SELF ASSESSMENT ANSWERS an Interesting Case of Thirst and Polyuria a Proliferating Pimple

Home , Erythema gyratum repens, Menkes disease

Postgrad Med J 2002;78:251–254 251 Postgrad Med J: first published as 10.1136/pmj.78.918.254 on 1 April 2002. Downloaded from SELF ASSESSMENT ANSWERS A proliferating pimple Q1: What is the differential diagnosis

99m on clinical examination? An interesting case of thirst uptake on Tc thyroid uptake scan (fig 1; see p 248) and positive TSHRAb. The possible differential diagnosis on clinical and polyuria TSHRAb binds to the thyroid stimulating examination is: Q1: What are the possible causes of hormone receptor, activates adenylate cyclase, • Dermatofibroma. thirst and polyuria in this woman? and increases thyroid hormone production • Pyogenic granuloma. The two likely causes of thirst and polyuria in and secretion. The TSHRAb in Graves’ disease • Malignant melanoma. this patient are central diabetes insipidus sec- is referred to as stimulating or agonist type • Metastatic oat cell carcinoma. ondary to previous pituitary surgery and TSHRAb, while other varieties including a • Angiosarcoma. hypercalcaemia. In our patient, a normal blocking TSHRAb may also be present. The water deprivation test excluded central blocking antibody may be coincident with the Q2: What does the histology reveal diabetes insipidus. stimulating antibody. TSHRAb are not detect- (see p 249) and what histological Cranial surgery accounts for 20% cases of able in the normal population. A total of 80% techniques are used to establish the central diabetes insipidus in adults. After to 100% of untreated hyperthyroid patients diagnosis? pituitary surgery, persistent polyuria develops with Graves’ disease have detectable TSHRAb only when the injury is sufficiently high in the with thyroid stimulating activity.1 The histology reveals malignant round cells supraopticohypophyseal tract to cause degen- 99mTechnetium pertechnate, like iodine, is consistent with a Merkel cell carcinoma or eration of the supraoptic and paraventricular actively concentrated by the thyroid gland, trabecular carcinoma. This is a rare primary nucleus. Thus although transient diabetes undergoes negligible organic binding, and cutaneous neuroendocrine tumour arising insipidus may follow any injury to the neuro- diffuses out of the thyroid as the plasma con- from Merkel cells. hypophysis, permanent cranial diabetes insip- centration decreases. The short half life (six History 1 idus is uncommon after pituitary surgery. hours) and consequent low radiation makes it The Merkel cell is a round cell in the basal Hypercalcaemia causes transient nephro- suitable for thyroid imaging. Thyroid scinti- layer of the epidermis named after Fredrick genic diabetes insipidus manifested primarily graphy is used in the evaluation of nodular Sigmund Merkel who discovered it in 1875. as a defect in maximum renal concentrating thyroid disease, thyroid cancer, ectopic thyroid These round cells may be isolated or arranged ability accompanied by a reduction in tissue, and thyroiditis. It is not recommended in clusters around hair follicles, which are glomerular filtration rate. Other factors may in the evaluation of straightforward Graves’ innervated and function as touch receptors. include reduction in medullary solute content The tumour was first described by Toker in and inhibition by calcium of adenylate cyclase disease. In our patient, a diffusely increased 1972 who, along with Tang in 1978, described activation by arginine vasopressin in hormone uptake (even though thyroxine replacement sensitive epithelia.1 was stopped only seven days earlier) con- the intracytoplasmic dense core granules firmed the diagnosis of autoimmune hyper- similar to those seen in neuroendocrine cells.1 Q2: What are the possible causes of thyroidism. Q3: Discuss the clinical features and hypercalcaemia? management of this lesion The possible causes of hypercalcaemia include Q4: Is there an association between Clinical features thyrotoxicosis, relative glucocorticoid insuffi- acromegaly and thyrotoxicosis? ciency during