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Indian Pediatrics 2000;37: 31-36 |
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Wilson's disease with hepatic presentation in childhood |
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Aysel Yuce, Nurten Kocak, Figen Gurakan and Hasan Ozen From the Division of Gastroenterology, Department of Pediatrics,
Hacettepe University, Faculty of Medicine, Ankara, Turkiye Objective: To evaluate clinical, laboratory findings, treatment and long-term follow-up of children with Wilson's disease with hepatic presentation. Design: Retrospective study with a median follow-up period of 9 years. Setting: University medical center. Subjects: Thirty-four children with hepatic involvement, ranging in age from three to fifteen years, were diagnosed as Wilson's disease over an eighteen year period. Methods: The diagnosis was based on the presence of family history and Kayser-Fleischer rings, low serum ceruloplasmin levels and increased urinary and hepatic copper concentrations. Results: Four patients had also neurological manifestations. Eight patients were diagnosed as fulminating hepatic failure resulting in death in a few days. The most common symptoms were abdominal distension and abdominal pain. Hepatomegaly was the predominant physical finding and serum transaminases were elevated in most of the patients. Twenty patients had cirrhosis and six had chronic hepatitis histopathologically. All patients with fulminating hepatic failure had hyperbilirubinemia with normal alkaline phosphatase and higher aspartate aminotransferase than alanine aminotransferase. Patients were treated with D-penicillamine and zinc sulphate. Three patients underwent liver transplantation. Four more patients besides patients with fulminating hepatic failure died due to end stage liver disease. Twenty-two patients were followed for median 9 years. Four patients with poor compliance progressed to decompensated cirrhosis and the others were stable. Conclusion: Liver disease with unknown origin with positive family history and parental consanguinity should imply Wilson's disease strongly. Key words: Cirrhosis, Wilson's disease. Wilson 'S disease (WD), which was first described in 1912 by Wilson, is transmitted through a recessive gene located on chromosome 13 which codes for a copper transport P-type adenosine triphosphatase. More than 40 unique mutations on the WD gene have been identified(1,2). The disease has a worldwide incidence of about 30 per million and the heterozygote carrier state is about 1 in 100 persons(3). WD patients exhibit impaired biliary excretion of copper causing hepatic copper overload. At later stages, copper accumulates in a variety of other organs such as brain, kidneys and eyes. The biochemical defect is present at birth, but clinical symptoms are observed after the age of three years(4). Patients typically present with hepatic and/or neuro-logical dysfunction. Hepatic involvement is prominent during childhood and mimics the features of a variety of acute and chronic liver diseases. It is fatal if untreated(3,4). As most of the studies related to WD have been done in adults, we evaluated the clinical, laboratory findings, treatment and long-term follow-up of 34 WD patients with hepatic presentation during childhood. Methods Thirty-four WD patients from 33 families with hepatic involvement, ranging in age from three to 15 years (median 9 years), identified at Hacettepe University Children's Hospital between 1980 and 1998 were retrospectively evaluated. The diagnosis of WD was made on the basis of following clinical and biochemical criteria: family history of WD, presence of Kayser-Fleischer rings on opthlamologic examination, reduced serum ceruloplasmin level (<20 mg/dL), elevated 24-hour urinary copper excretion (>100 mg/day) and increased hepatic copper concentration (>250 mg/dry weight)(3). Routine biochemical studies including serum alanine (ALT) and aspartate aminotransferase (AST), alkaline phosphatase, bilirubin levels and serum total protein and albumin values were studied at diagnosis and 6 months intervals during follow-up period. Serum alpha 1 antitrypsin, hepatitis A, B, C serological testing, and auto-immune markers were determined in order to exclude other liver diseases. Serum cerulo-plasmin determination was based on the rate of oxidation of p-phenylenediamine with Coleman Junior II model 6120 spectrophotometry (normal range 20-45 mg/dl). Urinary copper excretion were measured by atomic absorption spectroscopy (Perkin-Elmermodel 103) (normal 40-80 mg/24 hour). The quantitation of hepatic copper concentrations were performed by atomic absorption spectrophotometry (normal <50 mg/g dry weight). Liver