AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Glucose homeostasis is essential for life. Because most of an organism's life is spent in a fasting state (ie, between meals), no fewer than 3 major mechanisms have evolved to maintain glucose homeostasis during a fast. These mechanisms are gluconeogenesis, glycogenolysis, and lipolysis.

In the immediate postprandial period, glycogenolysis represents the major homeostatic process to maintain euglycemia. In neonates, gluconeogenesis is particularly important for maintaining euglycemia. Fructose 1,6-diphosphatase (FDPase) (also termed fructose 1,6-bisphosphatase) is a focal enzyme in gluconeogenesis via its conversion of fructose 1,6-diphosphate (FDP) to fructose 6-phosphate (F-6-P), which permits endogenous glucose production from gluconeogenic amino acids (eg, alanine and glycine), glycerol, or lactate.

Deficiency of hepatic FDPase was first confirmed in 1970 by Baker and Winegrad.¹ They reported the dramatic clinical picture of acidosis in response to D-fructose challenge.

Of broader clinical interest, excess hepatic FDPase action contributes to hyperglycemia in patients with type 2 diabetes. The development of specific FDPase inhibitors has opened a novel avenue for treating patients with type 2 diabetes.

Pathophysiology

FDPase catalyzes the conversion of FDP to F-6-P, which is a central step in gluconeogenesis. When challenged with D-fructose, patients lacking FDPase accumulate intrahepatocellular FDP, which inhibits gluconeogenesis and, if intracellular phosphate stores are depleted, inhibits glycogenolysis. The inability to convert lactic acid or glycerol into glucose leads to hypoglycemia, lactic acidosis, and glyceroluria.

Frequency

International

Incidence is approximately 1 in 20,000 live births worldwide.

Mortality/Morbidity

Patients develop severe hypoglycemia with metabolic acidosis upon ingestion of fructose. Fatal hepatic or renal injury following ingestion of fructose has been reported in these patients.

Early diagnosis of this disorder allows clinicians to advise patients regarding the avoidance of prolonged fasting and to initiate administration of intravenous dextrose promptly during illnesses associated with inadequate dextrose absorption (eg, vomiting or severe diarrhea).

Sex

Males and females appear to be affected in equal numbers.

Age

Patients with FDPase deficiency typically present in the newborn period with symptoms or signs related to hypoglycemia and metabolic acidosis following ingestion of fructose.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Focus on symptoms of hypoglycemia induced by foods that contain fructose and by infant formulas. Symptoms of hypoglycemia include hunger, irritability, light-headedness, fatigue, and lethargy. Signs of hypoglycemia include seizures, loss of consciousness, trembling, and sympathetic signs such as tachycardia, hypertension, or miosis.

Physical

Patients may only exhibit hepatomegaly during the metabolic crisis, which promptly resolves with administration of dextrose (ie, cessation of fasting).

Causes

The gene encoding FDPase was reported in 1995,² and several mutations resulting in loss of function have subsequently been reported in American and Japanese patients.^{3, 4, 5}

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hepatic aldolase B deficiency
Reye syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Determine serum levels of lactate, glucose, glycerol, and insulin during hypoglycemia.
• • Hypoglycemia is defined by the author as a blood glucose concentration below 60 mg/dL as determined in a hospital laboratory.
  • Portable glucometers are notoriously inaccurate and imprecise in the hypoglycemic range. However, their convenience and wide distribution often place them as the first diagnostic tool in the evaluation of patients with hypoglycemia.
  • To improve the chance of obtaining a diagnostic sample during the metabolic crisis, the practitioner should obtain 10 mL of whole blood in a red top tube during the crisis (seizure, loss of consciousness) or when hypoglycemia is suspected.
  • The laboratory should process the blood immediately to separate the serum by centrifugation and to store it at -70°C for subsequent analysis of metabolic intermediates.
  • The next voided urine specimen (obtained as close to the crisis as possible) is equally valuable.
• The most specific, minimally invasive, diagnostic test for fructose 1,6-diphosphatase (FDPase) deficiency is D-fructose challenge; however, this provocative test is dangerous and should be avoided during an acute crisis. In patients with FDPase deficiency, blood glucose levels fall below 60 mg/dL in response to D-fructose challenge, and the serum lactate levels rise (typically >2 standard deviations above the mean).
• Direct enzymatic assay of hepatic FDPase activity from hepatic specimens remains the most specific diagnostic test for this disorder. The assay is performed by a handful of reference laboratories (eg, Chen at Duke University).
• A prolonged fast can induce lactic acidosis with hypoglycemia in patients with FDPase deficiency as a result of impaired gluconeogenesis.
• Elevated urinary excretion of glycerol-3-phosphate appears to be specific to the disorder. The presence of glyceroluria at or shortly after the time of the metabolic crisis is a useful adjunct to confirm intact lipolytic pathways. However, hyperglyceroluria is not specific because it also can occur in patients with glycerol kinase deficiency.
• A controlled fasting study or D-fructose challenge under the supervision of a pediatric endocrinologist in the hospital setting permits recapitulation of the presentation to confirm the diagnosis. Less dangerous diagnostic techniques are available at few medical centers. However, simple peripheral blood specimens can be mailed to these centers for diagnosis while supportive care is provided to the patient.
• Glycerol challenge results in glyceroluria in patients with FDPase deficiency, although this result also occurs with disorders of glycerol metabolism (eg, glycerol kinase deficiency).
• In Japan, Iga et al reported a breakthrough for the screening of FDPase deficiency based on routine urine specimens.⁶ Their work suggests that this method can rapidly determine FDPase deficiency in these patients either during a metabolic crisis or during the stable clinical condition. The technique combines modifications of the Matsumoto and Kuhara method of urinalysis with gas chromatography and mass spectrometry in the selected-ion monitoring mode. This landmark paper delineates the possibility of identifying many asymptomatic patients who may be undiagnosed, as well as patients misclassified with sudden infant death syndrome or Reye syndrome.
• Kikawa et al reported a minimally invasive diagnostic test using cultured lymphocytes.⁷ This test is presently available only by contacting these investigators.

