Liver Transplantation for Wilson s Disease: A Single-Center Experience

Transcription

1 Liver Transplantation for Wilson s Disease: A Single-Center Experience ORIGINAL ARTICLES Bijan Eghtesad,* Nosrat Nezakatgoo, Lynda C. Geraci, Nicolas Jabbour, William D. Irish, Wallis Marsh, John J. Fung, and Jorge Rakela Wilson s disease is a hereditary defect in copper excretion leading to the accumulation of copper in the tissues, with subsequent tissue damage. The most serious sequela is that of progressive central nervous system involvement. The use of orthotopic liver transplantation (OLT) has been controversial for those patients with neurological symptoms attributed to Wilson s disease. The aim of this study is to determine the effectiveness of OLT for patients with Wilson s disease, including those with neurological involvement attributed to copper accumulation in the central nervous system. OLT was performed in 45 patients (19 men [42.2%], 26 women [57.8%]) with Wilson s disease between 1971 and 1993 who were followed up for at least 4 years. The age at diagnosis of Wilson s disease ranged from 3 to 41 years (mean, years). The age at OLT ranged from 8 to 52 years (mean, years). Nineteen patients (42.2%) were aged younger than 18 years at OLT. The indications for OLT included chronic hepatic failure in 15 patients (33.3%) and fulminant (FHF) or subfulminant hepatic failure in 30 patients (66.6%). All but 1 of the 19 pediatric patients (94.7%) were in the latter group. Twenty-five patients (55.5%) were receiving D-penicillamine, 9 patients for more than 1 year; none of the patients treated long term presented as FHF. Thirty-three patients (73.3%) survived more than 5 years after OLT. Fourteen patients (31%) died during the posttransplantation period; 7 of the 14 patients (50%) were aged younger than 18 years. Twelve patients died during the first 3 months after OLT of complications of disease and surgery, 10 of whom underwent transplantation for FHF. The other 2 patients died 6 and 9 years after transplantation of infectious problems. Eleven patients (24.4%) required retransplantation because of a primary nonfunctioning graft (n 6), chronic rejection (n 4), and hepatic artery thrombosis (n 1). Seventeen patients (37.7%) presented with neurological abnormalities; 14 patients with Wilsonian neurological manifestations and 3 patients with components of increased intracranial pressure. Ten of the 13 surviving patients with hepatic insufficiency and neurological abnormalities at OLT showed significant neurological improvement. Our experience shows OLT is a lifesaving procedure in patients with end-stage Wilson s disease and is associated with excellent long-term survival. The neurological manifestation of the disease can improve significantly after OLT. Earlier transplantation in patients with an unsatisfactory response to medical treatment may prevent irreversible neurological deterioration and less satisfactory improvement after OLT. Copyright 1999 by the American Association for the Study of Liver Diseases W ilson s disease is an autosomal-recessive inherited disorder of copper metabolism. 1,2 The gene was identified on chromosome 13 and encodes ATP7B, a copper-transporting P-type adenosine triphosphatase. 3-5 The disease is characterized by excessive deposition of copper throughout the body, predominantly in the liver, brain, cornea, and kidneys. Severity and time of presentation of the liver disease or neurological manifestations or sex preponderance could be related to gene mutations. 5,6 Thus far, more than 60 mutations throughout the gene have been reported. 5 The most common presentation of this disease is with neurological symptoms in adolescents and young adults and signs of progressive hepatic decompensation. 2 Medical therapy with chelating agents has proven to be an effective treatment for Wilson s disease, leading to remarkable improvement and resolution of symptoms, even in rather advanced conditions. 2,7-9 Orthotopic liver transplantation (OLT) is the accepted treatment for this disease if medical treatment fails The clinical course of neurologi- From the *Division of Transplantation Surgery, University of New Mexico, Albuquerque, NM; Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA; and the Division of Transplantation, University of Southern California, Los Angeles, CA. Address reprint requests to Bijan Eghtesad, MD, Department of Surgery, University of New Mexico, 2211 Lomas Blvd NE, Albuquerque, NM beghtesad@salud.unm.edu Copyright 1999 by the American Association for the Study of Liver Diseases /99/ $3.00/0 Liver Transplantation and Surgery, Vol 5, No 6 (November), 1999: pp