histological data were available in all patients including patients with fulminant hepatic failure (FHF), whose liver tissues were obtained at postmortem. Renal involvement was investigated with urine analysis, renal function tests, microalbuminuria and abdominal ultrasonography. All patients were treated with D-Penicilla-mine in daily doses of 20 mg/kg three times a day before meals, and zinc sulphate with the daily doses of 300 mg. A low copper diet was also recommended. Liver transplantation was performed in three patients. Mann-Whitney U test was used for statis-tical analysis. Results Thirty-four patients (19 boys, 15 girls) were diagnosed with WD. Parental consanguinity was noted in 19 out of 33 families (57.3%). One family had two affected children and there was positive family history for WD in 15 patients (44.1%). All 34 patients fulfilled at least three diagnostic criteria. Kayser-Fleischer rings were positive in four patients with neurological involvement and 63% of patients with sole hepatic presentation (total 67.6%). Serum ceruloplasmin were low in all but four patients (0-14 mg/dL). All the patients had increased copper excretion in 24-hour urine (range, 100-4480 mg/day; mean � SD, 724.7 � 979.7 mg/day) and high hepatic copper concentrations (range, 160-1200 mg/dry weight; mean � SD 451.4 � 281.2 mg/g dry weight). Two patients with cirrhosis had 160 and 190 mg/g dry weight hepatic copper respectively, the others had hepatic copper content above 250 mg/g dry weight. Four patients with normal cerulo-plasmin levels had family history and increased levels of urinary and hepatic copper contents. Thirty patients had only hepatic involvement whereas four had hepatocerebral manifestations. Eight of the patients were diagnosed as fulminating hepatic failure (FHF). The median time between the onset of initial symptoms and a definitive diagnosis was seven months (range, 2 days to 4 years). Clinical features of the 26 patients except patients with FHF at the time of diagnosis are summarized in Table I. The most common presenting symptoms were abdominal pain and icterus. The common neurological symptoms were apathy, dysarthria, and difficulties in hand writing. Hepatomegaly was the predominant finding followed by splenomegaly and jaundice. Laboratory findings showed elevated AST and ALT levels in 92.3% and 42.3% of the patients respectively, anemia in twelve patients (eight with Coombs' negative hemolytic anemia and four with iron deficiency) and hematuria in two. Table I__ Clinical and Laboratory Characteristics of 26 Patients with Wilson's Disease Presenting Without Fulminating Hepatic Failure.
AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PT: Prothrombin time. Clinical and laboratory findings of the patients with FHF were shown in Table II. All patients presented with coma and icterus. Conjugated bilirubin values ranged from 6.6 to 50.0 mg/dL (mean � SD 27.8 � 16.4 mg/dL). None had increased alkaline phosphatase levels. Serum AST levels were between 168 and 1366 IU/L (mean � SD 471.5 � 135.8 IU/L) and ALT levels between 19 and 534 IU/L (mean � SD 136.4 � 60.5 IU/L). Seven had Coombs negative hemolytic anemia, two had renal tubular disturbances (amino aciduria, proteinuria). Table II__ Clinical and Laboratory Characteristics of Eight Fulminant Wilson's Disease Patients
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase Liver biopsy revealed that 20 patients (58.8%) had cirrhosis, 6 (17.7%) chronic hepatitis including one asymptomatic patient diagnosed during screening because of a dead sibling with WD. Eight patients (23.5%) with FHF had massive hepatic necrosis on necropsy materials. The ages of patients with cirrhosis and chronic hepatitis ranged between 6-14 (mean � SD; 9.6 � 2.2 years) and 3-11 (6.8 � 2.9 years) years, respecively (p <0.05). Twelve patients died; 8 with FHF in 2 to 11 days of admission. Four of six patients with decompensated cirrhosis at diagnosis showed poor compliance and died with liver failure due to end-stage liver disease in 3 months to 7 years. Twenty-two patients had been followed for 1 and 14 years (median 9 years). Two patients with ascites and jaundice at presentation improved clinically within 6 months. Only four patients with compensated cirrhosis at presenta-tion, whose compliance was poor, developed decompensated liver disease with ascites, and jaundice. The others were stable during follow-up. Six of ten patients with icterus had no jaundice at the third month of treatment. Kayser-Fleischer rings faded in 12 of 16 patients during follow-up. Hepatosplenomegaly did not resolve in any of the patients. The condition of the patients with neurological manifestations showed slight improvement with