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Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption., (© 2024. The Author(s).)

Context: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates., Objective: To translate these experimental findings to the human situation., Design: Case-control study., Setting: Outpatient clinic for inborn errors of metabolism., Patients or Other Participants: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15)., Main Outcome Measure: IHTG content, assessed by proton magnetic resonance spectroscopy., Results: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009)., Conclusions: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis., (Copyright © 2019 Endocrine Society.)

Objective: To study fructose malabsorption in children and adolescents with abdominal pain associated with functional gastrointestinal disorders. As an additional objective, the association between intestinal fructose malabsorption and food intake, including the estimated fructose consumption, weight, height, and lactulose fermentability were also studied., Methods: The study included 31 patients with abdominal pain (11 with functional dyspepsia, 10 with irritable bowel syndrome, and 10 with functional abdominal pain). The hydrogen breath test was used to investigate fructose malabsorption and lactulose fermentation in the intestinal lumen. Food consumption was assessed by food registry. Weight and height were measured., Results: Fructose malabsorption was characterized in 21 (67.7%) patients (nine with irritable bowel syndrome, seven with functional abdominal pain, and five with functional dyspepsia). Intolerance after fructose administration was observed in six (28.6%) of the 21 patients with fructose malabsorption. Fructose malabsorption was associated with higher (p<0.05) hydrogen production after lactulose ingestion, higher (p<0.05) energy and carbohydrate consumption, and higher (p<0.05) body mass index z-score value for age. Median estimates of daily fructose intake by patients with and without fructose malabsorption were, respectively, 16.1 and 10.5g/day (p=0.087)., Conclusion: Fructose malabsorption is associated with increased lactulose fermentability in the intestinal lumen. Body mass index was higher in patients with fructose malabsorption., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia., Objective: We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population., Design: Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially., Results: Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P < 0.01), but not in control subjects (-1.1%, ns)., Conclusions: Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106.

Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.

Objective: Fructose consumption has been implicated in the development of obesity and insulin resistance. Emerging evidence shows that fibroblast growth factor 21 (FGF21) has beneficial effects on glucose, lipid, and energy metabolism and may also mediate an adaptive response to fructose ingestion. Fructose acutely stimulates circulating FGF21 consistent with a hormonal response. We aimed to evaluate whether fructose-induced FGF21 secretion is linked to metabolic outcomes in obese humans before and after bariatric surgery-induced weight loss., Methods: We recruited 40 Roux-en-Y gastric bypass patients and assessed the serum FGF21 response to fructose (75-g fructose tolerance test) and basal and insulin-mediated glucose and lipid fluxes during a 2-step hyperinsulinemic-euglycemic clamp with infusion of [6,6- 2 H 2 ] glucose and [1,1,2,3,3- 2 H 5 ] glycerol. Liver biopsies were obtained during bariatric surgery. Nineteen subjects underwent the same assessments at 1-year follow-up., Results: Serum FGF21 increased 3-fold at 120 min after fructose ingestion and returned to basal levels at 300 min. Neither basal FGF21 nor the fructose-FGF21 response correlated with liver fat content or liver histopathology, but increased levels were associated with elevated endogenous glucose production, increased lipolysis, and peripheral/muscle insulin resistance. At 1-year follow-up, subjects had lost 28 ± 6% of body weight and improved in all metabolic outcomes, but fructose-stimulated FGF21 dynamics did not markedly differ from the pre-surgical state. The association between increased basal and stimulated FGF21 levels with poor metabolic health was no longer present after weight loss., Conclusions: Fructose ingestion in obese humans stimulates FGF21 secretion, and this response is related to systemic metabolism. Further studies are needed to establish if FGF21 signaling is (patho)physiologically involved in fructose metabolism and metabolic health., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Diets low in fermentable sugars (low-FODMAP diets) are increasingly adopted by patients with functional gastrointestinal disorders (FGID), but outcome predictors are unclear., Aim: To identify factors predictive of an efficacious response to a low-FODMAP diet in FGID patients with fructose or lactose intolerance thereby gaining insights into underlying mechanisms., Methods: Fructose and lactose breath tests were performed in FGID patients to determine intolerance (positive symptom score) and malabsorption (increased hydrogen or methane concentrations). Patients with fructose or lactose intolerance consumed a low-FODMAP diet and global adequate symptom relief was assessed after 6-8 weeks and correlated with pre-diet clinical symptoms and breath test results., Results: A total of 81% of 584 patients completing the low-FODMAP diet achieved adequate relief, without significant differences between FGID subgroups or types of intolerance. Univariate analysis yielded predictive factors in fructose intolerance (chronic diarrhoea and pruritus, peak methane concentrations and fullness during breath tests) and lactose intolerance (peak hydrogen and methane concentrations and flatulence during breath tests). Using multivariate analysis, symptom relief was independently and positively predicted in fructose intolerance by chronic diarrhoea [odds ratio (95% confidence intervals): 2.62 (1.31-5.27), P = 0.007] and peak breath methane concentrations [1.53 (1.02-2.29), P = 0.042], and negatively predicted by chronic nausea [0.33 (0.16-0.67), P = 0.002]. No independent predictive factors emerged for lactose intolerance., Conclusions: Adequate global symptom relief was achieved with a low-FODMAP diet in a large majority of functional gastrointestinal disorders patients with fructose or lactose intolerance. Independent predictors of a satisfactory dietary outcome were only seen in fructose intolerant patients, and were indicative of changes in intestinal host or microbiome metabolism., (© 2017 John Wiley & Sons Ltd.)