illness and stress, dehydration, The Merkel cell carcinoma is a rare but acromegaly, and hyperparathyroidism as part Acromegaly is well known to be associated aggressive tumour presenting as a dark red to of multiple endocrine neoplasia syndromes. with goitre as part of generalised organo- dark blue papule. It usually arises on the head, Total serum calcium is raised in 27% and megaly. In a series of 80 patients with neck, and the extremities of the elderly.2 It is ionised calcium raised in up to 47% hyperthy- acromegaly from an iodine deficient region, often associated with other neoplasms, most roid patients.2 Patients have low PTH and 71% had goitre compared with 35% in commonly with a squamous cell carcinoma 1,25-dihydroxycholecalciferol concentrations, patients with prolactinomas. Goitres were previously resected from the same anatomical 1

and hypercalciuria. Serum calcium concen- more common in female acromegalic patients site. The two may also coexist. It is also asso- http://pmj.bmj.com/ trations are generally less than 2.7 mmol/l, but compared with males. Hyperthyroidism was ciated with Bowen’s disease and basal cell life threatening hypercalcaemia has been noted in 5% cases and none were due to carcinoma. The most important differential described. Thyroid hormones absorb bone Graves’ disease.6 Graves’ disease in patients diagnosis is metastatic oat cell carcinoma as directly, although indirect resorption may also with active or previous acromegaly has been there are no speciﬁc histological differentiat- occur by activation of local factors such as reported very rarely in the literature and pre- ing features between the two. It is, therefore, interleukin-1 or by increasing sensitivity to sented an unusual diagnostic challenge in this important to undertake a careful history and 3 β circulating PTH. -Adrenergic blocking case, specially as she was on thyroxine examination followed by chest radiography to 1 agents can reverse the hypercalcaemia as can replacement therapy after hypopituitarism. rule out a primary lung lesion. The tumour deﬁnitive therapy with carbimazole.3

has a high incidence of local recurrence (39%) on September 27, 2021 by guest. Protected copyright. Hypercalcaemia is detected in 6% cases of Final diagnosis and regional recurrence (46%). Distant me- primary adrenal insufficiency but it is less tastasis occur to bones, liver, and lung. common in secondary hypoadrenalism. Thyrotoxicosis due to Graves’ disease causing Raised calcium binding proteins caused by hypercalcaemia in a patient with hypopitui- Histology haemoconcentration are a factor, but volume tarism after treatment of acromegaly. The cellular pattern ranges from trabecular to repletion with saline does not restore calcium an insular or to a diffuse growth but all may concentrations to normal, for which glucocor- References coexist in a single tumour. The lesion tends to ticoid replacement is required.1 occupy the whole of the dermis with sparing Wilson JD Growth hormone stimulation of renal 1α- 1 , Foster WD, Kronenberg HM, et of epidermis by a thin zone of Grenz. al, eds. Williams textbook of endocrinology. Cytologically the cells are monomorphic with hydroxylase activity increases serum 1,25- 9th Ed. Philadelphia: W B Saunders, 1998. dihydroxycholecalciferol concentrations re- 2 Diamond T, Vine J, Smart R, et al. Thyrotoxic scanty cytoplasm and homogenous nuclei sulting in increased intestinal calcium bone disease in women: a potentially with a central nucleolus (arrowed fig 1A). absorption and hypercalciuria. Hypercalcae- reversible disorder. Ann Intern Med They may show a moulding effect as seen in mia is uncommon in the absence of associated 1994;120:8–11. small cell carcinomas. 1 hyperparathyroidism and has been reported 3 Pont A. Unusual causes of hypercalcemia. Staining techniques in none4 to 10%5 of cases in various series of Endocrinol Metab Clin North Am Silver stains are negative, indicating the small patients with acromegaly. 