Glycogen Storage Disease

Grace E. Kim, MD

Key Facts

Etiology/Pathogenesis

Inborn error of carbohydrate metabolism caused by gene mutations in proteins involved in glycogen synthesis, degradation, or regulation
- Results in different enzymatic defects in liver that are classified as GSD types 0, I, II, III, IV, VI, and IX
- 80% of hepatic GSD is types I, III, and IX

Clinical Issues

Most patients present with hepatomegaly and hypoglycemia
Increased incidence of hepatic adenoma and hepatocellular carcinoma in GSD I and also GSD III
Liver transplantation corrects primary hepatic enzyme defect and is used primarily for GSD IV

Microscopic Pathology

Assess liver for mosaic pattern of hepatocytes, glycogenated nuclei, fatty change, and fibrosis
- GSD 0 has decreased glycogen
- GSD IV has characteristic cytoplasmic inclusions
Cirrhosis occurs frequently in GSD IV and can occur in III and IX

Ancillary Tests

Lysosomal-bound glycogen for GSD II
Fibrillar glycogen for GSD IV

Top Differential Diagnoses

Glycogen hepatopathy
Other entities with ground-glass cytoplasm

The mosaic pattern results from swollen hepatocytes compressing the sinusoids in this case of GSD Ia. The cell membranes are accentuated, and prominent glycogenated nuclei

are seen.

Reticulin stain highlights the abnormal architecture, loss of reticulin fibers

, and pseudorosette formation

in this hepatocellular carcinoma arising in a patient with GSD Ia.

TERMINOLOGY

Abbreviations

Glycogen storage disease (GSD)

Synonyms

Glycogenoses

ETIOLOGY/PATHOGENESIS

Inborn Error of Carbohydrate Metabolism

Gene mutation in proteins involved in glycogen synthesis, degradation, or regulation
- Hepatic enzyme deficiency
  - GSD types 0, I, II, III, IV, VI, and IX
  - 80% of hepatic GSD is types I, III, and IX
- Abnormal concentration or structure of glycogen
  - GSD 0 results in decreased hepatic glycogen
  - Remaining types of GSD display increased hepatic glycogen
Inherited as autosomal recessive trait
- Exception is GSD IX (X-linked disorder)

CLINICAL ISSUES

Presentation

Hepatomegaly
- Occurs in GSD I, III, IV, VI, and IX
- Rarely in GSD II
- Not in GSD 0
Hypoglycemia
- Occurs in GSD 0, I, and III
- Mild in VI and IX
- Rarely in GSD IV
- Not in GSD II

Laboratory Tests

Confirmation of diagnosis
- Enzymatic assay on liver
  - GSD 0, I, II, III, VI, and IX
- DNA mutation analysis

Treatment

Options, risks, complications
- Increased incidence of hepatocellular neoplasia
  - Hepatic adenoma is frequent in GSD I and can occur in GSD III
  - Hepatocellular carcinoma occurs in GSD I and is reported in GSD III
- GSD Ib has been associated with Crohn-like disease
  - Granulomatous colitis
  - Responds to inflammatory bowel disease treatment regimen
- Dietary intervention
  - Prevent hypoglycemia, particularly for GSD 0 and I, less stringent in GSD III
Surgical approaches
- Liver transplantation corrects primary hepatic enzyme defect
  - Has been performed for GSD I, III, and IV
  - Best treatment option for GSD IV

Prognosis

Variable based on type of GSD
- GSD II (infantile form) usually results in death in 1st year of life
- GSD IV (classic hepatic form) has rapid disease progression with liver failure from 3-5 years of age

MICROSCOPIC PATHOLOGY

Histologic Features

Histologic features are not generally diagnostic of GSD
- Exception is characteristic cytoplasmic inclusion in GSD IV
  - Weakly basophilic to colorless inclusion, retracts from surrounding cytoplasm
  - PAS positive and partially digested on PAS-D
Mosaic architecture
- In GSD I, III, VI, and IX
- Attributed to enlarged, pale-staining, swollen hepatocytes
- Compression of sinusoid by expanded hepatocytes
- Excess glycogen is PAS positive, PAS-D negative
  - Glycogen may wash out with formalin processing
  - Glycogen can be retained with alcohol fixation
Fibrosis
- Initially in periportal region
- GSD III, IV, VI, IX; may occur in GSD I
  - Frequently progresses to cirrhosis in GSD IV
  - Cirrhosis can occur in III and IX
Features of hepatocytes
- Glycogenated nuclei
  - In GSD I (prominent) and III (less)
- Thickened cytoplasmic membrane
  - Resulting from organelles at periphery of cytoplasm
Cytoplasmic lipid in all GSD
- More pronounced in GSD I