Although fructose was discovered in 1794, it was realised in recent decades only that its malabsorption can lead to intestinal symptoms while its excessive consumption induces metabolic disturbances. Fructose is a monosaccharide found naturally in most fruits and vegetables. Dietary intake of fructose has gradually increased in the past decades, especially because of the consumption of high fructose corn syrup. With its 16.4 kg/year consumption, Hungary ranks secondly after the United States. Fructose is absorbed in the small intestine by facilitated transport mediated by glucose transporter proteins-2 and -5, and arrives in the liver cells. Here it is transformed enzymatically into fructose-1-phosphate and then, fructose-1,5-diphosphate, which splits further into glyceraldehyde and dihydroxyacetone-phosphate, entering the process of glycolysis, triglyceride and uric acid production. The prevalence of fructose intolerance varies strongly, depending on the method used. The leading symptoms of fructose intolerance are similar, but less severe than those of lactose intolerance. Multiple secondary symptoms can also occur. A symptom-based diagnosis of fructose intolerance is possible, but the gold standard is the H 2 breath test, though this is less accurate than in lactose testing. Measuring fructosaemia is costly, cumbersome and not widely used. Fructose intolerance increases intestinal motility and sensitivity, promotes biofilm formation and contributes to the development of gastrooesophageal reflux. Long-term use of fructose fosters the development of dental caries and non-alcoholic steatohepatitis. Its role in carcinogenesis is presently investigated. The cornerstone of dietary management for fructose intolerance is the individual reduction of fructose intake and the FODMAP diet, led by a trained dietetician. The newly introduced xylose-isomerase is efficient in reducing the symptoms of fructose intolerance. Orv. Hetil., 2016, 157(43), 1708-1716.

Background: Hydrogen breath tests (HBT) are used to confirm the diagnosis of carbohydrate intolerance or small intestinal bacterial overgrowth (SIBO)., Objective: Determine the existence of a correlation between the presence and intensity of symptoms experimented by the patient after the ingestion of a carbohydrate load and the test result., Materials and Methods: This is an observational, retrospective and analytic study, in which all patients' files from year 2008 to 2014 containing a report of a HBT performed at Hospital San José TEC de Monterrey were revised. Using a visual analogue scale (VAS), the patient reported the intensity of gastrointestinal symptoms during the test. Descriptive statistics were obtained, and exclusively for lactose HBTs, Pearson's correlation coefficient (r) between maximum hydrogen concentration in breath and symptom intensity was calculated., Results: A HBT was performed in 33 patients: 23 with lactose, 5 with fructose, and 5 with lactulose as substrate. Of these, 10, 2, and 5 tests were positive, respectively. For lactose HBTs, the symptom with most sensitivity was flatulence (80%), which also had the greatest likelihood ratio for a positive test (1.73). Diarrhea had the greatest specificity (84.6%). A tendency for positivity was observed when patients presented symptoms. A moderately positive correlation between hydrogen ppm and symptom intensity was found (r=0.427, p=0.023)., Conclusions: A correlation between symptom intensity and test positivity was found in patients with lactose intolerance. The presence of flatulence after lactose loading may be indicative of a positive test.

