An unusual case of massive hepatosplenomegaly.

Sir,

Gaucher disease (GD), a rare genetic disorder but commonest amongst the lysosomal storage disorders, has even few reporting in resource limited countries like India, the largest series being a study of 07 cases from the Malabar coastal region of Kerala amongst Mappila Muslims.[1]

A 25-year-old Hindu lady, (product of a non-consanguineous marriage and no previous medical/family history), presented with easy fatigability, early satiety, gum bleeds with minor trauma and secondary amenorrhea of one year duration. Examination revealed pallor and massive hepatosplenomegaly (liver span 20 cm and palpable spleen size of 19 cm) [Figure 1]. She had pancytopenia with low corrected reticulocyte count, microcytic hypochromic picture with features of hemolysis on peripheral blood smear. Serum bilirubin, serum LDH, serum transaminases and alkaline phosphatase were raised. Lipid profile revealed low levels of total cholesterol, Low density lipoproteins (LDL) and High density lipoproteins (HDL) with hypertrygliceridemia. Workup for malaria, kala-azar and thalessemia were negative. Bone marrow studies revealed Gaucher cells [Figure 2]. Skeletal survey revealed generalized osteopenia skull and typical Ehrlenmeyer flask deformity [Figure 3].

Figure 1

Distended abdomen with enlarged liver (span: 20cm) and a massive splenomegaly (19cms below the left sub costal margin)

Figure 2

Bone marrow aspiration and biopsy, high power view: sheets of histiocytes, with the abundant, granular and fibrillar cytoplasm resembling a crumpled tissue paper. Most of them had single nucleus and stained positive with PAS, consistent with Gaucher cells

Figure 3 (a-c)

Generalised osteopenia in the skull and the typical Ehrlenmeyer flask deformity in the distal femur

Deficiency of glucosylceramidebeta glucosidase (in peripheral leucocytes) was detected (value <0.37nmol/hr/mg versus normal values >4mol/hr/mg).

On basis of age, mode of presentation and evidence on bone marrow with enzyme deficiency, a diagnosis of GD Type I was made. Patient was managed splenectomy and enzyme replacement (part of clinical trial).

GD (autosomal recessive disorder) results from mutation of the Gaucher gene on chromosome 1q21 that codes for the lysosomal enzyme glucosylceramidebeta glucosidase, which catalyses the metabolism of the glucocerebroside (glucosylceramide) resulting in the accumulation of glucosylceramide in the cells of macrophage-monocyte system leading to enlargement of different visceral organs.[2]

GD has 03 phenotypic variants depending on the age of onset, age of death, hepatosplenomegaly, neurological deficit, ethnicity, other organ involvement and mutation analysis. Accordingly it is classified as type I, II and III.

Type 1 (adult onset, non-neuronopathic type) has variability in signs, symptoms, severity, and progression even among siblings with the same genotype. The anemia is both hypoproliferative as well as due to increased peripheral destruction. Congestive and infiltrative hepatomegaly results in raised transaminases. Hypocholesterolemia in GD is due to an abnormal clearance of cholesterol by LDL macrophages.[3] In addition to the skeletal features seen in our patient, other manifestations are bone pains, pathologic fractures, and avascular necrosis of the long bones.

Type II and III are associated with onset at infancy and early childhood, neurological involvement and with higher mortality and shorter life expectancy.

The detection of insufficient enzyme activity in peripheral leucocytes (gold standard)/cultured skin fibroblasts or other nucleated cells is required for the diagnosis of GD. Where not available, demonstration of Gaucher cells in bone marrow is sufficient for the diagnosis.

ERT (started in early 1990s) and substrate reduction therapy (SRT) form the backbone of management. The drugs available are placenta derived beta glucocerebrosidase (Alglucerase), recombinant Imiglucerase and now Velaglucerase alfa (gene-activated human fibroblast cell line).[4]

Indications for ERT and targets for follow up have been developed by consensus of international experts.[5]

Advances in the management of orphan disorders like GD continue to be hindered by high cost and rarity of the disease. This case is unusual because of lack of consanguinity or family history. Differential diagnosis of storage disorders should always be considered while dealing with patients with massive hepatosplenomegaly.