Liver & intrahepatic bile ducts

Metabolic diseases

Glycogen storage diseases



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PubMed Search: Glycogen storage diseases

Nigar Anjuman Khurram, M.D.
Monika Vyas, M.D.
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Cite this page: Khurram NA, Vyas M. Glycogen storage diseases. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverglycogenstoragedisease.html. Accessed March 29th, 2024.
Definition / general
Essential features
  • Rare disorder
  • Group of rare inborn disorders of glycogen metabolism
  • Variable expressivity and most patients present with hepatomegaly and hypoglycemia
  • Increased incidence of hepatic adenoma and hepatocellular carcinoma
ICD coding
  • ICD-10:
    • E74.00 - glycogen storage disease, unspecified
    • E74.04 - McArdle disease
    • E74.09 - other glycogen storage disease
Type 0
Definition / general
  • Also called aglycogenosis
  • Rare, autosomal recessive
  • Deficiency in glycogen synthase (chromosome 12p12.2)
  • Clinically, hyperglycemia, glycosuria, hyperlactic acidemia, which alternate with hypoglycemia and hyperketonemia during fasting
    • Due to the hyperglycemia and hyperuricemia, the child may be thought to have an early stage of diabetes, especially considering that the liver is not enlarged
    • Symptoms of GSD type 0 are those associated with hypoglycemia
    • Developmental delay may be seen in some children


Diagnosis
  • Liver biopsy
  • Enzymatic evaluation of the liver tissue reveals low to absent glycogen synthase activity
  • Genetic / molecular testing can be performed with either liver or muscle tissue to further confirm that there is mutation of the glycogen synthase gene (chromosome 12p12.2)


Treatment
  • Symptoms ameliorate with protein rich meals and bedtime feeding of uncooked cornstarch in low fat or skim milk


Microscopic (histologic) description
  • Small amounts of glycogen and moderate steatosis
Type I
Definition / general
  • Also known as von Gierke disease or hepatorenal glycogenosis
  • Occurs in an autosomal recessive pattern
  • 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
  • Incidence of GSD type Ia is 1 per 100,000 - 400,000 births per year in the White population
  • May present as severe hypoglycemia and increased lactic acid, triglycerides and uric acid shortly after birth
  • Older children have short stature and may develop eruptive xanthomas, rickets, anemia, chronic renal disease due to hyperuricemia and renal stones
  • Tissue type affected is different with the GSD type I subtypes: type Ia - liver, kidney, intestine; type Ib - liver; and type Ic - liver
  • Diagnosis of GSDI established in a proband by identification of biallelic pathogenic variants in either G6PC1 (GSDIa) or SLC37A4 (GSDIb)


Microscopic (histologic) description
  • Distended liver cells with a uniform distribution of glycogen
  • Liver cells arranged in mosaic pattern with plant like appearance
  • Steatosis with hyper glycogenated nuclei
  • Fibrosis may also be present


Microscopic (histologic) images

Contributed by Nigar Anjuman Khurram, M.D.
Uniform hepatic parenchyma

Uniform hepatic parenchyma

Hepatocyte mosaics with cytoplasmic clearing

Hepatocyte mosaics with cytoplasmic clearing

Enlarged hepatocytes with pale cytoplasm

Enlarged hepatocytes with pale cytoplasm




Electron microscopy description
  • Abundant and uniform distribution of glycogen within enlarged hepatocytes
  • Increased cytoplasmic glycogen, enlarged organelles, lipid droplets, glycogenated nuclei
Type Ia
Definition / general
  • Rare
  • Caused by the deficiency of glucose-6-phosphatase (G6Pase) catalytic activity
  • Laboratory findings include hypoglycemia, deranged liver function tests (LFTs), lactic acidosis, hyperuricemia and hyperlipidemia
  • Clinical presentation: hypoglycemia and marked hepatomegaly in first year of life; later in life, short stature, chronic lactic acidosis, focal segmental glomerulosclerosis, hepatic adenomas, iron deficiency, enterocolitis, gout, osteoporosis


Diagnosis
  • Biallelic pathogenic variants in G6PC1 (GSDIa) or SLC37A4 (GSDIb) on molecular genetic testing
  • Deficient hepatic enzyme activity (glucose-6-phosphatase catalytic activity [GSDIa]) from a liver biopsy specimen


Case reports

Treatment
  • Continuous dietary nasogastric infusion of glucose or frequent oral uncooked cornstarch at 3 - 6 hour intervals during the day and at night
  • Liver transplantation may be necessary if not compliant with dietary restrictions or with refractory hyperglycemia or hepatocellular carcinoma (World J Gastroenterol 2007;13:2541)
  • Gene therapy using adenovirus vectors has been evaluated in murine models of GSD type I (World J Gastroenterol 2007;13:2541)


Gross description
  • Massive hepatomegaly
  • May have variable sized tumor nodules


Microscopic (histologic) description
  • Large hepatocytes with prominent cell membrane and glycogenated nuclei
  • PAS+ accumulated glycogen
  • Rarely contains Mallory hyaline and steatosis in hepatic adenomas
Type Ib
Definition / general
  • Caused by a defect in glucose-6-phosphate exchanger SLC37A4 (transporter)
  • Normal G6Pase activity in frozen tissue and lowered activity in fresh specimens
  • Recurrent infections, neutropenia and neutrophil dysfunction are recognized as distinctive features (J Pediatr 2000;137:187)
  • Another distinctive feature of GSD-Ib is the observation of inflammatory bowel disease (Crohn's)-like colitis (J Pediatr 1986;109:55, Turk J Pediatr 2005;47:180)
  • Clinical presentation: young children may have frequent otitis, gingivitis, boils, intermittent diarrhea; although it is rare, terminal kidney disease may develop and kidney transplantation may be necessary
  • Treatment includes dietary therapy, granulocyte colony stimulating factor (G-CSF) therapy may restore myeloid functions and liver transplantation to prevent malignant transformation of hepatic adenomas and for refractory hypoglycemia
Type Ic and Id
Definition / general
  • Liver microsomal transport of phosphate and glucose is deficient in GSD-Ic and GSD-Id
Type III
Definition / general
  • Also called Cori disease
  • Autosomal recessive
  • Rare disease of variable clinical severity affecting primarily the liver, heart and skeletal muscle
  • Deficiency of debrancher enzyme amylo-1,6-glucosidase due to various mutations causes hypoglycemia (Hum Mol Genet 2009;18:2045)
  • Most individuals with GSD III survive into adulthood
  • GSD IIIa: most common subtype (85%), liver and muscle involvement
  • GSD IIIb: 15%; liver involvement only


Diagnosis
  • Demonstration of excessive and structurally abnormal glycogen accumulation with shorter outer branches and deficient debranching enzyme activity in frozen liver or muscle biopsy samples
  • Deficient identification of pathogenic mutations in the AGL gene on both alleles


Case reports

Treatment
  • Individuals with GSD III and advanced liver disease should be considered for liver transplant


Gross description
  • Hepatomegaly


Microscopic (histologic) description
  • Liver or muscle biopsy demonstrate a vacuolar accumulation of nonmembrane bound glycogen primarily in the cytoplasm
  • Lipid vacuoles are less frequent in GSD III (compared to GSD I)
  • Steatosis, hepatocyte ballooning
  • Presence of fibrosis, ranging from minimal periportal fibrosis to micronodular cirrhosis, is noted in GSD III (not in GSD I)
  • Stored material in GSD III is periodic acid-Schiff positive and diastase sensitive within the cytoplasm


Electron microscopy description
  • Increased cytoplasmic glycogen, lipid droplets, glycogenated nuclei
Type IV
Definition / general
  • Also called Andersen disease, Brancher deficiency, amylopectinosis, glycogen branching enzyme deficiency
  • 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
  • Clinically, extremely heterogeneous, owing in part to variation in tissue involvement
  • Fatal perinatal neuromuscular subtype: in utero with fetal akinesia, polyhydramnios and fetal hydrops; death usually in the neonatal period
  • Congenital neuromuscular subtype: newborn period with profound hypotonia, respiratory distress and dilated cardiomyopathy; death usually in early infancy
  • Classic (progressive) hepatic subtype: may appear normal at birth but rapidly develop failure to thrive
    • Hepatomegaly, liver dysfunction and progressive liver cirrhosis, hypotonia and cardiomyopathy
    • Without liver transplantation, death from liver failure usually occurs by age 5
  • Nonprogressive hepatic subtype: hepatomegaly, liver dysfunction, myopathy and hypotonia; likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle or neurologic involvement
  • Childhood neuromuscular subtype: rare, variable course, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade


Diagnosis

Case reports

Treatment
  • Liver transplantation
  • Liver transplantation is helpful also for muscular involvement due to systemic microchimerism after liver allotransplantation and amelioration of pancellular enzyme deficiencies (Eur J Pediatr 1999;158:S43, N Engl J Med 1991;324:39)


Microscopic (histologic) description
  • Hepatocellular periodic-acid Schiff positive, diastase resistant inclusions of the abnormal glycogen deposits


Electron microscopy description
  • Filamentous nonbranching cytoplasmic aggregates


Differential diagnosis
  • Lafora disease:
    • Similar inclusions but not coarsely clumped, older age with epilepsy, myoclonus, dementia
Type VI
Definition / general
  • Also called Hers disease; liver glycogen phosphorylase deficiency
  • Rare, autosomal recessive
  • Most commonly affected group is the Mennonite community
  • Clinically, asymptomatic hepatomegaly and growth retardation
  • Usually has a benign course with mild to moderate hypoglycemia


Diagnosis
  • Enzyme assay using liver, leukocytes and erythrocytes
  • Gene mutation analysis can also be performed


Treatment
  • Avoiding prolonged fasting and ingestion of a bedtime snack to avoid early morning hypoglycemia


Microscopic (histologic) description
  • Small mosaic pattern and irregular distension of the hepatocytes due to glycogen deposition
  • Microsteatosis, mild periportal fibrosis and septal formation may be present


Microscopic (histologic) images

Contributed by Miguel Reyes-Mugica, M.D. and Nigar Anjuman Khurram, M.D.
plant cell-like morphology

Plant cell-like morphology

Intracytoplasmic glycogen

Intracytoplasmic glycogen

Digestion of glycogen stores

Digestion of glycogen stores




Electron microscopy description
  • Large pools of monoparticulate glycogen interspersed with glycogen rosettes and lipid vacuoles with glycogen embedded
  • Hepatocytes have irregularly shaped aggregates of low density granular material scattered within the glycogen, giving a starry sky appearance


Electron microscopy images

Contributed by Miguel Reyes-Mugica, M.D. and Nigar Anjuman Khurram, M.D.
Intracytoplasmic free glycogen

Intracytoplasmic free glycogen




Additional references
Type IX
Definition / general
  • Deficiency in phosphorylase kinase (PhK)
  • Types involving the liver are mainly classified into 2 forms: the X linked liver form (there are 2 subtypes; XLG-I and XLG-II) and autosomal recessive form
  • X linked liver phosphorylase kinase (alpha subunit) deficiency (PHKA2 related GSD type IX)
    • Mildest GSD with low phosphorylase activity in the absence of adenosine monophosphate
    • Most common signs and symptoms present between 1 and 5 years and include hepatomegaly, growth retardation (68%), hypotonia, deranged liver function tests, fasting hyperketosis, hypoglycemia
      • Hepatomegaly and growth retardation usually resolve during puberty
      • Splenomegaly and cirrhosis are very rare
  • Autosomal liver and muscle phosphorylase kinase (beta subunit) deficiency (PHKB related GSD type IX)
    • Autosomal recessive
    • Deficiency in the beta subunit of phosphorylase kinase
    • Hepatomegaly with abdominal distension, mild growth retardation and lipidemia
      • When symptoms are present, the liver is primarily affected with the potential for cirrhosis
  • Autosomal liver phosphorylase kinase (gamma subunit) deficiency (PHKG2 related GSD type IX)
    • Autosomal recessive
    • Deficiency in the gamma subunit of liver phosphorylase
    • Associated with liver cirrhosis, renal tubular acidosis or neurologic disorders


Diagnosis
  • Diagnosis can be made with enzyme analysis of liver tissue and by gene mutation analysis


Treatment
  • Symptoms ameliorate with protein rich meals and bedtime feeding of uncooked cornstarch in low fat or skim milk