1989;18:753–64. In this patient the hypercalcaemia was due 4 Pumarino H, Oviedo S, Michelsen H, et al. number of neurosecretory granules. to thyrotoxicosis and glucocorticoid defi- [Active acromegaly and gigantism: some Immunohistochemistry ciency. It responded partially to rehydration clinical characteristics of 50 patients.] Rev This is helpful in differentiating Merkel cell with isotonic saline and intravenous hydro- Med Chil 1991;119:897–907. Ezzat S carcinoma from other tumours such as cortisone and normalised completely after 5 , Melmed S, Endres D, et al. Biochemical assessment of bone formation lymphoma, melanoma, and metastatic oat cell hyperthyroidism was treated with pro- and resorption in acromegaly. J Clin carcinoma. pranolol and carbimazole. Endocrinol Metab 1993;76:1452–7. The useful markers studies are: Wuster C Q3: What is the cause of her 6 , Steger G, Schmelzle A, et al. • Positive for low molecular weight keratins Increased incidence of euthyroid and thyrotoxicosis? hyperthyroid goiters independently of such as AE1 or CAM 5.2, epithelial mem- Her thyrotoxicosis is due to Graves’ disease as thyrotropin in patients with acromegaly. Horm brane antigen, neuron specific enolase (fig proved by homogenously increased tracer Metab Res 1991;23:131–4. 1B), and chromagranin.3

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Discussion Postgrad Med J: first published as 10.1136/pmj.78.918.254 on 1 April 2002. Downloaded from Erythema gyratum repens is one of several paraneoplastic eruptions which, while rare, are important for signifying the presence of internal malignancy. Such rashes often pre- cede the clinical identification of an underlying tumour by months or years. Conse- quently, their discovery should prompt an extensive screen for occult malignancy which needs to be repeated regularly for at least several years, but possibly up to 5–10 years after the rash’s disappearance. Examples of some of these rashes are listed in table 1. These rashes have in common the fact that they do not arise from malignant infiltration of the skin, or from local tumour pressure effects (for example, lymphoedema), but are the result of immune, metabolic or endocrine effects, that have been identified in only some Figure 1 (A) Haematoxylin and eosin stain showing Merkel cells. Arrow shows a typical cell cases. with a central nucleolus. (B) Merkel cells showing positive staining with neuron specific In the case of erythema gyratum repens 2 enolase. evidence exists for an immunological basis. Techniques employing immunohistochemistry have shown a B cell lymphocytic and eosi- nophilic infiltrate around dermal vessels, with • Negative for S-100 protein, carcinoembry- An episodic eruption an inconsistent presence of immunoglobulin onic antigen, and lymphocytic markers. and C3 deposits in either the basement membrane or epidermis. Theories for the rash’s Q1: What is the name given to this Management aetiology include cross reaction of tumour rash (see p 249), and how is the antigens in association with specific human Some Merkel cell carcinomas have been 4 appearance described? leucocyte antigen (HLA) haplotypes or im- reported to regress spontaneously. The opti- mune complex deposition.7 Interestingly, the mal treatment is not well defined due to its The rash is erythema gyratum repens. The rash conforms in its spatiotemporal pattern to rarity and the limitations of retrospective specific features of this figurate rash are con- that seen in a chemical reaction diffusion data.5 Early lesions can be managed by surgi- centric erythematous arcs and rings, as well as model—the Belousov-Zhabotinskii reaction— cal resection alone. Moh’s microsurgery, serpiginous bands and stripes in alignment. The whorly pattern was initially described in that describes other biological patterns, such which involves immediate histological assess- as that found in slime mould.29 ment of resection margins, has a role in 1953 by Gammel as “knotty cypress wood grain”.1 The rash spreads over the skin at a Rashes with a paraneoplastic association ensuring tumour clearance at the lateral and may also occur in patients in whom no malig- deep margins.6 It is not known whether rate of about 1 cm a day, and