What enzyme is deficient in von Gierke disease?

Glucose-6-phosphatase (gene G6PC1) in type Ia, about 80% of cases, or the glucose-6-phosphate transporter (SLC37A4) in type Ib, about 20%. The transporter carries glucose-6-phosphate into the endoplasmic reticulum, where the phosphatase converts it to glucose in the final step of both glycogenolysis and gluconeogenesis. Both types are autosomal recessive, and the overall incidence is about 1 in 100,000.

Why does von Gierke disease cause lactic acidosis, hyperuricemia and hyperlipidemia?

Glucose-6-phosphate that cannot become glucose is diverted. It runs down glycolysis to lactate; lactate competes with uric acid for renal excretion, and low phosphate in liver cells speeds the breakdown of adenine nucleotides to uric acid. Excess acetyl-CoA becomes malonyl-CoA, which drives fatty acid synthesis and inhibits CPT-1, raising triglycerides while keeping ketone production low.

Why doesn't glucagon raise blood glucose in von Gierke disease?

Glucagon stimulates glycogen breakdown, but the glucose-6-phosphate it produces still cannot be converted to free glucose, so blood glucose barely rises and lactate climbs instead. For the same reason, glucagon should not be used to treat hypoglycemia in GSD I: it is ineffective and may worsen lactic acidosis. Treatment relies on frequent carbohydrate and uncooked cornstarch.

How is von Gierke disease different from Cori disease?

Cori disease (GSD III) is a debranching enzyme deficiency. It also causes hypoglycemia and a large liver, but glucose and lactate are high after meals and low after a fast, the reverse of type I's fasting lactic acidosis, and hypoglycemia appears later in a fast. Cori disease often involves muscle weakness and sometimes cardiomyopathy, and liver size usually returns to normal during adolescence.

What foods should be avoided in von Gierke disease?

Sucrose (glucose plus fructose) and lactose (glucose plus galactose) are usually limited, which cuts back table sugar, fruit, juice and dairy. Fructose and galactose cannot correct the hypoglycemia and add to lactic acidosis. Instead, patients eat frequent meals high in complex carbohydrates and take uncooked cornstarch (about every 3–4 hours in young children), including at bedtime and overnight; infants may need continuous overnight tube feeds.

Von Gierke Disease (GSD I): Enzyme, Labs & Treatment

Von Gierke disease is glycogen storage disease type I (GSD I): the liver and kidney cannot turn glucose-6-phosphate into free glucose. Type Ia (about 80% of cases) is a deficiency of glucose-6-phosphatase (gene G6PC1); type Ib (about 20%) is a defect in the glucose-6-phosphate transporter (SLC37A4); both are autosomal recessive. Untreated infants present at about 3–4 months with hepatomegaly, severe fasting hypoglycemia, lactic acidosis, hyperuricemia and hypertriglyceridemia, and glucagon produces little or no rise in blood glucose. Treatment is to keep glucose coming: frequent carbohydrate feeds, uncooked cornstarch and overnight feeding, with sucrose, fructose and galactose limited. Type Ib adds neutropenia, with infections and mouth and bowel ulcers.

Why one missing enzyme causes five lab abnormalities

In the fasting liver, glycogen breakdown and gluconeogenesis both end at the same molecule, glucose-6-phosphate (G6P). To leave the cell as glucose, G6P is carried into the lumen of the endoplasmic reticulum by the transporter (SLC37A4, in exchange for phosphate) and hydrolyzed there by glucose-6-phosphatase (G6PC1); together they perform the final step of both pathways:

$\text{glucose-6-phosphate} + \text{H}_2\text{O} \rightarrow \text{glucose} + \text{P}_i$

When that last step fails, the liver cannot release glucose from either source, and the trapped G6P is pushed into every other pathway it feeds.

