Chapter 70

### Abstract

1. Fructose is an important source of dietary carbohydrates. In Western societies, daily intake by adults is presently approximately 100 g. The liver, kidney, and small intestine are the main sites of fructose metabolism, but adipose tissue also participates. Fructose, given intravenously in high doses, is clearly toxic and causes hyperuricemia, hyperlactatemia, and ultrastructural alterations in liver and intestinal cells.

2. Essential fructosuria, an autosomal-recessive disorder, is a benign, asymptomatic metabolic anomaly caused by the absence of fructokinase. Alimentary hyperfructosemia and fructosuria are the principal signs. Despite the interruption of the specific fructose pathway, up to nine tenths of the administered fructose is retained by fructokinase-deficient subjects.

3. Hereditary fructose intolerance, an autosomal-recessive disorder, is characterized by severe hypoglycemia and vomiting shortly after the intake of fructose. Prolonged fructose ingestion in infants leads to poor feeding, vomiting, hepatomegaly, jaundice, hemorrhage, proximal renal tubular syndrome, and finally, hepatic failure and death. Patients develop a strong distaste for noxious food. Therefore, a chronic course is observed only in preschool-aged children. Fructaldolase B of liver, kidney cortex, and small intestine is deficient. Hypoglycemia after fructose ingestion is caused by fructose 1-phosphate–inhibiting glycogenolysis at the phosphorylase level and gluconeogenesis at the mutant aldolase level. Patients remain healthy on a fructose- and sucrose-free diet. The severity of the disease phenotype appears to be independent of the nature of the aldolase B gene mutations so far identified.

4. Hereditary fructose 1,6-bisphosphatase deficiency, an autosomal-recessive disorder, is characterized by episodic spells of hyperventilation, apnea, hypoglycemia, ketosis, and lactic acidosis, with a precipitous and often lethal course in the newborn infant. Later episodes are often triggered by fasting and febrile infections. Due to the enzyme defect, gluconeogenesis is severely impaired. Gluconeogenic precursors such as amino acids, lactate, and ketones accumulate as soon as liver glycogen stores are depleted. Patients do not vomit after fructose intake, and aversion to sweets does not develop. Their tolerance to fasting grows with age. Patients past early childhood seem to develop normally.

5. D-glyceric aciduria, erythrocyte aldolase deficiency, and incomplete fructose absorption are briefly mentioned.

### Introduction

Three inherited abnormalities of fructose metabolism are known. Two of these are caused by a defect of one of the enzymes of the specialized fructose pathway—essential fructosuria and hereditary fructose intolerance—the former a harmless and the latter a potentially lethal condition. Although not a defect of the specialized fructose pathway, hepatic fructose 1,6-bisphosphatase deficiency is usually classified as an error of fructose metabolism. The defect of this enzyme of the gluconeogenic pathway becomes clinically manifest through hypoglycemia and lactic acidosis on fasting and also may be life threatening. The description of the clinical symptoms and biochemical anomalies in the three inborn errors of metabolism is preceded by an outline of the metabolism of fructose. The potential toxic effects of fructose in humans also are discussed: it is essential to understand these toxic effects in order to comprehend the pathophysiology of hereditary fructose intolerance and of fructose 1,6-bisphosphatase deficiency.

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