Laboratory Studies
Enzyme activity testing
Diagnosis can be confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic. Heterozygotes generally have half-normal enzyme activity, but as much as 20% overlap with activity levels of healthy controls has been reported, rendering enzymatic testing for carrier status unreliable.
Genotype testing
Molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom 6 GBA1 mutations (ie, N370S, c.84insG, L444P, IVS2+1g>a, V394L, and R496H) account for most disease alleles. In other ethnicities, sequencing of the exons of GBA1 is necessary in order to accurately establish the genotype. Mutation analysis has some, albeit limited, predictive value with respect to disease progression. Caution should be taken in relying solely on PCR-based test results for individual mutations because they cannot reveal the presence of recombinant alleles associated with greater disease severity.
CBC count
Obtain a CBC count with a platelet count and differential to assess the degree of cytopenia.
Liver function enzyme testing
Minor elevations of liver enzyme levels are common, even in patients who are mildly affected with Gaucher disease; however, the presence of jaundice or impaired hepatocellular synthetic function merits a full hepatic evaluation. Coagulations studies should be monitored.
Associated marker testing
Angiotensin-converting enzyme levels are typically elevated, as are total acid phosphatase and ferritin levels. These levels may normalize or may remain elevated with treatment. Monitoring levels of another enzyme, chitotriosidase, is also useful in monitoring the disease, except in the 10% of the population who have a deficiency in this protein. Monitoring levels of glucosylsphingosine, a downstream metabolic product of glucosylceramide, may also be useful, as they have also been shown to correlate with response to therapy. [11]
Imaging Studies
Ultrasonography of the abdomen can reveal the extent of organomegaly. MRI is more accurate than ultrasonography in determining organ size and can be used for volumetric assessment. MRI may be useful in revealing early skeletal involvement, such as avascular necrosis and spinal degradation, as well as in delineating the degree of bone marrow infiltration. Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease. Perform chest radiography to evaluate pulmonary manifestations. Dual-energy x-ray absorptiometry (DEXA) is useful in evaluating osteopenia. Bone scans may be useful in diagnosing bone crises.
Other Tests
Echocardiograms are helpful in evaluating the possibility of pulmonary hypertension.
In neuronopathic Gaucher disease, depending on phenotypic presentation, EEG, brainstem-evoked potential, swallow studies, and neuro-ophthalmologic evaluation should be performed at regular intervals.
Procedures
Bone marrow aspiration
In the past, the diagnosis was confirmed with the finding of classic glycolipid-laden macrophages in bone marrow aspirate collected because of hematological abnormalities; however, aspiration is not a recommended diagnostic tool. Similar pseudo-Gaucher cells have also been described in individuals with other disorders, including chronic granulocytic leukemia, thalassemia, multiple myeloma, Hodgkin disease, plasmacytoid lymphomas, acquired immunodeficiency syndrome (AIDS), and Mycobacterium avium– intracellulare infection.
Bone marrow aspiration should not be the initial diagnostic test because the blood enzyme test is sensitive, specific, and much less invasive; in fact, such biopsies are rarely indicated.
Liver biopsy
Liver biopsy is occasionally performed to assess unexplained hepatomegaly. However, it should be avoided in most patients when the diagnosis is suspected because a specific diagnostic test is available.
Histologic Findings
In Gaucher disease, classic glycolipid-laden macrophages are found in bone marrow aspirate or in liver biopsy samples. On liver biopsy samples, glycolipid-laden Gaucher cells are evident in the sinusoids, but the hepatocytes do not manifest overt glycolipid storage, presumably because of biliary excretion of glucocerebroside and because exogenous glycolipid turnover is handled by the mononuclear phagocytes. The sparing of hepatocytes is consistent with the low incidence of liver failure in individuals with Gaucher disease.
The pathologic hallmark of Gaucher disease is the presence of Gaucher cells in the macrophage-monocyte system, particularly in the bone marrow. These cells, which are 20-100 mm in diameter, have a characteristic wrinkled-paper appearance, resulting from intracytoplasmic substrate deposition, and stain strongly positive with periodic acid–Schiff. Histologic evaluation of biopsy specimens should not be used as a first-line diagnostic tool.
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Autosomal recessive inheritance pattern.
