Signs, Symptoms & Clinical presentations

Infiltration of Gaucher cells into organs and tissues in which macrophages are normally found accounts for the multisystemic nature of Gaucher disease. Signs and symptoms may include one or more of the following:

Splenomegaly (Figure 1) is usually characteristic and progressive, with enlargement up to 100 or more times normal volume and weight.^[1] Gaucher splenic volumes range from 300 cc to 10,000 cc. Hypersplenism, infarcts, fibrosis (with possible calcification), scarring and nodules may develop. Hepatomegaly (Figure 1) also is common, with liver volumes generally increased 1.5 to 2.0 times, but sometimes up to 10 times normal. Some patients experience fibrosis (pseudocirrhosis) or portal hypertension. Pulmonary and renal involvements are less common, but may cause significant morbidity.

Skeletal involvement

Frequently under-recognized, skeletal involvement can be the most debilitating aspect of Gaucher disease, affecting over 80% of patients with Type 1 Gaucher disease ^{[2, 3, 4]}. Indeed, a study surveying several hundred patients found radiologic bone lesions as prevalent as splenomegaly^[5]. Patients may have a variety of functional and metabolic bone defects and additional major complications such as: bone marrow infiltration with Gaucher cells (Figure 2), failure of remodeling (Figure 3), osteopenia (Figure 4), osteonecrosis (Figure 5), osteosclerosis (Figure 6), bone crisis and/or chronic bone pain, lytic lesions and pathologic fractures (figure 7).^{[5, 6]} Gaucher bone disease generally has a progressive course and can become disabling.^[7] Dramatic deterioration may follow years of apparently “stable” disease, and Gaucher bone involvement has never been observed to resolve spontaneously.^[3]

A) B)
Fig. 2: Bone marrow infiltration in Gaucher disease; T1- weighted image of the femura. (A) Healthy normal control subject; (B) Patient with Gaucher disease^[8]

A) B)
Fig. 5: Osteonecrosis in Gaucher disease. Plain radiography (A) and magnetic resonance imaging (B) of same patient illustrating osteonecrosis of both femoral heads of both femoral heads seen on plain X-ray as well as MRI.^[8]

Splenic sequestration and overactivity, along with infiltration of the bone marrow and displacement of haematopoietic elements by Gaucher cells, frequently produce laboratory and/or clinical haematologic abnormalities. Among these abnormalities are anaemia, thrombocytopenia, neutropenia, pancytopenia, coagulopathy and bleeding and bruising tendencies.^{[10, 11, 12]}

Individuals with Gaucher disease have been shown to have an over 40% greater than normal resting energy expenditure^{[13, 14]}. This metabolic burden may contribute to the sometimes considerable fatigue that afflicts many patients. Together with chronic anaemia and hepatosplenomegaly, it also may help to explain the pubertal delay and growth retardation that can occur with this disorder.^[12] Growth retardation appears to affect both sexes equally and to correlate positively with earlier onset and increased severity of disease.^[15]

Gaucher disease can severely impair the quality of life of patients and their families.^[1] Skeletal involvement may be a particularly prominent cause of decreased ability to perform normal activities of daily living (ADL). Complications can include excruciating, acute and/or chronic pain, infections, bone or joint destruction, often with flawed healing, kyphosis and related phenomena such as lordosis or scoliosis. These complications in turn may require hospitalisation and/or costly and complex surgical interventions such as total joint replacement. Severe anaemia or thrombocytopenia may require regular blood or platelet transfusions.

Singly or in combination, the symptoms of Gaucher disease may diminish patients’ feelings of well-being and functional health and prevent them from working or pursuing family or leisure activities.

References
1. Brady RO, Pentchev PG, Gal AE, et al: Replacement therapy for inherited enzyme deficiency: use of purified glucocerebrosidase in Gaucher’s disease. N Engl J Med 291:989-993, 1974

2. Beighton B, Goldblatt J, Sacks S: Bone involvement in Gaucher disease. In Desnick RJ, Gatt S, Grabowski GA, eds. Gaucher disease: a century of delineation and research. New York: Alan R. Liss, Inc., pp. 107-129, 1982

3. Pastores GM, Einhorn TA: Skeletal complications of Gaucher disease: pathophysiology, evaluation, and treatment. Seminars in Hematology 32(3, suppl 1):20-27, 1995

4. Silverstein MN, Kelly PJ: Osteo-articular manifestations of Gaucher’s disease. Am J Med Sci 253:569-577, 1967

5. Stowens DW, Teitelbaum SL, Kahn AJ, et al: Skeletal complications of Gaucher disease. Medicine (Baltimore) 64(5):310-322, 1985

6. Pastores GM, Wallenstein S, Desnick RJ, Luckey MM: Bone density in Type 1 Gaucher disease. J Bone and Mineral Res 11(11):1801-1807, 1996

7. Einhorn TA: Managing Orthopedic Manifestations of Gaucher Disease. Pawling, NY: Caduceus Medical Publishers, pp. 1-14, 1993

8. Maas M, Poll LW; Terk MR. Imaging and quantifying skeletal involvement in Gaucher disease. Br. J; Radiol. 2002;75 (suppl 1):A13-A24

9. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Br J Radiol. 2002;75 (suppl 1): A2-A12

10. Barranger JA, Rice E: An overview of Gaucher disease. Gaucher Clinical Perspectives 1(1):1-5, 1993

11. Esplin JA: Clinical effects of enzyme replacement therapy of Gaucher disease: a review of various dosing regimens. Seminars in Hematology 32(3, suppl 1):28-32, 1995

12. Barton DJ, Ludman MD, Benkov K, et al: Resting energy expenditure in Gaucher’s disease Type 1: effect of Gaucher’s cell burden on energy requirements. Metabolism 38:1238-1243, 1989

13. Goldblatt, J: Type I Gaucher disease. J Med Genetics 25:425-418, 1988

14. Pastores GM, Lenz P: Growth and development in children with Type 1 Gaucher disease. Gaucher Clinical Perspectives 3(1):1-5, 1995

15. Kaplan P, Mazur A: Growth in children with Type 1 Gaucher disease, treated with Ceredase™. Gaucher Clinical Perspectives 3(1):5-9, 1995

16. Verderese CL, Graham OC, Holder-McShane CA, et al: Gaucher’s disease: a pilot study of the symptomatic responses to enzyme replacement therapy. J Neurosci Nurs 25(5):296-301, 1993