Sandbox : anmol
|
Glycogen storage disease type I Microchapters |
|
Differentiating Glycogen storage disease type I from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
Sandbox : anmol On the Web |
|
American Roentgen Ray Society Images of Sandbox : anmol |
|
Directions to Hospitals Treating Glycogen storage disease type I |
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]
Pathophysiology
Pathophysiology
- GSD type 1 results due to defects in either hydrolysis or transport of glucose-6-phosphate
- GSD type 1a is due to the deficiency of enzyme glucose-6-phosphatase (G6Pase).
- GDS type 1b is due to defect in glucose-6-phosphate translocase (T1 deficiency).
- 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.
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:
- 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.
- Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.
- There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.[1][2][3]
- 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:[4][5]
- 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.[6]
- 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:[7][8][9]
- 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.[10]
- 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:[11]
- Enhanced endoplasmic reticulum stress
- Oxidative stress
- Apoptosis of neutrophils
- Patients with GSD type 1b associated with neutropenia are at increased risk of:
- Infections
- Gingivitis
- Mouth ulcers
- Upper respiratory infections
- Deep abscesses
- Enterocolitis
- Also, there is dysfunction of monocytes leads to:[12]
- Granuloma formation
- Chronic inflammatory responses
Genetics
- 80% Cases of GSD 1 are of GSD type 1a.[13]
- G6Pase gene is located on chromosome locus 17q21.
- Glucose-6-phosphate translocase is located on chromosome locus 11q23.
- GSD type 1 follows an autosomal recessive pattern.
Hypoglycemia
Hypoglycemia is the central clinical problem, the one that is most damaging, and the one that most often prompts the initial diagnosis. Maternal glucose transferred across the placenta prevents hypoglycemia in a fetus with GSD I, but the liver is enlarged with glycogen at birth. The inability to generate and release glucose soon results in hypoglycemia, and occasionally in lactic acidosis fulminant enough to appear as a primary respiratory problem in the newborn period. Neurological manifestations are less severe than if the hypoglycemia were more acute. The brain's habituation to mild hypoglycemia is at least partly explained by use of alternative fuels, primarily lactate.
More commonly, infants with GSD I tolerate without obvious symptoms a chronic, mild hypoglycemia and compensated lactic acidosis between feedings. Blood glucose levels are typically 25 to 50 mg/dl (1.4-2.8 mM). These infants continue to need oral carbohydrates every few hours. Many never sleep through the night even in the second year of life. They may be pale, clammy, and irritable a few hours after a meal. Developmental delay is not an intrinsic or inevitable effect of glucose-6-phosphatase deficiency but is common if the diagnosis is not made in early infancy.
Although mild hypoglycemia for much of the day may go unsuspected, the metabolic adaptations described above make severe hypoglycemic episodes, with unconsciousness or seizure, uncommon before treatment. Episodes which occur are likely to happen in the morning before breakfast. GSD I is therefore a potential cause of ketotic hypoglycemia in young children.
Once the diagnosis has been made, the principal goal of treatment is to maintain an adequate glucose level and prevent hypoglycemia.
Glycogen also accumulates in kidneys and small intestine. Hepatomegaly, usually without splenomegaly, begins to develop in fetal life and is usually noticeable in the first few months of life. By the time the child is standing and walking, the hepatomegaly may be severe enough to cause the abdomen to protrude. The liver edge is often at or below the level of the umbilicus. Other liver functions are usually spared, and liver enzymes and bilirubin are usually normal.
However, there is a risk of developing tumors of the liver by adolescence or adult ages, and periodic ultrasound examinations of the liver are recommended from late childhood onward. Occasional cases of various types of liver disease and failure have been reported in children and adults with GSD I.
Lactic acidosis
Impaired gluconeogenesis results in elevations of lactic acid (4-10 mM) even when the child is well. In an episode of metabolic decompensation, lactic acid levels abruptly rise and can exceed 15 mM, producing severe metabolic acidosis. Uric acid, ketoacids, and free fatty acids further increase the anion gap. Manifestations of severe metabolic acidosis include vomiting and hyperpnea, which can exacerbate hypoglycemia by reducing oral intake. Repeated episodes of vomiting with hypoglycemia and dehydration may occur in infancy and childhood, precipitated by (or mimicking) infections such as gastroenteritis or pneumonia.
Growth failure
Without treatment, growth failure is common, due to chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, calorie insufficiency, and/or malabsorption.
Hyperlipidemia and blood vessel effects
A secondary effect of low insulin levels is hypertriglyceridemia. Triglycerides in the 400–800 mg/dl range may produce visible lipemia, and even a mild pseudohyponatremia due to a reduced aqueous fraction of the serum. Cholesterol is only mildly elevated.
Hyperuricemia and joint problems
A further effect of chronic lactic acidosis in GSD I is hyperuricemia, as lactic acid and uric acid compete for the same renal tubular transport mechanism. Increased purine catabolism is an additional contributing factor. Uric acid levels of 6-12 mg/dl are typical of GSD I.
Kidney effects
Kidneys are usually 10 to 20% enlarged with stored glycogen. This does not usually cause clinical problems in childhood, with the occasional exception of a Fanconi syndrome with multiple derangements of renal tubular reabsorption, including proximal renal tubular acidosis with bicarbonate and phosphate wasting. However, prolonged hyperuricemia can cause uric acid nephropathy. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to renal failure.
Bowel effects
Intestinal involvement can cause mild malabsorption with sloppy stools but usually requires no treatment.
Infection risk
Blood clotting problems
Impaired platelet aggregation is an uncommon effect of chronic hypoglycemia. It may cause clinically significant bleeding, especially epistaxis.
Neurodevelopmental effects
Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Because normal brain and muscle cells contain no glucose-6-phosphatase, GSD I causes no other neuromuscular effects.
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.