may leave a similarly patterned scale in its wake. It is not nancy is ever found, despite extensive investi- prophylactic lymph node dissection and/or gation and follow up. Moreover, such rashes adjuvant radiotherapy increases the survival. raised, and is associated with pruritus (50%) and eosinophilia. have a tendency to co-occur: there are several Merkel cell carcinoma is a radiosensitive reports of erythema gyratum repens coexist- tumour and the field of treatment should ing with pemphigus, pemphigoid, icthyosis, include both the primary and the regional Q2: What underlying diseases does it 7 hyperkeratotic palms and soles, and psoriasi-

suggest? http://pmj.bmj.com/ lymphatics. The role of chemotherapy is still form lesions. controversial and should be considered in The rash is most commonly associated with Erythema gyratum repens appears to per- patients with advanced disease who are unﬁt internal malignancy. In one literature review 8 sist in those cases where carcinoma is for surgery. of 49 cases the most common accompanying recognised, but it may resolve with steroid neoplasms were bronchial (32%), or were treatment in both patients with and without Final diagnosis found in the oesophagus (8%) or breast (6%), coincident malignancy.8 Dapsone has also Merkel cell carcinoma. or were unidentiﬁed metastatic malignancies been effective in a patient with hypereosi- (6%); less common were tumours of the phar- nophilic syndrome.5 In the one case associated ynx, stomach, bowel and pancreas, as well as with Sjogren’s syndrome, secondary to rheu- References 2 of the genitourinary tract. Lymphoreticular on September 27, 2021 by guest. Protected copyright. 1 Tang C-K, Toker C. Trabacular carcinoma of matoid arthritis, the rash appeared episodi- the skin. An ultrastructural study. Cancer neoplasms were under-represented. In addi- cally, corresponding to adjustments (up and 1978;42:2311–21. tion, the rash has been found in association down) to the dose of prednisolone.3 Our 2 Shaw JH, Rumball E. Merkel cell tumour, with tuberculosis, limited systemic sclerosis patient’s dose of prednisolone remained con- clinical behaviour and treatment. BrJSurg (CREST syndrome), secondary Sjogren’s stant throughout. 1991;78:138–42. syndrome,3 virginal breast hypertrophy 4 and 3 Haneke E, Schulze HJ, Mahrle G. hypereosinophilic syndrome,5 although most Course Immunohistochemical and immunoelectron of these are single case reports. In about 20% The patient was screened for occult malig- microscopic demonstration of chromagrannin of cases, in whom follow up has continued for nancy, but thorough clinical examination, A in formalin fixed tissue of merkel cell one to three years, there is no associated an oesophagogastroduodenoscopy, barium carcinoma. J Am Acad Dermatol 6 1993;28:222–6 underlying disease. enema, and computed tomography of the 4 Inoue T, Yoneda K, Manabe M. Spontaneous regression of merkel cell carcinoma: a comparitive study of tunnels index and tumour infiltrating lymphocytes between spontaneous Table 1 regression and nonregression group. J Paraneoplastic rashes, with the most common associations shown Dermatol Sci 2000;24:203–11. Rash Commonent associated malignancy 5 Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of Erythema gyratum repens Bronchial carcinoma the literature. J Am Acad Dermatol Dermatomyositis Bronchial carcinoma 2000;43:755–67. Necrolytic migratory erythema Pancreatic glucagonoma 6 O’Connor WJ, Brodland DG. Merkel cell carcinoma. Dermatol Surg 1996;22:262–7. Superficial migratory thrombophlebitis Pancreatic glucagonoma (Trousseau’s sign) 7 Suntharalingam M, Rudoltz MS, Mendenhall Acanthosis nigricans Gastrointestinal malignancy, especially gastric WM, et al. Radiotherapy for Merkel cell Flushing Carcinoid carcinoma of the skin of the head and neck. Nodular panniculitis Pancreatic carcinoma Head Neck 1995;17:96–101. Icthyosis/pruritus Lymphoma 8 Nathu RM, Mendenhall WM, Parsons JT. Merkel cell carcinoma of the skin. Radiat Other: Hypertrichosis lanuginosa, hyperhidrosis, hyperpigmentation, hyperkeratosis. Oncol Invest 1998;5:233–9.

