Ver el código de «Hereditary fructose intolerance»

==Background==
*Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by deficiency of aldolase B, an enzyme essential for fructose metabolism in the liver, kidney, and intestine.<ref name="StatPearls">Hereditary Fructose Intolerance. ''StatPearls''. NCBI. 2023.</ref> When individuals with HFI ingest fructose, sucrose, or sorbitol, the toxic metabolite fructose-1-phosphate (F-1-P) accumulates, causing hypoglycemia, lactic acidosis, hepatic failure, and renal tubular dysfunction.<ref name="WJClinPed">Singh SK, Sarma MS. Hereditary fructose intolerance: A comprehensive review. ''World J Clin Pediatr''. 2022;11(4):321-329. PMC9331401.</ref> HFI is entirely asymptomatic when fructose is avoided and potentially fatal when it is not.
*The emergency physician encounters HFI as an infant with vomiting, hypoglycemia, and liver failure temporally related to the introduction of weaning foods, or as a known HFI patient with accidental fructose exposure.
*Autosomal recessive; prevalence approximately 1 in 20,000-30,000 live births; carrier frequency ~1 in 70<ref name="Orphanet">Hereditary fructose intolerance. ''Orphanet''. 2024.</ref>
*Caused by mutations in the ALDOB gene (chromosome 9q22.3); most common mutations are A149P, A150P, and A174D
*Symptoms only occur after ingestion of fructose, sucrose, or sorbitol — patients are completely well on a fructose-free diet
*Typically presents at '''4-6 months of age''' when weaning foods (fruits, vegetables, sweetened cereals, juices) are introduced<ref name="StatPearls"/>
* Breastfed infants are protected — breast milk contains lactose (glucose + galactose) but no fructose; symptoms begin when breast milk is supplemented or weaning starts
* Deaths occur primarily from diagnostic delay — once recognized, the treatment (dietary fructose avoidance) is simple and completely effective<ref name="Wiki_HFI">Hereditary fructose intolerance. ''Wikipedia''. 2025.</ref>

===Mechanism===
*Fructose is phosphorylated by fructokinase → fructose-1-phosphate (F-1-P)
*Aldolase B normally cleaves F-1-P → glyceraldehyde + dihydroxyacetone phosphate (enter glycolysis/gluconeogenesis)
*In HFI: aldolase B is absent or deficient → F-1-P accumulates → multiple downstream effects:
** Intracellular phosphate trapping: F-1-P sequesters inorganic phosphate (Pi) → depletion of ATP
** Hypoglycemia: F-1-P inhibits both glycogenolysis (glycogen phosphorylase) AND gluconeogenesis (glucose-6-phosphate isomerase) — a dual block on glucose production<ref name="WJClinPed"/>
** Glucagon resistance: hypoglycemia in HFI does NOT respond to glucagon (because glycogenolysis is blocked)<ref name="WJClinPed"/>
** Lactic acidosis: F-1-P activates pyruvate kinase → increased lactate production
** Hyperuricemia: ATP depletion → AMP degradation → increased urate production
** Hepatocellular and renal tubular toxicity: direct cytotoxic effects of F-1-P accumulation → liver failure, [[Fanconi syndrome]]

===Key dietary sources of fructose (EM-relevant)===
* Fruits (all), fruit juices, honey
* Sucrose (table sugar) — sucrose = glucose + fructose; present in nearly all sweetened foods, candy, cookies, soft drinks
* Sorbitol — sugar alcohol used as sweetener in "sugar-free" products; also found in many medications (syrups, elixirs, chewable tablets) — a critical hidden source
* High-fructose corn syrup — ubiquitous in processed foods
*Many vegetables contain small amounts of fructose (especially peas, sweet corn, sweet potato)
* IV fructose or sorbitol solutions (historically used in some parenteral nutrition formulations — now rarely used but must be actively avoided)

==Clinical features==
===Acute presentation (the ED encounter)===
====Infant with new diagnosis (classic presentation)====
* Previously healthy breastfed infant, 4-6 months old
*Symptoms begin within minutes to hours of ingesting fructose-containing food or formula for the first time
* Vomiting (often violent/repeated)
* Profound hypoglycemia (lethargy, seizures, diaphoresis, pallor)
* Abdominal pain/distress
* Poor feeding, irritability
*With continued fructose exposure:
** Hepatomegaly (progressive)
** Jaundice (conjugated hyperbilirubinemia)
** Coagulopathy (elevated INR — hepatic synthetic failure)
** Bleeding (GI hemorrhage, oozing from puncture sites)
** Ascites, edema
** Renal tubular dysfunction ([[Fanconi syndrome]]: glycosuria, aminoaciduria, phosphaturia, metabolic acidosis)
** Failure to thrive
** Seizures, coma, death — in severe untreated cases