Fructose accumulates in tissue and body fluids of patients affected by hereditary fructose intolerance (HFI), a disorder caused by the deficiency of aldolase B. We investigated the effect of acute fructose administration on the biochemical profile and on the activities of the Krebs cycle enzymes in the cerebral cortex of young rats. Rats received a subcutaneous injection of NaCl (0.9 %; control group) or fructose solution (5 μmol/g; treated group). Twelve or 24 h after the administration, the animals were euthanized and the cerebral cortices were isolated. Peripheral blood (to obtain the serum) and cerebral spinal fluid (CSF) from the animals were also collected. It was observed that albumin levels were decreased and cholesterol levels were increased in CSF of animals 12 h after the administration of fructose. In addition, serum lactate levels were increased 12 h after the administration, as compared to control group. Furthermore, malate dehydrogenase activity was increased in cerebral cortex from treated group 24 h after the administration of this carbohydrate. Herein we demonstrate that fructose administration alters biochemical parameters in CSF and serum and bioenergetics parameters in the cerebral cortex. These findings indicate a possible role of fructose on brain alterations found in HFI patients.

Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 μmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients.

Carbohydrate malabsorption is a frequent clinical condition, often associated with abdominal symptoms. Although lactose represents the most commonly malabsorbed sugar, also other carbohydrates, such as fructose, trehalose and sorbitol may be incorrectly absorbed in the small intestine. Fructose malabsorption seems more common in patients with functional bowel disease, even if randomized and controlled studies on these topic were few and on small samples. Interpretation of breath hydrogen testing is difficult. In particular, neither studies comparing this test with a gold standard, nor validated doses and concentrations to be used, are available. Trehalose malabsorption due to trehalase deficiency represents a very rare condition and available studies do not support its relevance in clinical practice. Sorbitol absorption is dose and concentration related, and depends on the entity of intestinal absorption surface. Nevertheless, the finding of its malabsorption is not expression of a specific cause of intestinal bowel damage. From available data, it is not possible to draw definite conclusions about clinical relevance of fructose, trehalose and sorbitol malabsorption, as well as, about diagnostic accuracy of commonly used tests to detect all these conditions. On the other hand, in patients who refer abdominal discomfort after ingestion of different carbohydrate-containing foods, a small intestinal bacterial overgrowth, should be promptly considered. This is because the large amount of intestinal bacteria may unspecifically ferment sugars, causing an abnormal H2 production and consequently a misleading diagnosis of sugar malabsorption.

Background: Incomplete resorption of fructose results in increased colonic hydrogen production and is a frequent cause of abdominal symptoms. The only treatment available is diet., Aim: To study whether orally administered xylose isomerase (XI), an enzyme that catalyses the reversible isomerisation of glucose and fructose, can decrease breath hydrogen excretion in patients with fructose malabsorption., Methods: Patients received 25 g fructose in 100 mL water together with either placebo or XI capsules. Primary endpoint was the reduction in breath hydrogen excretion, as assessed by the area under the breath hydrogen curve over 4 h (AUC). A secondary endpoint was the reduction in abdominal pain, bloating and nausea assessed on a visual analogue scale (VAS, range: 0-10). A P value <0.05 was considered statistically significant., Results: Sixty-five patients in whom fructose malabsorption had been diagnosed by positive breath hydrogen test within the previous year, were included in the study [15 males, 50 females; mean age 43.3 (s.d. = 14.4), range: 21-73 years]. The median AUC was 885 ppm/240 min in the XI group compared to 2071 ppm/240 min in the placebo group (P = 0.00). Median scores for abdominal pain (0.7 vs. 1.3) and nausea (0.2 vs. 0.6), but not for bloating (P = 0.053), were significantly improved after XI (P = 0.009 and P = 0.005) as compared with placebo., Conclusions: Oral administration of xylose isomerase significantly decreased breath hydrogen excretion after ingestion of a watery fructose solution. Nausea and abdominal pain were significantly improved by xylose isomerase., (© 2012 Blackwell Publishing Ltd.)

Objective: African Americans commonly have lower liver fat accumulation than Hispanics, despite a similar propensity for obesity. Both ethnicities exhibit high consumption of fructose-containing beverages, which has been associated with high liver fat owing to the lipogenic properties of fructose. Therefore, differences in fructose absorption may be an important factor in regulating liver fat deposition. We hypothesized that fructose malabsorption in African Americans may reduce hepatic delivery of fructose, thus contributing to lower liver fat deposition compared to Hispanics., Methods: Thirty-seven obese young adults aged 21.4 ± 2.1 years (16 African American, 21 Hispanic) underwent a 3-hour hydrogen (H2) breath test to assess fructose malabsorption. Magnetic resonance imaging was used to determine visceral and subcutaneous adipose tissue volume and liver fat. Fructose malabsorption was expressed as an area under the curve for H2 production (H2 AUC)., Results: Compared to Hispanics, African Americans had lower liver fat (5.4% ± 5.0% vs 8.9% ± 2.3%, p = 0.02) and a higher prevalence of fructose malabsorption (75.0% vs 42.9%; p = 0.05). Liver fat was negatively related to the extent of fructose malabsorption in African Americans (r = -0.53, p = 0.03), and this relationship was independent of the volumes of total fat and subcutaneous and visceral adipose tissue. There were no significant relationships between liver fat and fructose malabsorption in Hispanics., Conclusion: African Americans have both a higher prevalence and a greater magnitude of fructose malabsorption than Hispanics. In African Americans, fructose malabsorption was negatively correlated with liver fat, which may be protective against fatty liver disease.