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thorax, abdomen, and pelvis failed to identify anaemia, and the low serum alkaline phos- Discussion Postgrad Med J: first published as 10.1136/pmj.78.918.254 on 1 April 2002. Downloaded from any neoplasm. A skin biopsy showed non- phatase level. Liver biopsy findings are com- Wilson’s disease is a rare inborn error of specific acute inflammatory changes, consist- patible with Wilson’s disease, since the vast metabolism (frequency between one in ent with a toxic erythema. The rash was seen majority of Wilson’s disease patients have evi- 30 000 and one in 100 000 live births), due to to disappear and then reappear over a two dence of fibrosis, despite widely varying levels mutations in the recently discovered ATP7B week period. It was not seen again over the and patterns of hepatic inflammation and gene. The Wilson’s disease gene encodes for a remaining 13 months of her life. Her cause of injury. P-type ATPase responsible for the transport of death was staphylococcal septicaemia that she In other causes of fulminant hepatic fail- copper across cellular membranes, using ATP acquired after a leg amputation, performed ure, anaemia is not uncommon, and it is usu- as an energy source.1 Dietary copper is for osteomyelitis of the right foot. ally due to either bone marrow aplasia or absorbed in excess with respect to body In the majority of cases of erythema coagulopathy and bleeding. Amanita phalloides requirements: since it is toxic, mainly through gyratum repens associated with malignancy, releases a potent haemolysin, which, however, the generation of free radicals, in humans it is the tumour was diagnosed within seven is not absorbed by the gastrointestinal tract actively excreted via the hepatobiliary route. months of the rash appearing; the longest and is not involved in the pathogenesis of In the hepatocyte, the ATP7B protein has both time was six years.2 signs and symptoms of the intoxication. An a perinuclear location, where it is probably association between Budd-Chiari syndrome involved in delivering copper to apocerulo- Final diagnosis and haemolysis is reported only in patients plasmin, and a plasma membrane location, Erythema gyratum repens associated with where obstruction of the hepatic veins com- where it may be responsible for the efflux of secondary Sjogren’s syndrome. plicates paroxismal nocturnal haemoglobinu- copper from the hepatocyte. Its function can ria (a chronic disease). Haemolysis is one of be altered by a very large number of different References the cardinal manifestations of HELLP syn- disease specific mutations, including single 1 Gammel JA. Erythema gyratum repens.AMA drome, which is a late complication of base insertions and deletions, frame shifts Archives of Dermatology and Syphilis pregnancy: being due to red cell membrane and missense, non-sense, and splice site 66 1953; :495–505. injury, in patients with HELLP syndrome a mutations (A continuously updated database 2 Boyd SA, Neldner KH, Menter AM. Erythema peripheral blood smear must show red blood can be freely downloaded at the web site of gyratum repens: a paraneoplastic eruption.J 2 cell fragments and/or red blood cells with a the University of Alberta. ) Most patients are Am Acad Dermatol 1992;26:757–62. compound heterozygotes. As a result of any of Matsumura T thorny or spiculated surface. 3 , Kumakiri M, Sato-Matsumura these mutations, progressive copper accumu- KC, et al. Erythema gyratum repens-like A further possibility to be considered is lation occurs. The excess copper is initially eruption in a patient with Sjogren syndrome leptospirosis, where haemolysis can contrib- bound to metallothionein and distributed [letter]. Acta Derm Venereol 1995;75:327. ute to anaemia, since exposure to environ- evenly throughout the cytoplasm. When the 4 Shelley WB, Hurley HJ. An unusual mental sources, in the present case, was binding capacity of metallothionein is ex- autoimmune syndrome. Arch Dermatol possible or even likely. In Weil’s syndrome, 1960;81:889–897. ceeded, copper is partly deposited in lyso- 5 Morita A, Sakakibara N, Tsuji T. Erythema however, haemolytic anaemia is invariably of somes, leading to hepatic dysfunction. It also gyratum repens associated with the microangiopathic type. leaks out into the blood and is deposited in hypereosinophilic syndrome. J Dermatol the brain and other tissues. 