A 5-year-old south Asian female was incidentally found to have hepatomegaly on a trip to India, where she became acutely ill with fever, vomiting, and abdominal pain. Blood work done at that time demonstrated mildly elevated liver function tests (AST 48 U/L, ALT 80 U/L), and an abdominal ultrasound revealed hepatomegaly without biliary or splenic abnormalities. She was prescribed an antibiotic and her symptoms gradually resolved.A month after her return to the United States, her pediatrician noted persistent hepatomegaly and the new development of fever. She was referred to the emergency department because of suspicion of a tropical infectious disease. A repeat ultrasound demonstrated persistent hepatomegaly. Her transaminases (AST 133 U/L, ALT 112 U/L) remained elevated. The infectious workup was negative for cytomegalovirus, hepatitis A, Lyme disease, and malaria. She did have a positive Epstein-Barr virus IgM. Repeat blood work was obtained at follow-up infectious disease clinic visit where she was again found to have hepatomegaly (7 cm below the costal margin) and mildly abnormal transaminases. A computed tomography of the abdomen and pelvis (Figure 1) was performed that demonstrated hepatomegaly but had otherwise normal findings. Her fever resolved within 2 weeks. She was otherwise well and was not on any medications. There was no family history of liver disease. Her immunizations were up to date. Because of persistent hepatomegaly, she was referred to the liver clinic.Open in a separate windowFigure 1Computed tomography of abdomen and pelvis. The liver is enlarged, measuring up to 17 cm in width and craniocaudal dimension. The contour is smooth. The hepatic parenchyma is homogenous without a focal mass. There is no intrahepatic biliary dilatation. The portal and hepatic venous systems are patent and nondilated.In the liver clinic, she was noted to have an enlarged, firm liver, palpable 8 cm below the costal margin with no associated splenomegaly. Test results for autoimmune hepatitis, WD, and alpha-1-antitrypsin deficiency were negative. Nonfasting lipid levels were abnormal; repeat testing showed a fasting total cholesterol of 305 mg/dL and a triglyceride level of 142 mg/dL.On the basis of a clinical suspicion of a diagnosis of CESD, a liver biopsy was performed. It revealed diffuse, microvesicular steatosis in the hepatic parenchyma (Figure 2(a)). Portal tracts were expanded by foamy macrophages containing finely vacuolated material, which was periodic acid-Schiff positive and resistant to diastase digestion. Trichrome stain for collagen showed mild portal fibrosis with early delicate bridging fibrosis. Ultrastructurally, the cytoplasm had a moth-eaten appearance with the presence of lipid droplets and cholesterol crystals (Figure 2(b)). There was no evidence of hepatocellular necrosis, cholestasis, or bile duct proliferation.Open in a separate windowFigure 2(a) Liver biopsy, periodic acid-Schiff stain with diastase (magnification, ×40). Lipid demonstrated within the hepatocellular cytoplasm (arrows). (b) Electron micrograph (direct magnification, ×2500). The hepatocellular cytoplasm in places has a moth-eaten appearance with lipid droplets (arrows). Additionally, some foci show cholesterol crystals (∗) free in the hepatocellular cytoplasm.Liver tissue was sent to Dr. D. Wenger's Lysosomal Diseases Testing Laboratory at Thomas Jefferson University. She was found to have a low acid lipase activity of 7.2 (no units provided by Dr. D. Wenger's laboratory) in the liver. Follow-up testing through a commercial laboratory demonstrated low level of lysosomal acid lipase activity (0.008 nmol/punch/h) in blood. Lysosomal acid lipase gene sequence analysis was performed, which demonstrated that she was heterozygous for the following two mutations: c.57_60delTGAG and c.894G>A. Both parents underwent mutation analysis. The mother was confirmed to have the c.894G>A mutation while the father carried the c.57_60delTGAG mutation. The c.57_60delTGAG is a new mutation not previously described in the literature in patients with CESD.Go to:

2.2.1. Patient #F061The patient was an Italian male, born from a consanguineous marriage, who was admitted to the hospital at 2 months of age for diarrhea and steatorrhea associated with abdominal distension, anemia (RBC 3.02 × 106/μL; Hb 7.7 g/dL), hepatosplenomegaly, increased liver enzymes (AST 86 IU/L—n.v. 10–40; ALT 38 IU/L—n.v. 5–35), hypoproteinemia (4.8 g/dL—n.v. 6.1–7.9) and failure to thrive. Peripheral blood smear showed the presence of vacuolated leukocytes; bone marrow biopsy showed vacuolization in histiocytes suggesting intralysosomal and cytoplasmic accumulation of lipids (foam cells). The adrenal glands were markedly enlarged and extensively seeded with calcific deposits. LAL activity in skin fibroblasts was 1.4 nmol/mg protein/min (n.v. 55.8 ± 15.6 nmol/mg protein/min). The clinical features and the severe LAL defect were consistent with the diagnosis of WD. The patient died of hepatic and adrenal failure at 6 months of age.