Concern exists that increasing fructose consumption, particularly in the form of high-fructose corn syrup, is resulting in increasing rates of fructose intolerance and aggravation of clinical symptoms in individuals with irritable bowel syndrome. Most clinical trials designed to test this hypothesis have used pure fructose, a form not commonly found in the food supply, often in quantities and concentrations that exceed typical fructose intake levels. In addition, the amount of fructose provided in tests for malabsorption, which is thought to be a key cause of intolerance, often exceeds the normal physiological absorption capacity for this sugar. To help health professionals accurately identify and treat this condition, this article reviews clinical data related to understanding fructose malabsorption and intolerance (i.e., malabsorption that manifests with symptoms) relative to usual fructose and other carbohydrate intake. Because simultaneous consumption of glucose attenuates fructose malabsorption, information on the fructose and glucose content of foods, beverages, and ingredients representing a variety of food categories is provided.

Hereditary fructose intolerance is a rare, but potentially lethal, inherited disorder of fructose metabolism, caused by mutation of the aldolase B gene. Treatment currently relies solely on dietary restriction of problematic sugars. Biochemical study of defective aldolase B enzymes is key to revealing the molecular basis of the disease and providing a stronger basis for improved treatment and diagnosis. Such studies have revealed changes in enzyme activity, stability and oligomerisation. However, linking these changes to disease phenotypes has not always been straightforward. This review gives a general overview of the features of hereditary fructose intolerance, then concentrates on the biochemistry of the AP variant (Ala149Pro variant of aldolase B) and molecular pathological consequences of mutation of the aldolase B gene.

Adamowicz and colleagues raised the alert in 2007 about patients with atypical hereditary fructose intolerance (HFI) primarily misdiagnosed as CDG Ix. We describe a girl with neonatal hypertonia, facial trismus, absent swallowing and coughing reflexes, gastro-oesophageal reflux and sporadically elevated Krebs cycle metabolites and lactate. At 14 months microcephaly and hepatomegaly were noted, with hypertransaminasaemia but normal blood coagulation, glucose, phosphate, and absent urinary reducing substances. Neurological impairment persisted. Because of hepatic and neurological abnormalities with developmental delay, Tf IEF was performed and showed a severe type 1 pattern, resulting in a wrong diagnosis of CDG. Subsequently, an aversion to fruits suggested HFI, confirmed by the finding of ALDOB mutations (p.A150P/p.N335K). The girl improved with fructose-free diet, but liver cirrhosis led to hepatic transplantation. She is now 7 years old with good evolution; facial trismus and hypertonia reversed, but microcephaly persists. Transferrin MALDI-TOF MS characterization revealed underoccupation of glycosylation sites and glycan abnormalities, which reversed with dietary treatment. High maternal fructose concentrations might have caused neonatal abnormalities. Although in our patient's mother there is no fructose accumulation at present, it is possible that increased ingestion of fruits and vegetables during pregnancy, together with her heterozygosity, caused an accumulation of fructose that finally affected the fetus. We also describe slightly abnormal transferrin isoelectric focusing and MALDI-TOF MS patterns of intact transferrin and N-glycans in a fructose-1,6-bisphosphatase (FBP1)-deficient patient. While HFI is a well-known cause of secondary CDG, we found no reports of abnormal transferrin isoelectric focusing patterns in FBP1 deficiency and we introduce this condition as a possible secondary cause for altered transferrin isoelectric focusing.

Important dietary carbohydrates such as fructose and sorbitol are incompletely absorbed in the normal small intestine. This malabsorption is sometimes associated with abdominal complaints and diarrhea development, symptoms indistinguishable from those of functional bowel disease. Recently, polymerized forms of fructose (fructans) also were implicated in symptom production in patients with irritable bowel syndrome (IBS). Evidence from uncontrolled and controlled challenge studies suggests that malabsorbed sugars (fructose, sorbitol, lactose) and fructans may act as dietary triggers for clinical symptoms suggestive of IBS. Further placebo-controlled studies are needed to obtain definite conclusions about the role of dietary sugar malabsorption in functional bowel disease.