2 468 Eghtesad et al cal manifestations in patients with Wilson s disease (extrapyramidal and cerebellar signs, dementia, and psychosis), specifically their improvement or lack of improvement after OLT, has been a matter of controversy in reported cases In this review, we present our experience with OLT in 45 patients with Wilson s disease at a single center and describe their clinical presentation and outcome after this procedure. Patients and Methods This is a retrospective analysis of 45 patients with Wilson s disease who underwent OLT and were followed up (for 2 to 26 years) at the Thomas E. Starzl Transplantation Institute (Pittsburgh, PA). There were 19 men (42.2%) and 26 women (57.8%) with an age range of 8 to 52 years ( years [mean SD]) at the time of OLT. Nineteen patients (42.2%) were aged younger than 18 years: 7 boys (37%) and 12 girls (63%). The age at diagnosis of the disease was 3 to 41 years ( years). Thirty-seven of these patients underwent OLT with the diagnosis of Wilson s disease based on (1) different combinations of copper studies, presence of Kayser- Fleischer Ring (KFR), and neurological manifestations of the disease in 26 patients (57.7%) and (2) positive family history, copper studies, neurological findings, and liver biopsy in 12 patients (26.6%). Diagnosis of Wilson s disease was made after transplantation in the remaining 7 patients (15.6%) based on the hepatic explant findings and retrospective blood studies. Fulminant hepatic failure (FHF) was defined as asymptomatic patients who presented with evidence of acute liver injury and hepatic encephalopathy within 8 weeks from the onset of symptoms. Subfulminant hepatic failure (SHF) was attributed to those asymptomatic patients who presented with evidence of acute liver injury and hepatic encephalopathy more than 8 weeks from the time of onset of symptoms. Patients with chronic hepatic failure (CHF) are those patients who had abnormal liver function test results, with prolonged prothrombin time and hypoalbuminemia, for more than 6 months from the time of presentation. These patients also presented with clinical evidence of end-stage liver disease: ascites, leg edema, jaundice, portal hypertensive bleeding, or hepatic encephalopathy. It was attempted to differentiate between signs of hepatic encephalopathy or increased intracranial pressure and those of neurological manifestations of Wilson s disease in our patient population and correlate them with the patient s history and presentation at the time of OLT. Ceruloplasmin, urinary copper, and hepatic copper concentrations were measured by standardized assays in our medical center. Patient and graft survival were calculated by life-table analysis (Kaplan-Meier). Statistical comparison was performed by log-rank test. P less than.05 is considered a statistically significant difference. Results Information on pretransplantation medical therapy in our 45 patients who underwent OLT for Wilson s disease was evaluated. Fifteen patients had no history of medical treatment. Sixteen patients had less than 1 year of D-penicillamine therapy (13 patients 2 months, 1 patient for 3 months, and 2 patients for 4 months). Nine patients had more than a year of D-penicillamine therapy (range, 8 to 20 years; mean, years). History of previous medical therapy was not available for 5 patients. Stigmata of CHF was the indication for OLT in 15 patients (33.3%). There were 9 men and 6 women presenting with CHF. Four patients in this group had multiple episodes of variceal bleeding, and none of the patients presented with hemolysis. Eight patients in this group received medical treatment for more than 8 years. The reasons for OLT in these patients were complications of cirrhosis in 6 patients and neurological problems in the remaining 2 patients. Two patients who received a transplant because of intractable neurological manifestations (dysarthria, tremor, severe ataxia, swallowing difficulty, and cerebral atrophy on computed tomographic scan) were not responding to medical therapy. Both patients had cirrhosis on the explants. OLT did not improve their neurological status. The remaining 30 patients (66.6%) underwent OLT for FHF or SHF. There were 10 men (33.3%) and 20 women (66.6%) in this group of patients. The difference between men and women presenting as FHF compared with CHF was not statistically significant (P.5722). Twenty-one patients (70%) in this group had hemolysis. Eighteen patients (60%) in the FHF group were aged younger than 18 years (6 boys, 12 girls). The ceruloplasmin levels ranged between 0.12 and 31.8 mg/dl (mean, mg/dl). Twentyfour percent of our patients had normal or borderline low-normal levels. Urinary copper levels were uniformly elevated, as well as hepatic copper concentrations measured in the explanted livers (Table 1). One patient who showed a low hepatic copper level on the explant had been receiving medical therapy for 20 years. He underwent OLT

