Most people in developed countries ingest 50 to 150 g fructose equivalents daily in their diet and the use of this sugar in food and drinks is increasing globally. Fructose is absorbed rapidly by a carrier mechanism that facilitates transport across the intestinal epithelium, metabolized (mainly in the liver) by the enzymes ketohexokinase (fructokinase), aldolase B, and triokinase, and eventually converted into glucose or glycogen. Dietary sugar has particular effects on those whose capacity to metabolise fructose is limited. Fructose occurs either as a free monosaccharide, as a component of sucrose, a disaccharide from which it is released by digestion; fructose may also be derived from the metabolism of the sugar alcohol, sorbitol.
‘Fructose malabsorption’—describes incomplete absorption of fructose that is associated with abdominal symptoms and diarrhoea reminiscent of intestinal disaccharidase deficiency after ingestion of fructose- or sorbitol-rich foods and drinks such as apple juice, but this condition does not have a defined genetic cause. Symptoms improve when these sugars are excluded from the diet.
Three inborn errors of fructose metabolism are recognized: (1) essential or benign fructosuria due to fructokinase deficiency—a very rare disorder with no ill effects; (2) hereditary fructose intolerance (fructosaemia) caused by deficiency of aldolase B; and (3) fructose-1,6-diphosphatase deficiency.
Hereditary fructose intolerance—an autosomal recessive disease; typically presents at weaning but may come to light at any age with postprandial abdominal pain and vomiting, symptomatic hypoglycaemia (which may induce seizures), hypophosphataemia, acidosis and other metabolic disturbances after consumption of offending foods and drinks. Unrecognized disease causes failure to thrive/growth retardation, a Fanconi-like renal syndrome with nephrocalcinosis, and jaundice with lethal liver injury. Parenteral infusion of fructose or its congeners can be fatal. Diagnosis depends upon demonstration of deficient aldolase B isozyme activity in biopsy material from liver, small intestine, or kidney, or molecular analysis of the aldolase B gene. Treatment requires institution of a strict sugar-exclusion diet supplemented by water-soluble vitamins. Early diagnosis and dietary modification are critical for well-being and normal development.
Fructose-1,6-diphosphatase deficiency—a very rare disease of infancy and childhood associated with failure of hepatic gluconeogenesis causing bouts of severe hypoglycaemia, ketosis, and lactic acidosis that are provoked by infection and starvation, and aggravated by dietary fructose, related sugars and ketogenic fat. Diagnosis depends on identification of a gluconeogenic defect and enzymatic assay of fructose-1,6-diphosphatase in fresh liver biopsy samples. Treatment requires prompt control of intercurrent illnesses and scrupulous attention to nutrition, with a fructose-exclusion diet containing abundant carbohydrate energy, restricted fat and protein. Acute episodes of acidosis or hypoglycaemia are controlled by intravenous infusion of glucose, with bicarbonate if required.
Metabolism of fructose
Fructose is a burgeoning component of the modern diet; it occurs as a free monosaccharide in fruit, nuts, honey, confectionary and some vegetables, but either as the free monosaccharide, or as a component of sucrose, fructose is a common additive in many foods and drinks. Free fructose is released from the disaccharide sucrose in the gut lumen by the sucrase–isomaltase complex at the brush-border membrane of the mucosal epithelium. Finally, the sugar alcohol sorbitol (a constituent of medicines and tablets, as well as some foods for diabetics) is converted quantitatively to fructose in the liver and intestine. Most people in developed countries ingest 50 to 150 g fructose equivalents daily in the diet. Global production of sugar (sucrose from cane and beet) is rising, but over the last three decades manufacture of fructose as a high-fructose syrup, enzymatically derived from starch in maize (corn), has also burgeoned. This intensely sweet sugar is now used extensively as a sweetener in drinks and processed foods.
The pathways of fructose metabolism are summarized in Fig. 18.104.22.168. Phosphorylated forms of fructose are critical intermediates in the glycolytic and gluconeogenic metabolic pathways in all cells. Fructose is absorbed rapidly by a carrier mechanism that facilitates transport across the intestinal epithelium; this process is mediated by the glucose transporter isoforms GLUT5 and GLUT2, the latter probably contributing to efflux across the basolateral membrane of the enterocyte.
Fructose is then conveyed via the portal bloodstream to the liver, where it is assimilated. The jejunal mucosa and proximal tubule of the kidney are subsidiary sites of fructose metabolism. Assimilation of fructose depends on the concerted activities of the enzymes ketohexokinase (fructokinase), aldolase B, and triokinase, which are expressed specifically in these tissues. Uptake of fructose occurs independently of insulin and its incorporation into intermediary metabolism bypasses the regulation of glycolysis at the level of phosphofructokinase-1. For these reasons, solutions of fructose or sorbitol were advocated and, in the past, extensively used for parenteral nutrition. However, the occurrence of lactic acidosis, hyperuricaemia, and other serious consequences has led to withdrawal of fructose and sorbitol from parenteral hyperalimentation regimens in most, if not all, countries.