Introduction: Whether dietary fructose intolerance causes symptoms of irritable bowel syndrome (IBS) is unclear. We examined the prevalence of fructose intolerance in IBS and long-term outcome of fructose-restricted diet., Methods: Two hundred and nine patients with suspected IBS were retrospectively evaluated for organic illnesses. Patients with IBS (Rome II) and positive fructose breath test received instructions regarding fructose-restricted diet. One year later, their symptoms, compliance with, and effects of dietary modification on lifestyle were assessed using a structured interview., Results: Eighty patients (m/f=26/54) fulfilled Rome II criteria. Of 80 patients, 31 (38%) had positive breath test. Of 31 patients, 26 (84%) participated in follow-up (mean=13 mo) evaluation. Of 26 patients, 14 (53%) were compliant with diet; mean compliance=71%. In this group, pain, belching, bloating, fullness, indigestion, and diarrhea improved (P<0.02). Of 26 patients, 12 (46%) were noncompliant, and their symptoms were unchanged, except belching. The mean impact on lifestyle, compliant versus noncompliant groups was 2.93 versus 2.57 (P>0.05)., Conclusions: About one-third of patients with suspected IBS had fructose intolerance. When compliant, symptoms improved on fructose-restricted diet despite moderate impact on lifestyle; noncompliance was associated with persistent symptoms. Fructose intolerance is another jigsaw piece of the IBS puzzle that may respond to dietary modification.

Fructose malabsorption is linked to gastrointestinal and other unusual symptoms. Polymers of fructose are also recognized prebiotics. While some prebiotics can self-adapt when consumed regularly (resulting in decreased breath hydrogen and symptoms), we wondered whether self-adaptation occurs with basic fructose. We evaluated 90 subjects (61 females). Each completed a diet questionnaire and underwent a fructose challenge. Breath hydrogen and quantified symptom scores were recorded. Group comparisons for sum of breath hydrogen and total symptom scores were evaluated with the Mann-Whitney U test. Spearman's correlation coefficient and chi(2) or Fisher's exact test were used as appropriate. Malabsorption occurred in 29 patients (32.2%) and low-grade symptoms without malabsorption in 30 (33%). Women complained of symptoms more frequently (p = 0.04) and exhibited more fructose malabsorption (p = 0.0527). Breath hydrogen correlated with symptoms (r = 0.516, p = 0.0037). Adaptation with increasing pretest fructose intake was absent. We conclude that gender may influence fructose malabsorption and there is no adaptation to regular consumption.

Abnormalities in protein glycosylation are reported in fructosemia (HFI) and galactosemia, although, particularly in HFI, the published data are limited to single cases. The purpose was to investigate the usefulness of the carbohydrate-deficient transferrin (CDT) profile for identification and monitoring of these disorders. First we analyzed CDT values before and shortly after the diagnosis in 10 cases of HFI and 17 cases of galactosemia. In all patients, elevated CDT levels were found that significantly (p < 0.0001) decreased with the therapeutic diet (27.3 +/- 11.5% versus 9.3 +/- 5.1% for HFI and 43.8 +/- 14.1% versus 11.2 +/- 4.0% for galactosemia). To evaluate the use of CDT test in monitoring compliance, the test was performed in 25 HFI patients on fructose-restricted diet. We found an elevated CDT level on 104 from 134 tests (mean 11.3 +/- 5.5%, control 1.5%-6.2%). The fructose intake was found to be 90 +/- 70 mg/kg/d, and the diet was unbalanced. A number of patients presented lower height, elevated urinary uric acid excretion, and hypercalciuria. In conclusion, abnormal percentage of CDT (%CDT) values may allow prompt detection of HFI (or galactosemia). Persistence of some abnormalities in HFI on treatment may be caused by trace amounts of fructose ingestion and/or a deficient diet. Regular %CDT measurements are suggested for HFI treatment monitoring.

Infusions of boronophenylalanine-fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

Thirteen Turkish patients with hereditary fructose intolerance (HFI) were screened for the three common mutations, A149P, A174D and N334K, in the aldolase B gene that have been detected frequently in European population. We found that nine of the patients carry the A149P mutation in both alleles, which corresponds to a frequency of about 55%. Single-strand conformation analysis of all coding exons of the gene was also performed to detect unknown mutations in four patients not carrying the three common mutations. No aberrant migration patterns were observed in these patients.

