Glycogen storage disease type I pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Pathophysiology

  • GSD type 1 results due to defects in either hydrolysis or transport of glucose-6-phosphate.[1][2]
  • GSD type 1a is due to the deficiency of enzyme glucose-6-phosphatase (G6Pase).[3]
  • GDS type 1b is due to defect in glucose-6-phosphate translocase (T1 deficiency).[4][5]

Mechanism of hypoglycemia

  • G6Pase is primarily expressed in expressed primarily in the gluconeogenic the liver and kidney. It is also expressed to a lesser extent in the intestine and pancreas.
  • Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis.
  • This defects hinders the conversion of glucose-6 phosphate to glucose in organs.
  • This leads to accumulation of glycogen in organs including liver, kidney, and intestine.
  • The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia.
  • This also results in the development of various secondary metabolic and biochemical abnormalities including hyperlactacidemia, hyperuricemia, and hyperlipidemia.

Mechanism of hyperuricemia

  • Hyperuricemia in glycogen storage disease type 1 is due to:[6][7][8][9][10][11][12][13]
    • Decrease uric acid excretion: High blood lactate and ketoacid levels cause a decrease in renal clearance of uric acid.
    • Urate overproduction

Hepatomegaly and liver disorders

  • Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly.
  • Hepatomegaly is more pronounced when the child is young and decreases as the age progresses. The hepatomegaly leads to protrusion of the abdomen.
  • Patients with GSD type 1 may develop hepatic lesions including:[14][15][16][17][18][19]
    • Hepatocellular adenoma (most common)
    • HCC
    • Hepatoblastoma
    • Focal fatty infiltration
    • Focal fatty sparing
    • Focal nodular hyperplasia
    • Peliosis hepatis
  • The prevalence of hepatocellular adenoma increases as the age progress. 70 - 80 % Patients have at least one lesion of hepatocellular adenoma by the time they reach the age of 25 years.

Renal disorders

  • Patients with GSD type 1 have renal manifestations early in childhood.[20]
  • Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.[21][22]
  • There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.[23][24][25]
  • Glycogen storage and metabolic disturbances in patients with GSD type 1 leads to progressive glomerular injury and finally end-stage renal disease requiring renal transplantation.

Hematologic Disorders

Anemia

  • Anemia in GSD type 1 is due to an array of factors including:[2][26]
    • The restricted nature of the diet
    • Chronic lactic acidosis
    • Renal disorders
    • Bleeding diathesis
    • Chronic nature of the illness
    • Suboptimal metabolic control
    • Hepatic adenomas
    • Inflammatory bowel disease (specifically in GSD type 1b)
  • Abnormal expression of hepacidin in GSD type 1 leads to refractory iron deficiency anemia.[27]
  • In GSD type 1b associated with inflammatory bowel disease is believed to be due to Interleukin-6. Increased expression of Interleukin-6 due to inflammation leads to upregulation of hepcidin leading to anemia.

Bleeding diathesis

  • Bleeding diathesis in GSD type 1 secondary to metabolic abnormalities and include:[28][29][30]
  • Acquired platelet dysfunction with prolonged bleeding times
  • Decreased platelet adhesiveness
  • Abnormal aggregation of platelets

Neutropenia and neutrophil dysfunction

  • Neutropenia and neutrophil dysfunction is specific fo GSD type 1b.[31]
  • Neutropenia and neutrophil dysfunction in glycogen storage disease type Ib is thought to be due to loss of glucose-6-phosphate translocase activity leading to:[32]
    • Enhanced endoplasmic reticulum stress
    • Oxidative stress
    • Apoptosis of neutrophils
  • Patients with GSD type 1b associated with neutropenia are at increased risk of:[33][34]
    • Infections
    • Gingivitis
    • Mouth ulcers
    • Upper respiratory infections
    • Deep abscesses
    • Enterocolitis
  • Also, there is dysfunction of monocytes leads to:[35]
    • Granuloma formation
    • Chronic inflammatory responses

Genetics

  • 80% Cases of GSD 1 are of GSD type 1a.[36]
  • G6Pase gene mutation is responsible for GSD type 1a and is located on chromosome locus 17q21.[3]
  • Glucose-6-phosphate translocase defect is responsible for GSD type 1b and is located on chromosome locus 11q23.[37][5]
  • GSD type 1 follows an autosomal recessive pattern.

Gross Pathology

On microscopic histopathological analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases.

