VOLUME 9 | ISSUE 6 | NOVEMBER 1989

Case Report Font size: Decrease font Enlarge font

Fatal Fulminant Hepatitis in Wilson's Disease: Report of Two Cases

Abdul Rahman A. Issa, MRCP; David L. Wright, PhD, FCACB; Saad A. M. Tahboob, DCH; Ahmad S. Teebi, DHCG(Lond.)

From the Paediatric Department (Dr. Ali Issa), Al-Sabah Hospital; Laboratories (Dr. Wright), Ibn Sina and Al-Razi Hospitals; Paediatric Department (Dr. Tahboob), Infectious Diseases Hospital; Kuwait Medical Genetics Centre (Dr. Teebi), Kuwait.

How to cite this article:

ARA Issa, DL Wright, SAM Tahboob, AS Teebi, Fatal Fulminant Hepatitis in Wilson's Disease: Report of Two Cases. 1989; 9(6): 605-608

Wilson's disease (hepatolenticular degeneration) is a rare autosomal recessive disorder of copper metabolism.1 It results in the accumulation of excessive toxic amounts of copper in the liver, brain, kidneys, and cornea.2,3 Wilson's disease manifests itself in various ways.1,4,5 In childhood, the usual presentation is as chronic liver disease.6,7 The classic triad of the disease consists of neurologic dysfunction, chronic liver disease, and Kayser-Fleischer rings, and is not commonly associated with any other disease entity.3,8 Acute fulminant hepatitis together with hemolysis is a rare but nonetheless well-established manifestation of this disease,7,9-17 which is not sufficiently stressed in textbook descriptions.

 

Our aim in this report is threefold. First, we wish to highlight the need for the inclusion of Wilson's disease in the differential diagnosis of acute fulminant hepatitis; second, to stress that a good laboratory indicator for Wilson's disease is the discordant observation of a markedly raised serum bilirubin level and only mildly elevated liver transaminase activity; and third, to note that, although fulminant hepatitis is an ominous sign in the patient with Wilson's disease, a correct diagnosis will benefit other asymptomatic members of the family who are affected by it.

Case

Patient 1

This patient was born by cesarean section after a normal full-term pregnancy. His parents are cousins of the first degree, and he has two brothers and three sisters, all healthy. The patient's health remained normal until age 9, when he was admitted to the Infectious Diseases Hospital with hepatitis. His general condition continued unchanged, with occasional attacks of vomiting and epigastric pain until the 20th day after admission, when ascites and edema of the lower limbs developed. At this point, the liver was no longer palpable, and the spleen was enlarged.


Results of laboratory investigations performed during this period are detailed in Table 1. Abdominal ultrasound revealed hepatosplenomegaly with normal echogenicity. The gallbladder was dilated, but without calculi; both the kidneys and pancreas were normal. Ascites was recorded as persisting on the 23rd day. Barium swallow showed no esophageal varices.


At this stage, slit-lamp examination of the eyes revealed early Kayser-Fleischer rings. During hospitalization at the Infectious Diseases Hospital, the patient received a transfusion of albumin, plasma, and (once) whole blood, as well as medication with spironolactone, multivitamin tablets, and vitamin K injection.

 

One month after admission, the patient was transferred to Sabah Hospital because of suspected Wilson's disease. He was generally weak and weighed 32 kg. His breath was sweet-smelling, he had angular stomatitis, the sclera were yellow, and there was moderate abdominal distention with some ascites. The liver was not palpable, but the spleen was 3 cm below the costal margin. There was pitting edema of the lower limbs, and there was gynecomastia but no skin rash. Repeat slit-lamp examination of the eyes confirmed the presence of Kayser-Fleischer rings.

 

Table 1. Laboratory results in Patient 1 on intial hospital admission.

Chemistry

Total bilirubin, 120 μmol/L

Conjugated bilirubin, 3.6 μmol/L

Alanine transaminase (SGOT), 2.35 μkat/L

Aspartate transaminase (SGPT), 4.55 μkat/L

Albumin, 24 g/L

Total protein, 55 g/L

Urea, 3.8 mmol/L

Sodium, 135 mmol/L

Potassium, 3.8 mmol/L

Immunoglobulin

G, 20 g/L (reference interval, 7.0-18.0)

A, 8.7 g/L (reference interval, 0.7-3.6)

M, 3.5 g/L (reference interval, 0.4-1.7)

Alphafetoprotein, 60 IU/mL (reference interval, below

10 IU/mL)

Virology

Hepatitis A-specific Ig , negative

Hepatitis B-specific antigen, negative

 

Table 2. Laboratory results in Patient 1 after transfer to Sabah Hospital.

