Version May 2024
INTRODUCTION — Glucose-6-phosphatase deficiency (G6PD; MIM #232200), also known as von Gierke disease, is a glycogen storage disease (GSD). It was the first GSD to have the responsible enzyme defect identified and therefore is designated GSD I (table 1). The defective enzymes involved in GSD I are mainly active in the liver and kidney. Patients present with manifestations related to hypoglycemia around three to four months of age. The diagnosis is confirmed by genetic testing. Treatment is focused on maintenance of physiologic glucose levels.
GSD I is reviewed in detail here. Other GSDs are reviewed separately. (See "Liver glycogen synthase deficiency (glycogen storage disease 0)" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)" and "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)" and "Glycogen debrancher deficiency (glycogen storage disease III, Cori disease)" and "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)" and "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)" and "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)".)
A broader overview of GSD is also presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
EPIDEMIOLOGY — The incidence of GSD I is 1/100,000 live births [1]. It is one of the most common types of GSDs.
PATHOGENESIS AND CLASSIFICATION — The hydrolysis and transport of glucose-6-phosphate (G6P) require a catalytic hydrolase and microsomal transporters for G6P, pyrophosphate, and glucose (figure 1). GSD I is caused by defects in the hydrolase (phosphatase) or translocase:
●GSD Ia is due to a deficiency in the enzyme G6P hydrolase (glucose-6-phosphatase [G6Pase]) and comprises over 80 percent of cases of GSD I. G6Pase is expressed in the liver, intestine, and kidney.
●GSD Ib (G6P transporter deficiency) is caused by a defect in the enzyme G6P translocase that is functionally associated with G6Pase. The translocase is ubiquitously expressed and functions as both a G6P transporter and a phosphate antiporter [2]. The enzyme also plays a role in neutrophil homeostasis and function [3].
Deficiency of either G6Pase or its transporter leads to progressive glycogen accumulation, mainly in the liver, and fasting hypoglycemia, which results in a number of secondary metabolic perturbations described below.
GENETICS — GSD I is an autosomal-recessive disorder. The G6Pase gene, G6PC, is located on chromosome 17q21, while the glucose-6-phosphate translocase gene, solute carrier family 37 member 4 (SLC37A4), is localized to chromosome 11q23.
Over 100 pathogenic variants have been identified in the G6PC gene [4,5]. Most are missense/nonsense mutations. Small deletions, insertions, and spice-site mutations have also been reported. Several common mutations exist in patients with GSD Ia:
●c.247C>T (R83C) and c.1039C>T (Q347X) are the most prevalent variants found in White patients [6,7].
●c.379_380dupTA (p.Tyr128Thrfs) and c.247C>T (R83C) are the most prevalent variants in Hispanic patients [6,7].
●c.648G>T (L216L), a splicing mutation, and c.248G>A (R83H) are the most prevalent variants in the Chinese population [4,6,7].
●c.648G>T (L216L) accounts for 91 percent of mutant alleles in Japan [4,8] and 75 percent of mutant alleles in Korea [4].
●c.247C>T (R83C) accounts for 98 percent of variants in the Ashkenazi Jewish population [9].
Over 100 pathogenic variants in SLC37A4 have been identified in patients with GSD Ib [5]. The majority are missense and nonsense mutations, but a significant number of deletions and splicing mutations are also seen.
●c.1015G>T (G339C) and c.1042_1043delCT are the most common variants in White patients [7,10].
●c.352T>C (W118R) accounts for 50 percent of mutant alleles in the Japanese population [7,11].
CLINICAL FEATURES — Affected patients most commonly present between three to six months of age with hepatomegaly, signs and symptoms of hypoglycemia, poor growth, and doll-like facies. In a report from the collaborative European study on GSD I, patients with GSD Ia and GSD Ib presented at a median age of six months (range 1 day to 12 years) and four months (range 1 day to 4 years), respectively [12]. The majority of both types presented before one year of age in this series.
In the European study, the following were the dominant presenting features [12]:
●Protruding abdomen – 83 percent
●Metabolic derangement, including hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia – 71 percent
●Growth failure (short stature, thin legs) – 25 percent
●Recurrent bacterial infections – 3 percent in GSD Ia, 41 percent in GSD Ib
●Muscular hypotonia – 13 percent
●Delayed psychomotor development – 7 percent
Hypoglycemia — Hypoglycemia is the hallmark finding in patients with GSD I. Unlike other GSDs, hypoglycemia in GSD I is characterized by hypoketosis due to inhibition of fatty acid oxidation by malonic acid [13]. Affected individuals have poor fasting tolerance, especially infants and young children, and may develop hypoglycemia within an hour or two after a meal. Symptoms of hypoglycemia include fatigue, irritability, nighttime waking to feed, and seizures. Patients often adapt to hypoglycemia and may be asymptomatic despite low blood glucose values.
Lactic acidosis — Lactic acidosis is observed after fasting as G6Pase, in addition to its role in glycogen breakdown, is required for the final step of gluconeogenesis. Untreated patients may have serum lactate concentration between 5 to 10 mmol/L.
Hyperuricemia — Many patients have hyperuricemia, which is secondary to decreased kidney clearance and increased production via degradation of adenine nucleotides [14]. Gout rarely develops before puberty [7].
Hyperlipidemia — Marked hyperlipidemia, especially hypertriglyceridemia, occurs and can lead to xanthoma formation and pancreatitis. De novo triglyceride synthesis has been shown to increase over 10-fold in affected individuals, and the conversion of very-low-density lipoprotein (VLDL) to low-density lipoprotein (LDL) is delayed [15]. The relationship between hyperlipidemia and cardiovascular disease in patients with GSD I is unclear. Studies have shown both increased and normal carotid intima media thickness, and case series have yielded inconsistent observations regarding vascular dysfunction and markers of cardiovascular risk [16-19].
Hematologic abnormalities — Anemia, while uncommon in treated patients, can be observed in both the pediatric and adult populations. It can result from chronic kidney disease, nutritional deficiencies, hemorrhage of hepatic adenomas, enterocolitis in type Ib patients, and other factors [1]. Platelet dysfunction can result in easy bruising and epistaxis. Patients with GSD Ib also have intermittent or chronic neutropenia and neutrophil dysfunction. In a report from a European registry of 57 GSD Ib patients, neutropenia occurred in 54 [20]. It was documented before one year of age in 64 percent of patients and first noted between six and nine years in 18 percent. Neutropenia was intermittent without a clear cyclical course in 45 patients and persistent in 5. (See "Congenital neutropenia".)
Gastrointestinal disease — Inflammatory bowel disease (IBD) is common in GSD Ib [21,22]. Commonly reported symptoms include chronic abdominal pain, bloody diarrhea, perioral and perianal infections, and abscesses. IBD can occur in GSD Ia and may be underrecognized [23].
Endocrine disorders — Short stature is common if patients are not appropriately managed. Puberty is often delayed, and menstrual cycles are frequently irregular [24]. Polycystic ovaries and menorrhagia have been observed. Fertility does not seem to be reduced, and successful pregnancies without the use of assistive reproductive measures have been reported [1,24,25]. An increased prevalence of thyroid autoimmunity and hypothyroidism has been reported in patients with GSD Ib [26]. Vitamin D levels are often low [27].
Kidney disease — Kidney disease results from glycogen accumulation in the kidney. Proteinuria, hematuria, nephrocalcinosis, and altered creatinine clearance typically follow a period of asymptomatic hyperfiltration. Stones result both from hypercalciuria and hyperuricosuria. The kidney appears enlarged, and histologic examination reveals focal segmental glomerulosclerosis and interstitial fibrosis [14,28-30]. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)
Hypertension (table 2 and table 3) is common, and onset is typically in the second decade or later. A subset of patients develop progressive renal insufficiency and end-stage kidney disease [28].
Neurologic abnormalities — Patients with GSD I are at risk for hypoglycemic seizures, which, if recurrent, can lead to neurodevelopmental impairment. Intelligence quotient (IQ) can be normal, but brain function and structure may be altered as a result of recurrent, severe hypoglycemia. In one study comparing brain function and morphology in patients with GSD I and age- and sex-matched controls, subjects with GSD I had increased prevalence of abnormal electroencephalograms (26 versus 3 percent), visual evoked potentials (38 versus 8 percent), somatosensory evoked potentials (23 versus 0 percent), brainstem auditory evoked potentials (16 versus 0 percent), and abnormal magnetic resonance imaging (MRI) studies (57 versus 0 percent) [31]. MRI abnormalities included dilation of the occipital horns and/or hyperintensity of subcortical white matter in the occipital or parietal lobes. Some of these abnormalities correlated with the frequency of hypoglycemic episodes requiring hospitalization, but the contribution of other factors, directly or indirectly related to GSD I, remains unclear. Intelligence quotient (IQ) was normal and similar between patients and controls (mean 97.2 and 100.1, respectively).
Hepatic adenomas — Most adults develop liver adenomas in the second to third decade of life. The adenomas may lead to intrahepatic hemorrhage and undergo malignant transformation in approximately 10 percent of cases [32]. Enlargement of preexisting hepatic adenomas or appearance of new adenomas during pregnancy has been reported in GSD I patients [24]. Other focal hepatic lesions include hepatoblastoma, focal nodular hyperplasia, and focal fatty infiltration or sparing.
Decreased bone density — Osteoporosis is seen in over half of adult patients with GSD Ia and Ib [33]. Decreased bone mineral density may be due to a chronic lactic acidosis, the effect of cortisol release (in response to hypoglycemia) on osteoblasts, and treatment of GSD itself, which involves dietary restriction of lactose and galactose that leads to vitamin D deficiency.
Pulmonary hypertension — A small number of patients develop pulmonary hypertension, which can lead to progressive heart failure [34,35].
DIAGNOSIS — GSD I should be suspected in patients with hypoglycemia, lactic acidemia, hypertriglyceridemia, hyperuricemia, and hepatomegaly, with or without neutropenia.
DNA testing is necessary to confirm the diagnosis of GSD Ia or Ib. Commercial sequencing of G6PC (G6Pase gene) and SLC37A4 (glucose-6-phosphate translocase gene) is widely available. Liver biopsies for histologic studies and enzyme analysis were performed historically but are rarely necessary nowadays. Liver histology demonstrates prominent storage of glycogen and considerable steatosis with minimal fibrosis.
A guideline for the diagnosis and management of GSD I is available from the American College of Medical Genetics and Genomics [1].
DIFFERENTIAL DIAGNOSIS — The main diagnoses to consider are the other hepatic forms of GSD that cause hypoglycemia. These are types 0, III, VI, and IX (table 1). Patients with GSD type III may have extremely elevated aspartate transaminase (AST) and alanine transaminase (ALT) and milder hypoglycemia. In addition, uric acid and lactic acid are normal. Ketosis is much more pronounced in GSD types 0, III, VI, and IX compared with type I. GSD type 0 does not cause hepatomegaly. Ultimately, genetic testing is necessary to confirm the specific type of GSD.
MANAGEMENT — Patients with GSD I should be managed by an experienced metabolic team including a biochemical geneticist, dietitian, nurse, and social worker. Other specialists may include a nephrologist, hepatologist, hematologist, and endocrinologist. A guideline for the diagnosis and management of GSD I is available from the American College of Medical Genetics and Genomics [1].
The goal of treatment is maintenance of physiologic glucose levels. Other clinical and biochemical parameters, such as somatic growth, lactic acidosis, and hypertriglyceridemia, improve in parallel with improved glucose control.
European guidelines for the management of GSD I recommend the following biochemical targets [36]:
●Preprandial blood glucose >3.5 to 4.0 mmol/L (63 to 72 mg/dL)
●Urine lactate/creatinine ratio <0.06 mmol/mmol
●Serum uric acid concentration in high normal range for age
●Venous blood bicarbonate >20 mmol/L (20 mEq/L)
●Serum triglyceride concentration <6.0 mmol/L (531 mg/dL)
●Normal fecal alpha-1 antitrypsin concentration for GSD Ib
●Body mass index between 0.0 and + 2.0 standard deviations (calculator 1 and calculator 2)
Prevention of hypoglycemia — Infants should be fed at regular, age-appropriate intervals. In rare instances, they may require more frequent feeding. Early on, infants should not be allowed to sleep through the night. Some may require continuous feeds through a nasogastric or gastrostomy tube. An optimal infusion should provide 8 to 10 mg/kg/minute of glucose for an infant and 4 to 8 mg/kg/minute of glucose in an older child [1]. After one year of age, children should be given at least three daily meals with snacks in between.
Between meals, glucose concentrations are maintained with frequent oral administration of glucose, usually in the form of uncooked cornstarch, which is a glucose polymer that is broken down slowly. In many cases, a dose of cornstarch is needed during the night. Long-term treatment with uncooked cornstarch improves growth in GSD I patients [37-39]. Adverse effects of uncooked cornstarch include diarrhea, increased flatulence, and excess weight gain. Other commercial glucose polymer products are available and may allow longer fasting intervals between meals [40].
The dose of uncooked cornstarch is 1.6 g/kg every three to four hours for young children and 1.7 to 2.5 g/kg every four to six hours for older children, adolescents, and adults (1 tablespoon equals approximately 8.6 grams) [1]. Dosing is adjusted for the individual patient. Since infants do not digest cornstarch well due to lack of salivary amylase expression, it is recommended to begin cornstarch therapy after 6 to 12 months of age, when amylase activity increases. The need for cornstarch support decreases with age, and failure to adjust the dose in older patients can lead to excessive weight gain, worsening hepatomegaly, and relative hyperinsulinism [41].
Nutrition — Working with a metabolic dietitian is essential in caring for patients with GSD I. Complex carbohydrates should comprise the majority of the diet (60 to 70 percent of total energy intake) [1]. Sugar, fruits, fruit juices, high-fructose corn syrup, and sorbitol should be avoided. Lactose, galactose, fructose, and sucrose should be limited since they also depend on G6Pase for metabolism. Infants should be fed a soy-based formula. Unlike other GSDs, a high-protein diet is not useful to maintain glucose in GSD I, since gluconeogenesis also depends upon hydrolysis of glucose-6-phosphate (G6P). Essential vitamins and minerals, especially calcium and vitamin D, should be provided through the diet or by supplementation if needed.
Treatment of lactic acidosis — Lactic acidosis, if persistent, can be treated with oral citrate or bicarbonate administration, which also alkalinizes the urine and decreases the risk of urolithiasis and nephrocalcinosis.
Treatment of hyperuricemia — There is no consensus as to when to treat hyperuricemia with medications. Allopurinol lowers uric acid levels and can be used in patients with persistently elevated uric acid or with recurrent attacks of gout. Colchicine may be used during acute attacks. Use of medium-chain triglyceride oil was shown in a small study to improve uric acid levels and reduce carbohydrate requirements [42].
Treatment of hyperlipidemia — Lipid-lowering agents such as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrate may be used. Dietary interventions (eg, administration of medium-chain triglycerides) may be effective at reducing triglyceride and lactic acid levels by improving fatty acid oxidation and reducing glycolysis but require additional evaluation [43]. However, hyperlipidemia in patients with GSD I only responds partially to drug therapy and/or dietary measures. It resolves completely after liver transplantation [44]. (See "Dyslipidemia in children and adolescents: Management" and "Hypertriglyceridemia in adults: Management".)
Fish oil does not persistently lower serum triglyceride and cholesterol concentration and may increase atherogenesis by increasing lipoprotein oxidation [45].
Neutropenia — Patients with GSD Ib and neutropenia should be treated with granulocyte colony-stimulating factor (G-CSF) [1,46]. Treatment with G-CSF increases neutrophil count, decreases the frequency and severity of infections, and improves inflammatory bowel symptoms [46,47]. Splenomegaly is the most serious complication of G-CSF.
The antidiabetic drug empagliflozin was shown to improve neutropenia and inflammatory bowel disease by reducing plasma levels of 1,5-anhydroglucitol-6-phosphate, a structural analog of G6P that accumulates in neutrophils of patients with GSD Ib [48,49]. Clinical trials are underway (NCT04986735 and NCT04930627).
Reactive oxygen species are thought to play a role in activating apoptosis in neutrophils of patients with GSD Ib, suggesting that antioxidant therapy may be beneficial. Supplementation with vitamin E has been shown to increase mean neutrophil count, decrease the frequency and severity of infections, and, in some cases, allow for dose reduction of G-CSF [50,51].These findings show promise as an adjunct or alternative treatment but should be replicated in larger, placebo-controlled trials before vitamin E therapy can be routinely suggested for the treatment of patients with GSD Ib.
Anemia — Treatment of anemia may include iron supplementation and erythropoietin, depending upon the severity [1].
Inflammatory bowel disease — IBD is treated with the usual approach. Patients have also responded to G-CSF and empagliflozin, which is used to treat neutropenia (see 'Neutropenia' above). Successful treatment of refractory GSD-related IBD with adalimumab has been reported [52]. (See "Overview of the medical management of mild (low risk) Crohn disease in adults" and "Medical management of moderate to severe Crohn disease in adults" and "Overview of the management of Crohn disease in children and adolescents" and 'Neutropenia' above.)
Short stature — Growth hormone does not affect the final height and should not be used, because it can lead to the development of or an increase in the size or number of liver adenomas [1,36]. Good metabolic control leads to improved height and weight.
Osteoporosis — Dual-energy x-ray absorptiometry (DXA) scans and vitamin D 25-OH levels should be checked regularly to monitor bone health. Calcium and vitamin D supplementation are necessary given the restricted nature of the diet [1].
Kidney disease — A kidney ultrasound should be obtained annually to assess for kidney enlargement and nephrolithiasis. Blood urea nitrogen, creatinine, urinalysis, quantitation of microalbumin, and other kidney function studies should be checked at routine intervals, typically annually in children and every six months in adults [1]. Alkalinization of the urine with oral citrate decreases the risk of stone formation. Potassium citrate is preferred over bicarbonate because hypocitraturia appears to worsen with age in GSD Ia [53].
An angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) should be started in patients with persistent microalbuminuria to decrease deterioration of kidney function [1,36,54]. Hypertension that persists despite ACE inhibition should also be treated. Kidney transplant, often combined with liver transplant, can be performed in patients with end-stage kidney disease.
Hepatocellular carcinoma — Hepatocellular carcinoma (HCC) is a known late complication GSD I [55]. Adenoma to HCC transformation may occur in persons with good metabolic control [56]. A liver ultrasound should be performed every 12 to 24 months in children <18 years of age to screen for HCC. Computed tomography (CT) or magnetic resonance imaging (MRI) with contrast is recommended every 6 to 12 months in older patients [1]. Oral contraceptive pills are contraindicated in women with GSD I since estrogen increases the risk for hepatic adenomas. However, progestin-only contraceptives are an option [1,24]. During pregnancy, adenomas must be monitored due to the risk for enlargement and rupture. (See 'Hepatic adenomas' above.)
Pulmonary hypertension — An echocardiogram should be performed starting at 10 years of age to screen for pulmonary hypertension [1,36]. This study should be repeated every three years or sooner if clinically indicated.
Liver transplantation — Liver transplantation is indicated in GSD I patients with poor metabolic control, worsening adenomas, HCC, and/or liver or kidney failure [1,57]. Transplantation results in resolution of hypoglycemia and secondary metabolic disturbances including lactic acidosis, hypertriglyceridemia, and hyperuricemia [44,57]. Patients can eat a normal diet after liver transplantation. Growth deficiency and neutropenia often persist in GSD Ib after transplantation [58].
Some patients with GSD Ia develop kidney failure after liver transplant. This may be due to natural disease progression or an adverse effect of immunosuppressive medications. Combined liver and kidney transplant can be done [59-62].
Other (or future) therapies — Clinical trials for gene therapy for GSD Ia are underway (NCT03517085). Gene therapy in mouse models of GSD Ib appears effective in restoring G6P translocase activity [63], and human trials may follow. A clinical trial investigating the use of empagliflozin to treat neutropenia in GSD Ib patients is ongoing (NCT04930627).
OUTCOME — Complications due to GSD I persist in adults. In one report, long-term outcomes were evaluated in 37 patients with GSD Ia and five patients with GSD Ib who were ≥18 years of age [64]. The following outcomes were noted:
●Hepatomegaly – 100 percent
●Short stature – 90 percent
●Hyperuricemia – 89 percent
●Anemia – 81 percent
●Hypercholesterolemia – 76 percent
●Increased serum triglycerides – 100 percent
●Hepatic adenomas – 75 percent
●Proteinuria or microalbuminuria – 67 percent
●Renal calcifications – 65 percent
●Osteopenia or fractures – 27 percent
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glycogen storage disease types I and II".)
SUMMARY AND RECOMMENDATIONS
●Glucose-6-phosphatase deficiency (G6PD; glycogen storage disease type I [GSD I]), also known as von Gierke disease, is an autosomal-recessive disorder caused by a deficiency of glucose-6-phosphate (G6P) hydrolase (type Ia) or G6P translocase (type Ib) (figure 1). (See 'Pathogenesis and classification' above and 'Genetics' above.)
●Affected patients typically present in early infancy with failure to thrive, hepatomegaly, hypoglycemia, seizures, and lactic acidosis. Additional manifestations include kidney disease, hyperuricemia, hypertriglyceridemia, and, in patients with type Ib GSD, recurrent infections due to neutropenia. (See 'Clinical features' above.)
●The diagnosis of GSD I is confirmed by genetic testing. (See 'Diagnosis' above and 'Genetics' above.)
●The goal of treatment is to maintain physiologic glucose levels. Other biochemical parameters, such as lactic acidosis and hypertriglyceridemia, improve in parallel with improved glucose control. (See 'Management' above.)
●Glucose concentrations are maintained with regular meals, snacks, and administration of uncooked cornstarch. (See 'Prevention of hypoglycemia' above.)
●Additional treatment measures may be necessary for hyperuricemia, hyperlipidemia, microalbuminuria, hypertension, neutropenia, and inflammatory bowel disease (IBD). (See 'Management' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William J Craigen, MD, PhD, who contributed to an earlier version of this topic review.
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