Microscopic Pathology

  • On microscopic histopathological analysis, the features of glycogen storage disease type 1 include:[38][39][40]
    • Distended liver cells by glycogen and fat
    • PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm
    • Normal or mildly increased glycogen as compared with that seen in other liver GSDs (especially GSDIII and GSDIX)
    • Large and numerous lipid vacuoles
    • No fibrosis and cirrhosis

References

  1. ↑ Moses SW (2002). "Historical highlights and unsolved problems in glycogen storage disease type 1". Eur J Pediatr. 161 Suppl 1: S2–9. doi:10.1007/s00431-002-0997-6. PMID 12373565.
  2. ↑ 2.0 2.1 Kishnani, Priya S.; Austin, Stephanie L.; Abdenur, Jose E.; Arn, Pamela; Bali, Deeksha S.; Boney, Anne; Chung, Wendy K.; Dagli, Aditi I.; Dale, David; Koeberl, Dwight; Somers, Michael J.; Burns Wechsler, Stephanie; Weinstein, David A.; Wolfsdorf, Joseph I.; Watson, Michael S. (2014). "Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics". Genetics in Medicine. doi:10.1038/gim.2014.128. ISSN 1098-3600.
  3. ↑ 3.0 3.1 Chou JY, Mansfield BC (2008). "Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease". Hum Mutat. 29 (7): 921–30. doi:10.1002/humu.20772. PMC 2475600. PMID 18449899.
  4. ↑ Veiga-da-Cunha M, Gerin I, Chen YT, Lee PJ, Leonard JV, Maire I; et al. (1999). "The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a". Eur J Hum Genet. 7 (6): 717–23. doi:10.1038/sj.ejhg.5200366. PMID 10482962.
  5. ↑ 5.0 5.1 Janecke AR, Lindner M, Erdel M, Mayatepek E, Möslinger D, Podskarbi T; et al. (2000). "Mutation analysis in glycogen storage disease type 1 non-a". Hum Genet. 107 (3): 285–9. PMID 11071391.
  6. ↑ Roe TF, Kogut MD (1977). "The pathogenesis of hyperuricemia in glycogen storage disease, type I." Pediatr Res. 11 (5): 664–9. doi:10.1203/00006450-197705000-00008. PMID 266162.
  7. ↑ Alepa FP, Howell RR, Klinenberg JR, Seegmiller JE (1967). "Relationships between glycogen storage disease and tophaceous gout". Am J Med. 42 (1): 58–66. PMID 5225563.
  8. ↑ Fine RN, Strauss J, Donnell GN (1966). "Hyperuricemia in glycogen-storage disease type 1". Am J Dis Child. 112 (6): 572–6. PMID 5224881.
  9. ↑ Jakovcic S, Sorensen LB (1967). "Studies of uric acid metabolism in glycogen storage disease associated with gouty arthritis". Arthritis Rheum. 10 (2): 129–34. PMID 6024734.
  10. ↑ Kelley, W.N.; Rosenbloom, F.M.; Seegmiller, J.E.; Howell, R. Rodney (1968). "Excessive production of uric acid in type I glycogen storage disease". The Journal of Pediatrics. 72 (4): 488–496. doi:10.1016/S0022-3476(68)80339-7. ISSN 0022-3476.
  11. ↑ Cohen JL, Vinik A, Faller J, Fox IH (1985). "Hyperuricemia in glycogen storage disease type I. Contributions by hypoglycemia and hyperglucagonemia to increased urate production". J Clin Invest. 75 (1): 251–7. doi:10.1172/JCI111681. PMC 423433. PMID 2856925.
  12. ↑ Benke PJ, Gold S (1978). "Uric acid metabolism in therapy of glycogen storage disease type I." Pediatr Res. 12 (3): 204–6. doi:10.1203/00006450-197803000-00008. PMID 273863.
  13. ↑ Howell, R. Rodney (1965). "The interrelationship of glycogen storage disease and gout". Arthritis & Rheumatism. 8 (4): 780–785. doi:10.1002/art.1780080441. ISSN 0004-3591.
  14. ↑ Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP (2002). "Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)". Eur J Pediatr. 161 Suppl 1: S20–34. doi:10.1007/s00431-002-0999-4. PMID 12373567.
  15. ↑ Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B; et al. (2005). "Hepatocellular carcinoma in glycogen storage disease type Ia: a case series". J Inherit Metab Dis. 28 (2): 153–62. doi:10.1007/s10545-005-7500-2. PMID 15877204.
  16. ↑ Reddy SK, Kishnani PS, Sullivan JA, Koeberl DD, Desai DM, Skinner MA; et al. (2007). "Resection of hepatocellular adenoma in patients with glycogen storage disease type Ia". J Hepatol. 47 (5): 658–63. doi:10.1016/j.jhep.2007.05.012. PMID 17637480.
  17. ↑ Kudo M (2001). "Hepatocellular adenoma in type Ia glycogen storage disease". J Gastroenterol. 36 (1): 65–6. PMID 11211215.
  18. ↑ Kelly PM, Poon FW (2001). "Hepatic tumours in glycogen storage disease type 1 (von Gierke's disease)". Clin Radiol. 56 (6): 505–8. doi:10.1053/crad.2000.0457. PMID 11428803.