3 Liver Transplantation for Wilson s Disease 469 Table 1. Copper Metabolism Parameters Ceruloplasmin: mg/dl (median, mg/dl) Urinary copper: mcg/24 h (median, mcg/24 h) Hepatic copper: mcg/g of liver (median, mcg/g of liver) NOTE. Normal values: ceruloplasmin, mg/dl; urinary copper, 70 mcg/24 h; hepatic copper, 55 mcg/g of liver. for the complications of cirrhosis, especially repeated variceal bleeding. KFR was described in 21 of 45 patients (46.6%). The KFR was present in 10 of 12 patients (83.3%) with true neurological manifestations of Wilson s disease and documented eye examination. The correlation in the ratios of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) and alkaline phosphatase to bilirubin was evaluated in our patients with FHF (Fig. 1). This correlation was used as a possible diagnostic tool for the diagnosis of fulminant presentation of Wilson s disease. Neurological manifestations of Wilson s disease at admission for OLT were described in 17 patients (Table 2). Ten patients underwent OLT for FHF or SHF and 7 patients for CHF. Four patients died after transplantation. Of the 17 patients presenting with neurological manifestations, 14 patients had true Wilsonian neurological or neuropsychiatric manifestations of the disease and 3 patients had some additional components of increased intracranial pressure and encephalopathy. Twelve of the 14 patients in the former group (85.7%) survived OLT. Nine of the 12 survivors (75%) showed complete neurological improvement. Of the 3 patients with no improvement, 2 patients underwent OLT mainly for this reason, and 1 patient with severe neurological dysfunction presented with SHF with a short period of medical therapy while awaiting OLT. Of the 3 patients with concomitant components of encephalopathy and increased intracranial pressure, 2 patients died and the survivor had a complete neurological recovery. Causes of death in Figure 1. AST-ALT and alkaline phosphatase bilirubin ratios in patients with FHF presentation of Wilson s disease.

4 470 Eghtesad et al Table 2. Presentation and Outcome in Patients With Neurological Manifestations Patient No. Sex Age at Dx (yr) Age at OLT (yr) Indication for OLT Neurological Signs Neurological Outcome 1 F 9 9 FHF Seizures, hypomania Deceased 2 M CHF Dysarthria, tremor, ataxia, swallowing No improvement difficulty 3 F SHF Muscular weakness Alive with improvement 4 M 3 20 CHF Hypomania Alive with improvement 5 F SHF Severe ataxia, dysarthria, cerebral No improvement atrophy 6 F CHF Dysarthria, ataxia Alive with improvement 7 F CHF Muscular weakness, hypomania Alive with improvement 8 F SHF Muscular weakness, headache Deceased 9 M FHF Muscular weakness, writing difficulty Alive with improvement 10 M CHF Dysarthria, ataxia, seizures, Partial improvement hypersalivation 11 M SHF Ataxia, dysarthria Alive with improvement 12 F FHF Seizures Alive with improvement 13 F 9 10 FHF Dysarthria, hypomania Deceased 14 M CHF Dysarthria, muscular weakness, Deceased hypomania 15 F CHF Severe tremor Alive with improvement 16 M SHF Tremor, writing difficulty Alive with improvement 17 M SHF Dysarthria, ataxia, swallowing disorder No improvement Abbreviation: Dx, diagnosis. patients with neurological manifestations were primary nonfunction of the graft and sepsis in 2 patients and intraoperative mortality in the remaining 2 patients (Table 3). Twelve patients died in less than 3 months, and 2 other patients died 6 and 9 years after OLT (Table 3), giving 1-year and 5-year survival rates of 73.3% and a 10-year and longer survival rate of 68.9% Table 3. Posttransplantation Death in Patients With Wilson s Disease Patient No. Sex Age at OLT (yr) Indication Time to Death (days) Cause of Death 1 F 18 SHF 11 PNF, MSOF 2 M 37 CHF 6 years Pneumonia, sepsis, MSOF 3 F 16 SHF/Neuro 3 PNF, hemodynamic failure after re-olt 4 F 8 SHF 26 Intra-abdominal abscess, sepsis, MSOF 5 F 16 SHF 14 Hemorrhagic pancreatitis, renal failure 6 F 9 FHF/Neuro 1 Intraoperative uncal herniation 7 F 21 SHF 4 Subarachnoid hemorrhage 8 F 30 CHF 9 years Pneumonia, sepsis 9 M 39 CHF/Neuro 17 PNF, re-olt, sepsis, MSOF 10 F 14 SHF 92 PNF, sepsis, MSOF 11 F 10 FHF/Neuro 6 Intraoperative uncal herniation 12 M 25 CHF 16 PNF, sepsis, MSOF 13 F 41 SHF 33 PNF, re-olt, sepsis, MSOF 14 F 19 SHF 15 Posttransplant intra-abdominal bleeding, hepatic artery thrombosis, graft failure Abbreviations: Neuro, neurological; PNF, primary nonfunction; MSOF, multisystem organ failure.

5 Liver Transplantation for Wilson s Disease 471 Figure 2. Overall graft and patient survival after transplantation for Wilson s disease. (Fig. 2). Graft survival rates at 1 year, 5 years, and 10 years and longer were 60%, 57.9%, and 54.3%, respectively (Fig. 2). There was a decrease in survival among patients who presented with FHF or SHF compared with those who underwent OLT for complications of CHF and intractable neurological problems; however, it did not reach statistical significance (Fig. 3). This increased mortality was noticeable only within the first 3 months after transplantation and not during the long-term follow-up. Eleven patients (24.4%) received a second liver transplant (9 patients in the first year, 2 patients after the second year) because of primary nonfunction (6 patients), chronic rejection (4 patients), and hepatic artery thrombosis (1 patient). Five patients in FHF or SHF and 6 patients in CHF required retransplantation. Two patients had a third transplant procedure performed because of chronic rejection. Both of these patients are living Figure 3. Patient survival after OLT in patients with Wilson s disease who underwent transplantation for chronic versus fulminant hepatic failure. and well, more than 15 years after retransplantation. Nineteen patients (42.2%) were aged 18 years or younger (range, 8 to 18 years; mean, years) at OLT; 18 of whom (94.7%) presented with FHF or SHF. Eleven patients in this group had no medical treatment, and the other 8 patients had less than 2 months of therapy. The short period of medical therapy was mostly because of the rapid deterioration of these patients with FHF or SHF and the urgent need for transplantation. Seven patients (36.8%) died after OLT (Table 3). Six patients died of complications shortly after OLT, and the 1 patient died 9 years after OLT of pneumonia and sepsis. Four patients in this group required retransplantation; 2 patients for primary nonfunction (both died) and 2 patients for chronic rejection (both alive). Neurological manifestations were present in 8 patients (42%) in this group. Three of the 5 survivors with neurological manifestations had complete recovery, and 2 survivors have shown minimal improvement. Discussion Wilson s disease is a genetic metabolic disorder in which the liver is unable to excrete copper into the bile. 1-6,22-24 This leads to the toxic accumulation of copper in the liver and other organs, such as the brain, kidneys, and corneas. Medical therapy with chelating agents has proven effective in controlling the disease progression and is effective in the prevention of central nervous system complications. 2,7-9 Despite the availability of effective medical therapy, some patients will present with progressive liver failure and its complications; severe neurological problems secondary to degenerative changes in the basal ganglia, putamen caudate nucleus, and thalamus 25 ; or rapid hepatic decompensation because of failure to make the appropriate diagnosis or drug noncompliance. 12 FHF can occur as the initial presentation of the disease in otherwise asymptomatic patients Under these circumstances, liver transplantation appears to be the treatment of choice, with correction of the complications of liver failure and acceptable longterm outcomes. Since the first successful liver transplantation for Wilson s disease in 1969, 29 a number of reports have been accumulated in the literature, addressing the role of transplantation in survival and reversibility of biochemical, 10,19,30 radiological, and neurological 14,19,32 manifestations of the disease. Nonimmune hemolysis is well

6 472 Eghtesad et al described in patients with fulminant Wilson s disease. 28,33,34 Seventy percent of our patients with FHF or SHF presented with hemolysis. This complication was not present in the patients with CHF. The overall 1-year survival rate in our patients was 73.3%, which is similar to other reported series. Survival was less in patients who underwent transplantation for FHF or SHF (67%) compared with CHF (87%). This difference in survival is likely caused by the greater disease severity in the former group. The need for early access to OLT in patients with FHF or SHF to prevent the high perioperative morbidity and mortality has been discussed. 35 The male female ratio in our patient population was 19:26; however, this ratio in our FHF or SHF group was 10:20, which was not statistically significant. This difference has been observed by others, and the question of hormonal factors in the induction of FHF has been raised. 