treatment. Two of three patients who underwent liver transplantation because of persistent liver failure, were symptom free during follow-up period of 6 months and ten years after trans-plantation, respectively. One died in a month of complications of surgery. D-penicillamine and zinc sulphate were well tolerated with no side effects. Discussion We evaluated 34 children with WD presented with hepatic manifestations. WD has recessive inheritance, therefore it is not rare in Turkey, because of high rate of parental consanguinity(5). Consanguinity rate was 57.3% in our patients and family history was also positive frequently. This study evaluated only patients with hepatic presentation who had a broad spectrum of liver diseases, such as fulminating hepatic failure, cirrhosis, and chronic hepatitis. As copper first accumulates in the liver during childhood, most patients present with primary hepatic involvement during childhood(4). Some patients had also neurological, hematologic and renal manifestations. Many of the initial clinical symptoms of WD are nonspecific as in our patients and may be misleading in establishing a definitive diagnosis. Therefore the lag time between initial symptoms and diagnosis lasted up to four years in this study. Clinical manifestations of WD are rarely apparent prior to age of 5 years. The youngest reported patient presenting with hepatic disease was 4 years old(4). In our study the youngest patient was a three-year old boy who was asymptomatic and diagnosed during the screening. Although he was asymptomatic, his liver biopsy showed chronic hepatitis. Screening of family members is important to detect and treat asymptomatic patients who will respond well to medical treatment, before severe disease develops. There is no single test for the diagnosis of WD. Clinical findings, family history and key laboratory tests are used together for the diagnosis. Kayser-Fleischer rings are pathogno-monic for WD. Although they are present in nearly all patients with neurological involve-ment, only 55 to 70% of patients with hepatic presentation show these rings(6,7). Kayser-Fleischer rings were detected in 63.3% of our patients with only hepatic manifestations and in all with neurological findings. A low serum ceruloplasmin concentration was found in all but four patients who were reported before(8). The other diagnostic tests were used to confirm the diagnosis in these patients. Although low ceruloplasmin has been used as one of the diagnostic means, normal ceruloplasmin levels have been reported in up to 27% of WD patients(6,9). Almost all symptomatic WD patients have an increased urinary copper excretion. Urinary copper levels is useful as a means of confirming the diagnosis and in evaluating compliance and response to therapy(10). Urinary copper content could not be estimated in our patients during follow-up. Quantification of hepatic copper conentration is a gold standard test for the diagnosis(3). Hepatic copper concentration below 250 mg/g dry weight in two patients with cirrhosis may be related to the sampling error because of the heterogeneous distribution of copper especially within the cirrhotic liver(11). In WD histologic abnormalities ranging from steatosis to cirrhosis are found. Cirrhosis is the most common histological finding and if untreated it is an inevitable course. Ferenci et al.(12) showed that 27 out of 64 (42.1%) patients had cirrhosis. Even though our patients were relatively young, 58.8% of them had cirrhosis histopathologically. This rapid pro-gression may be due to other environmental factors, such as malnutrition and/or high copper content of foods. The reason of the high incidence of serious forms of WD such as cirrhosis and FHF may also be due to our hospital being a tertiary medical center. The ages of the patients with chronic hepatitis were younger than that with cirrhosis, highlighting the importance of early diagnosis before severe disease develops. FHF is a rare, but fatal clinical form of WD. This presentation may mimic the other causes of fulminating hepatitis causing difficulties in the diagnosis of WD in patients with fulminant hepatitis. Presence of Coomb's negative hemolytic anemia, low alkaline phosphatase levels despite high bilirubin levels, relatively low elevations of aminotrasferase activities and higher levels of AST than ALT levels as in our patients should alert the physician to the diagnosis of WD(13,14). Correct diagnosis is very important in these patients to decide liver transplantation, which is the only treatment of fulminant Wilsonian patients(15). As liver transplantation could not be performed to our patients with fulminating hepatic failure, all died in a short time despite