Background: Carbohydrate malabsorption of lactose, fructose and sorbitol has already been described in normal volunteers and in patients with functional bowel complaints including irritable bowel syndrome. Elimination of the offending sugar(s) should result in clinical improvement., Objective: To examine the importance of carbohydrate malabsorption in outpatients previously diagnosed as having functional bowel disorders, and to estimate the degree of clinical improvement following dietary restriction of the malabsorbed sugar(s)., Methods: A cohort of 239 patients defined as functional bowel complaints was divided into a group of 94 patients who met the Rome criteria for irritable bowel syndrome and a second group of 145 patients who did not fulfill these criteria and were defined as functional complaints. Lactose (18 g), fructose (25 g) and a mixture of fructose (25 g) plus sorbitol (5 g) solutions were administered at weekly intervals. End-expiratory hydrogen and methane breath samples were collected at 30 minute intervals for 4 hours. Incomplete absorption was defined as an increment in breath hydrogen of at least 20 ppm, or its equivalent in methane of at least 5 ppm. All patients received a diet without the offending sugar(s) for one month., Results: Only 7% of patients with IBS and 8% of patients with FC absorbed all three sugars normally. The frequency of isolated lactose malabsorption was 16% and 12% respectively. The association of lactose and fructose-sorbitol malabsorption occurred in 61% of both patient groups. The frequency of sugar malabsorption among patients in both groups was 78% for lactose malabsorption (IBS 82%, FC 75%), 44% for fructose malabsorption and 73% for fructose-sorbitol malabsorption (IBS 70%, FC 75%). A marked improvement occurred in 56% of IBS and 60% of FC patients following dietary restriction. The number of symptoms decreased significantly in both groups (P < 0.01) and correlated with the improvement index (IBS P < 0.05, FC P < 0.025)., Conclusions: Combined sugar malabsorption patterns are common in functional bowel disorders and may contribute to symptomatology in most patients. Dietary restriction of the offending sugar(s) should be implemented before the institution of drug therapy.

A molecular analysis of human aldolase B genes in two newborn infants and a 4-year-old child with hereditary fructose intolerance, the offspring of a consanguineous union, has identified the novel mutation Ala337-->Val in homozygous form. This mutation was also detected independently in two other affected individuals who were compound heterozygotes for the prevalent aldolase B allele, Ala149-->Pro, indicating that the mutation causes aldolase B deficiency. To test for the effect of the mutation, catalytically active wild-type human aldolase B and the Val337 variant enzyme were expressed in Escherichia coli. The specific activities of the wild-type recombinant enzyme were 4.8 units/mg and 4.5 units/mg towards fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F-1-P) as substrates with Michaelis constants of 4 microM and 2.4 mM respectively. The specific activities of purified tetrameric Val337 aldolase B, which affects an invariant residue in the C-terminal region, were 4.2 units/mg and 2.6 units/mg towards FBP and F-1-P as substrates respectively; the corresponding Michaelis constants were 22 microM and 24 mM. The FBP-to-F-1-P substrate activity ratios were 0.98 and 1.63 for wild-type and Val337 variant enzymes respectively. The Val337 mutant aldolase had an increased susceptibility to proteolytic cleavage in E. coli and rapidly lost activity on storage. Comparative CD determinations showed that the Val337 protein had a distinct thermal denaturation profile with markedly decreased enthalpy, indicating that the mutant protein is partly unfolded. The undegraded mutant had preferentially decreased affinity and activity towards its specific F-1-P substrate and maintained appreciable activity towards FBP. In contrast, fluorescence studies of the mutant showed an increased binding affinity for products of the aldolase reaction, indicating a role for the C-terminus in mediating product release. These findings in a rare but widespread naturally occurring mutant implicate the C-terminus in the activity of human aldolase B towards its specific substrates and demonstrate its role in maintaining the overall stability of the enzyme tetramer.

Hereditary fructose intolerance (HFI) is a rare autosomal recessive, metabolic disorder, that results from a deficiency of aldolase B (fructose-biphosphate aldolase) in the liver, kidney and intestine. Recent molecular studies have identified the mutation A149P in most European patients. We describe the first case of HFI with molecular analysis in a Portuguese child, presenting the same mutation of the aldolase B gene. The role of molecular studies in the diagnosis of HFI risk patients and their families is emphasized.

Hereditary fructose intolerance (HFI, OMIM 22960), caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase, EC 4.1.2.13), is a recessively inherited condition in which affected homozygotes develop hypoglycaemic and severe abdominal symptoms after taking foods containing fructose and cognate sugars. Continued ingestion of noxious sugars leads to hepatic and renal injury and growth retardation; parenteral administration of fructose or sorbitol may be fatal. Direct detection of a few mutations in the human aldolase B gene on chromosome 9q facilitates the genetic diagnosis of HFI in many symptomatic patients. The severity of the disease phenotype appears to be independent of the nature of the aldolase B gene mutations so far identified. It appears that hitherto there has been little, if any, selection against mutant aldolase B alleles in the population: in the UK, approximately 1.3% of neonates harbour one copy of the prevalent A149P disease allele. The ascendance of sugar as a major dietary nutrient, especially in western societies, may account for the increasing recognition of HFI as a nutritional disease and has shown the prevalence of mutant aldolase B genes in the general population. The severity of clinical expression correlates well with the immediate nutritional environment, age, culture, and eating habits of affected subjects. Here we review the biochemical, genetic, and molecular basis of human aldolase B deficiency in HFI, a disorder which responds to dietary therapy and in which the principal manifestations of disease are thus preventable.