Fructokinase rapidly phosphorylates fructose that has entered cells, at the 1-carbon position. This enzyme has a high affinity for its substrates and cells of the renal cortex, the intestinal mucosa and liver rapidly convert fructose to fructose 1-phosphate; in other tissues, the capacity of hexokinase to phosphorylate fructose at the 6-carbon position is limited. Similarly, the fate of fructose 1-phosphate in the fructose-metabolizing tissues is dependent on a specific isozyme of aldolase, aldolase B. Aldolase B has greater activity towards fructose 1-phosphate than does its ubiquitous counterpart, in glycolysis, aldolase A, the natural substrate of which is fructose 1,6-diphosphate. Cleavage of fructose 1-phosphate generates glyceraldehyde and dihydroxyacetone phosphate. These trioses enter the intermediary pools of carbohydrate metabolism, and, as a result of triokinase activity, glyceraldehyde is phosphorylated so that the two triose phosphates may be condensed by aldolase A to form the glycolytic and gluconeogenic intermediate fructose 1,6-diphosphate.
Gluconeogenesis from triose phosphates, lactate, glycerol, amino acids, and Krebs’ cycle intermediates such as oxaloacetate, requires reversal of the committed reactions of glycolysis. It is the enzyme fructose-1,6-diphosphatase that releases the glucose precursor fructose 6-phosphate from fructose 1,6-diphosphate. Thus, when the remaining reactions of glycolysis are reversed, exogenous fructose provides a source of glucose or glycogen. Fructose-1,6-diphosphatase is active in the liver, kidney, and intestine, and it is a key enzyme of gluconeogenesis.
The occurrence of abdominal symptoms with postprandial bloating, flatulence, colonic pain and diarrhoea, reminiscent of intestinal disaccharidase deficiency, in response to ingested fructose is well recognized by gastroenterologists and often attributed to incomplete absorption of fructose: it is therefore called ‘fructose malabsorption’. The symptoms occur in adults and children after ingestion of fructose-rich or sorbitol-rich foods and drinks such as apple juice, and usually recede when the sugars are excluded from the diet. Many such individuals, as well as a high proportion of healthy control subjects, have findings suggestive of fructose malabsorption based on hydrogen breath tests, but often, definitive evidence of true malabsorption is lacking, and an operational diagnosis of irritable bowel syndrome is frequently offered. Unfortunately, the molecular basis of this syndrome and of the wide variation of tolerance to dietary fructose and its congeners is not known. Moreover, in several patients complaining of fructose-related intestinal symptoms, molecular analysis of the human GLUT5 gene, which encodes a major intestinal fructose transporter, has so far failed to identify causal mutations. Other studies have suggested that the distal small intestine and colon of patients who experience abdominal flatulence and diarrhoea after ingesting fructose-containing foods contain a bacterial population with enhanced uptake and anaerobic metabolism of fructose. No conclusive evidence has yet been provided to support these observations and more investigative studies are needed in those patients who experience symptoms attributed to malabsorption of this sugar, including measurement of intestinal fructose absorption, metabolism, transit and transport.
Essential (benign) fructosuria (OMIM 229800)
This is a rare disorder (estimated frequency 1 in 130 000) of little clinical consequence. The abnormality is transmitted as an autosomal recessive condition and is demonstrated by the presence of a reducing sugar in the blood and urine, especially after meals rich in fructose. The abnormality is caused by the deficiency of fructokinase activity in the liver and intestine, significantly reducing the capacity to assimilate this sugar. Mutations in the human ketohexokinase gene on chromosome 2p23.3–p23.2 have been identified in patients with essential fructosuria, thus confirming the suspected molecular defect in this condition. Fructose metabolism occurs slowly in essential fructosuria as a result of conversion to fructose 6-phosphate by hexokinase in adipose tissue and muscle, but, while plasma concentrations remain high postprandially, large amounts of fructose appear in the urine. Essential fructosuria may be confused with diabetes mellitus if the nature of the mellituria is not defined; with the use of glucose oxidase strips in preference to the older chemical methods for urinalysis, such confusion is now unlikely. No treatment beyond recognition and explanation appears to be necessary.
Hereditary fructose intolerance (fructosaemia) (OMIM 229600)
This disorder, first recognized in 1956, is the most common inherited defect of fructose metabolism with an estimated frequency of about 1 in 20 000 births in the United Kingdom and several populations of European origin. The disease has been reported in several diverse populations, including China and Israel. Hereditary fructose intolerance is transmitted as an autosomal recessive trait and, although it manifests itself first in early infancy, the effects of clinical disease may not be recognized until late childhood or adult life. Provided the diagnosis is made before visceral damage occurs, hereditary fructose intolerance responds completely to an exclusion diet and patients can survive to old age.
The cardinal features of the illness are vomiting, diarrhoea, abdominal pain, and hypoglycaemia, and are induced by the consumption of foods, drinks, or medicines that contain fructose, or the related sugars, sucrose or sorbitol. There is a generalized metabolic disturbance with lactic acidosis, hyperuricaemia, and hypophosphataemia. Hypoglycaemia causes trembling, irritability, and cognitive impairment. Attacks are associated with pallor, sweating, and, when severe, loss of consciousness sometimes accompanied by generalized seizures. These episodes usually occur within 30 min of meals that contain large quantities of fructose or sucrose. Continued ingestion of noxious sugars is associated with renal tubular disease, liver damage with jaundice and clinical enlargement of the liver, and defective blood coagulation with pathological brushing. The clinical picture is of failure to thrive in an infant or child with hepatomegaly, hepatitis-like episdoes and growth retardation. Persistent exposure to fructose and the related noxious sugars in infants leads to structural liver injury with cirrhosis, aminoaciduria, coagulopathy, and coma leading to death. The infant is first exposed to the offending sugars at weaning or on transfer from breast milk to artificial feeds. Survival is dependent on recognition of the effects of fruit and sugar in the diet by the mother or, especially in older infants, by vomiting or forcible rejection of food.
Infants who survive the stormy period of weaning, develop a strong aversion to sweet-tasting foods, vegetables, and fruits. This usually affords protection against the worst effects of fructose and sucrose, but abdominal symptoms with bouts of tremulousness, irritability, and altered consciousness and seizures due to hypoglycaemia usually continue. It has become clear that many cases escape diagnosis in infancy and childhood, but the risk of illness, related to dietary indiscretion, remains throughout life. Characteristically, children and adults with hereditary fructose intolerance show a striking reduction in, or absence of, dental caries.
Recently, a syndrome of chronic sugar intoxication has been recognized in older children and adolescents with hereditary fructose intolerance. General lack of vigour and developmental retardation are prominent features. Hypoglycaemia, though obvious after heavy fructose loading, may be insignificant after chronic low-level exposure in older children. Similarly, tests of hepatic and renal function may be only mildly abnormal. Persistent ingestion of fructose and sucrose is toxic to the kidney and liver, so that renal tubular acidosis (with cortical nephrocalcinosis and, occasionally, urinary calculi) as well as hepatosplenomegaly occur in younger patients. Severe growth retardation may be accompanied by rachitic bone disease that complicates the Fanconi-like syndrome of proximal renal tubular disturbance with bicarbonate wasting. Growth retardation responds to dietary treatment and is usually accompanied by regression of the other disease manifestations.
Provided that organ failure and serious tissue injury do not supervene, patients with hereditary fructose intolerance recover rapidly when the toxic sugars are withdrawn. Children who survive by acquiring the protective pattern of eating behaviour avoid foods which provoke abdominal symptoms. The aversion extends to most sweet-tasting items of food and drink as well as fruits and vegetables; it remains life long and consumption of fructose (as well as sucrose and sorbitol) is usually reduced to less than 5 g daily. It has been shown that normal growth and development can be assured in growing children and adolescents if less than 40 mg/kg fructose equivalents are ingested daily.
Hereditary fructose intolerance is caused by a deficiency of aldolase B in the liver, small intestine, and proximal renal tubule. These tissues experience injury as a result of persistent exposure to fructose in patients affected by the disorder. In the absence of the fructose 1-phosphate-splitting activity of aldolase B, the intracellular pool of inorganic phosphate is depleted. Studies in vivo by 31P magnetic resonance spectroscopy show that 80% of hepatic free phosphate is sequestrated as sugar phosphates after the infusion of small quantities of fructose (250 mg/kg body weight). The secondary metabolic disturbances are initiated by the accumulation of fructose 1-phosphate in a milieu where free inorganic phosphate is reduced: there is competitive inhibition of aldolase A and inhibition of phosphorylase activity so that glycogenolysis and gluconeogenesis are impaired. Thus, challenge with fructose leads to hypophosphataemia and hypoglycaemia that is refractory to glucagon or the infusion of gluconeogenic metabolites such as glycerol or dihydroxyacetone. During challenge with fructose, high concentrations of fructose 1-phosphate cause feedback inhibition of fructokinase, thereby limiting the incorporation of fructose in the liver. As a result, fructosaemia occurs and, when the blood concentration exceeds about 2 mmol/litre, fructosuria is apparent. Although the assimilation of fructose by the specialized pathway is blocked, only a small fraction of the fructose load is recovered in the urine. Studies show that 80% to 90% of the fructose is taken up under these circumstances by adipose tissue and muscle, where it can serve as an alternative substrate for hexokinase with conversion to fructose 6-phosphate.
Electrolytic disturbances occur during challenge with fructose. Hypokalaemia results from acute renal impairment with defective urinary acidification. There is a defect of proximal tubule function with bicarbonate wasting and acidosis. Occasionally, acute flaccid weakness due to hypokalaemia accompanies the other effects of fructose exposure. In patients with hereditary fructose intolerance, the administration of fructose reproducibly increases serum magnesium concentrations. This is probably explained by the breakdown of magnesium–ATP complexes, releasing intracellular magnesium ions as a result of nucleotide degradation by adenosine deaminase. Significant ingestion of fructose is thus also accompanied by marked hyperuricaemia in patients with hereditary fructose intolerance.
In the absence of acute exposure to fructose, only minor abnormalities of blood analytes are detectable and the blood glucose concentration is normal, even after prolonged fasting. Often the activity of serum transaminases becomes transiently elevated and this may be accompanied by biochemical or even frank jaundice; low serum and red-cell folate and white-cell ascorbate concentrations may occur as a result of restrictive dietary habits.
Pathology and molecular genetics
Persistent ingestion of fructose and related sugars in hereditary fructose intolerance causes hepatic and renal injury; there is diffuse fatty change and increased glycogen deposition. Hepatocyte necrosis with intralobular and periportal fibrosis occurs and fully developed cirrhosis results from continued exposure to fructose. After acute experimental challenge, electron microscopy has shown irregular electron-dense material surrounded by membranous structures, suggesting a florid lysosomal reaction to intracellular deposits of fructose 1-phosphate. Parenteral administration of fructose or sorbitol may induce the abrupt onset of hepatorenal failure associated with bleeding. Histological examination shows hepatic necrosis in these cases (Fig. 22.214.171.124). Loss of cellular functions, e.g. in the proximal renal tubule, is probably caused by depletion of ATP resulting from the arrested metabolism of fructose by the specialized pathway; interstitial nephrocalcinosis of the renal cortex may be apparent on radiological examination. The source of the severe abdominal pain that follows ingestion of fructose is unknown, but stimulation of visceral afferent nerves by the local release of purine nucleotides or lactate may be responsible.
The genetic basis of aldolase B deficiency has been studied intensively and numerous mutations responsible for hereditary fructose intolerance have been identified. The human aldolase B gene maps to chromosome 9q22.3. Several point mutations affecting the function of the enzyme are sufficiently widespread in patients of European origin to merit focused diagnostic investigation. One particular mutation, Ala149→Pro, which disrupts residues in a substrate-binding domain of aldolase B, is prevalent in populations of European descent. This mutation accounts for most alleles responsible for fructose intolerance, but others, including Ala174→Asp, Asn334→Lys, and a four-base deletion in exon 4, are sufficiently frequent and widespread to merit initial examination in a specialized molecular diagnostic laboratory (see below). The intragenic deletion has also been reported from China. Biochemical and structural studies of the expressed mutant enzymes reveal two main classes of aldolase B in hereditary fructose intolerance, active tetrameric variants which are unstable and readily lose their quaternary structure and mutant aldolases that retain their normal tetrameric structure but are catalytically impaired.
In infancy and childhood, hereditary fructose intolerance most characteristically causes persistent vomiting, with failure to thrive, acidosis, hypoglycaemia, and jaundice. The symptoms occur rapidly after ingestion of inappropriate foods and drinks. Clearly in very young infants there is a wide differential diagnosis, including Reye’s syndrome, but fructose intolerance may be indicated by the nutritional history and feeding difficulties. The differential diagnosis includes pyloric stenosis, galactosaemia, Reye’s syndrome, viral or toxin induced hepatitis, renal tubular disease including nephropathic cystinosis, Wilson’s disease, and hereditary tyrosinaemia.
Rarely, carbohydrate-deficient glycoprotein syndrome may be suspected on the basis of biochemical screening tests carried out during the course of investigations in severely ill children and infants with the disease, since untreated patients with hereditary fructose intolerance almost invariably show a type I pattern of carbohydrate-deficient serum transferrin on isoelectric focusing; this is corrected within a few weeks of fructose exclusion and is due to transient inhibition of phosphomannose isomerase implicated in glycoprotein processing and biosynthesis.
The presence of reducing sugar in the urine may indicate that fructosuria and amino acids may also be present. Older children and adults report food aversion and may show a striking absence of dental caries. If fructose intolerance is considered, then sucrose, sorbitol, and fructose should be excluded completely before definitive tests can be carried out. Striking improvement, suggestive of hereditary fructose intolerance, may be seen within a few days.
Since the prompt institution of strict dietary treatment has beneficial and, in infants and children, life-saving effects in those with fructose intolerance, every reasonable effort should be undertaken to make a definitive diagnosis. This will have important consequences for relatives of the propositus and will provide information critical for the introduction of a rigorous and life-long exclusion diet. Rigorous diagnosis of fructose intolerance requires the demonstration of fructose 1-phosphate aldolase deficiency in visceral tissue or the presence of two causal mutant alleles of the human aldolase B gene.
The intravenous controlled fructose tolerance test was formerly useful for diagnosis, particularly in adults; however, preparations of fructose suitable for intravenous use are now difficult to obtain and direct diagnosis by molecular analysis of the aldolase B gene is greatly preferred. In any event, failure to obtain fructose solutions suitable in small quantities for parenteral use should not encourage the administration of fructose or sucrose orally, since administration by this route may induce catastrophic effects with severe pain, acidosis, and even shock. Casual administration of an oral fructose- or sucrose challenge test ‘meal’ for facile diagnostic reasons carries with it the risk of inducing much distress and alienating the patient (especially a child)—the action is thus to be deplored on these as well as safety grounds. The author is aware of at least one patient who required admission to intensive care after such an episode; full recovery was prolonged for some months and complicated by the development of critical illness polyneuropathy.
If no other method for investigating the patient is available, then the intravenous tolerance test should be carried out under controlled conditions with medical personnel at hand. It requires the infusion of 0.25 g/kg (0.2 g/kg in infants) of d(+)-fructose as a 20% solution over a few minutes; blood samples for potassium ions, magnesium ions, phosphate ions, and glucose are taken before the administration and at regular intervals over a 2-h period. In fructose intolerance, epigastric and loin pain usually accompany the infusion, and hypoglycaemic coma may occur; hypophosphataemia is characteristic. The hypoglycaemia does not respond to glucagon, therefore glucose for parenteral injection must be available. Responses differ between individuals, and hypoglycaemia is usually milder in adults; typical responses in hereditary fructose intolerance and a control subject are shown in Fig. 126.96.36.199. Individuals who are heterozygous carriers of disease-causing mutations in aldolase B show normal responses in this test. The tolerance test should not be carried out in patients with overt signs of liver disease where it may occasionally yield misleading results, particularly in infants and children.
Aldolase B deficiency may be demonstrated definitively by enzymatic analysis of biopsy samples obtained from the liver, small intestinal mucosa or exceptionally, the kidney cortex. Biochemical assay of fructaldolases characteristically demonstrates markedly reduced (<10% of the healthy reference range) or absent fructose 1-phosphate cleavage activity with a partial deficiency of fructose 1,6-diphosphate aldolase. Accuracy in this biochemical diagnosis requires access to the reference range of enzymatic activities in samples of suitable control tissues. Since fructaldolase deficiency may accompany other parenchymal disease of the liver, and because liver biopsy for biochemical analysis is invasive, these assays are of limited value in the acutely ill or jaundiced patient.
Tests for fructose intolerance based on the analysis of DNA are increasingly used for diagnosis so that invasive or hazardous investigations using tissue biopsy procedures or parenteral challenge with sugar solutions can be avoided. Direct genetic diagnosis of hereditary fructose intolerance is now possible and straightforward laboratory protocols have been developed for their systematic clinical application in specialist centres; this is clearly the preferred method of diagnosis—particularly for patients of European ancestry. Molecular analysis of aldolase B genes for the presence of common mutations responsible for the disease can be carried out by specialized laboratories equipped for genetic testing; useful practical protocols for hierarchical mutation screening have been reported. Failure to identify two of the more frequent mutant alleles in patients with suspected hereditary fructose intolerance should encourage a systematic approach to molecular diagnosis, if necessary to include definitive sequencing of the aldolase B gene.
The ability to identify disease alleles by analysing genomic DNA obtained from very small samples of blood or tissue may not only be beneficial for the investigation of infants with this disorder but also for neonatal testing before dietary exposure occurs. There is a strong case for trials in which the utility of mass population screening for fructose intolerance, a preventable nutritional disease, is investigated.
Dietary treatment of fructose intolerance mitigates the disorder but requires the almost complete exclusion of sucrose, fructose, and sorbitol. The daily consumption of sugar should be reduced to less than 40 mg fructose equivalents per kilogram body weight (i.e. 2–3 g for an adult) in order to reverse the disease manifestations and establish normal development in affected infants and children. The ubiquity of fructose and its congeners in the western diet and in many commercial drinks, pharmaceuticals and health supplements presents serious difficulties. It should be remembered that sucrose in cane- and beet sugar is a disaccharide that is cleaved into fructose and glucose in equimolar quantities; high-fructose corn syrup increasingly used in soft drinks is 55% fructose and 41% glucose (4% other sugars). Adult patients with HFI who have survived infancy and childhood and are in reasonable health have usually restricted their consumption of fructose to less than 20 g daily and the source of the residual sugar may be difficult to establish. For this reason, the advice of an informed dietitian should be sought (Box 188.8.131.52). Particular care needs to be taken with sugar-coated pills and especially with liquid medications for paediatric use, as large amounts of fructose, sucrose, and sorbitol are frequently present. Children and adults with hereditary fructose intolerance may tolerate the taste of confectionery that contains large quantities of noxious sugars but in which the sweetness is masked by other flavours, such as peppermint, which they enjoy. This behaviour may lead to unexplained hypoglycaemic symptoms and other signs of sugar toxicity. Occasionally, patients are unable to tolerate certain foods that are permitted on their diet sheets; in doubtful cases it is advisable to avoid the offending item or to have it analysed. Patients with hereditary fructose intolerance may lack folic acid and vitamin C. Supplements of these vitamins in particular are recommended, especially during pregnancy, but, as with other medicines, care has to be taken to avoid harmful sugars contained in the preparation. Although the use of fructose-containing or sorbitol-containing preparations for intravenous nutritional supplementation has now been stopped, some medicines that are given parenterally are reconstituted in solutions containing harmful quantities of sorbitol or fructose. Hepatorenal failure has recently been reported after the administration of amiodarone in a polysorbate solution to a patient with hereditary fructose intolerance, with dire consequences.
a Further information is provided in the Further reading list.
