JS presents with physical examination findings of sleepiness, clamminess to touch, elevated respiratory rate, normal temperature, and a firm, protuberant abdomen that is not tender. Palpation reveals an enlarged, smooth liver located 4 cm below the right costal margin and symmetrical kidneys.

Further evaluation at the regional children's hospital confirms hepatomegaly and renomegaly through ultrasound studies, ruling out the presence of tumors. A liver biopsy is performed, revealing distended hepatocytes with abundant lipid (primarily triacylglycerol) and carbohydrate. The liver glycogen level is elevated but maintains a normal structure. An enzyme assay using liver homogenate treated with detergent demonstrates less than 10% of the normal activity of glucose 6-phosphatase, an enzyme found in the endoplasmic reticular membrane of the liver and kidneys.

The diagnosis for JS is glucose 6-phosphatase deficiency, specifically glycogen storage disease (GSD) type Ia, also known as von Gierke disease. Immediate treatment involves intravenous glucose administration, which initially brings JS's blood glucose level back to normal. However, as the day progresses, the levels drop well below normal. Glucagon administration does not affect blood glucose levels but does increase blood lactate. Continuous glucose infusion is required to maintain JS's blood glucose levels.

Prognosis for individuals with glucose 6-phosphatase deficiency includes the development of hepatic adenomas starting in the second decade of life and an increased risk of hepatic carcinoma. Kidney glomerular function impairment may lead to kidney failure. While there is an increased risk of developing gout, it rarely occurs before puberty.

Long-term medical nutrition therapy aims to maintain JS's blood glucose levels within the normal range. Frequent daytime feedings rich in carbohydrate, provided by slowly hydrolyzed uncooked cornstarch, and nighttime nasogastric infusion of glucose (pump-assisted) are recommended. Avoidance of fructose and galactose is advised due to their metabolism into glycolytic intermediates and lactate, which can worsen metabolic issues. Calcium and vitamin D supplements are also prescribed.

GSD Ia is an autosomal-recessive disorder caused by over 100 known mutations in the gene for glucose 6-phosphatase located on chromosome 17. It has an incidence of 1 in 100,000 and accounts for approximately 25% of all GSD cases in the United States. It is one of the few genetic causes of hypoglycemia in newborns. Routine screening for GSD Ia in newborns is not performed. (Note: GSD Ib is caused by a deficiency in the translocase responsible for moving glucose 6-phosphate into the ER, leading to hypoglycemia and neutropenia.)

Review Question 1 (RQ1): The reason for JS's hypoglycemia is that free (nonphosphorylated) glucose cannot be produced from either glycogenolysis or gluconeogenesis due to the deficiency in glucose 6-phosphatase.
Physical Examination (Pertinent Findings): JS appears sleepy and feels clammy to the touch. His respiratory rate is elevated. His temperature is normal. JS has a protuberant, firm abdomen that appears to be nontender. His liver is palpable 4 cm below the right costal margin and is smooth. His kidneys are enlarged and symmetrical.
Pertinent Test Results:
H = High; L = Low.
JS is sent to the regional children’s hospital for further evaluation. Ultrasound studies confirm hepatomegaly and renomegaly and show no evidence of tumors. A liver biopsy is performed. The hepatocytes are distended. Staining reveals large amounts of lipid (primarily triacylglycerol) and carbohydrate. Liver glycogen is elevated in amount and normal in structure. Enzyme assay using liver homogenate treated with detergent reveals <10% of the normal activity of glucose 6-phosphatase, an enzyme of the endoplasmic reticular (ER) membrane in the liver and the kidneys.
Diagnosis: JS has glucose 6-phosphatase deficiency (glycogen storage disease [GSD] type Ia, von Gierke disease).
Treatment (Immediate): JS was given glucose intravenously, and his blood glucose level rose into the normal range. However, as the day progressed, it fell to well below normal. Administration of glucagon had no effect on blood glucose levels but increased blood lactate. JS’s blood glucose levels were able to be maintained by constant infusion of glucose.
Prognosis: Individuals with glucose 6-phosphatase deficiency develop hepatic adenomas starting in the second decade of life and are at increased risk for hepatic carcinoma. Kidney glomerular function is impaired and can result in kidney failure. Patients are at increased risk for developing gout, but this rarely occurs before puberty.
Nutrition Nugget: Long-term medical nutrition therapy for JS is designed to maintain his blood glucose levels in the normal range. Frequent (every 2–3 hours) daytime feedings rich in carbohydrate (provided by uncooked cornstarch that is slowly hydrolyzed) and nighttime nasogastric infusion (pump assisted) of glucose are advised. Avoidance of fructose and galactose is recommended because they are metabolized to glycolytic intermediates and lactate, which can exacerbate the metabolic problems. Calcium and vitamin D supplements are prescribed.
Genetics Gem: GSD Ia is an autosomal-recessive disorder caused by >100 known mutations to the gene for glucose 6-phosphatase located on chromosome 17. It has an incidence of 1:100,000 and accounts for ~25% of all cases of GSD in the United States. It is one of the few genetic causes of hypoglycemia in newborns. GSD Ia is not routinely screened for in newborns. [Note: Deficiency of the translocase that moves glucose 6phosphate into the ER is the cause of GSD Ib. Hypoglycemia and neutropenia are seen.]
Review Questions: Choose the ONE best answer.
RQ1. JS is hypoglycemic because:
A. free (nonphosphorylated) glucose cannot be produced from either glycogenolysis or gluconeogenesis as a result of the deficiency in glucose 6-phosphatase.
B. glycogen phosphorylase is dephosphorylated and inactive, and glycogen cannot be degraded.
C. hormone-sensitive lipase is dephosphorylated and inactive, and fatty acid substrates for gluconeogenesis cannot be generated.
D. the decrease in the insulin/glucagon ratio upregulates glucose transporters in the liver and kidneys, resulting in increased uptake of blood glucose.