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Case Study- Hereditary Fructose Intolerance
A 3-year-old boy was brought to the emergency department after several episodes of vomiting and lethargy. His pediatrician was concerned about his failure to thrive and possible hepatic failure along with recurrent episodes of the vomiting and lethargy. After a careful history, it was observed, that these episodes occur after ingestion of certain types of food, especially high in fructose.
His blood sugar was checked in the emergency department and was extremely low (42 mg/dL). The test for reducing sugar in urine was positive.
What is the most likely diagnosis?
What is the biochemical basis for the clinical symptoms?
What is the treatment of the disorder?
The child is most probably suffering from ‘Hereditary fructose Intolerance’. The onset of symptoms after ingestion of fructose or fructose containing diet is a sign of hereditary fructose Intolerance’. All these symptoms of vomiting, lethargy, failure to thrive, hypoglycemia and liver failure are characteristic of this disease.
Hereditary fructose Intolerance
In the liver, kidney, and intestine, fructose can be converted to glycolytic/ gluconeogenic intermediates by the action of three enzymes—fructokinase, aldolase B, and triokinase (also called triose kinase). In these tissues, fructose is rapidly phosphorylated to fructose 1-phosphate (F1P) by fructokinase at the expense of a molecule of adenosine triphosphate (ATP). This has the effect of trapping fructose inside the cell. A deficiency in this enzyme leads to the rare but benign condition known as essential fructosuria.
In other tissues such as muscle, adipose, and red blood cells, hexokinase can phosphorylate fructose to the glycolytic intermediate fructose 6-phosphate (F6P). Fructose- 1-phosphate is further metabolized to dihydroxyacetone phosphate (DHAP) and glyceraldehyde by the hepatic isoform of the enzyme Aldolase, which catalyzes a reversible aldol condensation reaction. Aldolase is present in three different isoforms. Aldolase A is present in greatest concentrations in the skeletal muscle, whereas the B isoform predominates in the liver, kidney, and intestine. Aldolase C is the brain isoform. Aldolase B has similar activity for either fructose 1,6-bisphosphate (F16BP) or F1P; however, the A or C isoforms are only slightly active when F1P is the substrate. Glyceraldehyde may be converted to the glycolytic intermediate, glyceraldehyde 3-phosphate (GAP), by the action of the enzyme triokinase. This enzyme phosphorylates glyceraldehyde at the expense of another molecule of ATP. The GAP can then enter into the glycolytic pathway and be further converted to pyruvate, or recombine with DHAP to form F16BP by the action of Aldolase.
Figure-1- The metabolic pathway for the entry of fructose into the glycolytic pathway. Fructokinase rapidly converts fructose to fructose 1-phosphate, which in the liver is cleaved by Aldolase B to dihydroxyacetone phosphate (DHAP) and glyceraldehyde.
Hereditary fructose intolerance is caused by mutation in the gene encoding Aldolase B enzyme.
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. Because the maximal rate of fructose phosphorylation by fructokinase is so high (almost an order of magnitude greater than that of glucokinase), intracellular levels of both ATP and inorganic phosphate (Pi) are significantly decreased. The drop in ATP concentration adversely affects a number of cellular events, including detoxification of ammonia, formation of cyclic AMP (cAMP), and ribonucleic acid (RNA) and protein synthesis. The decrease in intracellular concentrations of Pi leads to a hyperuricemic condition as a result of an increase in uric acid formation. AMP deaminase is inhibited by normal cellular concentrations of Pi. When these levels drop, the inhibition is released and AMP is converted to IMP and, ultimately, uric acid.
The toxic effects of F1P can also be exhibited in patients that do not have a deficiency in aldolase B if they are parenterally fed with solutions containing fructose. Parenteral feeding with solutions containing fructose can result in blood fructose concentrations that are several times higher than can be achieved with an oral load. Since the rate of entry into the hepatocyte is dependent on the fructose gradient across the cell, intravenous loading results in increased entry into the liver and increased formation of F1P. Since the rate of formation of F1P is much faster than its further metabolism, this can lead to hyperuricemia and hyperuricosuria by the mechanisms described above.
Figure-2- showing the inhibition of AMP deaminase by inorganic phosphate (Pi). A decrease in [Pi] increases the activity of AMP deaminase and leads to increased production of uric acid. Competition between urate and lactate for renal tubule excretion accounts for the lactic acidemia.
The cause of severe hepatic dysfunction remains unknown but may be a manifestation of focal cytoplasmic degeneration and cellular fructose toxicity. The cause of renal tubular dysfunction also remains unclear; patients with renal tubular dysfunction primarily present with a proximal tubular acidosis complicated by aminoaciduria, glucosuria, and phosphaturia. Thus, in an infant who is homozygous for fructose 1-aldolase deficiency, fructose ingestion triggers a cascade of biochemical events that result in severe clinical disease.
Hereditary fructose intolerance is an autosomal recessive trait that is equally distributed between the sexes.
In many infants, the age at symptom onset leads to the diagnosis. An accurate dietary history can indicate a link between the introduction of fruits into the diet and symptom onset.
The incidence of hereditary fructose intolerance in the Caucasian population has been estimated at 1 in 20,000 births. 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.
These patients are healthy and asymptomatic until fructose or sucrose (table sugar) is ingested (usually from fruit, sweetened cereal, or sucrose-containing formula).
Clinical features include-
- Recurrent vomiting,
- Abdominal pain, and
- Hypoglycemia that may be fatal.
Older patients who survive infancy develop a natural avoidance of sweets and fruits early in life and as a result frequently are without any dental caries.
Long-term exposure to fructose can result in
- Liver failure
- Renal tubulopathy,
- Growth retardation.
- Progression of liver and kidney failure, eventually leading to death.
Based on the thorough dietary history of an ill child, the most straightforward approach to diagnosis of fructose 1-phosphate Aldolase deficiency is to demonstrate the presence of a non–glucose-reducing sugar in the urine. This is readily accomplished with Clinitest. Then, if test results are positive, thin-layer chromatographic separation should be used for confirmation.
Urine metabolic screening results may also provide evidence of glucosuria, proteinuria, and aminoaciduria, all of which are part of Renal Fanconi syndrome.
Plasma electrolyte levels are important to determine, because the renal tubular acidosis component of hereditary fructose intolerance (HFI) may significantly depress the total plasma bicarbonate level.
Obtain liver function test results to assess the degree of hepatocellular disease.
Elimination of dietary fructose is both a compulsory and therapeutic step. In patients who are ill, elimination may also serve as a diagnostic test because all symptoms should completely resolve.
Only asymptomatic patients in a controlled setting should undergo intravenous fructose tolerance testing; use oral fructose tolerance testing is avoided because of the potentially violent GI response.
The combination of a therapeutic response to fructose elimination and a positive response to the fructose tolerance test is sufficient to exclude obtaining a biopsy sample. However, a molecular analysis in leucocytes of the gene on chromosome 9 may provide definitive evidence of a mutation at the q22.3 band.
Consists of the complete elimination of all sources of sucrose, fructose, and sorbitol from the diet. With this treatment, liver and kidney dysfunction improve, and catch-up growth is common. Intellectual development is usually unimpaired. As the patient matures, symptoms become milder, even after fructose ingestion, and the long-term prognosis is good. Hepatomegaly may require months to resolve. Prolonged delay in diagnosis may result in cirrhotic changes with subsequent degeneration of function.
Drug therapy is not a component of the standard of care for this condition.
Morbidity is implicit in untreated patients. Hypoglycemia and acidosis may act together to cause organ shock or coma. Ongoing hepatocellular insult may result in cirrhosis and eventual hepatic failure. Failure to thrive progressing to cachexia is the rule. Mortality may result from any or all of the above conditions
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