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Liver and intrahepatic bile ducts-nontumor

Metabolic diseases

Glycogen storage disease

Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 30 April 2012, last major update April 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

Glycogen storage diseases

General
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● Called GSD, also glycogenosis and dextrinosis
● Due to defects in glycogen synthesis or breakdown within muscles, liver, other cell types; either genetic or acquired (Wikipedia)
● Estimated to occur in 1 per 20-25K births in US; 1 per 40K births elsewhere
● ~ 11 distinct types

Type I

General
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● Also known as von Gierke disease or hepatorenal glycogenosis
● Type Ia: glucose-6-phosphatase (G6Pase) deficiency
● Type Ib: translocase T1 deficiency
● Type Ic: translocase T2 deficiency (carries inorganic phosphates from microsomes into cytosol and pyrophosphates from cytosol into microsomes)
● Type Id: deficiency in transporter that translocates free glucose molecules from microsomes into cytosol (eMedicine)

Micro description
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● Mosaic pattern due to enlarged hepatocytes compressing sinusoids
● Fatty change, hyperglycogenated nuclei

Micro images
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Swollen hepatocytes in a mosaic pattern with compression of sinusoids

Electron microscopy description
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● Increased cytoplasmic glycogen, lipid droplets, glycogenated nuclei

Type Ia

General
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● Rare; due to absence of glucose-6-phosphatase, required for gluconeogenesis and glycogenolysis
● Symptoms: Hypoglycemia and marked hepatomegaly in first year of life; later short stature, chronic lactic acidosis, focal segmental glomerulosclerosis, hepatic adenomas, iron deficiency
● Diagnosis: deficient G6Pase activity in fresh and frozen liver tissue

Case reports
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● 28 year old woman with multiple hepatic adenomas (Arch Pathol Lab Med 2003;127:e402)

Treatment
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● Liver transplant (Transplant Proc 2011;43:1196)

Gross description
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● Enlarged, pale liver
● May have variable sized tumor nodules

Micro description
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● Large hepatocytes with prominent cell membrane and glycogenated nuclei
● PAS+ accumulated glycogen
● Rarely contains Mallory’s hyaline and steatosis in hepatic adenomas

Micro images
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Adenomas

Adenomas with steatosis and Mallory’s hyaline

Type Ib

General
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● Enzyme levels are normal but transmembrane transport protein translocase 1 is ineffective (Orphanet J Rare Dis 2011;6:27)
● Normal G6Pase activity in frozen tissue and lowered activity in fresh specimens
● Altered neutrophil functions predisposes to gram positive bacterial infections

Type II

General
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● Also called Pompe disease
● Deficiency of lysosomal acid α-glucosidase, causes massive lysosomal glycogen accumulation in cardiac and skeletal muscles (Wikipedia)
● Infantile form: severe hypotonia associated with hypertrophic cardiomyopathy; death from heart and respiratory failure may occur during the first year of life
● Late onset form: progressive muscle weakness

Treatment
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● Enzyme replacement therapy with recombinant human lysosomal hydrolase acid α-glucosidase (cost $300,000 per year), plus supportive and physical therapies (Curr Pharm Biotechnol 2011;12:902)

Micro description
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● Increased hepatocellular glycogen

Electron microscopy description
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● Intralysosomal glycogen

Type III

General
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● Deficiency of debrancher enzyme amylo-1,6-glucosidase due to various mutations causes hypoglycemia (Hum Mol Genet 2009;18:2045)
● Also called Cori's disease
● Variable liver, cardiac muscle, and skeletal muscle involvement (Glycogen Storage Disease Type III; GeneReviews™ [Internet]; 1993-2010 Mar 09 [updated 2011 Mar 15])
● GSD IIIa: most common subtype (85%), liver and muscle involvement
● GSD IIIb: 15%; liver involvement only

Micro description
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● Mosaic pattern due to enlarged hepatocytes compressing sinusoids
● Fatty change, hyperglycogenated nuclei

Micro images
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Hypertrophic hepatocytes with pale staining cytoplasm and portal fibrosis

Electron microscopy description
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● Increased cytoplasmic glycogen, lipid droplets, glycogenated nuclei

Type IV

General
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● Also called amylopectinosis, Andersen disease, Adult polyglucosan body disease
● Rare, autosomal recessive, caused by deficiency of glycogen branching enzyme on 3p14, leading to excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues, causing irreversible tissue and organ damage (J Inherit Metab Dis 2010 Jan 8 [Epub ahead of print])
● Classic form: progressive hepatic fibrosis through age 18 months causing hepatosplenomegaly, failure to thrive, death by 5 years
● Rare nonprogressive form: no cirrhosis, live to adulthood; adult-onset progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (GeneReviews-Adult Polyglucosan Body Disease; July 23, 2009)
● Neuromuscular form: severe hypotonia at birth causing death or myopathy in late childhood or nervous system dysfunction as adults
● Diagnosis: Amylopectin-like material in tissue

Case reports
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● 10 month old male with massive hepatomegaly (Arch Pathol Lab Med 2002;126:630)

Treatment
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● Liver transplantation

Micro description
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● Basophilic intracytoplasmic inclusions, PAS+, diastase partially resistant

Micro images
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H&E (inclusions), PAS, colloidal iron, EM

Cytoplasmic inclusions in hepatocytes

Electron microscopy description
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● Filamentous nonbranching cytoplasmic aggregates

Differential diagnosis
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● Lafora disease (similar inclusions but not coarsely clumped, older age with epilepsy, myoclonus, dementia)

End of Liver and intrahepatic bile ducts-nontumor > Metabolic diseases > Glycogen storage disease

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