Untreated hereditary fructose intolerance is a potentially fatal disease in infants and young children in whom it generally causes irreversible liver disease, renal injury and episodic, life-threatening hypoglycaemia. Occasionally, adolescents and adult patients may succumb to the inadvertent use of parenteral fructose or sorbitol, but this practice, which until the 1990s was popular in Germany and German-speaking countries, is now obsolete. Provided that there has not been irreversible hepatic disease or renal injury, with the introduction of a strict exclusion diet, the disorder is otherwise compatible with a normal quality and duration of life. The first patient to be described with this condition by Chambers and Pratt in 1956, and in whom homozygosity for the widespread A149P mutation in aldolase B has since been confirmed in the author’s laboratory, remains well and is now over eighty years old; at least one centenarian with the disorder has been reported.
Fructose diphosphatase deficiency (OMIM 229700)
This very rare, recessively inherited disorder presents with hypoglycaemia, ketosis, and lactic acidosis in early infancy. Fewer than 100 cases have been reported since its original description in 1970. Severe, sometimes fatal, acidosis is associated with infection and starvation, and most cases present within the first few days of life or in the neonatal period. Onset during the first year of life is the rule.
In newborn infants, the severe metabolic disturbance shows itself by acidotic hyperventilation, which may be accompanied by irritability, disturbed consciousness, seizures, or coma. The unusual combination of ketonaemia, lacticacidaemia, and hypoglycaemia is induced by fasting, the administration of fructose, sorbitol, and glycerol, and by ingestion of a diet rich in fat. Episodes in the neonatal period respond well to infusions of glucose and bicarbonate but, after an interval, further attacks occur, often provoked by intercurrent infection. Lethargy accompanied by hyperventilation is followed abruptly by prostration, coma, and seizures. Investigations reveal hypoglycaemia, ketosis, and profound lactic acidosis; there is also hyperuricaemia, aminoaciduria, and ketonuria. If the infant survives, hepatomegaly due to fatty infiltration may be detected but overt clinical disturbances of hepatic or renal tubular function are not seen. The untreated disease is associated with growth retardation.
The first infant to be affected by fructose diphosphatase deficiency in a given family may succumb before the diagnosis is established and in any case fares worse than siblings for whom the appropriate diet and prompt control of the condition are instituted. The response to treatment is favourable, however, and fructose diphosphatase deficiency is ultimately compatible with a benign course and with normal growth and development.
Deficiency of fructose-1,6-diphosphatase causes failure of gluconeogenesis in the liver, although the abnormality may be detected in intestinal mucosa, kidney, and in cultured mononuclear cells from peripheral blood. The muscle isozyme of fructose-1,6-diphosphatase is not affected.
Between meals, blood glucose is maintained by glycogenolysis and hence the onset of disturbed metabolism in fructose diphosphatase deficiency depends on the availability of hepatic glycogen. Since febrile illnesses accelerate the consumption of liver glycogen, the accompanying anorexia with or without vomiting may deplete glycogen stores critically. Acidosis results from the accumulation of gluconeogenic precursors including lactate, pyruvate, and alanine as well as ketone bodies, which cannot be utilized. Hypoglycaemia that is unresponsive to glucagon and associated with exhaustion of glycogen stores occurs; it does not respond to normal gluconeogenic substrates (e.g. glycerol, amino acid solutions, dihydroxyacetone, sorbitol, or fructose); indeed administration of these aggravates the metabolic disturbance.
The pathogenesis of hypoglycaemia and accompanying disturbances in fructose diphosphatase deficiency is complex and not completely explained by exhaustion of hepatic glycogen stores. Well-fed patients have a normal response to glucagon but are intolerant of high-fat diets, as well as fructose, sorbitol, alanine, glycerol, and dihydroxyacetone administration. Challenge with these nutrients induces hypoglycaemia, hyperuricaemia, and hypophosphataemia, accompanied by an exaggerated rise in blood lactate levels. The hypoglycaemia is then unresponsive to glucagon, indicating a secondary inhibition of phosphorylase activity in the liver, which results from the build-up of phosphorylated sugar intermediates that cannot be further metabolized in the context of reduced intracellular free inorganic phosphate. Adenosine deaminase is activated primarily because of reduced phosphate concentrations, so that purine nucleotides are broken down to uric acid. Failure to utilize glucogenic amino acids and metabolites such as dihydroxyacetone and glycerol appears to stimulate triglyceride formation in the liver, which induces steatosis. Unlike hereditary fructose intolerance (see above), high concentrations of hepatic fructose 1-phosphate do not occur, and profound disturbances of blood coagulation or hepatic or renal tubule function with progressive structural damage are absent in fructose diphosphatase deficiency. Similarly, aversion to foods that aggravate the disorder does not develop in affected infants and children; this may be explained by the absence of pain and abdominal symptoms in the condition.