1994;21:612–4. Course The most common initial clinical manifes- Kawakami T 6 , Saito R. Erythema gyratum The attending physicians considered fulmi- tations of Wilson’s disease are those of chronic repens unassociated with underlying nant Wilson’s disease and leptospirosis, 22 liver disease, fulminant hepatic failure, neuro- malignancy. J Dermatol 1995; :587–9. mainly in view of the history of exposure to 7 Caux F, Lebbe C, Thomine E, et al. Erythema logical disease, and haemolysis; affected rela- gyratum repens. A case studied with rat excrement, the two most likely diagnoses. tives of a proband can be identified in a immunofluoresence, immunoelectron Direct and indirect methods of leptospira presymptomatic stage by genetic screening.3 microscopy and immunohistochemistry. Br J detection, including a search for leptospira There appears to exist an association between Dermatol 1994;131:102–7. DNA in the blood by the polymerase chain age at the onset of symptoms and specific 8 Sanchez SR, Fernandez RS, Murillo EE, et al. reaction, were negative. The hepatic copper mutations: those predicted to destroy the Erythema gyratum repens: another case of a

content was 600 µg/g per dry weight (normal function of the gene result in an age at http://pmj.bmj.com/ rare disorder but no new insight into <50). The patient was listed for emergency presentation as young as 3 years (average 7.2 pathogenesis. Dermatology liver transplantation, but she died of multior- years),4 whereas the average age at presenta- 1996;193:336–7. 9 Stewart I. Before life began. Life’s other gan failure 36 hours later before a suitable tion of homozygotes for the most commonly secret. Harmondsworth: Penguin Books, organ could be found. Permission to perform a encountered His1069Gln mutation is 20 years. 1998:35–7. postmortem examination was denied. In compound His1069Gln heterozygotes, it is The results of genetic testing, performed on 15 years.5 a blood sample sent to a reference laboratory, The fulminant mode of presentation, A 15 year old girl with were obtained only several weeks later, and which, for unknown reasons, is more common in females, is not exclusive of specific showed a compound heterozygote genotype on September 27, 2021 by guest. Protected copyright. fever, jaundice, 6 (His1069Gln; Val1262Phe). mutations and can represent a formidable haemolysis, and sudden challenge for the clinician.3 It occurs suddenly, without clear precipitating factors, and is clinical deterioration almost invariably associated with haemolytic Q1: What does the liver biopsy show Box 1: Main causes of fulminant anaemia, as hepatocyte necrosis results in the hepatic failure massive release of copper ions into the (see p 250)? circulation. Thus, signs include jaundice, hae- A portal triad with marked oedema and fibro- moglobinuria, and renal failure; in this sis extending towards other portal triads is Drugs and toxins setting, diagnosis is a matter of extreme shown in fig 1A. Focal mononuclear cell infil- • Acetaminophen. urgency, since, if the patient is not promptly trates, ductular proliferation, and interface • Halothane. considered for liver transplantation, prognosis hepatitis are also visible. In fig 1B, hepatocyte is uniformly poor. • Isoniazid. ballooning and lytic necrosis are associated In patients with hepatic failure younger with feathery degeneration. • Valproate than 35 years, a high index of suspicion for These morphological findings are insuffi- • Amanita phalloides. fulminant Wilson’s disease is needed. In addi- cient by themselves to establish a diagnosis Infections tion, the presence of splenomegaly and of since they are shared by a number of different • Viral hepatitis (A to E). Coombs negative haemolysis favour Wilson’s liver diseases. disease with respect to other causes of fulmi- • Non-A to E hepatitis. nant hepatic failure. By contrast, confirma- Q2: What is the most likely diagnosis? Vascular diseases tory tests for Wilson’s disease (box 2) too The differential diagnosis in this case must • Budd-Chiari syndrome. often fail to add significant diagnostic infor- include all the most important causes of Metabolic diseases mation in this difficult setting. The value of fulminant hepatic failure (box 1). biochemical tests, such as serum ceruloplas- Nevertheless, fulminant Wilson’s disease • Acute fatty liver of pregnancy. min, serum copper concentration and urinary should be considered the leading diagnosis. • HELLP syndrome. copper excretion, is limited by both false The three most relevant clues pointing to Wil- • Reye’s syndrome. negative and false positive results. Kayser- son’s disease are the age of the patient, the • Wilson’s disease. Fleischer rings, golden brown deposits of cop- presence of Coombs negative haemolytic per encircling the iris and visible at slit lamp

