Clinical features, presentation and biochemical results
The most common clinical presentation of hepatic WD was decompensated liver disease 19 (47.5%) followed by chronic hepatitis in 15 (37.5%) and FHF in 5 (12.5%) patients, . The most frequent clinical signs of decompensation were coagulopathy 23 (57.5%), low serum albumin 17 (42.5%) followed by ascites 14 (35%), jaundice 11 (27.5%) and hepatic encephalopathy 9 (22.5%). 10 (25%) patients had mixed neurological and hepatic disease. The most common neurological signs noted were tremors, slurred speech and rigidity. All Patients with neurological signs had positive KF rings, low serum ceruloplasmin and abnormal brain MRI mainly involving basal ganglia, midbrain, thalami and pons making diagnosis easy to establish on clinical features alone. Wilson's disease was diagnosed by family screening in six (15%) patients by clinical, biochemical testing plus liver histology and genetic testing. Overall KF rings were present in 29/35 (82.5%) and a low (0.043 ± 0.024 g/L) ceroloplasmin in 37 (92.5%) patients, however those with pure hepatic WD KF rings were seen in 19/25 (76%) and low ceruloplasmin in 27/30 (90%). All patients had high (4.48 ± 1.18 μmol/d) 24 hour urinary copper excretion The liver biochemical tests were abnormal in all patients with decompensated liver disease and chronic hepatitis at presentation with serum bilirubin of 171 ± 133 μmol/L, serum ALT 96 ± 80 U/L, AST 98 ± 88U/L, serum albumin 34 ± 11.4g/L and International normalization ratio (INR) 1.65 ± 0.84. Genetic test results were available in 23 patients. Among these 9 patients had a novel mutation in exon 21 (Gln1399Arg), not seen in normal Saudi subjects. No mutations were found in 14 patients. Applying Leipzig score, majority (37 patients) met the diagnostic criteria (score 4 or more) for Wilson's disease having low serum ceruloplasmin and markedly elevated 24 h urinary copper.
Clinical presentation and patient's characteristics
Among the six asymptomatic patients diagnosed by family screening 3 patients had low serum ceruloplasmin, elevated 24 h urinary copper and copper positive stains on liver biopsy. The other 3 patients with normal ceruloplasmin and no KF rings had elevated 24 h urinary copper levels plus gene mutations on genetic testing.
Although six patients had low titres of positive ANA (1:10 to 1:40) and seven patients had positive Anti-smooth muscle antibody (ASMA) (1:40 to 1:80), none of these patients had abnormal serum immunoglobulin and did not meet the criteria for diagnosis of autoimmune hepatitis. All patients were negative for AMA and for serological evidence of hepatitis B or C infection.
Liver histology among 35 patients showed portal fibrosis in 31 (88.5%), steatosis in 26 (74.2%), positive copper stains in 23 (65.7%), sinusoidal apoptotic bodies in 13 (37.1%), cholestasis in 8 (22.8%), focal necrosis in 20 (57.1%), cholangiolar proliferation in 22 (62.8%), portal fibrosis in 17 (48.5%) and cirrhotic nodules in 13 (37.1%) patients.
Correlating the results of the various histological findings with clinical presentation, the patients with clinical chronic hepatitis had portal inflammation in 100%, steatosis in 86.6%, positive copper stains in 85.7%, focal necrosis in 35%, cholangiolar proliferation in 71.4%, and varying stages of portal fibrosis in 92.8%. Among patients with clinical end stage liver disease portal inflammation was present in 75%, steatosis in 68.7%, positive copper stains in 66.6%, focal necrosis in 62.5%, cholangiolar proliferation in 73.3%, portal fibrosis without cirrhosis in 18.7% and cirrhotic nodules in 81.2%. Patients who presented with FHF had portal inflammation in 100%, focal necrosis in 100%, sinusoidal apoptotic bodies in 80%, cholestasis in 60%, and portal fibrosis in 20%. However, positive copper stains were seen in only 20% and cirrhotic nodules in none. The results are summarized in .
Correlation of clinical presentation to liver histology findings in (35) patients
Response to medical/surgical treatment and outcome
Among 24 (9 patients with decompensated liver disease and 15 patients with chronic hepatitis) non-fulminant and non-transplanted patients who responded to medical treatment, normalization of ALT was documented in 18 (75%), AST in 22 (92%), serum albumin in 21 (87.5%), bilirubin and INR in 24 (100%) patients. The mean time to normalization of transaminases was 12.4 ± 6.1 months (range 4-32 months) while the mean time to normalization of bilirubin, albumin and INR was 24.2 ± 13.4 months (range 11-60 months).
Eight decompensated cirrhotic patients (4 males and 4 females) who failed to respond to medical treatment had successful deceased donor liver transplantation. During post-transplantation follow up of 68.0 ± 43.1 months, the clinical symptoms and signs of Wilson's disease including KF rings resolved after a period of 9.4 ± 6.1months (3.5-18 months) and patients had consistently normal serum ceruloplasmin and liver profile without additional copper chelating therapy. One patient died seven years post-transplantation from a motor vehicle accident.
The 5 patients (2 males and 3 females) who presented with FHF had various grades of hepatic encephalopathy, jaundice and coagulopathy and died in ICU while receiving medical therapy and awaiting liver transplantation. All 5 patients developed acute renal failure requiring hemodialysis. Three of them had documented bacterial sepsis. One patient died from intrapulmonary hemorrhage.
Among patients with non-fulminant presentation, 2 patients who presented with advanced neurological disease with severe dysphagia and decompensated liver cirrhosis died with liver failure, pneumonia and sepsis. One patient was lost early in follow-up.