Liver & intrahepatic bile ducts

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)
  • Currently, gene mutational analysis is performed to provide a definitive diagnosis (World J Gastroenterol 2007;13:2541)

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

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
  • GSD types Ib and Ic are even less frequent
  • Incidence of 1 in 20,000 in the Ashkenazi Jewish population (Ultrastruct Pathol 2011;35:183)
• 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)
  • If molecular genetic testing is inconclusive, hepatic enzyme activity analysis is only available for glucose-6-phosphatase catalytic activity (GSDIa) (GeneReviews: Glycogen Storage Disease Type I [Accessed 14 July 2023])

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.



Electron microscopy description

• Abundant and uniform distribution of glycogen within enlarged hepatocytes
• Increased cytoplasmic glycogen, enlarged organelles, lipid droplets, glycogenated nuclei

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

• 17 year old woman with hepatocellular carcinoma with glycogen storage disease type 1a (Pediatr Int 2020;62:744)
• 28 year old woman with multiple hepatic adenomas (Arch Pathol Lab Med 2003;127:e402)

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

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

Definition / general

• Liver microsomal transport of phosphate and glucose is deficient in GSD-Ic and GSD-Id

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

• 56 year old woman known to be affected by GSD III and liver cirrhosis complicated by hepatocellular carcinoma (J Clin Gastroenterol 2000;31:80)

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

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

• Demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle or skin fibroblasts
• Identification of biallelic pathogenic variants in GBE1 on molecular genetic testing (GeneReviews: Glycogen Storage Disease Type IV [Accessed 19 July 2023])

Case reports

• 10 month old boy with massive hepatomegaly (Arch Pathol Lab Med 2002;126:630)

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

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.



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.



Additional references

• Hum Mol Genet 1998;7:865, Mol Genet Metab 2003;79:142

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



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

• Hum Mol Genet 1997;6:1109, Mol Genet Metab 2013;109:179

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

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

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