Finding	Mechanism
Severe fasting hypoglycemia	Neither glycogenolysis nor gluconeogenesis can deliver free glucose to the blood
Lactic acidosis	Excess G6P runs down glycolysis to pyruvate and lactate
Hepatomegaly and enlarged kidneys	Glycogen and fat accumulate in the liver, kidney and intestinal mucosa
Hyperuricemia	Lactate competes with uric acid for renal excretion, and low phosphate inside the liver cell speeds the breakdown of adenine nucleotides to uric acid
High triglycerides and cholesterol	Excess acetyl-CoA is turned into malonyl-CoA and new fatty acids, and lipid clearance from the blood falls
Ketones low for the degree of hypoglycemia	Malonyl-CoA inhibits CPT-1, so fatty acids are not burned to make ketones
Nosebleeds and easy bruising	Impaired platelet function
No glucose rise after glucagon	Glucagon releases glycogen as G6P, which still cannot become glucose; lactate rises instead

The lipid and ketone rows use the same malonyl-CoA switch taught in fatty acid synthesis. Lactate is also a partial rescue: the brain can burn it, which is why some children have surprisingly few symptoms at very low glucose.

Type Ia vs type Ib

	GSD Ia	GSD Ib
Defect	Glucose-6-phosphatase, G6PC1	Glucose-6-phosphate transporter, SLC37A4
Share of GSD I	About 80%	About 20%
Inheritance	Autosomal recessive	Autosomal recessive
Metabolic picture	Hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly	Similar
Extra features	Usually none	Neutropenia with poor neutrophil and monocyte function: recurrent bacterial infections, gingivitis, oral and intestinal ulcers, inflammatory bowel disease
Extra treatment	None	G-CSF; off-label empagliflozin

In type Ib, 1,5-anhydroglucitol-6-phosphate builds up to toxic levels in neutrophils and inhibits hexokinase, their main glucose-phosphorylating enzyme. Empagliflozin, an SGLT2 inhibitor used off-label, lowers blood 1,5-anhydroglucitol and neutrophil 1,5-anhydroglucitol-6-phosphate; in published reports, neutrophil counts and function improved, mouth ulcers and bowel inflammation healed, and some patients could stop G-CSF.

How it shows up in a USMLE stem

An infant of about 3–4 months with a protuberant abdomen from a large liver, a doll-like face with full cheeks, thin arms and legs and, later, short stature.
Hypoglycemic seizures, sometimes as soon as 2–2.5 hours after a feed, with nosebleeds, xanthomas or diarrhea.
Enlarged kidneys on imaging.
Labs that suggest GSD I (ACMG guideline): hypoglycemia (in an untreated infant, glucose can fall below 40 mg/dL within 3–4 hours of a feed), lactic acidosis (lactate usually 10 mmol/L or more during hypoglycemia), and high uric acid, triglycerides and cholesterol.
Glucagon challenge: little or no glucose rise, with worsening lactic acidosis.

Diagnosis

Molecular genetic testing usually establishes the diagnosis: biallelic pathogenic variants in G6PC1 (type Ia) or SLC37A4 (type Ib). Less often, low glucose-6-phosphatase activity is shown in a liver biopsy.
Glucagon is not a treatment for hypoglycemia in GSD I: it is ineffective and may worsen lactic acidosis. For the same reason, the ACMG guideline advises against a glucagon stimulation test to make the diagnosis.

Treatment and long-term complications

Never let glucose run out: frequent meals and snacks rich in complex carbohydrates, plus uncooked cornstarch (a trial is often started between 6 and 12 months of age; young children usually take a dose every 3–4 hours), including at bedtime and overnight. Infants may get continuous overnight feeds by nasogastric or gastrostomy tube, and a modified cornstarch is available for overnight use.
Limit sucrose, fructose and galactose (so lactose too): these sugars cannot correct the hypoglycemia and add to the lactate. The fructose and galactose disorders themselves are compared in this fructose and galactose metabolism mnemonic.
Treat the complications: allopurinol to prevent gout, lipid-lowering drugs (statins, fibrates), ACE inhibitors or ARBs for microalbuminuria and citrate against kidney stones and nephrocalcinosis; G-CSF and off-label empagliflozin in type Ib.
Watch for: hepatic adenomas (usually appearing in the second or third decade and found in 70–80% of patients older than 25; some turn into hepatocellular carcinoma), kidney disease (proteinuria from focal segmental glomerulosclerosis, renal tubular acidosis, low urinary citrate with high urinary calcium, stones), gout, osteoporosis, delayed puberty, pulmonary hypertension, pancreatitis and polycystic ovaries.
Liver transplantation (sometimes combined with a kidney transplant) is needed in some patients; afterwards the hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia resolve.

Von Gierke vs the other glycogen storage diseases

Type (eponym)	Deficient enzyme	What the stem shows
I (von Gierke)	Glucose-6-phosphatase (Ia) or G6P transporter (Ib)	Severe fasting hypoglycemia, lactic acidosis, high uric acid and triglycerides, big liver and kidneys
II (Pompe)	Lysosomal acid α-glucosidase (acid maltase)	Cardiomyopathy with heart failure, severe hypotonia, macroglossia
III (Cori or Forbes; limit dextrinosis)	Debranching enzyme	Hypoglycemia, hepatomegaly and high liver enzymes plus muscle weakness, sometimes cardiomyopathy; lactate is high after meals and low when fasting
IV (Andersen)	Branching enzyme	Hepatomegaly with progressive cirrhosis, varices and ascites
V (McArdle)	Muscle glycogen phosphorylase	Exercise intolerance, cramps, rhabdomyolysis; venous lactate fails to rise with forearm exercise
VI (Hers)	Liver glycogen phosphorylase	Mild course that improves with age; hepatomegaly, growth retardation

For the lysosomal type, see the Pompe disease overview; for the branching-enzyme defect, see Andersen disease (GSD IV).

Exam traps

Glucagon given, glucose flat, lactate up: GSD I.
Recurrent infections or mouth ulcers in a child with GSD I: type Ib, from neutropenia.
Fructose or galactose will not rescue the glucose and will raise lactate, so sucrose and lactose are limited.
Hereditary fructose intolerance is the look-alike: aldolase B deficiency causes vomiting and hypoglycemia after fructose (fruit, juice) is introduced, not on fasting.
A liver mass in a teenager or young adult with GSD I suggests a hepatic adenoma, which can turn malignant.
"Type I" can mean either gene: the metabolic picture of Ia and Ib is similar; neutropenia is the tiebreaker.

Worked example

Vignette. A 4-month-old girl has a generalized seizure early in the morning. She has a protuberant abdomen with the liver edge 6 cm below the costal margin, full cheeks and thin extremities. Glucose is 32 mg/dL, lactate 8 mmol/L, uric acid 9 mg/dL and triglycerides 900 mg/dL, with an anion gap metabolic acidosis. After glucagon, glucose barely changes while lactate rises further. Which enzyme is most likely deficient?

Answer: Glucose-6-phosphatase (GSD Ia, von Gierke disease).

Why the distractors are wrong:

Debranching enzyme (Cori, GSD III): also causes hypoglycemia and a big liver, but glucose and lactate are high after meals and low after a fast (the reverse of type I's fasting lactic acidosis), hypoglycemia comes later in a fast, and muscle weakness is common.
Muscle glycogen phosphorylase (McArdle): a muscle disease of exercise intolerance, cramps and rhabdomyolysis, not infant hypoglycemia.
Lysosomal acid α-glucosidase (Pompe): glycogen builds up inside lysosomes; the hallmarks are cardiomyopathy with heart failure, severe hypotonia and macroglossia, none of which is in this stem.
Aldolase B (hereditary fructose intolerance): vomiting and hypoglycemia begin when fruit, juice or other fructose-containing foods enter the diet, and they follow fructose intake rather than fasting.

Key takeaways

Von Gierke = GSD I: glucose-6-phosphatase (Ia, about 80%) or the G6P transporter (Ib, about 20%); autosomal recessive; about 1 in 100,000.
The liver cannot release free glucose from glycogen or gluconeogenesis, so fasting hypoglycemia is severe.
Trapped G6P drives lactic acidosis, hyperuricemia, hypertriglyceridemia and glycogen-filled liver and kidneys; ketones stay relatively low.
Glucagon doesn't raise glucose and is not a treatment.
Treatment: frequent complex carbohydrate, uncooked cornstarch, overnight feeds; limit sucrose, fructose and galactose.
Type Ib adds neutropenia, infections, ulcers and bowel inflammation: G-CSF and off-label empagliflozin.
Long term: hepatic adenomas with a risk of hepatocellular carcinoma, kidney disease, gout and osteoporosis.