2,36 The presence of 18 patients with FHF or SHF out of a total of 19 patients aged younger than 18 years agrees with the observation by other groups that FHF caused by Wilson s disease occurs predominantly in children and adolescents and should always be excluded when FHF presents in this patient population. 2 The diagnosis of Wilson s disease in asymptomatic patients presenting with FHF can be difficult. Although low ceruloplasmin levels and the presence of KFR are said to be pathognomic for the diagnosis, not all these patients have low ceruloplasmin levels, and KFR may not be present in the younger age groups In our patients with FHF, KFR was present in only 60%. In our FHF patients, there was no correlation in the AST ALT ratio or serum alkaline phosphatase bilirubin ratio. The AST ALT ratio greater than 4 and alkaline phosphatase bilirubin ratio less than 2 have been previously suggested to be useful diagnostic criteria for FHF caused by Wilson s disease Neurological improvement in patients with Wilson s disease after OLT has been reported by others. 17,19,32 The largest previous report represented a collection from multiple centers from North America and Europe. 14 In this report, Schilski et al 14 reported some degree of recovery in 5 of 8 patients with neurological manifestations who underwent OLT. Isolated case reports are mostly suggestive of complete or near-complete neurological improvement, 17,19 though Guarino et al 21 reported no neurological improvement in his patient after OLT. 21 In our 17 patients with neurological presentation of Wilson s disease, 13 survived long enough to evaluate the neurological response to OLT. Complete neurological improvement occurred in 9 of the 13 survivors in our series; 4 patients did not show complete improvement. Of our 3 patients with no improvement, 2 were brothers from the Middle East who presented with advanced, severe neurological manifestations, including dysarthria, tremor, ataxia, and esophageal dysmotility, and in whom D-penicillamine was either ineffective or was associated with unacceptable toxicity (e.g., renal failure). A third patient received a liver transplant after showing no neurological improvement on D-penicillamine. Finally, 1 patient had a long history of Wilson s disease, diagnosed at the age of 21 years. He had been on D-penicillamine therapy for 14 years, until he stopped taking the medication. Because of his progressive CHF and neurological abnormalities, he underwent OLT at 52 years of age. This patient is alive, but with residual neurological dysfunction 7 years posttransplantation. In conclusion, these data confirm that OLT is a life-saving procedure in patients with end-stage Wilson s disease and is associated with an excellent long-term survival and good quality of life. We also confirm the observations that the neurological manifestations of the disease can improve significantly after OLT; however, we have extended the finding that those patients who present with severe neurological dysfunction (e.g., dysarthria) pre- OLT may not derive full neurological recovery even years after OLT. Because we lack a precise method of predicting the outcome of OLT for Wilson s disease, broad and early application of OLT for Wilson s disease that is refractory to medical therapy seems justifiable. References 1. Dank DM. Disorders of copper transport. In: Seriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989; Scheinberg IH, Sternlieb I. Wilson s disease. Philadelphia: Saunders, Petrukhin K, Fischer SG, Pirastu M, Tanzi RE, Chernov I, Devoto M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson s disease gene. Nat Genet 1993;5: Petrukhin K, Lutsenko S, Chernov I, Ross BM, Kaplan JH, Gillian TC. Characterization of Wilson s disease

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8 474 Eghtesad et al 40. Berman DH, Leventhal RI, Gavaler JS, Cardoff EM, Van Thiel DH. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterology 1991;100: Sallie R, Katsiyiannakis L, Baldwin D, Davies S, O Grady JO, Mowat A, et al. Failure of simple biochemical indexes to reliable differentiate fulminant Wilson s disease from other causes of fulminant liver failure. Hepatology 1992;15: Shaver WA, Bhatt H, Combes B. Low serum alkaline phosphatase activity in Wilson s disease. Hepatology 1986;6: