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Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is caused by an insufficiency of hepatic fructose-1-phosphate aldolase activity. It is an autosomal recessive disease. The disruption of fructose metabolism results in both gastrointestinal problems and hypoglycemia upon fructose consumption. The disease can have severe or even lethal consequences if untreated but can be easily managed if diagnosed.


Presentation

Patients suffering from HFI develop and grow normally while being only breastfed. Problems usually start to appear at the time of weaning, when fructose is first introduced into the diet through foods containing fructose, sucrose (a disaccharide containing glucose and fructose units), or sorbitol. Consumption of fructose-containing foods results in hypoglycemia, lactic acidosis, and ketosis and causes difficulties in feeding, repeated vomiting, and abdominal discomfort. In the long run, these symptoms will lead to failure to thrive. Continued feeding with sugars that either contain fructose or are converted to fructose may lead to liver and kidney failure, convulsions, coma, and possibly death [1] [2] unless the problem is addressed.

Patients who live beyond infancy develop a strong dislike for foods containing fructose, mainly fruits and sweets, and continue to have unfavorable reactions (vomiting and hypoglycemia) following fructose ingestion throughout the rest of their lives. In general, there is very little tooth decay in adults with HFI, which, in itself, may be an indication of the disease, and is probably due to the voluntary exclusion of sweets from their diet.

Pallor
  • The most frequent clinical findings were hepatomegaly (18X), pallor (14X), haemorrhages (13X). Ascites, oliguria, tachypnoea, fever, splenomegaly and rickets were less frequent.[ncbi.nlm.nih.gov]
  • These sweeteners are not common in formulas used today. [5] Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables.[en.wikipedia.org]
  • The patient was a healthy, breastfed infant; however, in his fourth month he developed an acute episode of repetitive vomiting, irritability, pallor, and shock.[pediatrics.aappublications.org]
  • The result is pallor, sweating, trembling, fear, convulsions and ultimately loss of consciousness because the brain cannot tolerate being deprived of glucose.[independent.co.uk]
Death in Infancy
  • Without treatment and continued ingestion of fructose, individuals may have worsening symptoms and early death in infancy.[evolvegene.com]
Vomiting
  • Referals were for vomiting of unknown aetiology (16X), pyloric stenosis or hiatus hernia (5X), toxic condition (3X), and hepatomegaly of unknown origin (5X).[ncbi.nlm.nih.gov]
  • We report on an infant with suspected HFI who presented with repeated episodes of vomiting and hypotension after ingestion of fruit-containing meals. The first episode occurred at age 4 months.[ncbi.nlm.nih.gov]
  • Infants will present with feeding difficulties, vomiting, failure to thrive and symptoms of hypoglycemia and acidosis.[symptoma.com]
  • Hereditary fructose intolerance is a rare autosomal recessive disease of fructose metabolism presenting as vomiting after intake of fructose.[ncbi.nlm.nih.gov]
  • Symptoms are present only after the ingestion of fructose, which leads to brisk hypoglycemia, and an individual with continued ingestion will exhibit vomiting, abdominal pain, failure to thrive, and renal and liver failure.[ncbi.nlm.nih.gov]
Nausea
  • These sweeteners are not common in formulas used today. [5] Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables.[en.wikipedia.org]
  • HEREDITARY fructose intolerance is an uncommon metabolic disorder, characterized by symptoms of nausea, vomiting, malaise, substernal pain, excessive sweating, tremor, confusion, coma and convulsions, that follows the ingestion of foods containing fructose[nejm.org]
  • The following are observed: HFI is asymptomatic in nature, before the intake of fructose Initial signs include diarrhea, vomiting, nausea, swollen abdomen with pain, hypoglycemia (low blood sugar).[dovemed.com]
Food Intolerance
  • You may even be suffering from more than one food intolerance . The research indicates that doing nothing can be a risk. Undiagnosed food intolerance can cause serious long-term health problems like osteoporosis, anaemia and many others.[foodintol.com]
  • On the Food Intolerance Network website we will use the term "fructose malabsorption", and sometimes "fructose intolerance", but in that case we never talk about hereditary fructose intolerance (HFI) unless this is referred to specifically![food-intolerance-network.com]
  • Living with Food Intolerance London, UK: Sheldon Press, 2006. Saville, A., Haynes, A. Food Intolerance Bible New York, NY: ThorsonsElement (Harpercollins), 2005. Minocha, A. Handbook of Digestive Diseases Thorofare, NJ: Slack Incorporated, 2004.[diet.com]
Recurrent Vomiting
  • Clinical description HFI usually presents in infancy at the time of weaning (when fructose is added to the diet), manifesting with hypoglycemia, lactic acidosis, ketosis with recurrent vomiting, abdominal pain and systemic manifestations following consumption[orpha.net]
  • Clinical features include-Recurrent vomiting, abdominal pain, and hypoglycemia that may be fatal.[usmle.biochemistryformedics.com]
  • Clinical features include- Recurrent vomiting, Abdominal pain, and Hypoglycemia that may be fatal.[namrata.co]
Hepatomegaly
  • He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function.[ncbi.nlm.nih.gov]
  • Referals were for vomiting of unknown aetiology (16X), pyloric stenosis or hiatus hernia (5X), toxic condition (3X), and hepatomegaly of unknown origin (5X).[ncbi.nlm.nih.gov]
  • Herein we report on a case of hereditary fructose intolerance with initial presentation of episodic unconsciousness, seizure, hypoglycemia, hepatomegaly, and abnormal liver function since the patient was 11 months old.[ncbi.nlm.nih.gov]
  • Abstract We describe a patient with failure to thrive, hepatomegaly, liver dysfunction, and elevation of multiple plasma lysosomal enzyme activities mimicking mucolipidosis II or III, in whom a diagnosis of hereditary fructose intolerance (HFI) was ultimately[ncbi.nlm.nih.gov]
  • As a result of this disorder individuals may have all of the following symptoms except: -reduced blood glucose levels during fasting -reducing sugar in the urine -inability to metabolize lactose -hepatomegaly The metabolic disease, which is resulted due[chegg.com]
Strabismus
  • Abstract This is a report of a five-year-old girl with phenylketonuria (PKU) and hereditary fructose intolerance (HFI) who underwent elective strabismus surgery.[ncbi.nlm.nih.gov]
Visual Impairment
  • Irreversible visual impairment after intraocular haemorrhage occurred once. In each case HFI could have been suspected immediately, had a detailed nutritional history been taken.[ncbi.nlm.nih.gov]
Oliguria
  • Ascites, oliguria, tachypnoea, fever, splenomegaly and rickets were less frequent. Laboratory findings were indicative of disturbed hepatic and renal tubular function and also of disturbed intermediary metabolism (hypokaliaemia, hypophosphataemia).[ncbi.nlm.nih.gov]
Seizure
  • Herein we report on a case of hereditary fructose intolerance with initial presentation of episodic unconsciousness, seizure, hypoglycemia, hepatomegaly, and abnormal liver function since the patient was 11 months old.[ncbi.nlm.nih.gov]
  • He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function.[ncbi.nlm.nih.gov]
  • Some infants have a more severe reaction to such sugars with lethargy, seizures and coma. Older children and adults develop a protective aversion to fruits and sweets.[disorders.eyes.arizona.edu]
  • Other complications may include seizures, gout, low blood sugar, bleeding and even death. Foods to Avoid Removing fructose from your child’s diet is the only way to prevent symptoms and reduce the risk of complications, like liver disease.[healthyeating.sfgate.com]
  • Common Features of the Disorder Failure to thrive in infancy Nausea Bloating Abdominal pain Diarrhea Vomiting Low blood sugar Jaundice Enlarged liver Liver disease (i.e. cirrhosis) Seizures Coma Growth delays Kidney failure Prognosis Hereditary Fructose[evolvegene.com]
Confusion
  • HEREDITARY fructose intolerance is an uncommon metabolic disorder, characterized by symptoms of nausea, vomiting, malaise, substernal pain, excessive sweating, tremor, confusion, coma and convulsions, that follows the ingestion of foods containing fructose[nejm.org]
  • There are characteristic symptoms in infants with this intolerance, but they are easy to confuse with other conditions. Fructose and Intolerance Fructose is a common sugar, found naturally in fruits and some vegetables.[mykidsfoodallergies.com]
  • Hereditary fructose intolerance should not be confused with a condition called fructose malabsorption.[ghr.nlm.nih.gov]
  • However, HFI is most commonly confused with fructose malabsorption . This is a non-life threatening and much more common condition. This site contains a helpful comparison of the two conditions. The treatment for both is similar.[sweetpoison.wikidot.com]
Lethargy
  • Because this non-immunoglobulin E-mediated gastrointestinal food hypersensitivity manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy, it may be misinterpreted as HFI.[ncbi.nlm.nih.gov]
  • Some infants have a more severe reaction to such sugars with lethargy, seizures and coma. Older children and adults develop a protective aversion to fruits and sweets.[disorders.eyes.arizona.edu]
  • Case details A 3-year-old boy was brought to the emergency department after several episodes of vomiting and lethargy.[namrata.co]
  • These sweeteners are not common in formulas used today. [5] Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables.[en.wikipedia.org]
  • QUESTION OF THE DAY A 3-month-old girl is brought to the pediatrician due to fussiness and lethargy.[usmle.biochemistryformedics.com]

Workup

Taking a detailed dietary history in individuals suspected of hereditary fructose intolerance is a crucial component of diagnosis. Infants will present with feeding difficulties, vomiting, failure to thrive [1] and symptoms of hypoglycemia and acidosis [3]. In older children and adults, the history is expected to show episodes of food refusal: affected infants and children will recoil from sweets after being taken ill several times. Sometimes, apparently healthy adults are given a diagnosis of HFI based on dietary history. As mentioned, a complete lack of tooth decay can also serve as an indicator for hereditary fructose intolerance.

A comprehensive history has to be followed up with laboratory tests and physical examination. There are several tests to verify suspected HFI, i.e. fructose 1-phosphate aldolase deficiency: one test determines if there is a reducing sugar in the urine that is not glucose. Reducing sugars are easily detected with Clinitest; if this is positive, the identity of the sugar can be established by further tests, such as thin-layer chromatography or enzyme assays [4]. Another test is the measurement of the aldolase enzyme activity in liver or intestinal mucosal biopsies: the enzyme’s function is impaired in HFI patients [5]. The latter test has been, to a large extent, superseded by molecular methods, which are non-invasive. DNA analysis can be performed using leukocytes. Sequencing of the aldolase gene (located on chromosome 9) will, in all probability, diagnose the disease and unambiguously identify the mutation responsible for it [6] [7] [8 [9] [10] [11]. These tests can define the mutational spectrum and can serve as the basis for designing targeted mutational tests [11].

The intravenous fructose tolerance test [5] is also non-invasive but has to be performed in a controlled hospital environment because of the hazards associated with fructose administration to HFI patients [1] [3]. Oral fructose tolerance testing should not be used because of the danger of severe gastrointestinal reaction. Observing relief of symptoms in response to the dietary exclusion of fructose also has strong diagnostic value.

Hepatic function tests should be performed to evaluate whether the liver is damaged. Patients, who do not receive treatment, usually show indications of hepatocellular injury, which may not be reversible [2]; the histology shows multiple abnormalities, such as fatty deposits in peripheral lobules. Except in cases where there is strong evidence for liver disease, liver biopsy should not be used for diagnosis.

Urine tests may show elevated levels of glucose, proteins, and amino acids, characteristic of renal Fanconi syndrome, which may be caused by fructose intolerance. Decreased tubular reabsorption of bicarbonate [12] lowers the blood bicarbonate concentration and contributes to metabolic acidosis. To test for tubular acidosis, plasma electrolyte levels should be determined.

Liver Biopsy
  • Liver biopsies were obtained from 35 children with HFI, 14 contrast persons and 10 controls (of which 9 organ donors) and examined enzymatically.[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]
  • Traditionally, diagnosis has been made by intravenous fructose challenge or by liver biopsy, both difficult and risky invasive tests.[ncbi.nlm.nih.gov]
  • She was diagnosed as Reye's-like syndrome according to a liver biopsy done at 20 months of age.[ncbi.nlm.nih.gov]
  • Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods.[ncbi.nlm.nih.gov]

Treatment

  • Major principles of treatment were similar, but the approach to allowing and quantifying dietary fructose differed.[ncbi.nlm.nih.gov]
  • Treatment currently relies solely on dietary restriction of problematic sugars.[ncbi.nlm.nih.gov]
  • [ edit ] Treatment of HFI depends on the stage of the disease, and the severity of the symptoms.[en.wikipedia.org]
  • Treatment Treatment for Hereditary Fructose Intolerance involves lifelong dietary restriction of fructose and other sugary substances (i.e. sucrose). Early diagnosis and treatment can prevent the symptoms of Hereditary Fructose Intolerance.[evolvegene.com]
  • An association between these two distinct genetic gastrointestinal disorders is important as treatment failure of celiac disease calls for careful evaluation for hereditary fructose intolerance.[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis depends on how soon the fructose intolerance diagnosis was made, how quickly fructose and sucrose are removed from the diet and the severity of the condition, according to Medline Plus.[healthyeating.sfgate.com]
  • Intolerance has a favorable prognosis with treatment.[evolvegene.com]
  • Intensive care and supportive measures may be required in case of acute intoxication Prognosis HFI prognosis is favorable with normal growth, intelligence and lifespan.[orpha.net]

Etiology

  • We also performed a review of the literature on the different etiologies of elevated lysosomal enzyme activities in serum or plasma. 2016 Wiley Periodicals, Inc.[ncbi.nlm.nih.gov]
  • Etiology HFI is caused by mutations in the ALDOB (9q22.3) gene, encoding the enzyme aldolase B.[orpha.net]
  • (Etiology) Hereditary Fructose Intolerance is caused by inheriting an autosomal recessive gene, which lies on chromosome 9 and is defective The problem gene (known as ALDOB), disturbs or changes the normal and physiologically programmed production of[dovemed.com]

Epidemiology

  • Summary Epidemiology The estimated prevalence is 1 in 20,000 in Europe and the carrier frequency is about 1 in 70. The prevalence of HFI in adult population is not known.[orpha.net]
  • Epidemiology Frequency United States Although the true prevalence has not been established, hereditary fructose intolerance may be more common than originally believed; many asymptomatic affected people may simply avoid the ingestion of most or all sweets[reference.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiologic classification of lactic acidosis.[reference.medscape.com]
  • Pathophysiology A defect in the Aldolase B gene results in a decrease in activity that is 15 percent or less than that of normal. This results in a buildup of F1P levels in the hepatocytes.[namrata.co]
  • The potential toxic effects of fructose in humans also are discussed: it is essential to understand these toxic effects in order to comprehend the pathophysiology of hereditary fructose intolerance and of fructose 1,6-bisphosphatase deficiency. ...[ommbid.mhmedical.com]
  • J Cell Physiol 209:701-705 Google Scholar Gitzelmann R (1995) Galactose-1-phosphate in the pathophysiology of galactosemia.[link.springer.com]

Prevention

  • Those who survive childhood learn to avoid sweets, effectively preventing further symptoms and complications. The disease is caused by a genetically defective hepatic enzyme, aldolase B.[ncbi.nlm.nih.gov]
  • Early diagnosis and treatment may prevent neurological complications of hereditary fructose intolerance. Copyright 2016 Elsevier Inc. All rights reserved.[ncbi.nlm.nih.gov]
  • Abstract Hereditary fructose intolerance (HFI) is an under-recognized, preventable life-threatening condition. It is an autosomal recessive disorder with subnormal activity of aldolase B in the liver, kidney and small bowel.[ncbi.nlm.nih.gov]
  • Abstract In two unrelated boys, 5.3 and 3.8 years of age with hereditary fructose intolerance, apparently isolated growth retardation (-2.71 S.D. and -2.40 S.D.) occurred after infancy, even though acute symptomatic fructose intoxication was prevented[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]

References

Article

  1. Baerlocher K, Gitzelmann R, Steinmann B, Gitzelmann-Cumarasamy N. Hereditary fructose intolerance in early childhood: a major diagnostic challenge. Survey of 20 symptomatic cases. Helv Paediatr Acta. 1978;33:465–487
  2. Odièvre M, Gentil C, Gautier M, Alagille D. Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients. Am J Dis Child. 1978 Jun;132(6):605-608.
  3. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998;35:353–65.
  4. Steinmann B, Santer R. Disorders of fructose metabolism. In: Saudubray JM, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. Berlin: Springer-Verlag; 2012;157–165.
  5. Steinmann B, Gitzelmann R. The diagnosis of hereditary fructose intolerance. Helv Paediatr Acta. 1981;36:297–316
  6. Bouteldja N, Timson DJ. The biochemical basis of hereditary fructose intolerance. J Inherit Metab Dis. 2010 Apr;33(2):105-12
  7. Steinman B, Gitzelmann R, van den Berghe G. Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Valle D, Sly WS, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001;1489–1520.
  8. Tolan DR. Molecular basis of hereditary fructose intolerance: Mutations and polymorphisms in the human aldolase B gene. Hum. Mutat. 1995;6:210–218.
  9. James CL, Rellos P, Ali M, Heeley AF, Cox TM. Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population. J Med Genet. 1996;33(10):837-41.
  10. Ferri L, Caciotti A, Cavicchi C, Rigoldi M, et al. Integration of PCR-sequencing analysis with multiplex ligation-dependent probe amplification for diagnosis of hereditary fructose intolerance. JIMD Rep. 2012;6:31-7.
  11. Coffee EM, Yerkes L, Ewen EP, Zee T, Tolan DR. Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. J Inherit Metab Dis. 2010 Feb;33(1):33-42.
  12. Morris RC Jr. An experimental renal acidification defect in patients with hereditary fructose intolerance. J Clin Invest. 1968;47:1648–63.

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Last updated: 2018-06-21 18:24