The importance of establishing the diagnosis of fructose diphosphatase deficiency cannot be overemphasized. Proper dietary control and protocols for the institution of appropriate therapy depend on recognizing the complex disturbance that underlies this disease.
Fructose diphosphatase deficiency should be considered in otherwise normal infants who develop unexplained severe lactic acidosis or hypoglycaemia associated with episodes, often trivial, of infection. The combination of ketosis and lactic acidosis with hypoglycaemia is highly suggestive of a disorder affecting the gluconeogenic pathway, including deficiency of glucose 6-phosphatase, pyruvate carboxylase, pyruvate dehydrogenase, and phosphoenolpyruvate carboxykinase. The absence of abdominal distress, haemolysis, jaundice, coagulopathy, and disturbances of the proximal renal tubule differentiates the condition from hereditary fructose intolerance, tyrosinosis, and Wilson’s disease. Confusion may arise with disorders associated with secondary defects in gluconeogenesis, especially the Reye’s-like syndrome caused by deficiencies of long-chain, medium-chain, and short-chain acyl coenzyme A dehydrogenase activities, as well as defects of carnitine metabolism. Organic acidaemias are also readily distinguished by biochemical screening methods. In acutely unwell patients with fructose diphosphatase deficiency, there is often an increased anion gap and this is accompanied by excess urinary excretion of glycerol which may be detected on analysis for organic acids; a recent report in several such patients of the presence of transient pseudo-hypertriglyceridemia due to excess glycerol in serum during the episode of metabolic decompensation—this may provide a further clue to the diagnosis.
Provocative tests using food deprivation and the administration of infusions of fructose, sorbitol, or glycerol should be avoided in the acutely ill infant or child with suspected deficiency of fructose-1,6-diphosphatase (or fructose intolerance). The definitive diagnosis depends on the demonstration of selectively decreased fructose diphosphatase activity in tissue samples. Most frequently, the enzymatic defect will be identified by biochemical assay of a freshly obtained liver biopsy specimen, which allows other metabolic disorders and gluconeogenic defects to be confidently excluded. The defect may also be demonstrated in biopsy samples of jejunal mucosa and in cultured monocyte-derived macrophages obtained from peripheral blood. However, the presence of fructose-1,6-diphosphatase in these tissues is metabolically inconsequential and, although useful for confirmation of the diagnosis where it is strongly suspected, in practice decisive identification of this disorder normally depends on a systematic biochemical analysis of liver tissue in an experienced laboratory. The human fructose-1,6-diphosphatase (FBP1) gene maps to chromosome 9q22.2–q22.3, and inactivating mutations have been identified in the disease. Unlike fructose intolerance, however, these mutations tend to be private and thus individually of less diagnostic significance for routine laboratory use in this disorder since mutational heterogeneity appears to be the rule. However, a minor exception to this occurs in the Japanese population, where one mutation (960–961 ins G) appears to account for almost one-half of mutant FBPI alleles.
Dietary control and avoidance of starvation with rapid relief of febrile illnesses are the mainstays of management. Minor infections and injuries require prompt attention, and intravenous glucose therapy should be instituted early in acute episodes to avoid hypoglycaemia and acidosis. Fasting should be avoided as far as possible, while night-time feeding may be needed in infants during recovery from injuries or infections, and after strenuous exercise in older children. The habit of taking meals at regular 4-h intervals is best inculcated when the patient is young. The diet should exclude excess fat; sorbitol, sucrose, and fructose must be strictly avoided. Breast milk is rich in lactose, which is readily assimilated, but difficulties arise on transfer to artificial feeds during weaning. In addition, medications and syrups containing fructose, sucrose, or sorbitol present a special danger to patients with fructose diphosphatase deficiency. A diet excluding these sugars but containing 56% calories as carbohydrate, with 32% calories as fat and 12% as protein, has produced normal growth and development. Acute episodes of acidosis or hypoglycaemia are controlled rapidly by intravenous administration of glucose with or without bicarbonate as required.