intensive supportive treatment and copper-chelating therapy. Liver biopsy was not available because of deranged clotting function when patients were alive. Elevated liver copper levels measured in postmortem liver tissues, confirmed the diagnosis of WD after death without any doubt. Correct diagnosis is also necessary for screening the other family members to detect asympto-matic patients(16). D-penicillamine, the gold standard of therapy effectively reduces excess copper stores and improves clinical symptoms. D-peni-cillamine is generally considered to be safe. In cases of adverse reactions to D-Penicillamine, alternative drugs such as trientine, zinc can be used(17,18). Zinc therapy may be adjunctive to penicillamine as used in our patients. If proper therapy is instituted, all manifestations of the disease are completely prevented, including improvement of hepatic histology(19). Kayser-Fleischer rings faded in 12 of 16 patients during follow-up. The patients with good compliance to the treatment improved. The major problem in WD patients is irreversible complications. In most patients signs and symptoms caused by irreversible organ damage such as cirrhosis and some neurological disorders often can not be improved(17). The prognosis of our patients with decompensated cirrhosis was poor. Liver transplantation is a life saving procedure in patients with decompensated cirrhosis un-responsive to medical treatment and in patient with FHF and irreversible hepatic insufficiency, Only three patients with end-stage liver disease could undergo liver transplantation, unfortunate-ly one died in a month with complications of surgery. Without treatment WD disease is uniformly fatal, therefore WD should be taken into account particularly in patients with liver and neuro-logical disease of unknown origin during childhood. Positive family history and parental consanguinity will suggest WD strongly. Early diangosis and treatment are important to prevent severe complications. Early and definitive diagnosis will also allow screening of other family members to detect asymptomatic patients. References 1. Thomas GJ, Forbes JR, Robers EA, Walshe JM, Cox DW. The Wilson's disease gene: Spectrum of mutations and their consequences. Nat Genet 1995; 9: 210-217. 2. Figus A, Angius A, Loudianos O, Bertini C, Dessi V, Loi A, et al. Molecular pathology and haplotype analysis of Wilson's disease in Mediterranean popoulation. Am J Genet 1995; 57: 1318-1324. 3. Gollan JL, Gollan TJ. Wilson disease in 1998: Genetic, diagnostic and therapeutic aspects. J Hepatol 1998; 28: 28-36. 4. Saito T. Presenting symptoms and natural history of Wilson's disease. Eur J Pediatr 1987; 46: 261-265. 5. Hacettepe University Institute of Population Studies. Demographic and Health Survey, October 1993, Ankara, Turkey. 6. Steindl P, Ferenci P, Dienes HP, Grimm G, Pabinger I, Madl C, et al. Wilson's disease in patients presenting with liver disease. Gastroenterology 1997; 113: 212-218. 7. Schoen RE, Sternlieb I. Clinical aspects of Wilson's disease. Am J Gastroenterol 1990; 85: 1453-1457. 8. Yuce A, Kocak N, Ozen H, Gurakan F. Wilson's disease patients with normal ceruloplasmin levels. Turk J Pediatr 1999; 41: 99-102. 9. Stremmel W, Meyerrose KW, Niederau C, Hefter H, Kreuzpaintner G, Strahmeyer G. Wilson disease: Clinical presentation, treatment and survival. Ann Intern Med 1991; 115: 720-726. 10. DaCosta CM, Baldwin D, Portman B, Lolin Y, Mount AP, Mieli-Vergani G. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease. Hepatology 1992; 15: 609-615. 11. McDonald JA, Snitch P, Painter D, Hensley W, Gallagher ND, McCaughan GW. Striking variability of hepatic copper levels in fulminating liver failure. J Gastroenterol Hepatol 1992; 7: 396-398. 12. Ferenci P. Wilson's disease. Clin Liv Dis 1998; 2: 31-49. 13. Berman DH, Leventhal RI, Gavaler JS, Cadoff EM, Van Thiel DH. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterology 1991; 100: 1129-1134. 14. Shaver WA, Bhatt H, Combes B. Low serum alkaline phosphatase activity in Wilson's disease. Hepatology 1986; 6: 859-863. 15. Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson's disease: Indications and outcome. Hepatology 1994; 19: 583-587. 16. Walshe JM. Diagnosis and treatment of presymptomatic Wilson's disease.Lancet 1988; 1: 435-437. 17. Brewer J, Yuzbasiyan-Gurkan L. Wilson's disease: An update, with emphasis on new approaches to treatment. Dig Dis 1989; 7: 178-193. 18. Calonkowaka A, Gadja J, Rodo M. Effect of long-term treatment in Wilson's disease with penicillamine and zinc sulphate. J Neurol 1996; 243: 269-273. 19. Scheinberg IH, Sternlieb I, Schilsky ML, Stockert RJ. Penicillamine may detoxify copper in Wilson's disease. Lancet 1987; 2: 95. |