Aspects of glucose metabolism have been investigated quantitatively employing stable isotopes for 20 year. Use of non-recycling [6,6-2H2] or [U-13C] glucose labels provides a value for total hepatic glucose production (glycogenolysis plus gluconeogenesis). Quantitation of gluconeogenesis with isotopic tracers has itself recently been revisited employing protocols and analytical options that purport to overcome the isotope exchanges (dilution) experienced at the level of oxaloacetate when the rate of incorporation of label into glucose from infused alanine, lactate or pyruvate is monitored. Labelled glucose has been employed to investigate metabolic disturbances of glycogen storage disease type I (GSD-I) and type III (GSD-III). Endogenous glucose production and glucose recycling have been studied in both these storage diseases employing a primed-continuous infusion of D-[U-13C] glucose and quantitation of isotope enrichments and isotopomer distribution observed in plasma glucose either by mass spectrometry or nuclear magnetic resonance spectroscopy. General aspects of glucose metabolism as investigated with stable isotopes are presented.

Isoelectrofocusing of serum sialotransferrins from patients with untreated hereditary fructose intolerance (HFI) shows a cathodal shift similar to that in carbohydrate-deficient glycoprotein (CDG) syndrome type I and in untreated galactosemia. This report is on serum lysosomal enzyme abnormalities in untreated HFI that are identical to those found in CDG syndrome type I but different from those in untreated galactosemia. CDG syndrome type I is due to phosphomannomutase deficiency, a defect in the early glycosylation pathway. It was found that fructose 1-phosphate is a potent competitive inhibitor (Ki congruent to 40 microM) of phosphomannose isomerase (EC 5.3.1.8), the first enzyme of the N-glycosylation pathway thus explaining the N-glycosylation disturbances in HFI.

Hereditary fructose intolerance is a human autosomal recessive disease caused by a deficiency of aldolase B that results in an inability to metabolize fructose and related sugars. Molecular analyses have shown that most defects are caused by point mutations in critical regions of the aldolase B gene. We have performed PCR-based DNA analysis of members of two Norwegian families with hereditary fructose intolerance. The affected individuals from both families contained a point mutation (A149P) in exon 5 of the aldolase B gene. Molecular diagnosis of fructose intolerance is rapid and specific, and causes no inconvenience to the patient. It should be preferred to conventional fructose intolerance tests and visceral biopsy analyses.

A novel 31P magnetic resonance spectroscopy procedure allows the estimation of absolute concentrations of certain phosphorus-containing compounds in liver. We have validated this approach by measuring ATP, phosphomonesters, and inorganic phosphate (Pi) during fasting and after an i.v. fructose bolus in healthy adults and in three adults with disorders of fructose metabolism and by comparing results with known metabolic concentrations measured chemically. During fasting, the ATP concentration averaged 2.7 +/- 0.3 (SD, n = 9) mmol/L, which, after due correction for other nucleoside triphosphates, was 2.1 mmol/L and corresponded well with known concentrations. Fructose-1-phosphate (F-1-P) could not be measured during fasting; its concentration after fructose was calculated from the difference of the phosphomonester signals before (2.9 +/- 0.2 mmol/L) and after fructose. Pi was 1.4 +/- 0.3 mmol/L and represented the one fourth of Pi visible in magnetic resonance spectra. In the three healthy controls after fructose (200 mg/kg, 20% solution, 2.5 min), the fructokinase-mediated increase of F-1-P was rapid, reaching 4.9 mmol/L within 3 min, whereas the uncorrected ATP decreased from 2.7 to 1.8 mmol/L and the Pi from 1.4 to 0.3 mmol/L. The subsequent decrease of F-1-P, mediated by fructaldolase, was accompanied by an overshooting rise of Pi to 2.7 mmol/L. In the patient with essential fructosuria, the concentrations of F-1-P, ATP, and Pi remained unchanged, confirming that fructokinase was indeed inactive. In the patient with hereditary fructose intolerance, initial metabolic changes were the same as in the controls, but baseline concentrations were not yet reestablished after 7 h, indicating weak fructaldolase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

A patient is described who presented with the signs and symptoms of hereditary fructose intolerance a few hours after her first fructose challenge. The diagnosis was confirmed by the demonstration of reduced activity of hepatic aldolase B towards fructose-1-phosphate. A second liver biopsy 10 months later had normal aldolase B activity towards fructose-1-phosphate and a fructose tolerance test was also normal. A possible explanation for these findings is proposed.

A patient with isolated fructose malabsorption presented with diarrhoea and colic during the first year of life and subsequently responded to a fructose free diet. Fructose malabsorption has been implicated in some cases of irritable bowel syndrome in adults and may also be an infrequently recognised cause of gastrointestinal symptoms in children.

Examination of glucose kinetics, pancreatic alpha and beta cell function, plasma lipids, urinary acidification and calcium excretion has been undertaken in a patient with hereditary fructose intolerance. This case was unusual as it was associated with insulin-requiring diabetes, type IV hyperlipemia, hypercalciuria and renal calculi. He also demonstrated the previously described fructose-induced defect of urine acidification. Glucagon and C-peptide assays showed that the pancreatic alpha cells were stimulated by fructose and that the beta cells did not respond to fructose. It is not known whether the latter was due to his diabetes or to the lack of a beta cell response to this sugar. Primed 14C-glucose infusions were used for the first time to study nonsteady state glucose kinetics in man. They showed that, 24 hours after the last insulin injection and under basal conditions, the glucose concentrations increased because glucose production exceeded glucose utilization. However, after the administration of sorbitol the plasma glucose concentration decreased because glucose production decreased. After the administration of sorbitol there was no change in the metabolic clearance of glucose. This reflects the lack of a peripheral insulin effect and is consistent with the lack of any measurable C-peptide. Glucose utilization also decreased, but this decrease was less than the decrease in glucose production. Because the metabolic clearance of glucose remained unchanged, it was concluded that the change in glucose utilization was solely due to the decrease in glucose concentration. The absence of C-peptide in the plasma indicated that changes in glucose turnover were not related to any changes in endogenous plasma insulin. Furthermore, the plasma glucagon concentration increased and, hence, changes in this hormone could not account for the decrease in glucose production. Therefore, it was concluded that the sorbitol-induced decline in glucose production was due to a direct effect on hepatic metabolism.

The effect of fructose on liver metabolism in patients with hereditary fructose intolerance (HFI) and in heterozygotes for HFI was studied by 31P magnetic resonance spectroscopy (31P-MRS). In patients with HFI (n = 5) ingestion of small amounts of fructose was followed by an increase in sugar phosphates and decrease in inorganic phosphate (Pi) in the liver that could be detected by 31P-MRS. 31P-MRS could be used to diagnose fructose intolerance and to monitor the patients' compliance with a fructose-restricted diet. In heterozygotes (n = 8) 50 g fructose given orally led to accumulation of sugar phosphates and depletion of Pi in the liver. Fructose also induced a larger increase in plasma urate in heterozygotes than in control subjects. The effect of fructose on liver Pi and plasma urate was most pronounced in heterozygotes with gout (n = 3). Heterozygosity for HFI may predispose to hyperuricaemia.

The utilization of fructose and glucose by fibroblast cultures obtained from patients with hereditary fructose intolerance (HFI) was studied in comparison with fibroblast controls. The cell growth, the time course of D-glucose or D-fructose uptake and the consumption of fructose were similar for both HFI and control cells. Some results showed significant differences between these two cell types: HFI cells consumed less glucose, produced less lactate and contained less glycogen than control cells. Furthermore, significantly less [U-14C]D-glucose and [U-14C]D-fructose was incorporated into lipids in HFI cells than in control cells. The mechanisms responsible for these differences observed between the two cell types are not known.

The kinetics parameters for D-glucose uptake were studied in human liver cell cultures under strictly defined experimental conditions. Using a wide concentration range (0.005 to 30 mmol/l), the kinetic data obtained suggested strongly that D-glucose in human liver cell cultures can be transported by two separate systems. For the high-affinity system, the apparent Km was 0.645 +/- 0.21 mmol/l and the Vmax, 12.49 +/- 3.74 nmol/mg protein per min. For the low-affinity system, the apparent Km was 6.91 +/- 0.58 mmol/l and the Vmax, 79.90 +/- 5.27 nmol/mg protein per min. At a concentration of 2.1 x 10(-7) mol/l, cytochalasin B preferentially inhibited the high-affinity D-glucose site or transport system. The time course of D-glucose uptake, studied in two cell lines from patients with hereditary fructose intolerance, was significantly higher than for the control lines.