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: Anmol Pitliya, M.B.B.S. M.D.[2]
Overview
Glycogen storage disease type 1 (GSD 1) results due to defects in either hydrolysis or transport of glucose-6-phosphate. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen also deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques. Hematologic disorders in GSD type 1 include anemia, bleeding diathesis, and neutropenia. Neutropenia and neutrophil dysfunction is specific of GSD type 1b. Abnormal expression of hepcidin in GSD type 1 leads to refractory iron deficiency anemia. GSD type 1 follows an autosomal recessive pattern. On gross pathology analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases. On microscopic histopathological analysis, the features of glycogen storage disease type 1 include distended liver cells by glycogen and fat, PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm, and numerous large lipid vacuoles.
Pathophysiology
- Glycogen storage disease type 1 (GSD 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]
Metabolic pathway
Mechanism of hypoglycemia
- G6Pase is primarily expressed in gluconeogenesis in the liver and kidney. It is also expressed to a lesser extent in the intestine and pancreas.[6][7]
- 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
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:[6][16][17][18][19][20]
- Hepatocellular adenoma (most common)
- Hepatocellular carcinoma
- 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.[21]
- Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.[22][23]
- There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.[24][25][26]
- 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][27]
- 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 hepcidin in GSD type 1 leads to refractory iron deficiency anemia.[28]
- 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:[29][30][31]
- Acquired platelet dysfunction with prolonged bleeding times
- Decreased platelet adhesiveness
- Abnormal aggregation of platelets
Neutropenia and neutrophil dysfunction
- Neutropenia and neutrophil dysfunction is specific of GSD type 1b.[32]
- 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:[33]
- Enhanced endoplasmic reticulum stress
- Oxidative stress
- Apoptosis of neutrophils
- Patients with GSD type 1b associated with neutropenia are at increased risk of:[34][35]
- Also, there is dysfunction of monocytes leads to:[36]
- Granuloma formation
- Chronic inflammatory responses
Genetics
- 80% Cases of GSD 1 are of GSD type 1a.[37]
- G6PC gene mutation is responsible for Glucose-1-phosphatase deficiency in GSD type 1a and is located on chromosome locus 17q21.[3]
- SLC37A4 gene mutation is responsible for Glucose-6-phosphate translocase defect in GSD type 1b and is located on chromosome locus 11q23.[38][5]
- GSD type 1 follows an autosomal recessive pattern.
Gross Pathology
On gross pathology 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:[39][40][41]
- 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 is present
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.
- ↑ 6.0 6.1 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.
- ↑ Wolfsdorf JI, Weinstein DA (2003). "Glycogen storage diseases". Rev Endocr Metab Disord. 4 (1): 95–102. PMID 12618563.
- ↑ 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.
- ↑ 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/