Chemistry*

Total bilirubin, 353 μmol/L

Alanine transaminase (SGOT), 1.60 μkat/L

Aspartate transaminase (SGPT), 3.27 μkat/L

Albumin, 22 g/L

Total urinary protein, 150 mg/d

Immunoglobulin

G, 24.0 g/L (reference interval, 7.0-18.0)

A, 8.3 g/L (reference interval, 0.7-3.6)

M, 3.4 g/L (reference interval, 0.4-1.7)

Alpha-1-antitrypsin, 47 μmol/L (reference interval, 34-63)

Circulating immune complex, 800 D (reference interval,

< 1000D)

Urinary copper excretion, 16.5 μmol/d (reference

 interval, 0-0.9)

Urinary copper excretion after penicillamine, 23.0 μmol/d

Serum copper, 9 μmol/L(reference interval, 11-22)

Ceruloplasmin, undetectable

*All values are for serum except where otherwise noted.

 

Further laboratory testing was performed, and the results are given in Table 2. A computed tomographic (CT) scan of the abdomen revealed the liver was not enlarged and had a normal structure (i.e., dilated intrabiliary or gallbladder ducts). CT scanning showed an enlarged spleen, but there were no focal defects; the pancreas was normal sized without focal enlargement. Ascites surrounded the liver.


The clinical impression was splenomegaly with ascites, possibly due to portal hypertension. A liver isotope scan (using technetium 99m) revealed grossly impaired liver function with ascites. The patient was put on spironolactone tablets (1 q.i.d.), folic acid tablets (5 mg daily), multivitamin tablets, and salt-free albumin transfusion (once per week). On the 40th hospital day, the patient was started on penicillamine (500 mg daily) and vitamin B6 (25 mg daily). Penicillamine dosage was subsequently increased to 250 mg every 8 hours.

 

The child's general condition continued to deteriorate slowly. Two months after his initial admission, hepatic encephalopathy developed, he became confused, restless, and then comatose, and died 36 hours after the onset of encephalopathy.


Patient 2

The patient was first seen at age 5 years as part of a family screening following confirmation of Wilson's disease in her brother (Patient 1). She had also been born by cesarean section following a normal gestation. There was no notable illness in her past history, and her developmental milestones were within normal limits.


Clinical examination showed a healthy looking girl with no evidence of liver disease except that the liver was palpable 4 cm below the costal margin. The spleen was not palpable. Kayser-Fleischer rings were absent.


Results of routine biochemical and hematologic tests were normal except for liver function tests (aspartate transaminase [AST], 2.28 μkat/L; alanine transaminase [ALT], 5.52 μkat/L; phosphatase, 5.93 μkat/L). However, the serum copper level was much reduced at 4 μmol/L (reference interval, 11-22 μmol/L) and serum ceruloplasmin was undetectable. Urinary excretion of copper was 1.6 μmol/d (reference interval, 0-0.9 μmol/d). This increased to 3.95 μmol/d after a penicillamine challenge test.


The child was evaluated at King's College Hospital, London. A technetium-colloid liver scan showed moderate patchy impairment of hepatic uptake, splenomegaly, and mild uptake in the bone marrow consistent with moderately severe liver disease. A liver biopsy showed marked widening of the portal tracts with some distortion ofthe liver parenchyma. There was a moderate inflammatory cell infiltrate in the portal tracts and a mild lobular hepatitis. The hepatocytes showed marked fatty infiltration and macrophages containing deposits of copper-associated protein. Liver copper level was 440 μg/g dry weight.


Wilson's disease was substantiated by the above findings, and the child was put on 20 mg/kg/d of penicillamine (200 mg twice daily) and 10 mg of pyroxidine daily.


Six months after initiation of therapy, liver function tests showed a decrease in the levels of AST (0.97 μkat/L) and ALT (0.92 μkat/L). At the same time, urinary copper excretion, which had increased to 21.7 μmol/d following penicillamine administration, dropped to 5.6 μmol/d, although it rose again to 9.0 μmol/d after commencement of zinc sulfate therapy.

 

Two years since the beginning of treatment, the child (now aged 7 years) remains asymptomatic and shows no clinical evidence of the disease.

Discussion

Our 2 patients, both suffering from Wilson's disease, exhibited the very wide spectrum of manifestations of this disease. Patient 1 showed the typical dramatic fulminant course that has been reported by others.7,9-17 This differs, of course, from the usual mode of presentation in childhood chronic liver disease.3,4,18,19 Diagnosis of Wilson's disease in this patient was based on the presence of Kayser-Fleischer rings, a low serum ceruloplas-min level, and elevated urinary copper excretion. The raised prothrombin time precluded a liver biopsy.

 

Kayser-Fleischer rings are not seen in pediatric disorders other than Wilson's disease; their presence is diagnostic.3 This differs from the situation in adults where they have been reported in those with chronic liver disease not related to Wilson's disease.20 Diagnosis of acute fulminant hepatic failure in Patient 1 was based on the rapid course of the disease; the presence of hyperbilirubinemia, hypoprothrombinemia, and hepatic encephalopathy; and the absence of clinical evidence of chronic liver disease. Hemolytic anemia was substantiated by the presence of anemia together with a high reticulocyte count.

 

The diagnosis in Patient 2 was confirmed by elevated liver copper and low serum copper levels, undetectable serum ceruloplasmin, and high urinary copper excretion both before and after a penicillamine challenge test.

 

The mechanism of hemolysis and hepatic failure in Wilson's disease is postulated to depend on the fate of hepatic cells that have been slowly and progressively accumulating copper. At some stage, this copper is redistributed from the cytoplasm to the lysosomes. In most patients this redistribution occurs slowly, without clinical consequences, but in a few instances hepatic cell necrosis develops. One consequence of this is liver failure. The release of copper from necrotic cells is responsible for a second consequence. This copper is taken up by red cells which then become much more prone to lysis, possibly because the amount of reduced glutathione is decreased, and consequently, the cell is vulnerable to oxidative damage.7,10,13,15,16 Ozsoylu21 noted a marked deficiency of vitamin E in one patient with Wilson's disease and hemolytic anemia, and suggested that this may also be a factor leading to oxidative damage.21

 

The serum copper level in Patient 1 was only slightly below the lower limit of the reference interval, and higher than levels usually associated with Wilson's disease (cf. Patient 2). An elevated urinary excretion of copper, as seen here, helps to resolve the question when serum copper results are equivocal. Liver enzyme levels were only moderately elevated, whereas the bilirubin content was markedly raised. The discordance is most unusual in other forms of hepatic failure, and its presence should alert the clinician to the possibility of Wilson's disease. Immunoglobulin levels (IgG, IgA, IgM) were raised in the serum; this is a recognized feature of patients with Wilson's disease.18,22 In the series discussed by Nazer et al,19 such elevations were found most commonly in cases resulting in death.19

 

Provided it is started early, and continued for life, D-penicillamine (20 mg/kg) is an effective treatment for Wilson's disease. When it is given to asymptomatic patients,6,23 the progression typical of untreated disease does not occur, and there is an absence of clinical manifestations.24 Patient 2's disease was, in fact, discovered in the pre-symptomatic stage, and the slightly impaired liver function (as shown by the elevated liver enzymelevels) resolved under penicillamine treatment, with a return to normal function. One of the consequences of the use of penicillamine is zinc deficiency,25 and we used both penicillamine and zinc sulfate in the second case to enhance copper excretion and, at the same time, preclude the complication of zinc deficiency. If the patient is intolerant to penicillamine, and another medication substituted, zinc sulfate can still be given (100 mg twice per day).

 

All patients with Wilson's disease who presented with acute fulminant hepatic failure have not responded to treatment with penicillamine.9 Peritoneal dialysis might be of benefit in this situation, by eliminating the copper and altering the course of this fulminant form of the disease. Hemodialysis is contraindicated, because it leads to a very rapid mobilization of copper with further clinical deterioration.26 Success has recently been reported with orthotopic liver transplantation in such cases.26,27

 

The most important lesson from our study relates to Patient 2, showing that treatment begun in time can be life-saving. Wilson's disease should be considered in the differential diagnosis of children presenting with liver disease.

References

1. Dastur DK, Manghani DK, Wadia NH. Wilson's disease in India: geographic, genetic and clinical aspects in 16 families. Neurology 1968;18:21-31.

