AUTHOR INFORMATION

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Authored by Robert J Ferry, Jr, MD, Associate Professor of Pediatrics, Training and Research Director, Division of Pediatric Endocrinology, Departments of Pediatrics, Cellular & Structural Biology, University of Texas Health Science Center, San Antonio; Field Surgeon, Army Medical Dept, Texas National Guard

Robert J Ferry, Jr, MD, is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Robert J Ferry, Jr, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, July 27 2006, VOLUME 7, Number 7

INTRODUCTION

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Background: Glucose homeostasis is essential for life. Since 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, namely, 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 Lester Baker and Alan Winegrad at The Children's Hospital of Philadelphia. 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. Recent development of specific FDPase inhibitors opens a novel avenue for treating patients with type 2 diabetes.

Pathophysiology: FDPase catalyzes a central step in gluconeogenesis: the conversion of FDP to F-6-P. 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:

• Internationally: 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

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

Causes: The gene encoding FDPase was reported in 1995, and several mutations resulting in loss of function have subsequently been reported in American and Japanese patients.

DIFFERENTIALS

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Acidosis, Metabolic
Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Growth Failure
Hypoglycemia
Lactose Intolerance
Sudden Infant Death Syndrome

Other Problems to be Considered:

Hepatic aldolase B deficiency
Reye syndrome

WORKUP

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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 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).



• Screening test: In Japan, Iga et al recently reported a breakthrough for the screening of FDPase deficiency based on routine urine specimens. 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, as detailed in an article published in 2000 (Iga, 2000). 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 recently reported a minimally invasive diagnostic test using cultured lymphocytes. This test is presently available only by contacting these investigators (kikawa@fmsrsa.fukui-med.ac.jp).

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

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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 FDPase deficiency. No other specific medical therapy is required.



• Patients may exhibit hepatomegaly during the metabolic crisis only, 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, usage and susceptibility to exposure are sufficiently variable that 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

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

FOLLOW-UP

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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, since most patients with fructose-1,6-diphosphatase are undiagnosed. Such agents can be fatal to them.

Deterrence/Prevention:

• Avoidance of food containing fructose prevents metabolic crisis resulting 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.

Patient Education:

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

MISCELLANEOUS

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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 FDPase deficiency can be fatal.



• Sorbitol is a constituent of many basic foodstuffs. The content of sorbitol usually is sufficiently low to be of no clinical consequence with appropriate intake of other sugars.

TEST QUESTIONS

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CME Question 1: A child presents with generalized seizure from hypoglycemia. Which of the following therapeutic interventions is most appropriate in this child?

A: Four ounces of orange juice by mouth
B: Intravenous administration of fructose
C: Intramuscular administration of glucagon 1 mg
D: Intravenous administration of glucagon 1 mg
E: Intravenous administration of 2 mL/kg of 10% dextrose

The correct answer is E: In the absence of an identified etiology for hypoglycemia at any age, the most appropriate therapeutic intervention is administration of dextrose. Fructose by any route could worsen the patient’s condition dramatically if the underlying cause is fructose 1,6-diphosphatase (FDPase) deficiency. Glucagon requires intact glycogen stores and intact glycogenolytic pathways, both of which are likely to be defective in patients with hypoglycemia.

CME Question 2: Which of the following tests is most useful in the diagnosis of fructose 1,6-diphosphatase (FDPase) deficiency?

A: Glucagon challenge
B: Fructose challenge
C: Insulin tolerance test
D: Controlled fasting study
E: Urinary glycerol determination

The correct answer is B: The hyperlacticemia and metabolic acidosis that result following D-fructose administration are diagnostic for FDPase deficiency. The most specific, most sensitive, diagnostic test for FDPase deficiency is direct assay of hepatic enzymatic activity, yet a liver biopsy must be performed for this test. The danger of the fructose challenge is offset if a positive result can prevent the need for liver biopsy. The fructose challenge should be performed only by an experienced pediatric endocrinologist or metabolic specialist in a controlled inpatient setting. New work by Iga et al may preclude the need for either the danger of fructose challenge or for performance of an invasive liver biopsy. When available to the clinician, urinalysis by mass spectrometry is the preferred first diagnostic test, whether the patient is stable or in metabolic crisis.

Pearl Question 1 (T/F): Parenteral administration of fructose or sorbitol to a patient with fructose 1,6-diphosphatase (FDPase) deficiency can be fatal.

The correct answer is True: Administration of fructose to an affected individual inhibits gluconeogenesis. If the patient is hypoglycemic, impairment of gluconeogenesis exacerbates the existing hypoglycemia. Death has occurred in patients with FDPase deficiency as a result of fructose administration.

Pearl Question 2 (T/F): Sorbitol is a constituent of many basic foodstuffs.

The correct answer is True: Discovered in 1872 as a constituent of mountain ash berries, sorbitol is a sugar alcohol (polyol) that has been used since the 1960s as an alternative bulk sweetener to sucrose. The US Food and Drug Administration classifies sorbitol as GRAS (generally recognized as safe). Some pharmaceutical and cosmetic products also contain sorbitol. Although many berries and fruits contain sorbitol, the current commercial source is the hydrogenation of glucose, yielding both crystalline and liquid forms. Consultation with a registered dietitian is advised for patients with fructose 1,6-diphosphatase (FDPase) deficiency.

Pearl Question 3 (T/F): Fruit juice (which contains fructose) or milk (which contains lactose) should be administered to patients with fructose 1,6-diphosphatase (FDPase) deficiency when they become hypoglycemic.

The correct answer is False: Metabolism of both fructose and lactose requires functional FDPase. Administration of significant amounts of these sugars to patients with FDPase deficiency may trigger or worsen hypoglycemia and lactic acidosis.

Pearl Question 4 (T/F): Glucagon is effective therapy for the treatment of hypoglycemia in patients with fructose 1,6-diphosphatase (FDPase) deficiency.

The correct answer is False: Glucagon can raise the blood glucose concentration only by mobilizing glycogen stores. Patients with FDPase deficiency manifest impaired glycogenolysis at the time of hypoglycemia, even in the face of residual glycogen stores. The best therapy for hypoglycemia in any patient is rapid administration of dextrose. In hypoglycemia or food-provoked symptoms of hypoglycemia, patients should be counseled to keep dextrose tablets with them at all times. Such tablets are inexpensive and readily available at most supermarkets or pharmacies.

BIBLIOGRAPHY

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