Self-assessment corner 311 Postgrad Med J: first published as 10.1136/pgmj.73.859.311 on 1 May 1997. Downloaded from Familial chronic fatigue

D Keith George, Richard M Evans, Ian R Gunn

A 53-year-old woman presented to her general practitioner with a long history of profound lethargy associated with insomnia and arthralgia mainly affecting her knees. The patient dated her symptoms to a 'flu-like' illness six months previously. Medical history was ofhypertension treated with an angiotensin-converting enzyme inhibitor and thiazide diuretic. She had also been taking oestrogen replacement since the menopause two years earlier. She had been a blood donor until 13 years previously, donating a total of 24 units ofblood. She drank four units of alcohol per week but did not smoke. Physical examination was normal. Initial investigations performed were full blood count, urea and electrolytes, , , random glucose, , calcium and urate. All were normal. Rheumatoid factor was negative and viral showed a raised IgG antibody titre to Epstein Barr virus, indicative of a past infection. X- Rays of the knee joints were normal. A diagnosis of chronic fatigue syndrome was made. Over the following months her symptoms Law Hospital, impaired her ability to work, shop and perform household tasks. Further Carluke, Lanark- medical consultations shire, ML8 SER, UK revealed no new features or abnormal tests and she took early retirement on the grounds of poor Department of health. Medicine Two years after her initial presentation, her brother, who had also been suffering from DK George longstanding fatigue, was diagnosed as having liver disease. Department of Biochemistry Questions RM Evans IR Gunn 1 Could liver disease account for the patient's illness, and if so, what is the most likely Correspondence to Dr diagnosis? Gunn 2 What tests would you request to investigate your suspected diagnosis? Accepted 28 February 1996 3 How would you confirm the diagnosis and manage her condition? http://pmj.bmj.com/ on September 28, 2021 by guest. Protected copyright. 312 George, Evans, Gunn

Answer mochromatosis but regular ultrasound scan- ning in combination with cx-fetoprotein testing,

QUESTION 1 particularly in male cirrhotics, may detect Postgrad Med J: first published as 10.1136/pgmj.73.859.311 on 1 May 1997. Downloaded from Fatigue is a common symptom of liver disease tumours small enough for treatment.2 Dietary which may be disabling and is often over- restrictions are not generally necessary but looked. Whilst arthralgia is not a typical feature patients should be told to avoid vitamin of chronic liver disease in general, fatigue and preparations containing iron and vitamin C. arthralgia are the commonest presenting symp- Screening of first degree relatives with toms of genetic haemochromatosis. fasting and serum levels (with additional HLA typing in siblings) QUESTION 2 should be undertaken. The heterozygote fre- Unlike virtually every other type of acute or quency of the abnormal gene is around 10% in chronic liver disease, liver function tests are the general population and so sons and often normal in haemochromatosis. Ultra- daughters of patients with haemochromatosis sound scanning is usually not helpful in have a 5% chance of being homozygotes. making the diagnosis, though hepatomegaly The patient had 65 units of blood (16 g of may be present. Fasting transferrin saturation iron stores) removed with a substantial im- and serum ferritin should be performed if the provement in her symptoms. diagnosis is suspected. An elevated fasting transferrin saturation (males >60%, females Discussion > 50%) and an elevated serum ferritin suggest the diagnosis of haemochromatosis,' though Genetic haemochromatosis is an autosomal the serum ferritin can be normal early in the recessive inherited disorder of iron disorder before significant iron overload devel- involving an inappropriately high level of iron ops. may be elevated but is often absorption from the small bowel. It is the normal and is not useful in establishing the commonest inherited liver disorder and one of diagnosis. If serum ferritin but not transferrin the commonest autosomal recessive disorders, saturation is elevated, then haemochromatosis occurring in approximately 1 in 300 people in is unlikely. Serum ferritin can be elevated in Caucasian populations.2 Although not yet inflammatory and carcinomatous conditions, cloned, the gene is known to lie close to the as well as liver diseases other than haemochro- HIA locus on the short arm of chromosome 6 matosis, such as alcoholic liver disease. and they are almost invariably inherited to- This patient had a fasting transferrin satura- gether. HLA A3 is the commonest HLA type tion of 84% (normal < 50%) and serum associated with haemochromatosis, occurring ferritin of 2823 ng/ml (normal < 200). in approximately 70% of cases. However, testing for this HLA type cannot be used to QUESTION 3 diagnose isolated cases of haemochromatosis The diagnosis is confirmed by liver biopsy. as HLA A3 occurs in approximately 30% ofthe

Histology of sections stained with Perls' stain Caucasian population.4 http://pmj.bmj.com/ shows the characteristic pattern of parenchy- Untreated, iron gradually accumulates in a mal iron overload. Measurement of the dry variety of tissues, and can eventually result in liver iron weight, if available, is also valuable as organ failure and the protean clinical signs and the 'hepatic iron index' can be calculated. symptoms of the disease. The classical triad of pigmentation, diabetes mellitus and , Hepatic iron index = dry liver iron weight (,umol/g) the most severe end age (years) however, represents only of a spectrum of clinical disease expression and on September 28, 2021 by guest. Protected copyright. A value > 2 reliably differentiates haemochro- haemochromatosis should be considered in the matosis from other conditions associated with differential diagnosis of a wide variety of increased hepatic iron stores.3 symptoms and presentations as shown in box HLA typing can be used to confirm the 1. Asymptomatic cases are now often diag- diagnosis in siblings of an index case. The nosed by family screening. patient was HLA identical to her brother who Fatigue is the commonest symptom present had had haemochromatosis diagnosed by liver at diagnosis regardless of whether cirrhosis is biopsy. However, if iron indices are elevated, it present or not. Although a symptom of liver is still important to perform liver biopsy to failure and cirrhosis, fatigue is often a promi- establish the presence or absence of cirrhosis, nent symptom of precirrhotic haemochroma- the most important prognostic factor in hae- tosis with normal liver function suggesting that mochromatosis. l it is iron overload per se that causes this Treatment is with regular venesection, usually once per week, until iron stores are depleted. To achieve this, venesection should Consider genetic haemochromatosis be continued until serum ferritin levels fall in the differential diagnosis of: below 100 ng/ml and anaemia develops. Main- * liver disease tenance venesection is then required, usually * heart failure two to four times per year. Ifcirrhosis is present * hyperglycaemia then there is a 200-fold increase in risk of the * arthritis patient developing a hepatocellular carcinoma, * hypogonadism even if iron stores are depleted.' Serum ax- * unexplained fatigue fetoprotein levels are often not elevated in hepatocellular carcinoma associated with hae- Box 1 Self-assessment corner 313

symptom. Liver function tests are often nor- Summary points mal, with one study showing two-thirds of

precirrhotic cases and one-third of cirrhotic * genetic haemochromatosis is a relatively Postgrad Med J: first published as 10.1136/pgmj.73.859.311 on 1 May 1997. Downloaded from cases having normal tests at diagnosis.' common disorder protean in its manifestations A number of studies have examined the * normal liver function tests do not exclude the diagnosis usefulness of a variety of investigations in the * pre- and peri-menopausal women are not assessment of patients presenting with chronic exempt from clinical expression of the disease fatigue in general practice. In general such * fasting serum transferrin saturation and serum investigations have not proved useful as only a ferritin are required to make a provisional low yield of abnormal results has been found. diagnosis However, such studies have not included * liver biopsy is required to confirm the diagnosis screening tests for haemochromatosis and and assess liver architecture sometimes not even liver function tests.5 Iron stores in haemochromatosis are pro- Box 2 moted by a diet rich in red meat and vitamin C and depleted by any cause of blood loss.2 It is normal. Although cirrhosis cannot be reversed often wrongly thought that premenopausal and the risk of hepatocellular carcinoma women are protected from iron overload and cannot be removed once cirrhosis has devel- organ damage by menstruation and the re- oped, liver function, cardiac function and quirements of pregnancy. However this pa- diabetic control may all improve with venesec- tient, who had cirrhosis due to tion as can symptoms such as fatigue.' haemochromatosis at diagnosis only four years after the menopause, illustrates that even Final diagnosis combined blood loss due to blood donation and menstruation may not prevent iron accu- Genetic haemochromatosis. mulation and subsequent organ damage. Venesection is required to deplete and Keywords: fatigue, haemochromatosis maintain iron stores at the lower limit of

1 Niederau C, Fisher R, Sonnenberg A, et al. Survival and 4 Simon M, Yaouanq J, Fauchet R, et al. Genetics of causes of death in cirrhotic and non-cirrhotic patients with haemochromatosis: HIA association and mode of inheri- primary haemochromatosis. N Engl Jf Med 1985; 313: tance. Ann NY Acad Sci 1988; 526: 11 - 22. 1256-62. 5 Ridsdale L, Evans A, Jerrett W, et al. Patients with fatigue in 2 Powell LW, Jazwinska E, Halliday JW. Primary iron general practice: a prospective study. BMJ' 1993; 307: 103- overload. In: Brock JH, Halliday JW, Pippard MJ, Powell 6. LW, eds. Iron metabolism in health and disease. London: WB Saunders, 1994; pp 227-70. 3 Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early haemochromatosis and determina- tion of the critical iron level associated with fibrosis. Hepatology 1986; 6: 24-9. http://pmj.bmj.com/

An unusual rectal polyp on September 28, 2021 by guest. Protected copyright. DS Bhandarkar, AW Caslin, MH Jamison

A 60-year-old woman underwent a flexible sigmoidoscopy for investigation of her complaint of minor rectal bleeding. The endoscopy revealed a 1-cm pale polypoidal lesion with normal overlying mucosa in mid-rectum and mild diverticular disease affecting the sigmoid colon. The polyp was snared and retrieved for histological examination. The microscopic appearance is shown in the figure.

Gwynedd Hospital, Bangor, Gwynedd Questions LL57 2PW, UK Department of Surgery 1 What is the most likely diagnosis? DS Bhandarkar 2 From which cell has this polyp originated? MH Jamison Department of Pathology AW Caslin Correspondence to Mr MH Jamison [w...... d...C.t Figure Haematoxylin and eosin stained section of Accepted 28 February 1996 polyp.