Clinical Quiz

A 10.5-month-old boy was admitted to the intensive care unit of the James Whitcomb Riley Hospital for Children in status epilepticus with respiratory compromise. He was a full-term product of a normal pregnancy with an uncomplicated perinatal history. Seizures developed when he was 8 months of age and were controlled with carbamazepine and valproic acid before admission. He had no hypoglycemia, and metabolic and genetic screening of urine and plasma produced negative results. He required ventilatory support in intensive care. Anticonvulsant therapy was changed to phenobarbital and phenytoin, with drug levels maintained slightly above the therapeutic range. His electroencephalogram remained abnormal, consistent with a severe diffuse encephalopathy. He manifested signs of hepatopathy at 11 months of age. A consultation with the pediatric gastroenterology department was requested. Physical examination showed an encephalopathic, very chubby infant with scleral but not cutaneous icterus. The liver edge was firm, extending 3 cm below the right costal margin and 1.5 cm below the xiphoid. There was no splenomegaly, ascites or other stigmata of chronic liver disease. Results of pertinent investigations (normal range) included albumin, 1.9 g/dl (3.06-4.2 g/dl), aspartate aminotransferase, 306 IU/l (25-45 IU/l), alanine aminotransferase, 128 IU/l (0-35 IU/l), γ-glutamyl transpeptidase, 606 IU/l (5-55 IU/l), alkaline phosphatase, 535 IU/l (48-277 IU/l), conjugated bilirubin, 6 mg/dl (0-0.2 mg/dl), unconjugated bilirubin 0.7 mg/dl (0-1 mg/dl), blood ammonia, 45 µmol/l (11-35 µmol/l), blood lactate, 2 mol/l (0.5-1.6 mol/l), prothrombin time, 18.7 sec (10.1-13.7 sec), partial thromboplastin time, 44 sec (23.1-35.7 sec), factor V, 27% (50-150%), and factor VII <1% (65-135%). Cerebrospinal fluid examination showed elevated protein and glucose with negative Gram stain and culture. Magnetic resonance imaging of the head showed mild diffuse atrophy (Fig. 1). A liver sonogram revealed hyperechoic hepatomegaly. The patient died of fulminant liver failure at 11.5 months of age. Postmortem examination was remarkable for the presence of a slightly shrunken and firm liver, an enlarged congested spleen, and a horseshoe kidney. Permission to examine the brain was not granted.

Fig. 1

This clinical course is consistent with:

A. Tyrosinemia

B. Zellweger syndrome

C. Drug-induced liver injury

D. Very-long-chain acyl-coenzyme A dehydrogenase deficiency

E. Alpers' disease

Answer: Alper's disease is an autosomal recessive disorder characterized by progressive central nervous system neuronal degeneration and hepatic cirrhosis at autopsy. The course includes intractable seizures, developmental delay, hypotonia, dementia, liver failure, and death. Physical findings of chronic liver disease are usually absent, although there is a marked impairment of hepatic synthetic function at the initial discovery of hepatic involvement. Early histologic findings are nonspecific and include microvesicular steatosis, portal inflammation, and individual hepatocyte necrosis. Hepatic failure develops rapidly, with autopsy findings of massive hepatocyte necrosis, neoductular proliferation, and lobular collapse (Fig. 2). Brain histology includes loss of cortical neurons and Purkinje's cells, with foci of demyelination and Alzheimer type II cells. The underlying metabolic defect has not been described. Findings in all metabolic studies are either normal or consistent with severe hepatic dysfunction.

Fig. 2