Procedures

• Assessment of hepatic FDPase isoenzyme activity is the definitive diagnostic procedure.
• Needle biopsy of the liver may be performed under local anesthesia. Most investigators prefer an open biopsy specimen to guarantee a sample of hepatic tissue sufficient to complete multiple enzymatic analyses.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Complete avoidance of fructose, its cognate sugars (eg, sorbitol) and prolonged fasting prevents hypoglycemia and lactic acidosis. Nevertheless, ingestion of small amounts of fructose and related sugars may be tolerated in most patients with fructose 1,6-diphosphatase (FDPase) deficiency. No other specific medical therapy is required.
• Patients may only exhibit hepatomegaly during the metabolic crisis, which resolves promptly with administration of dextrose.
• Parenteral administration of fructose or sorbitol to a patient with FDPase deficiency can be fatal.
• Sorbitol is a constituent of many basic foodstuffs and some sugarless chewing gums. The oral bioavailability of sorbitol from routine gum use is usually clinically insignificant. However, use and susceptibility to exposure widely vary; thus, sorbitol should be avoided by patients with FDPase deficiency whenever possible.

Consultations

• Consultation with a pediatric endocrinologist or metabolism specialist is recommended.

Diet

• Avoidance of fructose and cognate sugars is sufficient to prevent hypoglycemia and lactic acidosis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug therapy currently is not a component of the standard care for this disease.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Challenge with fructose or a fasting study should be performed only under the close supervision of a pediatric endocrinologist or metabolic specialist in an inpatient setting.
• Several Asian countries use glycerol solution containing 5% fructose to manage cerebral edema. Such solutions should not be administered to infants and children because most patients with fructose-1,6-diphosphatase (FDPase) deficiency are undiagnosed. These agents can be fatal.

Deterrence/Prevention

• Avoidance of food that contains fructose prevents the metabolic crisis that results from this disorder.

Complications

• Fatal hepatic or renal injury has been reported from the metabolic crisis associated with FDPase deficiency.

Prognosis

• With prompt diagnosis of this disorder, the prognosis is excellent. 
• Several successful pregnancies in affected mothers have been reported.⁸

Patient Education

• Parents and patients should be counseled by a dietitian regarding the fructose and sorbitol content of various foods.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make the diagnosis
• Inappropriate administration of fructose- or sucrose-containing foods to an affected individual, which may precipitate a crisis of metabolic acidosis with hypoglycemia

Special Concerns

• Parenteral administration of fructose or sorbitol to a patient with fructose 1,6-diphosphatase (FDPase) deficiency can be fatal.
• Sorbitol is a constituent of many basic foodstuffs. The content of sorbitol is usually sufficiently low to be of no clinical consequence with appropriate intake of other sugars.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Baker L, Winegrad AI. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet. Jul 4 1970;2(7662):13-6. [Medline].
2. el-Maghrabi MR, Lange AJ, Jiang W, et al. Human fructose-1,6-bisphosphatase gene (FBP1): exon-intron organization, localization to chromosome bands 9q22.2-q22.3, and mutation screening in subjects with fructose-1,6-bisphosphatase deficiency. Genomics. Jun 10 1995;27(3):520-5. [Medline].
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24. Nagai T, Yokoyama T, Hasegawa T, et al. Fructose and glucagon loading in siblings with fructose-1,6-diphosphatase deficiency in fed state. J Inherit Metab Dis. 1992;15:720-722. [Medline].
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Article Last Updated: Jul 1, 2008