  19. ↑ Lee PJ (2002). "Glycogen storage disease type I: pathophysiology of liver adenomas". Eur J Pediatr. 161 Suppl 1: S46–9. doi:10.1007/s00431-002-1002-0. PMID 12373570.
  20. ↑ Reitsma-Bierens WC (1993). "Renal complications in glycogen storage disease type I." Eur J Pediatr. 152 Suppl 1: S60–2. PMID 8319728.
  21. ↑ Reitsma-Bierens WC, Smit GP, Troelstra JA (1992). "Renal function and kidney size in glycogen storage disease type I." Pediatr Nephrol. 6 (3): 236–8. PMID 1616830.
  22. ↑ Chen YT, Coleman RA, Scheinman JI, Kolbeck PC, Sidbury JB (1988). "Renal disease in type I glycogen storage disease". N Engl J Med. 318 (1): 7–11. doi:10.1056/NEJM198801073180102. PMID 3422104.
  23. ↑ Weinstein DA, Somers MJ, Wolfsdorf JI (2001). "Decreased urinary citrate excretion in type 1a glycogen storage disease". J Pediatr. 138 (3): 378–82. doi:10.1067/mpd.2001.111322. PMID 11241046.
  24. ↑ Lee PJ, Dalton RN, Shah V, Hindmarsh PC, Leonard JV (1995). "Glomerular and tubular function in glycogen storage disease". Pediatr Nephrol. 9 (6): 705–10. PMID 8747109.
  25. ↑ Restaino I, Kaplan BS, Stanley C, Baker L (1993). "Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease". J Pediatr. 122 (3): 392–6. PMID 8441093.
  26. ↑ Wang DQ, Carreras CT, Fiske LM, Austin S, Boree D, Kishnani PS; et al. (2012). "Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib". Genet Med. 14 (9): 795–9. doi:10.1038/gim.2012.41. PMC 3808879. PMID 22678084.
  27. ↑ Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC (2002). "Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease". Blood. 100 (10): 3776–81. doi:10.1182/blood-2002-04-1260. PMID 12393428.
  28. ↑ Czapek EE, Deykin D, Salzman EW (1973). "Platelet dysfunction in glycogen storage disease type I." Blood. 41 (2): 235–47. PMID 4350560.
  29. ↑ Corby DG, Putnam CW, Greene HL (1974). "Impaired platelet function in glucose-6-phosphatase deficiency". J Pediatr. 85 (1): 71–6. PMID 4212074.
  30. ↑ Hutton RA, Macnab AJ, Rivers RP (1976). "Defect of platelet function associated with chronic hypoglycaemia". Arch Dis Child. 51 (1): 49–55. PMC 1545862. PMID 942229.
  31. ↑ Visser G, Rake JP, Labrune P, Leonard JV, Moses S, Ullrich K; et al. (2002). "Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1". Eur J Pediatr. 161 Suppl 1: S83–7. doi:10.1007/s00431-002-1010-0. PMID 12373578.
  32. ↑ Chou JY, Jun HS, Mansfield BC (2010). "Neutropenia in type Ib glycogen storage disease". Curr Opin Hematol. 17 (1): 36–42. doi:10.1097/MOH.0b013e328331df85. PMC 3099242. PMID 19741523.
  33. ↑ Franceschini R, Gianetta E, Pastorino A, Dallegri F, Cataldi A, Corsini G; et al. (1996). "Crohn's-like colitis in glycogen storage disease Ib: a case report". Hepatogastroenterology. 43 (12): 1461–4. PMID 8975948.
  34. ↑ Dieckgraefe BK, Korzenik JR, Husain A, Dieruf L (2002). "Association of glycogen storage disease 1b and Crohn disease: results of a North American survey". Eur J Pediatr. 161 Suppl 1: S88–92. doi:10.1007/s00431-002-1011-z. PMID 12373579.
  35. ↑ Kilpatrick L, Garty BZ, Lundquist KF, Hunter K, Stanley CA, Baker L; et al. (1990). "Impaired metabolic function and signaling defects in phagocytic cells in glycogen storage disease type 1b". J Clin Invest. 86 (1): 196–202. doi:10.1172/JCI114684. PMC 296707. PMID 2164043.
  36. ↑ Mansfield BC (1999). "Molecular Genetics of Type 1 Glycogen Storage Diseases". Trends Endocrinol Metab. 10 (3): 104–113. PMID 10322403.
  37. ↑ Veiga-da-Cunha M, Gerin I, Chen YT, de Barsy T, de Lonlay P, Dionisi-Vici C; et al. (1998). "A gene on chromosome 11q23 coding for a putative glucose- 6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic". Am J Hum Genet. 63 (4): 976–83. doi:10.1086/302068. PMC 1377500. PMID 9758626.
  38. ↑ Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A; et al. (2011). "Glucose-6-phosphatase deficiency". Orphanet J Rare Dis. 6: 27. doi:10.1186/1750-1172-6-27. PMC 3118311. PMID 21599942.
  39. ↑ Ozen H (2007). "Glycogen storage diseases: new perspectives". World J Gastroenterol. 13 (18): 2541–53. PMC 4146814. PMID 17552001.
  40. ↑ Bali DS, Chen YT, Austin S, et al. Glycogen Storage Disease Type I. 2006 Apr 19 [Updated 2016 Aug 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1312/

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