2. Warren CBM, Broughton PMG. Wilson's disease. Arch Dis Child 1962;37:242-52.

3. Sass-Kortsak A. Wilson's disease: a treatable liver disease in children. Ped Clin N Am 1975;22(4):963-84.

4. Slovia TL, Dubois RS, Rodgerson DO, Silverman A. The varied manifestations of Wilson's disease. J Pediatr 1971;78(4):578-84.

5. Walshe JM. Wilson's disease, the presenting symptoms. Arch Dis Child 1962;256(37):253-6.

6. Editorial. Don't forget Wilson's disease. Br Med J 1978;2:1384-5.

7. Sagen E, Lang O, Westgaard G, et al. Wilson's disease in two siblings–one with fatal outcome. Acta Med Scand 1986;219:331-5.

8. Werlin SL, Grand RJ, Perman JA, Walkins JB. Diagnostic dilemmas of Wilson's disease: diagnosis and treatment. Pediatrics 1978;62:47-51.

9. Kraut JR, Yoge VR. Fatal fulminant hepatitis with hemolysis in Wilson's disease: criteria for diagnosis. Clin Pediatr 1984;23(11):637-40.

10. Doering ED 3rd, Savage RA, Dittmer DT. Hemolysis, coagulation defects, and fulminant hepatic failure as a presentation of Wilson's disease. Am J Dis Child 1979;133:440-1.

11. McCullough AJ, Fleming R, Thistle JL, et al. Diagnosis of Wilson's disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161-7.

12. Deiss A, Lee GR, Cartwright GE. Hemolytic anemia in Wilson's disease. Ann Intern Med 1970;73:413-8.

13. McIntyre N, Clink HM, Levi AJ, et al. Hemolytic anemia in Wilson's disease. N Engl J Med 1967;276:439-44.

14. Robitaille GA, Piscatelli RL, Majeski EJ, et al. Hemolytic anemia in Wilson's disease: a report of three cases with transient increase in hemoglobin A2. JAMA 1977;237:2402-3.

15. Iser JH, Stevens BJ, Stening GF, et al. Hemolytic anemia of Wilson's disease. Gastroenterology 1974;67:290-3.

16. Roche-Sicot J, Benhamon JP. Acute intravascular hemolysis and acute liver failure associated as a first manifestation of Wilson's disease. Ann Intern Med 1977;86:301-3.

17. Hamlyn AN, Gollan J, Douglas AP, Sherlock S. Fulminant Wilson's disease with haemolysis and renal failure: copper studies and assessment of dialysis regimen. Br Med J 1977;2:660-3.

18. Sternlieb I, Scheinberg H. Chronic hepatitis as a first manifestation of Wilson's disease. Ann Intern Med 1972;76:59-64.

19. Nazer H, Ede RJ, Mowat EAP, Williams R. Wilson's disease in childhood: variability of clinical presentation. Clin Pediatr 1983;22(11):755-7.

20. Fleming CR, Dickson ER, Wahner HW, et al. Pigmented corneal rings in non-Wilsonian liver disease. Ann Intern Med 1977;86:285-8.

21. Ozsoylu S. Fatal fulminant hepatic failure? Clin Pediatr 1985;24(8):470.

22. Strickland CGT, Leu ML. Wilson's disease-clinical and laboratory manifestations in 40 patients. Medicine 1975;54:113-37.

23. Caillie-Bertrand MV, Degenhart HJ, Luijendijk I, et al. Wilson's disease: assessment of D penicillamine treatment. Arch Dis Child 1985;60:652-55.

24. Van Wouwe JP, Van Weel-Sipman MH, Giesberts MAH, et al. Effective D penicillamine treatment of an early diagnosed patient with Wilson's disease (letter). Eur J Pediatr 1984;143:77.

25. Van Caillie-Bertrand M. Oral zinc sulphate for Wilson's disease. Arch Dis Child 1985;60(7):654-9.

26. Rakeia J, Kurtz SB, McCarthy JT, et al. Fulminant Wilson's disease treated with post dilution hemofiltratory and orthotopic liver transplantation. Gastroenterology 1986;90:2004-7.

27. Skol RJ, Francis PD, Gold SH, et al. Orthotopic liver transplantation for acute fulminant Wilson's disease. J Pediatr 1985;107(4):549-52.


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