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==Pathophysiology==
==Pathophysiology==
===Normal carbohydrate balance and maintenance of blood glucose levels===
*GSD type 1 results due to defects in either hydrolysis or transport of glucose-6-phosphate
[[Glycogen]] in liver and (to a lesser degree) kidneys serves as a form of stored, rapidly accessible glucose, so that the blood glucose level can be maintained between meals. For about 3 hours after a [[carbohydrate]]-containing meal, high [[insulin]] levels direct liver cells to take glucose from the blood, to convert it to [[glucose-6-phosphate]] (G6P), and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of [[triglyceride]]s and exported for storage in [[adipose tissue]] as [[fat]].  
*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.


When [[digestion]] of a meal is complete, insulin levels fall, and enzyme systems in the liver cells begin to remove glucose molecules from strands of glycogen in the form of G6P. This process is termed [[glycogenolysis]]. The G6P remains within the liver cell unless the phosphate is cleaved by [[glucose-6-phosphatase]]. This [[dephosphorylation]] reaction produces free glucose and free PO<sub>4</sub> [[anion]]s. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the [[brain]] and other organs of the body. Glycogenolysis can supply the glucose needs of an adult body for 12-18 hours.
===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.


When fasting continues for more than a few hours, falling insulin levels permit [[catabolism]] of [[muscle]] protein and triglycerides from adipose tissue. The products of these processes are [[amino acid]]s (mainly [[alanine]]), [[free fatty acid]]s, and [[lactic acid]]. Free fatty acids from triglycerides are converted to [[ketone]]s, and to [[acetyl-CoA]]. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of [[gluconeogenesis]]. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO<sub>4</sub>.
===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.<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>
*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.


Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. In fact the effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis.
===Hematologic Disorders===
====Anemia====
*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>
**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.<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>
*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.


===Pathophysiology of the metabolic effects of glucose-6-phosphatase deficiency===
====Bleeding diathesis====
The principal metabolic effects of deficiency of glucose-6-phosphatase are:
*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>
*[[Hypoglycemia]]
*Acquired platelet dysfunction with prolonged bleeding times
*[[Lactic acidosis]]
*Decreased platelet adhesiveness
*[[Hypertriglyceridemia]]
*Abnormal aggregation of platelets
*[[Hyperuricemia]]


The '''hypoglycemia''' of GSD I is termed "fasting", or "post-absorptive", meaning that it occurs after completion of digestion of a meal-- usually about 4 hours later. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both [[glycogenolysis]] and [[gluconeogenesis]]. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low [[insulin]] levels and high levels of [[glucagon]] and [[cortisol]].
====Neutropenia and neutrophil dysfunction====
*Neutropenia and neutrophil dysfunction is specific fo GSD type 1b.<ref name="pmid12373578">{{cite journal| author=Visser G, Rake JP, Labrune P, Leonard JV, Moses S, Ullrich K et al.| title=Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1. | journal=Eur J Pediatr | year= 2002 | volume= 161 Suppl 1 | issue=  | pages= S83-7 | pmid=12373578 | doi=10.1007/s00431-002-1010-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12373578  }} </ref>
*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:<ref name="pmid19741523">{{cite journal| author=Chou JY, Jun HS, Mansfield BC| title=Neutropenia in type Ib glycogen storage disease. | journal=Curr Opin Hematol | year= 2010 | volume= 17 | issue= 1 | pages= 36-42 | pmid=19741523 | doi=10.1097/MOH.0b013e328331df85 | pmc=3099242 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19741523  }} </ref>
**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:<ref name="pmid2164043">{{cite journal| author=Kilpatrick L, Garty BZ, Lundquist KF, Hunter K, Stanley CA, Baker L et al.| title=Impaired metabolic function and signaling defects in phagocytic cells in glycogen storage disease type 1b. | journal=J Clin Invest | year= 1990 | volume= 86 | issue= 1 | pages= 196-202 | pmid=2164043 | doi=10.1172/JCI114684 | pmc=296707 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2164043  }} </ref>
**Granuloma formation
**Chronic inflammatory responses


'''Lactic acidosis''' arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD<sup>+</sup> to [[pyruvic acid]] and then converted via the gluconeogenenic pathway to G6P. Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored.
==Genetics==
 
*80% Cases of GSD 1 are of GSD type 1a.<ref name="pmid10322403">{{cite journal| author=Mansfield BC| title=Molecular Genetics of Type 1 Glycogen Storage Diseases. | journal=Trends Endocrinol Metab | year= 1999 | volume= 10 | issue= 3 | pages= 104-113 | pmid=10322403 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10322403  }} </ref>
'''Hypertriglyceridemia''' resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, [[ketones]], and ultimately glucose is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of "metabolic control".
*G6Pase gene is located on chromosome locus 17q21.
 
*Glucose-6-phosphate translocase is located on chromosome locus 11q23.
'''Hyperuricemia''' results from a combination of increased generation and decreased excretion of [[uric acid]], which is generated when increased amounts of G6P are metabolized via the [[pentose phosphate pathway]]. It is also a byproduct of [[purine]] degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue.
*GSD type 1 follows an autosomal recessive pattern.


==References==
==References==

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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
  • 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.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Czapek EE, Deykin D, Salzman EW (1973). "Platelet dysfunction in glycogen storage disease type I." Blood. 41 (2): 235–47. PMID 4350560.
  8. ↑ Corby DG, Putnam CW, Greene HL (1974). "Impaired platelet function in glucose-6-phosphatase deficiency". J Pediatr. 85 (1): 71–6. PMID 4212074.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Mansfield BC (1999). "Molecular Genetics of Type 1 Glycogen Storage Diseases". Trends Endocrinol Metab. 10 (3): 104–113. PMID 10322403.

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