Clinical Quiz

A 29-month-old male toddler presented with a 9-month history of worsening balance, unsteady gait, regression in language skills and recurrent episodes of epistaxis. He was a term delivery with no perinatal complications and had maintained normal growth and development throughout the first year. There was a history of a patchy rash that the parents thought was due to allergy to wheat. The parents had therefore put him on a gluten-free diet at 1 year of age. The diet was supplemented with vitamin drops that the mother was also using to treat a “bleeding disorder.” He developed dry scaling skin, hair loss and gradual progression of the presenting symptoms at age 18 months. On physical examination, head circumference was 56 cm (>95th percentile) and weight and height were both at ∼25th percentile. There was icterus, pallor, cheilosis, patchy alopecia, dry skin and a generalized exfoliating skin rash. The abdomen was moderately distended with hepatosplenomegaly (liver palpated 6-cm below the right costal margin; spleen palpable 7-cm below left costal margin) but no ascites. He was unable to stand without assistance and had an ataxic gait with generalized hyperreflexia and a positive Babinski sign. Funduscopic examination revealed papilledema. The cranial nerves were intact. Laboratory examinations obtained were: hemoglobin 9.5 g/dl; MCV 93 FL; platelets 58,000/mm3; WBC 4.500/mm3; albumin 2.6 g/dL; direct bilirubin 1.5 mg/dl; alkaline phosphatase 343 IU/L; ALT 22 IU/L; AST 82 IU/L; GGT 145 IU/L; prothrombin time 21.1s; INR: 1.75. Celiac disease screen and plasma amino acid, fatty acid and urine organic acid profiles were normal. Abdominal ultrasound revealed hepatosplenomegaly with normal Doppler flow. A MRI of the head revealed prominent ventricle width and atrophy of the periventricular frontal horns suggesting increased intracranial pressure. Liver biopsy was performed. (Figs. 1 and 2).FIG. 1FIG. 21. What is the diagnosis? A. Niemann-Pick disease B. Zellweger syndrome C. Chronic vitamin A intoxication D. Kwashiorkor E. Hunter syndrome ANSWER/DISCUSSION ANSWER C: Chronic vitamin A intoxication The vitamin supplement that the boy received for 16 months contained vitamin A 15,000 IU/drop (15,000-75,000 IU/d). The recommended dietary intake for vitamin A in children 1 to 9 years of age is 1,200-1,600 IU/day (1). The clinical course was consistent with chronic vitamin A intoxication. The diagnosis was confirmed by the characteristic hepatic histopathologic finding of Ito cell hyperplasia (Figs. 1 and 2). The arrows in Fig. 1, ect. Symptoms of vitamin A intoxication include alopecia, anorexia, fatigue, irritability, skin desquamation and erythema, fissuring at lip corners, bone pain and tenderness, bulging fontanels, craniotabes, pseudotumor cerebri, photophobia, hepatomegaly and hypoplastic anemia (2). Thrombocytopenia and other signs of hypersplenism develop secondary to intrahepatic portal hypertension. A high index of suspicion is required for a positive diagnosis of vitamin A intoxication. Regular diets do not pose a risk for vitamin A intoxication. Intoxication typically occurs in the setting of supplement use. Pre-morbid scenarios that increase susceptibility to intoxication include protein-energy malnutrition, viral hepatitis, alcoholism, cirrhosis, and other liver diseases (2). Serum levels of vitamin A are insensitive and not diagnostic. About 90% of total body vitamin A is stored in the liver, predominantly in Ito (stellate) cells (79-84%); a smaller proportion (<20%) is in the hepatic parenchyma (3,4). The classic histologic changes in vitamin A intoxication are Ito cell hyperplasia with numerous lipid vacuoles (Figs. 1 and 2). The hyperplastic Ito cells are activated to fibrogenesis with obliteration of the spaces of Disse (5). There is progression to hepatic fibrosis, cirrhosis, portal hypertension and hepatic failure over time. Management of intoxication involves immediate discontinuation of vitamin A supplements and the restriction of vitamin A-rich food. The half-life of vitamin A is ∼286 days; therefore, spontaneous mobilization of the hepatic vitamin A may take several months (6). The histologic similarity to primary biliary cirrhosis has led some to also recommend ursodeoxycholic acid (5).