Elsevier

Journal of Hepatology

Volume 31, Issue 4, October 1999, Pages 741-746
Journal of Hepatology

Case Report
Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase −1 exon 8 splice junction mutation

https://doi.org/10.1016/S0168-8278(99)80356-0Get rights and content

Abstract

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed “sea-blue histiocytes”, vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G→A mutation at position −1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype −6Thr, 2Gly, 894 G→A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.

Section snippets

Case Report

A 36-year-old female patient was admitted because of hepatosplenomegaly and anemia. At the age of 2 years, icterus and slightly raised brownish skin spots had developed and hepatomegaly was diagnosed. A lipid storage disease was suspected and a fat-restricted diet was recommended. Five years before admission, subtotal thyroid gland resection had been performed for goiter. The patient did well until 1995, when she developed rheumatoid arthritis, which was treated with cortisone and methotrexate.

Chitotriosidase determination

EDTA plasma samples were drawn from the patient and immediately frozen at −20°C. Chitotriosidase activity was determined as described earlier (12) with some minor modifications. The EDTA plasma was diluted 10 times with phosphate-buffered saline containing 1 mg/ml bovine serum albumin (BSA). The chitotriosidase activity was measured by incubation of 10 μl of diluted EDTA plasma with 100 μl of 4-methylumbelliferyl-β-D-N,N′,N″-triacetylchitotriose (Sigma) as substrate in citrate/phosphate buffer

Results

Chitotriosidase activity was increased to 827 nmol/ml plasma/h in this CESD patient, representing a 27-fold increase over control values (mean 30±20 nmol/ml/h, n=50, range 7–124), but far below the excessive increases of chitotriosidase activity found in adult symptomatic Gaucher type I patients (21 397±15 203 nmol/ml/h, n=47, range 2085–74 173).

Cultured fibroblasts from a skin biopsy were assayed for β-glucocerebrosidase and sphingomyelinase activity using radiolabeled lipid substrates as

Discussion

In a patient with hepatosplenomegaly and anemia, the presence of lysosomal storage disease was suggested by: a) the absence of malignancy, primary hematologic or liver disease, b) the presence of sea-blue histiocytes and vacuolation of macrophages and plasma cells in bone marrow smears, and c) an increase in plasma chitotriosidase activity.

The patient was finally diagnosed with cholesteryl ester storage disease (CESD) by: (i) the accumulation of cholesteryl esters found in fibroblast cultures,

References (36)

  • MT Vanier et al.

    Niemann-Pick diseases

  • K Harzer et al.

    A simple sphingomyelinase determination for Niemann-Pick disease: differential diagnosis of types A, B and C

    J Neurochem

    (1973)
  • JA Burke et al.

    Deficient activity of hepatic acid lipase in cholesterol ester storage disease

    Science

    (1972)
  • HR Sloan et al.

    Enzyme deficiency in cholesteryl ester storage disease

    J Clin Invest

    (1972)
  • GTN Besley et al.

    Cholesterol ester storage disease in an adult presenting with sea-blue histiocytosis

    Clin Genet

    (1984)
  • NW Barton et al.

    Replacement therapy for inherited enzyme deficiency-macrophage-targeted glucocerebrosidase for Gaucher's disease

    N Engl J Med

    (1991)
  • EO Rice et al.

    Gaucher disease: studies of phenotype, molecular diagnosis and treatment

    Clin Genet

    (1996)
  • CM Hollak et al.

    Marked elevation of plasma chitotriosidase activity: a novel hallmark of Gaucher disease

    J Clin Invest

    (1994)
  • Cited by (0)

    View full text