogawa [17] 34, M, painter 1 month Unknown Abdominal pain 73.1 10.5 EDTA

6 Ogawa [17] 30, M, painter 2 months 2 months Chest, back and 96.3 12.4 EDTA abdominal pain, nausea

7 Dounias [18] 33, F, battery 3 months 2 weeks Abdominal pain, 90.0 8.0 DMSA worker malaise 8 Barber [5] 26, M, Unknown 2 weeks Abdominal pain, 157.8 Unknown (-) unknown , erratic behavior

9 Verheiji [19] 40, M, Unknown A few Abdominal pain 86.0 9.2 EDTA unknown weeks

10 Shamshirsaz Unknown, F, Unknown 9 days Abdominal pain, 102.0 9.3 DMSA [20] unknown , loss of appetite

M: male; F: female; Hb: hemoglobin; EDTA: intravenous calcium-ethylenediaminetetraacetic acid; DMSA: oral meso-2,3-dimercaptosuc- cinic acid. doctor even though preceding nonspecific complaints such 15, 17]. Basophilic stippling, caused by aggregation of ribo- as fatigue, malaise and headache had been tolerated [5, 17, nucleic acid within erythrocytes due to inhibition of pyrimi- 19-21]. None of the reported cases had severe encephalopa- dine 5’-nucleotidase [3, 8], was observed in seven of the cas- thy. Routine hematology and biochemistry testing may show es. Although basophilic stippling was also found in 27% of anemia, which is typically hypochromic and microcytic and consecutive internal medicine patients without lead exposure generally appears when the blood lead concentration exceeds and in patients with thalassemia [18, 22], it is worth remem- 50 µg/dL [8]. Anemia is therefore not observed in all pa- bering that this finding may indicate lead intoxication [19]. tients with lead intoxication, and bone marrow biopsy does An elevated urinary δ-ALA or level in the absence not show specific findings [18]. It should be noted that the of urinary porphobilinogen may enable definitive diagnosis hemoglobin concentration was above 10 g/dL in three cases of lead intoxication, and diagnostic testing for porphyria is (cases 3, 5 and 6) despite high blood lead concentrations [8, therefore recommended [5, 18]. A high blood zinc protopor-