Afroze B, et al. (2013). Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency. European Journal of Pediatrics, Jul 24 [Epub ahead of print].Find this resource:
Ali M, Rosien U, Cox TM (1993). DNA diagnosis of fatal fructose intolerance from archival tissue. QJM, 86, 25–30.Find this resource:
Ali M, Cox TM (1995). Diverse mutations in the aldolase B gene that underlie the prevalence of hereditary fructose intolerance. Independent segregation of four mutant alleles in ten affected members of a large kindred. Am J Hum Genet, 56, 1002–5.Find this resource:
Ali M, Rellos P, Cox TM (1998). Hereditary fructose intolerance. J Med Genet, 35, 353–65.Find this resource:
Baker L, Wingrad AI (1970). Fasting hypoglycaemia and metabolic acidosis associated with deficiency of fructose-1,6-diphosphatase deficiency. Lancet, ii, 13–16.Find this resource:
Bell L, Sherwood WG (1987). Current practices and improved recommendations for treating hereditary fructose intolerance. J Am Diet Assoc, 87, 721–8.Find this resource:
Boesinger P, et al. (1994). Changes of liver metabolite concentrations in adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic resonance spectroscopy. Pediatr Res, 36, 436–40.Find this resource:
Chambers RA, Pratt RTC (1956). Idiosyncrasy to fructose. Lancet, ii, 340.Find this resource:
Coffee EM, Tolan DR (2010). Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. Journal of Inherited Metabolic Disease, 33, 715–25.Find this resource:
Cox TM (1993). Iatrogenic deaths in hereditary fructose intolerance. Arch Dis Child, 69, 413–15.Find this resource:
Cox TM (1994). Aldolase B and fructose intolerance. FASEB J, 8, 62–71.Find this resource:
Cox TM (2002). The genetic consequences of our sweet tooth. Nat Rev Genet, 3, 481–7.Find this resource:
Cox TM (2009). Hereditary fructose intolerance (fructosaemia). In: Lifton R, et al. (eds) Genetic diseases of the kidney, pp. 619–43. Elsevier, New York.Find this resource:
Cross NCP, et al. (1988). Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell, 53, 881–5.Find this resource:
Curran BJ, Havill JH (2002). Hepatic and renal failure associated with amiodarone infusion in a patient with hereditary fructose intolerance. Crit Care Resusc, 4, 112–15.Find this resource:
Douillard C, et al. (2012). Hypoglycaemia related to inherited metabolic diseases in adults. Orphanet J Rare Dis, 7, 26.Find this resource:
Gibson PR, et al. (2007). Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther, 25, 349–63.Find this resource:
Greenwood J (1989). Sugar content of liquid prescription medicines. Pharm J, 243, 553–7.Find this resource:
James CJ, et al. (1996). Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population. J Med Genet, 33, 837–41.Find this resource:
Kikawa Y, et al. (2002). Diagnosis of fructose 1,6-bisphosphatase deficiency using cultured lymphocyte fraction: a secure and noninvasive alternative to liver biopsy. J Inherit Metab Dis, 25, 41–6.Find this resource:
Kriegshäuser G, et al. (2007). Semi-automated, reverse-hybridization detection of multiple mutations causing hereditary fructose intolerance. Mol Cell Probes, 21, 226–8.Find this resource:
Krishnamurthy V, et al. (2007). Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis, 30, 819.Find this resource:
Michelakakis H, et al. (2009). Plasma lysosomal enzyme activities in congenital disorders of glycosylation, galactosemia and fructosemia. Clinica Chimica Acta, 401, 81–3.Find this resource:
Mock DM, et al. (1983). Chronic fructose intoxication after infancy in children with hereditary fructose intolerance: a cause of growth retardation. N Engl J Med, 309, 764–70.Find this resource:
Odièvre M, et al. (1978). Hereditary fructose intolerance in childhood. Diagnosis, management and course in 55 patients. Am J Dis Child, 132, 605–8.Find this resource:
Pagliara AS, et al. (1972). Hepatic fructose-1,6-diphosphatase deficiency. A cause of lactic acidosis and hypoglycaemia in infancy. J Clin Invest, 51, 2115–23.Find this resource:
Pronicka E, et al. (2007). Elevated carbohydrate-deficient transferrin (CDT) and its normalization on dietary treatment as a useful biochemical test for hereditary fructose intolerance and galactosemia. Pediatr Res, 62, 101–5.Find this resource:
Reimers A, Spigset O (2003). Declaration of fructose and fructose-related adverse effects in commercial drug preparations in European countries. Drug Saf, 26, 1057–9.Find this resource:
Sachs B, Sternfeld L, Kraus G (1942). Essential fructosuria: its pathophysiology. Am J Dis Child, 63, 252.Find this resource:
Santer R, et al. (2005). The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat, 25, 594.Find this resource:
Steinmann B, Gitzelmann R, Van den Berghe G (2001). Disorders of fructose metabolism. In: Scriver CR, et al. (eds) The metabolic and molecular bases of inherited disease, 8th edition, vol. II, pp. 1489–520. McGraw-Hill, New York, www.ommbid.com [updated January 2008].Find this resource:
Thabet F, et al. (2002). Severe Reye syndrome: report of 14 cases managed in a pediatric intensive care unit over 11 years. Arch Pediatr, 9, 581–6.Find this resource:
Wasserman D, et al. (1996). Molecular analysis of the fructose transporter gene (GLUT5) in isolated fructose malabsorption. J Clin Invest, 98, 2398–402.Find this resource: