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INTRODUCTION

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Fructose is a quantitatively important source of carbohydrates, especially in the Western diet. It is a component of table sugar (sucrose, Glc-Fru disaccharide) and is contained in large amounts in honey, fruits, and various vegetables. Fructose, sucrose, and sorbitol (metabolized mainly via fructose) are frequent food additives. A special concern is sucrose-containing infant formulas which may elicit a potentially fatal response in an affected newborn. Fructose also constitutes the main carbohydrate in seminal fluid. The average daily dietary intake by Americans was estimated to be 100 g.1,2 In the last century fructose and sorbitol were used as carbohydrates in parenteral nutrition, for example, equimolar solutions of glucose and fructose prepared by hydrolysis of sucrose as “invert sugar.” IV solutions containing fructose or sorbitol can be toxic to patients with fructose intolerance and should no longer be used. Oral fructose is absorbed in the small intestine and mainly metabolized in the liver. Significant fructose metabolism also takes place in the kidney and the small intestine, explaining the organ manifestations of genetic diseases of fructose metabolism (see below).

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Normal fructose metabolism comprises three enzymes (Figure 7-1). The irreversible phosphorylation of fructose by fructokinase yields fructose-1-phosphate. A genetic defect of fructokinase results in essential fructosuria, an incidental finding and benign condition. Fructose-1-phosphate is cleaved by aldolase B (EC 4.1.2.13) into phosphorylated C3-metabolites that enter glycolysis or gluconeogenesis.3 The third enzyme, fructose-1,6-bisphosphatase, is an important participant in gluconeogenesis, converting fructose-1,6-biphosphate, synthesized from 3-carbon compounds to fructose-6-phosphate.

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FIGURE 7-1.

Normal fructose metabolism. Aldolase B is responsible for reversible splitting of fructose 1-phosphate (F-1-P) to D-glyceraldehyde and dihydroxyacetone phosphate as well as reversible splitting of fructose-1,6-biphosphate into D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. FK, fructokinase; F-1,6-BPase, fructose-1,6-biphosphatase; fructose-1-6-bis-P, fructose-1-6-biphosphate; aldo, aldolase; TPI, triosephosphate isomerase; TK, transketolase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; TA, transaminase; ACC, acetyl-CoA-carboylase; PC, pyruvate carboxylase.

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AT-A-GLANCE Disorders of Fructose Metabolism

Hereditary fructose intolerance (HFI) and fructose 1,6-bisphosphatase (FBP1) deficiency are two distinct disorders of fructose metabolism. HFI results from deficiency of aldolase B, which is found in liver, kidney, and intestine. Ingestion of fructose results in gastrointestinal symptoms and secondary hypoglycemia, which may be life-threatening. Diagnosis is established by detailed history and mutation analysis. Management of this condition is by avoidance of fructose/sucrose/sorbitol in the diet. Prompt identification of this condition is essential to avoid complications. The long-term effects of untreated HFI result in growth failure and liver failure and can lead to death. FBP1 deficiency is also considered an inborn error of fructose metabolism although it is not a part of the fructose pathway. It results in hypoglycemia, and acidosis often already in the neonatal period and can be potentially life threatening. Management includes avoidance of fasting and fructose in the diet, and treatment of acidosis, if present, should be initiated.

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