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phyrin level is also useful for diagnosis [13, 19]. Increased 2. Pollock CA, Ibels LS. Lead intoxication in paint remov- serum alanine aminotransferase or creatinine levels may be al workers on the Sydney Harbour Bridge. Med J Aust. observed [5, 20, 21], but these findings are also nonspecific. 1986;145(11-12):635-639. In some patients, especially those with no obvious history of 3. Rae CE, Bell CN, Jr., Elliott CE, Shannon M. Ten cases occupational lead exposure, diagnosis may be delayed from of acute lead intoxication among bridge workers in Lou- the time of first presentation with symptoms and it may take isiana. DICP. 1991;25(9):932-937. several months to start appropriate treatment for lead intoxi- 4. Rempel D. The lead-exposed worker. JAMA. cation [16]. In case 1, the occasional use of a mug with a 1989;262(4):532-534. ceramic inner surface that contained lead caused intoxica- 5. Barber T, Jacyna M. Acute lead intoxication from tion [16]. In case 8, ingestion of purchased online purchased online presenting with recur- for erectile dysfunction led to acute lead intoxication [5]. A rent abdominal pain and encephalopathy. J R Soc Med. recent study also reported cases of lead intoxication due to 2011;104(3):120-123. regular use of lead-contaminated opium (case 9) or alterna- 6. Grimsley EW, Adams-Mount L. Occupational lead tive medications (case 10) [19, 20]. Physicians should there- intoxication: report of four cases. South Med J. fore be aware that lead intoxication can be associated with 1994;87(7):689-691. food preparation or storage habits, medications and opium 7. Beritic T. Lead concentration found in human blood addiction, as well as occupational lead exposure. in association with lead colic. Arch Environ Health. In conclusion, we reported a patient who presented with 1971;23(4):289-291. lead intoxication after 2 months of occupational lead inhala- 8. Gordon JN, Taylor A, Bennett PN. Lead poisoning: case tion despite appropriate use of a respirator. Chelation thera- studies. Br J Clin Pharmacol. 2002;53(5):451-458. py with oral D-penicillamine was effective and his clinical 9. Molina-Ballesteros G, Zuniga-Charles MA, Sanchez- course was good. Abdominal pain is the most frequent symp- Anzaldo FJ, Gonzalez-Ramirez JD. Urinary delta-ami- tom in patients with acute-onset symptoms of lead intoxica- nolevulinic acid as a biological indicator throughout tion, and concomitant symptoms are nonspecific for making penicillamine therapy in lead intoxication. Arch Environ a diagnosis. Thus, it may be difficult for physicians to make Health. 1978;33(6):308-313. a rapid diagnosis of lead intoxication. Physicians should be 10. Llobet JM, Domingo JL, Paternain JL, Corbella J. Treat- aware of the possibility of lead intoxication and the potential ment of acute lead intoxication. A quantitative compari- causes of plumbism when investigating patients with fre- son of a number of chelating agents. Arch Environ Con- quent abdominal pain with no obvious cause. tam Toxicol. 1990;19(2):185-189. 11. Chisolm JJ, Jr. Treatment of acute lead intoxication- -choice of chelating agents and supportive therapeutic Acknowledgements measures. Clin Toxicol. 1970;3(4):527-540. 12. Aposhian HV. DMSA and DMPS--water soluble anti- The authors would like to thank Mr. Yousuke Kitadume for dotes for heavy metal poisoning. Annu Rev Pharmacol his assistance in preparing blood smear samples and Miss Toxicol. 1983;23:193-215. Hisae Kuribara for her secretarial assistance under the fi- 13. Dsouza HS, Dsouza SA, Menezes G, Thuppil V. Evalu- nancial support provided by Social Insurance Gunma Chuo ation and treatment of wrist drop in a patient due to lead General Hospital. poisoning: case report. Ind Health. 2009;47(6):677-680. 14. D’Souza H S, Dsouza SA, Menezes G, Venkatesh T. Diagnosis, evaluation, and treatment of lead - Grant Support ing in general population. Indian J Clin Biochem. 2011;26(2):197-201. None. 15. Cullen MR, Robins JM, Eskenazi B. Adult inorganic lead intoxication: presentation of 31 new cases and a re- view of recent advances in the literature. Medicine (Bal- Financial Disclosure timore). 1983;62(4):221-247. 16. Ziegler S, Wolf C, Salzer-Muhar U, Schaffer A, Kon- All the authors report no conflicts of interest. naris C, Rudiger H, Osterode W. Acute lead intoxication from a mug with a ceramic inner surface. Am J Med. 2002;112(8):677-678. References 17. Ogawa M, Nakajima Y, Kubota R, Endo Y. Two cases of acute lead poisoning due to occupational exposure to 1. International Program on Chemical Safety (IPCS). Envi- lead. Clin Toxicol (phila). 2008;46(4):332-335. ronmental Health Criteria 379. Geneva: WHO, 2013. 18. Dounias G, Rachiotis G, Hadjichristodoulou C. Acute

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lead intoxication in a female battery worker: Diagnosis abdominal pain during . Obstet Gynecol. and management. J Occup Med Toxicol. 2010;5:19. 2009;114(2 Pt 2):448-450. 19. Verheij J, Voortman J, van Nieuwkerk CM, Jarbandhan 21. Carton JA, Maradona JA, Arribas JM. Acute-subacute SV, Mulder CJ, Bloemena E. Hepatic morphopathologic lead poisoning. Clinical findings and comparative study findings of lead poisoning in a drug addict: a case report. of diagnostic tests. Arch Intern Med. 1987;147(4):697- J Gastrointestin Liver Dis. 2009;18(2):225-227. 703. 20. Shamshirsaz AA, Yankowitz J, Rijhsinghani A, Grein- 22. Cheson BD, Rom WN, Webber RC. Basophilic stippling er A, Holstein SA, Niebyl JR. Severe lead poisoning of red blood cells: a nonspecific finding of multiple eti- caused by use of health supplements presenting as acute ology. Am J Ind Med. 1984;5(4):327-334.

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