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examination, are absent at the time of 3 Steindl P, Ferenci P, Dienes HP, et al. Postgrad Med J: first published as 10.1136/pmj.78.918.254 on 1 April 2002. Downloaded from Box 2: Diagnostic tests for fulminant presentation in the majority of fulminant Wilson’s disease in patients presenting with cases. Liver histology may show micronodular Wilson’s disease liver disease: a diagnostic challenge. Gastroenterology 1997;113:212–8. cirrhosis, without specific features; immuno- 4 Thomas GR, Forbes JR, Roberts EA, et al.The histochemical techniques for copper staining • Serum ceruloplasmin concentration. Wilson disease gene: spectrum of mutations are notoriously of little diagnostic value. • Serum copper concentration. and their consequences. Nat Genet Indeed, in fulminant forms, even measure- • Urinary copper excretion. 1995;9:210–7. 5 Shah AB, Chernov I, Zang HT, et al. ment of the hepatic copper content, that many • Hepatic copper concentration. would consider the golden standard for diag- Identification and analysis of mutations in the • Alkaline phosphatase to bilirubin ratio. Wilson disease gene (ATP7B): population nosis of Wilson’s disease, may be below the frequencies, genotype-phenotype correlation, diagnostic level, because of massive release of and functional analyses. Am J Hum Genet copper from necrotic hepatocytes. Due to the 1997;61:317–28. heterogeneity of the genetic defect, the time 6 Riordan SM, Williams R. The Wilson’s needed to perform genetic testing is usually gramme. While awaiting for an organ, plasma disease gene and phenotypic diversity. J too long to meet clinical needs, although it exchange with fresh frozen plasma replace- Hepatol 2001;34:165–71. 7 Loudianos G, Dessì V, Lovicu M, et al. may be a feasible option in selected patients ment should be instituted. This has been shown to be a more efficient method to Molecular characterization of Wilson disease (for example, in subjects from Sardinia, where in the Sardinian population—evidence of a 85% of cases are due to only five mutations).7 remove copper from the circulation than founder effect. Hum Mutat 1999;14:294– For unclear reasons, serum alkaline phos- haemodialysis, peritoneal dialysis, and 303. haemofiltration, with net copper removal 8 Berman DH, Leventhal RI, Gavaler JS, et al. phatase may be low (and sometimes unmeas- 10 urable) in fulminant Wilson’s disease: a ratio reaching up to 12 mg per session. Clinical differentiation of fulminant wilsonian hepatitis from other causes of fulminant of alkaline phosphatase to total serum bi- Final diagnosis hepatic failure. Gastroenterology lirubin of less than 2, in association with an Fulminant Wilson’s disease. 1991;100:1129–34. aspartate aminotransferase to alanine amino- 9 Sallie R, Katsiyiannakis L, Baldwin D, et al. transferase ratio of greater than 4 has been References Failure of simple biochemical indexes to considered suggestive of wilsonian liver fail- reliably differentiate fulminant Wilson’s 1 Bull PC, Thomas GR, Rommens JM, et al.The ure by some,8 but not by others.9 disease from other causes of fulminant hepatic Wilson disease gene is a copper transporting failure. Hepatology 1992;16:1206–11. As soon as a diagnosis of fulminant P-type ATPase similar to the Menkes disease 10 Kiss JE, Berman D, van Thiel D. Effective Wilson’s disease is contemplated, the patient gene. Nat Genet 1993;5:344–50. removal of copper by plasma exchange in should be promptly transferred to a hospital 2 http://www.medgen.med.ualberta.ca/ fulminant Wilson’s disease. Transfusion with an active liver transplantation pro- database.html 1998;38:327–31.

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(0)20 8741 1311, fax: +44 (0)20 8741 0611, Pregnancy on September 27, 2021 by guest. Protected copyright. email: [email protected], web: www.oaa-anaes.ac.uk). 2 June 2002, Freiburg, Germany. Disease Progression and Professional Updating in Falk Symposia Carcinogenesis in the Epidemiology. Design of Gastrointestinal Tract Exogenous Factors in Colonic Vaccination Programmes: From 9–10 October 2002, Freiburg, Germany. Carcinogenesis Sero-Epidemiology to Cost-Effectiveness 2–3 May 2002, Würzburg, Germany. For further information on the above contact the Falk Foundation eV, Congress Division, 8–12 July 2002, University of Warwick, Bile Acids: From Genomics to Leinenweberstr 5, PO Box 6529, D-79041 Coventry, UK. The course intends to develop Disease and Therapy Freiburg, Germany (tel: +49 761 15140, fax: understanding of the epidemiological princi- +49 761 1514359, email: symposia@falk ples of vaccine programme design, including 30 May–1 June 2002, Freiburg, Germany. foundation.de).