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.[2]
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
- ↑ 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.
- ↑ 2.0 2.1 2.2 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.
- ↑ 3.0 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.
- ↑ 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.
- ↑ 5.0 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.
- ↑ 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.
- ↑ 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.
- ↑ Fine RN, Strauss J, Donnell GN (1966). "Hyperuricemia in glycogen-storage disease type 1". Am J Dis Child. 112 (6): 572–6. PMID 5224881.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Kudo M (2001). "Hepatocellular adenoma in type Ia glycogen storage disease". J Gastroenterol. 36 (1): 65–6. PMID 11211215.
- ↑ 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.
- ↑ 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.
- ↑ Reitsma-Bierens WC (1993). "Renal complications in glycogen storage disease type I." Eur J Pediatr. 152 Suppl 1: S60–2. PMID 8319728.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Czapek EE, Deykin D, Salzman EW (1973). "Platelet dysfunction in glycogen storage disease type I." Blood. 41 (2): 235–47. PMID 4350560.
- ↑ Corby DG, Putnam CW, Greene HL (1974). "Impaired platelet function in glucose-6-phosphatase deficiency". J Pediatr. 85 (1): 71–6. PMID 4212074.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Mansfield BC (1999). "Molecular Genetics of Type 1 Glycogen Storage Diseases". Trends Endocrinol Metab. 10 (3): 104–113. PMID 10322403.
- ↑ 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.
- ↑ 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.
- ↑ Ozen H (2007). "Glycogen storage diseases: new perspectives". World J Gastroenterol. 13 (18): 2541–53. PMC 4146814. PMID 17552001.
- ↑ 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/