Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease.

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

Nonalcoholic steatohepatitis and hepatic adenomatosis: casual or causal relationship?

Hepatic adenomatosis is a benign disease defined as the presence of multiple adenomas in a normal liver. It is an uncommon condition and there are less than a hundred reported cases in the literature. The etiology is unknown, although it has been associated with the use of oral contraceptives, anabolic steroids, certain storage diseases and some genetic mutations linked to maturity onset diabetes of the young. The coexistence of hepatic adenomatosis and nonalcoholic steatohepatitis has been recently described in two patients suffering from metabolic syndrome. This association is particularly interesting due to the growing prevalence of nonalcoholic fatty liver disease in developed countries and the possibility of a common causal pathway. We report the case of a young woman with fructosemia and hepatic steatosis; multiple hepatic adenomas associated to steatohepatitis lesions were also found during clinical follow-up. The possible implications are discussed.

[Fructose intolerance in patients with irritable bowel syndrome: a case-control study]. / Intolerancia a la fructosa en pacientes con síndrome de intestino irritable; un estudio de casos y controles.

INTRODUCTION: Recently it has been reported that prevalence of fructose intolerance (FI) in patients with functional gastrointestinal disorders range between 38% -75%. OBJECTIVE: To determine the prevalence of FI in subjects diagnosed with irritable bowel syndrome (IBS). METHODS: We studied 25 subjects (17 women, average age 36 years) with IBS (Rome II) and 25 healthy controls (14 women, mean age 37 years) who underwent a breath test after oral loading with fructose (Gastrolyzer ®, Bedfont Scientific Ltd., UK). The load consisted of 25 grams of fructose dissolved in 250 ml of water (10% solution). Breath test analysis of the particles per million (ppm) of hydrogen exhaled were performed every 15 minutes for 3 hours. The fructose breath test was considered positive when concentrations of hydrogen were higher than at 20 ppm or a raising greater than 5 ppm in 3 consecutive samples was detected. RESULTS: According to the Rome II criteria, 10 patients (40%) had IBS-C, 9 (36%) had IBS-D and 6 (24%) had IBS-M. Thirteen (52%) of IBS patients had IF, while only 4 (16%) of control subjects (p = 0.01). Patients with IBS and fructose intolerante tend to suffering from diarrhea predominant IBS (p = 0.053). CONCLUSIONS: Fructose intolerance may be responsible for gastrointestinal symptoms in at least half of IBS patients, especially in the group of patients with IBS-D.

Fructose intolerance in IBS and utility of fructose-restricted diet.

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 may be gender dependent and fails to show compensation by colonic adaptation.

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.

Coincidental malabsorption of lactose, fructose, and sorbitol ingested at low doses is not common in normal adults.

Normal subjects may incompletely absorb either lactose, fructose, or sorbitol and may therefore have abdominal symptoms. The frequency of coincidental malabsorption of these sugars is not known. This is clinically important, since we often ingest them during the same day and malabsorption may cause abdominal symptoms. To shed light on this issue we studied 32 normal subjects. Volunteers drank in random order the following solutions: 20 g lactulose, 50 g sucrose, 50 and 25 g lactose, 50 and 25 g fructose, 20 and 10 g sorbitol. Semiquantitative carbohydrate malabsorption was estimated with lactulose standards. Frequency of 50-g lactose (69%), 50-g fructose (81%), and 20-g sorbitol (84%) malabsorption was not significantly different (P = 0.3). The estimated median fraction of the ingested high dose malabsorbed was 42, 19, and 68% for lactose, fructose, and sorbitol, respectively. At low challenging doses, 63% of the volunteers absorbed two of three or all three sugars, and 88% were asymptomatic to two or all three sugars. In conclusion, the frequency of coincidental malabsorption of lactose, fructose, and sorbitol and intolerance to these sugars is not common, when normal adults ingest them at low doses.

[Repeated perioperative administration of fructose and sorbitol in a female patient with hereditary fructose intolerance [HFI)]. / Wiederholte perioperative Applikation von Fructose und Sorbit bei einer Patientin mit hereditärer Fructoseintoleranz (HFI).

The present paper reports on an adult female patient whose hereditary fructose intolerance (HFI) was at first not diagnosed and who, within the space of 2 years after repeated elective surgery and the perioperative administration of fructose and sorbitol, developed "hepatic and renal failure of unclear origin." At a later stage we were able to establish the diagnosis of HFI by means of a fructose tolerance test in both she and her brother, for whom intolerance to fruit and desserts had been known since early childhood. In addition, literature references to fatalities following the parenteral application of fructose and sorbitol were analyzed. During the course of fructose infusion in both the patient and her brother with HFI, the following metabolic changes were noted: hypoglycemia, elevated rise in the blood fructose concentration, hyperlactacidemia, elevated rise in the blood fructose concentration, hyperlactacidemia, and hyperammonemia. These metabolic changes proved to be reversible after discontinuing the fructose infusion. Analysis of the literature on the fatalities following parenteral fructose administration established that fruit and dessert intolerance was known for all collated patients with HFI, and that, clearly, no regular metabolic tests had been conducted.

Current practices and improved recommendations for treating hereditary fructose intolerance.

A study of treatment practices of pediatric centers managing hereditary fructose intolerance and a review of recent literature on this subject were undertaken in an attempt to establish the degree of dietary liberalization allowable with age and the acceptability of foods containing trace amounts of fructose. The information was needed to plan optimal therapy and thus avoid the consequences of the disorder, namely intestinal dysfunction, metabolic imbalance, and hepatic and renal damage. Fifty responses to 113 letters to centers in Canada and the United States, as well as data from The Hospital for Sick Children, Toronto, Ontario, identified only 29 affected children and provided information on their care, including food lists and literature references. Major principles of treatment were similar, but the approach to allowing and quantifying dietary fructose differed. In response to the apparent need for standardization of treatment, the authors formulated improved recommendations for the control of dietary fructose (less than 1.5 gm/day). Only a few foods of vegetable origin are allowed, including a limited selection of vegetables and cereal products from grain endosperm. Repeated dietary counseling is advocated with regard to allowed foods, sweeteners, and medications to ensure long-term dietary compliance.