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| __NOTOC__ | | __NOTOC__ |
| {{Glycogen storage disease type I}}
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| {{CMG}}; {{AE}} {{Anmol}} | | {{CMG}}; {{AE}} {{Anmol}} |
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| | | ==Tables== |
| =Pathophysiology=
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| ==Pathophysiology==
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| *GSD type 1 results due to defects in either hydrolysis or transport of glucose-6-phosphate
| | !Diagnosis |
| *GSD type 1a is due to the deficiency of enzyme glucose-6-phosphatase (G6Pase).
| | !Lab findings |
| *GDS type 1b is due to defect in glucose-6-phosphate translocase (T1 deficiency).
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| *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.
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| *Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis.
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| *This defects hinders the conversion of glucose-6 phosphate to glucose in organs.
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| *This leads to accumulation of glycogen in organs including liver, kidney, and intestine.
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| *The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia.
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| *This also results in the development of various secondary metabolic and biochemical abnormalities including hyperlactacidemia, hyperuricemia, and hyperlipidemia.
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| ===Hepatomegaly and liver disorders===
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| *Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly.
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| *Hepatomegaly is more pronounced when the child is young and decreases as the age progresses. The hepatomegaly leads to protrusion of the abdomen.
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| *Patients with GSD type 1 may develop hepatic lesions including:
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| **Hepatocellular adenoma (most common)
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| **HCC
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| **Hepatoblastoma
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| **Focal fatty infiltration
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| **Focal fatty sparing
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| **Focal nodular hyperplasia
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| **Peliosis hepatis
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| *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.
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| ===Renal disorders===
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| *Patients with GSD type 1 have renal manifestations early in childhood.
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| *Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.
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| *There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.<ref name="pmid11241046">{{cite journal| author=Weinstein DA, Somers MJ, Wolfsdorf JI| title=Decreased urinary citrate excretion in type 1a glycogen storage disease. | journal=J Pediatr | year= 2001 | volume= 138 | issue= 3 | pages= 378-82 | pmid=11241046 | doi=10.1067/mpd.2001.111322 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11241046 }} </ref><ref name="pmid8747109">{{cite journal| author=Lee PJ, Dalton RN, Shah V, Hindmarsh PC, Leonard JV| title=Glomerular and tubular function in glycogen storage disease. | journal=Pediatr Nephrol | year= 1995 | volume= 9 | issue= 6 | pages= 705-10 | pmid=8747109 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8747109 }} </ref><ref name="pmid8441093">{{cite journal| author=Restaino I, Kaplan BS, Stanley C, Baker L| title=Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease. | journal=J Pediatr | year= 1993 | volume= 122 | issue= 3 | pages= 392-6 | pmid=8441093 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8441093 }} </ref>
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| *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.
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| ===Hematologic Disorders===
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| ====Anemia====
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| *Anemia in GSD type 1 is due to an array of factors including:<ref name="KishnaniAustin2014">{{cite journal|last1=Kishnani|first1=Priya S.|last2=Austin|first2=Stephanie L.|last3=Abdenur|first3=Jose E.|last4=Arn|first4=Pamela|last5=Bali|first5=Deeksha S.|last6=Boney|first6=Anne|last7=Chung|first7=Wendy K.|last8=Dagli|first8=Aditi I.|last9=Dale|first9=David|last10=Koeberl|first10=Dwight|last11=Somers|first11=Michael J.|last12=Burns Wechsler|first12=Stephanie|last13=Weinstein|first13=David A.|last14=Wolfsdorf|first14=Joseph I.|last15=Watson|first15=Michael S.|title=Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics|journal=Genetics in Medicine|year=2014|issn=1098-3600|doi=10.1038/gim.2014.128}}</ref><ref name="pmid22678084">{{cite journal| author=Wang DQ, Carreras CT, Fiske LM, Austin S, Boree D, Kishnani PS et al.| title=Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib. | journal=Genet Med | year= 2012 | volume= 14 | issue= 9 | pages= 795-9 | pmid=22678084 | doi=10.1038/gim.2012.41 | pmc=3808879 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22678084 }} </ref>
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| **The restricted nature of the diet
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| **Chronic lactic acidosis
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| **Renal disorders
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| **Bleeding diathesis
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| **Chronic nature of the illness
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| **Suboptimal metabolic control
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| **Hepatic adenomas
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| **Inflammatory bowel disease (specifically in GSD type 1b)
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| *Abnormal expression of hepacidin in GSD type 1 leads to refractory iron deficiency anemia.<ref name="pmid12393428">{{cite journal| author=Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC| title=Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. | journal=Blood | year= 2002 | volume= 100 | issue= 10 | pages= 3776-81 | pmid=12393428 | doi=10.1182/blood-2002-04-1260 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12393428 }} </ref>
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| *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.
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| ====Bleeding diathesis====
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| *Bleeding diathesis in GSD type 1 secondary to metabolic abnormalities and include:<ref name="pmid4350560">{{cite journal| author=Czapek EE, Deykin D, Salzman EW| title=Platelet dysfunction in glycogen storage disease type I. | journal=Blood | year= 1973 | volume= 41 | issue= 2 | pages= 235-47 | pmid=4350560 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4350560 }} </ref><ref name="pmid4212074">{{cite journal| author=Corby DG, Putnam CW, Greene HL| title=Impaired platelet function in glucose-6-phosphatase deficiency. | journal=J Pediatr | year= 1974 | volume= 85 | issue= 1 | pages= 71-6 | pmid=4212074 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4212074 }} </ref><ref name="pmid942229">{{cite journal| author=Hutton RA, Macnab AJ, Rivers RP| title=Defect of platelet function associated with chronic hypoglycaemia. | journal=Arch Dis Child | year= 1976 | volume= 51 | issue= 1 | pages= 49-55 | pmid=942229 | doi= | pmc=1545862 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=942229 }} </ref>
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| *Acquired platelet dysfunction with prolonged bleeding times
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| *Decreased platelet adhesiveness
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| *Abnormal aggregation of platelets
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| ==Genetics==
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| *80% Cases of GSD 1 are of GSD type 1a.
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| *G6Pase gene is located on chromosome locus 17q21.
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| *Glucose-6-phosphate translocase is located on chromosome locus 11q23.
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| *GSD type 1 follows an autosomal recessive pattern.
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| ===Hypoglycemia===
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| [[Hypoglycemia]] is the central clinical problem, the one that is most damaging, and the one that most often prompts the initial diagnosis.
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| 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.
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| 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.
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| 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.
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| Once the diagnosis has been made, the principal goal of treatment is to maintain an adequate glucose level and prevent hypoglycemia.
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| 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.
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| 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.
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| ===Lactic acidosis===
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| 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) [[infection]]s such as [[gastroenteritis]] or [[pneumonia]].
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| ===Growth failure===
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| Without treatment, [[growth failure]] is common, due to chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, [[calorie]] insufficiency, and/or [[malabsorption]].
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| ===Hyperlipidemia and blood vessel effects===
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| A secondary effect of low insulin levels is hypertriglyceridemia. Triglycerides in the 400–800 mg/dl range may produce visible [[lipaemia|lipemia]], and even a mild pseudohyponatremia due to a reduced aqueous fraction of the [[blood plasma|serum]]. [[Cholesterol]] is only mildly elevated.
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| ===Hyperuricemia and joint problems===
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| 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.
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| ===Kidney effects===
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| 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]].
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| ===Bowel effects===
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| Intestinal involvement can cause mild [[malabsorption]] with sloppy stools but usually requires no treatment.
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| ===Infection risk===
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| ===Blood clotting problems===
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| Impaired platelet aggregation is an uncommon effect of chronic hypoglycemia. It may cause clinically significant bleeding, especially epistaxis.
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| ===Neurodevelopmental effects===
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| [[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.
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |