Case 1: A 12-year-old boy with acute liver failure

A previously well 12-year-old boy presented with a four-day history of decreased energy and appetite. On day 3 of this illness, his parents noticed yellowing of his sclera and his urine was “dark” in colour. He was found to have elevated total and conjugated bilirubin, and elevated transaminase and gamma-glutamyl transferase levels, with normal alkaline phosphatase. His albumin level was low, along with an elevated international normalized ratio (INR), which did not respond to intravenous doses of vitamin K. He was found to have a low hemoglobin level, requiring packed red blood cell transfusions, with signs of nonautoimmune hemolytic anemia (low haptoglobin, increased lactate dehydrogenase levels and reticulocyte count, and negative Coomb’s test). There was no pruritus and no fever.

He had no sick contacts or pertinent travel history, no history of ingestion of acetaminophen or other drugs or naturopathic remedies, and no family history of liver disease. Serology for hepatitis A, B and C was negative. His urine toxicology screen was negative, total immunoglobulin G level was normal, and he had negative titres for antinuclear, antismooth muscle and antiliver kidney microsomal antibodies.

His blood and urine cultures were negative, and an abdominal ultrasound revealed no focal liver lesions, a normal biliary tree and patent hepatic veins.

CASE 1 DIAGNOSIS: WILSON DISEASE

The patient continued to deteriorate. By day 5 of his hospitalization, he had developed hepatopulmonary syndrome and encephalopathy, and required mechanical ventilation in the critical care unit. He was placed on the wait list for liver transplantation.

Acute liver failure (ALF) is defined by the presence of biochemical evidence of liver injury, with hepatic-based coagulopathy (INR >2.0 after parenteral replenishment of vitamin K, or INR >1.5 if encephalopathy is present) in the absence of evidence of chronic liver disease (1). It is an uncommon presentation in the previously well child. In general, symptoms are vague and include anorexia, fatigue and jaundice, while the underlying pathophysiology relates to loss of liver function and its subsequent sequelae (ie, coagulation abnormalities, encephalopathy, hemodynamic instability and renal failure) (2).

The differential diagnosis for ALF includes infective, toxic, autoimmune, metabolic and vascular causes, and varies according to age. In neonates and infants, gestational alloimmune liver disease, inborn errors of metabolism and hemophagocytic lymphohistiocytosis are the main causes of ALF. In older children, viral infections, drug-induced hepatotoxicity and autoimmune hepatitis are more common. Idiopathic ALF represents up to 50% of most reported cohorts (2).

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism, affecting approximately one in 30,000 to 40,000 individuals. WD may present as nonspecific elevation of liver enzyme levels, cirrhosis or with ALF. It results from mutations in the ATP7B protein, which functions to incorporate copper into ceruloplasmin – a necessary step for biliary copper excretion. As such, serum ceruloplasmin and copper levels are usually reduced, with simultaneous increases in 24 h urinary copper excretion. The pathological features of WD emerge from copper accumulation in various tissues, especially the liver and brain. Diagnosis is aided by identification of Kayser-Fleischer rings in the eyes and typical features on liver biopsy. ALF due to WD is typically lethal without liver transplantation (3).

Treatment of WD relies on copper chelation with penicillamine or trientine therapy, low copper diet and use of zinc to reduce copper absorption in the gut. Zinc stimulates metallothionein production in enterocytes of the intestinal tract. Metallothionein is a protein with great affinity for copper and, as such, copper is then excreted when the enterocytes naturally shed into the lumen of the intestinal tract (3).

This patient presented with classic findings of WD (3): ALF with only a modest rise in liver enzyme levels and bilirubin accompanying a nonautoimmune hemolytic anemia. His ceruloplasmin level was found to be low (67 mg/L [normal 242 mg/L to 396 mg/L]), and he was started on empirical penicillamine and zinc pending definitive diagnosis from examination of liver tissue for total copper content and from genetic testing for ATP7B mutations. He developed kidney failure and atrial fibrillation, likely related to copper toxicity of the cardiac conducting tissue, which improved with plasmapheresis and albumin dialysis. On day 7 of hospitalization, he received a liver transplant.

Although not found on initial examination, as an outpatient, Kayser-Fleisher rings were seen on slit-lamp examination. A liver specimen obtained during transplant demonstrated elevated liver copper levles (622 μg/g [normal 10 μg/g to 35 μg/g], WD likely if >250 μg/g).

Genetic testing found a p.N1270S variant on chromosome 13, consistent with a mutation in the ATP7B gene, and a known causal factor in the development of WD. This patient’s family was screened for WD and the patient’s eight-year-old brother was found to have a low ceruloplasmin level (39 mg/L [normal 242 mg/L to 396 mg/L]), high urine copper level and screened positive on genetic testing. He has been started on zinc therapy and a low copper diet, and is currently doing well.

Our patient has experienced episodes of acute liver rejection, but is maintained on immunosuppressive therapies.

CLINICAL PEARLS

• New-onset jaundice in children should prompt immediate measurement of INR and, if INR is elevated, emergency referral to an expert centre.

• WD should be suspected in a child presenting with ALF, especially in the context of nonautoimmune hemolytic anemia and a modest rise in liver enzyme levels.

• ALF due to WD is frequently fatal and, therefore, immediate referral for evaluation for liver transplantation is required