Microscopic (histologic) description
  • X linked liver phosphorylase kinase (alpha subunit) deficiency (PHKA2 related GSD type IX)
    • Biopsy shows irregular distension of hepatocytes with glycogen
    • Hepatocytes are organized into a mosaic pattern
    • Microsteatosis may be seen
  • Autosomal liver and muscle phosphorylase kinase (beta subunit) deficiency (PHKB related GSD type IX): both liver and muscle biopsies show glycogen accumulation by light and electron microscopy


Microscopic (histologic) images

Contributed by @RaulSGonzalezMD on Twitter
Glycogen storage disease Glycogen storage disease

Glycogen storage disease




Electron microscopy description
  • X linked liver phosphorylase kinase (alpha subunit) deficiency (PHKA2 related GSD type)
    • Extensive monoparticulate glycogen, glycogen rosettes and frequent lipid vacuoles containing glycogen particles
    • Starry sky pattern attributed to scattered areas with finely granular organelle free clear zones alternating with densely packed glycogen particles
    • Mitochondria tend to be decreased in size and numbers; skeletal muscle is normal


Additional references
Type XI
Definition / general
  • Also called Fanconi-Bickel syndrome
  • Rare, autosomal recessive
  • Responsible gene is glucose transport 2 gene (GLUT2), localized to 3q26.1-q26
  • Defective transport of monosaccharide across the membranes
  • Clinically, hepatorenal glycogen accumulation, fasting hypoglycemia, postprandial hyperglycemia and hypergalactosemia, proximal renal tubular dysfunction, marked stunted growth, dwarfism in older patients, hypercholesterolemia, hyperlipidemia, pancreatitis, generalized osteopenia


Diagnosis
  • Detected by neonatal screening for galactose


Case reports
  • 2 siblings with familial Fanconi syndrome with malabsorption and galactose intolerance, normal kinase and transferase activity (Acta Paediatr Scand 1981;70:527)


Treatment
  • Liver transplantation
  • Liver transplantation helpful also for muscular involvement due to systemic microchimerism after liver allotransplantation and amelioration of pancellular enzyme deficiencies (Eur J Pediatr 1999;158:S43, N Engl J Med 1991;324:39)


Microscopic (histologic) description
  • Excessive glycogen accumulation with steatosis
Sample pathology report
  • Liver, needle biopsy:
    • Hepatic parenchyma with features suggestive of glycogen storage disease (see comment)
    • Comment: The morphologic features are classic for glycogen storage disease (GSD), with a plant cell-like morphology, intracytoplasmic glycogen on PAS staining, which disappears after digestion with diastase. There is also mild steatosis and no significant nuclear glycosylation. The electron microscopic analysis also shows massive amounts of intracytoplasmic free glycogen. The main variants of GSD with features of this appearance are I, III, VI and IX. However, these diseases have overlapping histopathologic features and therefore are best distinguished enzymatically and genetically. Given the lack of significant hypoglycemia, types VI and IX are favored. Further genetic / enzymatic analysis is required to definitively establish the specific subtype of GSD. Glycogen storage disease enzyme assay is pending and will be reported in an addendum.
Board review style question #1
Deficiency of amylo-1,6-glucosidase debranching enzyme results in which of the following glycogen storage disease (GSD) types?

  1. GSD type 0, aglycogenosis
  2. GSD type I, hepatorenal glycogenosis / von Gierke disease
  3. GSD type III, Cori disease
  4. GSD type IV, Andersen disease
  5. GSD type XI, Fanconi-Bickel syndrome
Board review style answer #1
C. GSD type III, Cori disease. In GSD type III / Cori disease, deficiency of debrancher enzyme amylo-1,6-glucosidase due to various mutations causes hypoglycemia. Answer A is incorrect because GSD type 0 / aglycogenosis is caused by deficiency of glycogen synthase. Answer B is incorrect because GSD type 1, hepatorenal glycogenosis / von Gierke disease is caused by glucose-6 phosphatase deficiency. Answer D is incorrect because GSD type IV / Andersen disease is caused by a deficiency of glycogen branching enzyme on 3p14. Answer E is incorrect because GSD type XI / Fanconi-Bickel syndrome is caused by glucose transport 2 gene.

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Reference: Glycogen storage diseases
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