Reza Malekzadeh MD•, Taghi Amiriani MD

 

Author’s affiliation: Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.

•Corresponding author and reprint: Reza Malekzadeh MD, Digestive Disease Research Center, Shariati Hospital, North Kargar Ave., Tehran 14114, Iran. Fax: +98-21-22253635, E-mail: malek@ams.ac.ir.

 

 

 

 

42- year-old gentleman was referred by a hematologist to liver clinic for possible chronic liver disease. The major findings were pancytopenia and a huge splenomegaly. He mainly complained of  fatigue, bone pain, and abdominal fullness in last six months. His past medical history was positive for sudden weight loss in early childhood and avascular necrosis of femoral head in late childhood (Figure A).

 Physical examination revealed huge splenomegaly, hepatomegaly (span = 20 cm), and decreased range of motion of both hip joints.

Positive laboratory data were mild normochromic, normocytic anemia, leukopenia, and thrombocytopenia. Liver function tests were normal and viral markers were negative. In ultrasonography, patency of portal, splenic, and hepatic veins were reported. Esophageal varices were not seen in upper endoscopy.

Images from liver needle biopsy (Figure B) and bone marrow  biopsy (Figure C) are shown in the above.

 

 

 

What is Your Diagnosis?

                                                                                                        See the next page for the diagnosis.

 

 

 

 

 

 

aucher disease is the most common lysosomal storage disease which is   inherited as an autosomal recessive disorder. The main metabolic problem in this disease is the defective recycling of cellular glycolipids. Glucocerebroside and some related glycolipid compounds are the component of cell membrane and are distributed widely in many organs. They ordinarily are degraded to glucose and lipid. In Gaucher disease, they do not degrade and instead accumulate within the lysosomes of cells. It results from deficiency of glucocerebrosidase, a lysosomal enzyme.¹

In affected patients, the deficiency of glucocerebrosidase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages (Gaucher cells) that are a cardinal feature of the disease. Gaucher cells have a characteristic histologic appearance of wrinkled tissue paper. The clinical manifestations of Gaucher disease result from the accumulation of the lipid-laden macrophages in the spleen, liver, bone marrow, and bone.^{1, 2}

Gaucher disease consists of three clinical types, in all affected patients; the disease involves the visceral organs, bone marrow, and bone. Type 1 is the most common and occurs predominantly in the Ashkenazi Jewish population. It is distinguished from type 2 and type 3 by the lack of involvement of the central nervous system.² The age of onset for type 1 is extremely variable. Some patients present between 12 and 24 months of age, whereas others have no clinical signs until late adulthood. The glucocerebrosidase gene is located on chromosome 1q21 and more than 150 distinct mutations are reported up to now. In patients with the most common mutation (N370S), the mean age of onset is 30 years. However, some remain asymptomatic throughout life. Splenomegaly is the most common presenting sign. Other manifestations are hepatomegaly, bone disease (osteopenia and avascular necrosis), bleeding, and easy bruising. Many affected children grow poorly and have delayed puberty. Less common manifestations of Gaucher disease include interstitial lung disease and cardiovascular calcifications. The clinical course of type 1 Gaucher disease is slowly progressive. In general, obvious worsening occurs in childhood. In contrast, the disease progresses slowly in adults.¹ In paraclinical evaluation thrombocytopenia and anemia are the typical finding; liver enzymes may be mildly elevated. Serum angiotensin-converting enzyme may be increased. Serum acid phosphatase is elevated in patients with active bone disease. Radiographs of the long bones demonstrate the characteristic Erlenmeyer flask deformity of the distal femur.¹

The diagnosis of Gaucher disease is confirmed by direct enzyme analysis of glucocerebrosidase in peripheral blood leukocytes. Also, DNA analysis to detect the most common mutations is an effective method for patient classification and carrier diagnosis.³

Gaucher disease is one of the few inherited metabolic disorders that can be treated by replacement of the deficient enzyme. Two preparations of glucocerebrosidase are available for enzyme replacement therapy (ERT): alglucerase and imiglucerase. In type 1 disease, most clinicians begin treatment in patients with clinical manifestations. The initial dose for type 1 patients is 60 U/kg, followed by individualized dose adjustment. Treatment is continued throughout the patient’s life. The mean dose used for long-term therapy is approximately 30 U/kg every two weeks.^{4, 5} Substrate reduction therapy is an option in patients who are unwilling or unable to receive ERT. In this approach, glycolipid accumulation is reduced by decreasing the level of substrate available rather than by replacing the deficient enzyme. Miglustat, an inhibitor of glucosylceramide synthase, was approved by the FDA.^{6, 7} Bone marrow transplantation can provide a definitive cure for Gaucher disease. However, this procedure is associated with substantial morbidity and mortality and has been replaced by ERT.²

 

References

 

1       Beutler E, Grabowski GA. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001: 3635.

2       Rice EO, Mifflin TE, Sakallah S, Lee RE. Gaucher disease: studies of phenotype, molecular diagnosis, and treatment. Clin Genet. 1996; 49: 111 – 118.

3       Wenger DA, Clark C, Sattler M, Wharton C. Synthetic substrate beta-glucosidase activity in leukocytes: a reproducible method for the identification of patients and carriers of Gaucher’s disease. Clin Genet. 1978; 13: 145 – 153.

4       Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med. 1991; 324: 1464 – 1470.

5       Hollak CE, Aerts JM, Goudsmit R, et al. Individualised low-dose alglucerase therapy for type 1 Gaucher’s disease. Lancet. 1995; 345: 1474 – 1478.

 6       Zimran A, Elstein D. Gaucher disease and the clinical experience with substrate reduction therapy. Philos Trans R Soc Lond B Biol Sci. 2003;             358: 961 – 966.

7       Moyses C. Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci. 2003; 358: 955 – 960.

 

 

 

 

 

Erratum   In the article entitled “A serological survey in suspected human patients of Crimean-Congo hemorrhagic fever in Iran by determination of IGM-specific ELISA method during 2000 – 2004”  published in the journal (Volume 8, Number 1, January 2005, Page 52 – 55):    1.       On page 53, column one, paragraph 5, line 1, “Seven hundred and eighty-three” must be replaced by “Six hundred and eighty-three”. 2.       On page 53, column one, paragraph 5, line 4, “27 persons died” must be replaced by “24 persons died”. 3.        On page 53, column two, paragraph 2, line 1, “14 of the 28 provinces must be replaced by 15 of the 28 provinces”.