====Known HFI patient with accidental exposure====
*Acute episode after accidental ingestion of fructose-containing food or medication
*Rapid-onset vomiting, hypoglycemia, malaise
*May be mild (self-limited vomiting) or severe (hypoglycemia, acidosis, liver decompensation) depending on fructose load

===Diagnostic clues===
* Temporal relationship to food introduction: symptoms began when weaning started or when a new food/formula containing fructose or sucrose was introduced
* Aversion to sweets: older children and adults with undiagnosed HFI develop a strong natural aversion to sweet foods and fruits — this is a classic historical clue<ref name="Orphanet"/>
* Absence of dental caries: lifelong fructose avoidance results in remarkably healthy teeth — another diagnostic pearl<ref name="Orphanet"/>
* Symptoms resolve completely when fructose is removed from the diet

==Differential diagnosis==
===Infant with vomiting, hypoglycemia, and liver failure===
* [[Galactosemia]] — very similar presentation but triggered by lactose/galactose (present in breast milk and standard formula); ''E. coli'' sepsis association; cataracts; reducing substances in urine
* [[Tyrosinemia|Tyrosinemia type 1]] — liver failure + coagulopathy + very high AFP; boiled cabbage odor; Fanconi syndrome; not temporally related to specific food introduction
* [[Sepsis]] — ill-appearing; fever; positive cultures
* [[Neonatal hepatitis]] (other causes)
* [[Neonatal hemochromatosis]] (GALD) — presents at birth, not at weaning
* Glycogen storage diseases — hepatomegaly + hypoglycemia; not food-specific
* Fructose-1,6-bisphosphatase deficiency — similar presentation (hypoglycemia + acidosis + hepatomegaly) but triggered by fasting rather than fructose ingestion; important to distinguish
* Urea cycle defects, organic acidemias
* Food protein-induced enterocolitis syndrome (FPIES) — profuse vomiting after specific food; no hypoglycemia or liver disease

===Key distinguishing features of HFI===
*Symptoms temporally linked to fructose/sucrose introduction
* Hypoglycemia that does NOT respond to glucagon
* Hypophosphatemia (phosphate trapping by F-1-P) — relatively specific finding
* Hyperuricemia — unusual in an infant; should raise suspicion
*Resolution with fructose withdrawal

==Evaluation==
===ED workup===
* Blood glucose: expect hypoglycemia (may be severe/refractory)
* BMP: hypophosphatemia (characteristic), metabolic acidosis, elevated creatinine (if renal involvement)
* Hepatic panel: elevated AST/ALT (hepatocellular injury); elevated bilirubin (conjugated)
* Coagulation studies: elevated PT/INR (hepatic synthetic failure in severe cases)
* Uric acid: '''hyperuricemia''' (ATP depletion → AMP breakdown → urate production)<ref name="StatPearls"/>
* Lactate: lactic acidosis
* Magnesium: hypermagnesemia (released from damaged cells with ATP depletion)
* CBC: thrombocytopenia (in severe hepatic failure)
* Urinalysis: glycosuria (normal blood glucose), aminoaciduria, phosphaturia (Fanconi pattern); fructosuria may be present
* Ammonia: may be elevated in severe hepatic failure
* AFP: may be elevated (liver injury; less markedly than tyrosinemia)

===Characteristic laboratory constellation===
Hypoglycemia + hypophosphatemia + hyperuricemia + lactic acidosis + liver dysfunction in an infant following fructose exposure = highly suspicious for HFI

===Confirmatory testing (arrange via specialist)===
* ALDOB gene sequencing: preferred confirmatory test; noninvasive; high sensitivity and specificity<ref name="WJClinPed"/>
* Liver biopsy: for aldolase B enzyme activity measurement — invasive; reserved for cases where genetic testing is inconclusive
* Fructose tolerance test: NO LONGER RECOMMENDED — dangerous; causes profound hypoglycemia and can precipitate acute liver failure<ref name="Wiki_HFI"/>
* Urine reducing substances: may be positive (fructosuria) after fructose ingestion; non-specific
* Carbohydrate-deficient transferrin (CDT): often abnormal in untreated HFI (secondary glycosylation defect)

==Management==
===Acute emergency management===
*'''Stop all fructose, sucrose, and sorbitol intake immediately''' — this is the single most important intervention
* IV dextrose (D10W): correct and prevent hypoglycemia with '''glucose-containing fluids only'''<ref name="StatPearls"/>
**'''Do NOT give fructose or sorbitol-containing IV solutions'''
**'''Do NOT give sucrose-containing oral medications'''
* Correct metabolic acidosis: sodium bicarbonate if pH <7.1 or bicarbonate severely depressed; often improves with dextrose and fructose withdrawal
* Correct coagulopathy: vitamin K, FFP if active bleeding
* Treat hepatic failure per standard protocols (see [[Acute liver failure]])
* Monitor and correct electrolytes: phosphate supplementation if severely hypophosphatemic; monitor potassium, magnesium
* Glucagon is NOT effective for hypoglycemia in HFI — both glycogenolysis and gluconeogenesis are blocked by F-1-P; give IV dextrose instead<ref name="WJClinPed"/>

===Medication safety — critical for the EM physician===
*Many common pediatric liquid medications contain sorbitol or sucrose as sweeteners — these are dangerous in HFI<ref name="WJClinPed"/>
* Before administering ANY oral medication to a known or suspected HFI patient, check the excipient/inactive ingredient list for fructose, sucrose, or sorbitol
*Safer alternatives: use tablet formulations (crushed if needed), or IV formulations
*Common offenders: acetaminophen syrups, ibuprofen suspensions, antibiotic suspensions, cough syrups, chewable tablets
* Consult pharmacy to verify medication safety

===Long-term management (arrange via metabolic specialist)===
* Lifelong strict dietary exclusion of fructose, sucrose, and sorbitol — this is the definitive and only treatment<ref name="StatPearls"/>
* Nutritionist referral — extensive dietary education required; hidden fructose sources are ubiquitous
* Vitamin and mineral supplementation — patients on fructose-free diets may develop deficiencies in vitamin C, folate, and fiber (from restricted fruit/vegetable intake)
*Life expectancy is completely normal with dietary compliance
*No liver transplant required (unlike [[Tyrosinemia|tyrosinemia type 1]] or [[Crigler-Najjar syndrome]])

==Disposition==
* Infant with suspected new diagnosis (vomiting + hypoglycemia + liver dysfunction after fructose introduction):
**Admit
**Stop all fructose/sucrose/sorbitol sources
**IV dextrose, supportive care
**Metabolic/genetics consultation
**Arrange ALDOB gene testing
* Known HFI patient with mild accidental exposure (vomiting, mild hypoglycemia, no liver failure):
**Treat hypoglycemia with oral glucose or IV dextrose
**Observe until asymptomatic and blood glucose stable
**May discharge if well, tolerating fructose-free diet, glucose stable, and family is reliable
* Known HFI patient with severe exposure (liver failure, refractory hypoglycemia, acidosis):
**Admit (PICU if critically ill)
**Aggressive IV dextrose, correct acidosis and coagulopathy
**Metabolic team consultation
* Ensure all families receive:
**Written dietary guidance (fructose, sucrose, sorbitol avoidance)
** Medical alert identification for the child
**Guidance on medication safety (sorbitol in syrups)
**Metabolic specialist follow-up

==See Also==
*[[Galactosemia]]
*[[Tyrosinemia]]
*[[Fanconi syndrome]]
*[[Neonatal hepatitis]]
*[[Acute liver failure]]
*[[Hypoglycemia]]
*[[Neonatal hemochromatosis]]

==External Links==
*[https://www.ncbi.nlm.nih.gov/books/NBK559102/ StatPearls — Hereditary Fructose Intolerance]
*[https://www.ncbi.nlm.nih.gov/books/NBK557761/ StatPearls — Fructose-1-Phosphate Aldolase Deficiency]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC9331401/ World J Clin Pediatr — Hereditary fructose intolerance: A comprehensive review (2022)]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC10969590/ Diseases — Clinical Practice Guidelines for HFI (2024)]
*[https://www.orpha.net/en/disease/detail/469 Orphanet — Hereditary fructose intolerance]

==References==
<references/>

[[Category:Pediatrics]]
[[Category:GI]]