Hereditary Fructose Intolerance

Overview

Plain-Language Overview

Hereditary Fructose Intolerance is a rare genetic condition that affects how the body processes a sugar called fructose. People with this condition lack a specific enzyme needed to break down fructose properly. When they eat foods containing fructose, it can cause symptoms like nausea, vomiting, and low blood sugar. Over time, eating fructose can also harm the liver and kidneys. This condition usually appears in infancy or early childhood when fructose-containing foods are introduced.

Clinical Definition

Hereditary Fructose Intolerance (HFI) is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme aldolase B, which is essential for the metabolism of fructose-1-phosphate in the liver, kidney, and small intestine. The accumulation of fructose-1-phosphate leads to inhibition of glycogenolysis and gluconeogenesis, resulting in severe hypoglycemia and potential hepatic and renal dysfunction. Clinical manifestations typically begin after the introduction of fructose, sucrose, or sorbitol into the diet, presenting with symptoms such as vomiting, abdominal pain, lethargy, and failure to thrive. Laboratory findings often include hypoglycemia, elevated liver enzymes, hyperuricemia, and metabolic acidosis. If untreated, chronic exposure to fructose can cause progressive liver damage, renal tubular dysfunction, and growth retardation. Diagnosis is confirmed by genetic testing for mutations in the ALDOB gene or by enzymatic assay of aldolase B activity. Management involves strict dietary avoidance of fructose, sucrose, and sorbitol to prevent acute and chronic complications.

Inciting Event

Ingestion of fructose, sucrose, or sorbitol containing foods or medications initiates symptoms.

Latency Period

Symptoms typically develop within hours after fructose ingestion.

Diagnostic Delay

Symptoms may be mistaken for common gastrointestinal illnesses, leading to delayed diagnosis.
Lack of awareness and rarity of the condition contribute to diagnostic delay.

Clinical Presentation

Signs & Symptoms

Severe hypoglycemia after ingestion of fructose-containing foods.
Vomiting and abdominal pain following fructose intake.
Failure to thrive and growth retardation in infants.
Jaundice and hepatomegaly due to liver dysfunction.

History of Present Illness

After ingestion of fructose-containing foods, patients develop nausea, vomiting, abdominal pain, and hypoglycemia.
Symptoms may include lethargy, seizures, and jaundice in severe cases.
Symptoms improve with fructose avoidance.

Past Medical History

History of recurrent episodes of hypoglycemia and vomiting after eating sweets or fruit.
Failure to thrive or poor feeding in infancy may be present.

Family History

Autosomal recessive inheritance pattern with possible affected siblings.
Family history may reveal relatives with similar symptoms triggered by fructose ingestion.

Physical Exam Findings

Hepatomegaly due to fatty infiltration and glycogen accumulation.
Jaundice may be present in cases with significant liver dysfunction.
Signs of hypoglycemia such as diaphoresis and pallor may be observed.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Hereditary Fructose Intolerance is based on clinical suspicion in patients presenting with hypoglycemia, vomiting, and abdominal pain after fructose ingestion, supported by laboratory evidence of hypoglycemia, elevated liver enzymes, and metabolic acidosis. Definitive diagnosis requires identification of pathogenic mutations in the ALDOB gene through genetic testing or demonstration of deficient aldolase B enzyme activity in liver biopsy specimens.

Pathophysiology

Key Mechanisms

Hereditary Fructose Intolerance is caused by a deficiency of the enzyme aldolase B, leading to accumulation of fructose-1-phosphate in the liver, kidney, and small intestine.
Accumulation of fructose-1-phosphate depletes intracellular phosphate and ATP, impairing gluconeogenesis and glycogenolysis.
The resulting energy deficit causes hypoglycemia and liver dysfunction after fructose ingestion.

Involvement	Details
Organs	The liver is the main organ affected, resulting in hypoglycemia, jaundice, and potential liver failure.
Tissues	Liver tissue is damaged due to intracellular accumulation of toxic metabolites causing hepatomegaly and dysfunction.
Cells	Hepatocytes are the primary cells affected due to accumulation of toxic metabolites causing liver dysfunction.
Chemical Mediators	Accumulation of fructose-1-phosphate inhibits aldolase B, leading to toxic metabolic effects.

Treatment

Pharmacological Treatments

none
- Mechanism: none
- Side effects: none

Non-pharmacological Treatments

Strict dietary avoidance of fructose, sucrose, and sorbitol prevents symptoms and liver damage.

Prevention

Pharmacological Prevention

none

Non-pharmacological Prevention

Strict avoidance of dietary fructose, sucrose, and sorbitol to prevent symptoms.
Early diagnosis through newborn screening or genetic testing to guide dietary management.
Nutritional counseling to ensure adequate caloric intake without fructose exposure.

Outcome & Complications

Complications

Severe hypoglycemic seizures if fructose ingestion is not avoided.
Progressive hepatic failure due to ongoing liver damage.
Renal tubular dysfunction leading to renal failure in advanced cases.

Short-term Sequelae	Long-term Sequelae
Acute hypoglycemia causing lethargy and seizures. Vomiting and dehydration following fructose ingestion.	Chronic liver cirrhosis from repeated hepatic injury. Growth retardation due to chronic metabolic disturbances. Potential development of renal failure from tubular damage.

Differential Diagnoses

Hereditary Fructose Intolerance versus Fructokinase deficiency (Essential fructosuria)

Hereditary Fructose Intolerance	Fructokinase deficiency (Essential fructosuria)
Severe symptoms including hypoglycemia, vomiting, and hepatomegaly after fructose ingestion.	Benign condition with asymptomatic fructose excretion in urine.
Presence of aldolase B deficiency causing toxic metabolite accumulation.	No evidence of hypoglycemia, vomiting, or liver dysfunction after fructose ingestion.
Potential for liver and kidney damage if fructose is not avoided.	Normal growth and development without metabolic complications.

Hereditary Fructose Intolerance versus Fructose-1,6-bisphosphatase deficiency

Hereditary Fructose Intolerance	Fructose-1,6-bisphosphatase deficiency
Symptoms occur specifically after ingestion of fructose-containing foods.	Severe hypoglycemia with metabolic acidosis during fasting or illness.
Hypoglycemia accompanied by hepatic and renal dysfunction due to toxic metabolite accumulation.	Normal tolerance to fructose ingestion without acute symptoms.
Lack of significant lactic acidosis during episodes.	Elevated lactate and ketones during hypoglycemic episodes.

Hereditary Fructose Intolerance versus Galactosemia

Hereditary Fructose Intolerance	Galactosemia
Deficiency of aldolase B causing accumulation of fructose-1-phosphate.	Presence of galactose-1-phosphate uridyltransferase deficiency leading to accumulation of galactose-1-phosphate.
Symptoms triggered by ingestion of fructose, sucrose, or sorbitol rather than milk.	Onset of symptoms shortly after milk ingestion in neonates.
Absence of cataracts and neonatal sepsis; presentation typically after weaning.	Findings of cataracts and E. coli sepsis in affected infants.