Approach Considerations
Hepatomegaly and hypoglycemia in a child should raise suspicion for a beta oxidation disorder, galactosemia, and glycogen degradation pathway disorder—in particular GSD I, GSD III, and GSD VI.
The American College of Medical Genetics and Genomics (ACMG) suggests performing the following tests in a patient with hypoglycemia and hepatomegaly [2] :
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Blood glucose
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Blood lactate
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Uric acid
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Hepatic profile including liver function studies
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Serum lipid profile
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Plasma creatine kinase (CK)
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Plasma total and free carnitine
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Plasma acylcarnitine profile
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Plasma amino acids
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Urinalysis
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Urine organic acids
Laboratory results suggestive of GSD III include ketotic hypoglycemia after short fasting, elevated transaminase levels, and elevated fatty acid concentrations. [3] Levels of CK can be elevated in GSD IIIa. Uric acid and lactate levels can help in the differential diagnosis of GSD: lactate and uric acid levels are usually elevated in GSD I but normal in GSD III.
Additional clinical features help differentiate the GSD subtypes. GSD I presents early in life with severe fasting hypoglycemia. GSD III and GSD VI usually have a less severe disease because gluconeogenesis compensates for the lack of glycogenolysis.
Laboratory Studies
According to the ACMG guidelines, [2] diagnosis of GSD III is based on the following: (1) demonstration of excessive and structurally abnormal glycogen accumulation with shorter outer branches and deficient debranching enzyme activity in frozen liver and/or muscle biopsy samples or (2) identification of pathogenic mutations in the AGL gene on both alleles.
In a patient with suspected GSD III, gene sequencing is usually performed first as it is a widely available, noninvasive technique. Analysis of debranching enzyme activity is reserved for cases in which molecular genetic analysis is inconclusive due to its more invasive nature—it requires liver and/or muscle biopsy.
There are no clear genotype-phenotype correlations. [13] As an exception, an association between exon 3 mutations and GSDIIIb have been previously described.
Other Tests
Electromyography
Electromyography patterns are diverse and vary from patient to patient. Electromyograms (EMG) and nerve conduction studies (NCS) show myopathic (short duration, low amplitude, increased complexity, and early recruitment) and neuropathic (long duration, large amplitude, and late recruitment) patterns. [16, 17]
Glucagon administration
In GSD III, the administration of glucagon 2 hours after a carbohydrate-rich meal provokes a normal increase in blood glucose (BG), whereas after an overnight fast, glucagon typically provokes no change in BG level. [2]
Ischemic forearm test
The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.
Instruct the patient to rest. Position a loosened blood pressure cuff on the arm and place a venous line for blood samples in the antecubital vein.
Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.
Obtain a urine sample for myoglobin analysis.
Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.
Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.
Collect a final urine sample for myoglobin analysis.
Interpretation of ischemic forearm test results
With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.
Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 µg/dL. Levels will return to baseline.
If neither level increases, the exercise was not strenuous enough and the test is not valid.
Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.
Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all GSDs have a positive result on ischemic test.
Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
In Cori disease, the ischemic forearm test result is positive
Histologic Findings
Liver biopsy shows hepatocyte distention and abundance of cytoplasmic glycogen—the stored glycogen is periodic acid-Schiff positive and diastase sensitive. Lipid vacuoles are present; however, they are less frequent and smaller than in GSD I. The presence of fibrosis ranges from minimal periportal fibrosis to micronodular cirrhosis. [2]
Muscle, when affected, exhibits glycogen particle accumulation between intact myofibrils and in the subsarcolemmal position, locations in which glycogen usually occurs but not in such abundance.
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Metabolic pathways of carbohydrates.
