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Metabolism of fructose-Lecture-2 (Clinical significance of fructose metabolism)
For Metabolism of fructose Lecture-1
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1) Hereditary fructose Intolerance
Biochemical defect- Hereditary fructose intolerance is caused by mutation in the gene encoding Aldolase B enzyme.
Inheritance- It is an autosomal recessive trait that is equally distributed between the sexes.
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
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 Fructose-1-P levels in the hepatocytes.
The hypoglycemia that results following fructose uptake is caused due to
a) Inhibition of glycogenolysis, by fructose-1-phosphate, interfering with the phosphorylase action; and
b) Inhibition of gluconeogenesis at the deficient aldolase step.
Since the rate of fructose phosphorylation by fructokinase is so high, intracellular levels of both ATP and inorganic phosphate (Pi) are significantly decreased. The drop in ATP concentration adversely affects a number of cellular events, such as:
i) A hyperuricemic condition as a result of an increase in uric acid formation- See the details below (Figure 1)
ii) Severe hepatic dysfunction may be a manifestation of focal cytoplasmic degeneration and cellular fructose toxicity.
iii) Renal tubular dysfunction-The cause remains unclear; patients with renal tubular dysfunction primarily present with a proximal tubular acidosis complicated by aminoaciduria, glucosuria, and phosphaturia.
- Urine analysis for the presence of reducing sugar- 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.
i) Complete elimination of all sources of sucrose, fructose, and sorbitol from the diet. With this treatment, liver and kidney dysfunction improve, and symptoms become milder, even after fructose ingestion, and the long-term prognosis is good.
ii) Hepatomegaly may require months to resolve.
Prolonged delay in diagnosis may result in cirrhotic changes with subsequent degeneration of function.
2) Essential Fructosuria
Biochemical defect- Essential fructosuria, also known as hepatic fructokinase deficiency or keto hexokinase deficiency, is a hereditary metabolic disorder caused by a deficiency of hepatic fructokinase, leading to fructose being excreted in the urine.
Inheritance– The inheritance is autosomal recessive.
Essential fructosuria, apparently a harmless condition, is an extremely rare error of metabolism, the recognition of which is of importance because it may be mistaken for diabetes mellitus.It is characterized by the patient’s inability to utilize fructose normally, whether it is ingested as simple fructose or as a substance capable of yielding fructose on digestion, such as cane sugar. It is manifested clinically by a symptom less excretion of fructose in the urine.
Essential fructosuria should not be confused with hereditary fructose intolerance which is a very serious condition, and is due to deficiency of Aldolase B enzyme. It causes a rise in uric acid, growth abnormalities, in severe cases hepatic or renal failure and finally coma or death.
On the other hand, being symptomless, Fructosuria is commonly left undetected or undiagnosed.
3) Hyperuricemia upon excessive fructose ingestion
Fructose is mainly metabolized through Fructose-1-p pathway. Unlike phosphofructokinase, which is involved in glucose metabolism, fructokinase has no negative feedback system to prevent it from continuing to phosphorylate its substrate, i.e. Fructose to form fructose -1 phosphate, and as a consequence ATP can be depleted(Figure –1). ADP formed from the first step is converted to AMP, which is a substrate for AMP deaminase enzyme for further metabolism.
Figure-1-The phosphorylation of fructose catalyzed by fructokinase is faster than subsequent cleavage by Aldolase, as a consequence ATP pool is depleted, with the resultant rapid degradation of ADP to AMP and finally to uric acid through intermediate formation of IMP, hypoxanthine and uric acid.
AMP deaminase enzyme that causes conversion of AMP to IMP (Inosine monophosphate) is regulated by inorganic phosphate. The rising concentration of inorganic phosphate inhibits this enzyme to prevent degradation of AMP. Upon excessive fructose ingestion, inorganic phosphate pool is depleted as a result the inhibition of AMP deaminase is lost. The overactive AMP deaminase converts AMP to IMP at an enhanced rate. IMP, is subsequently converted to hypoxanthine then to xanthine and finally to uric acid. Excessive uric acid generation leads to gout or renal stones.
Figure 2- 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 to uric acid, thus excess uric acid is formed upon excessive fructose ingestion.
4) Obesity upon excessive fructose consumption
Excessive fructose intake (>50 g/d) has been found to be one of the underlying etiologies of obesity, insulin resistance and metabolic syndrome. The mechanism responsible for the metabolic changes may be described as follows-
Synthesis of triglycerides – Carbons from dietary fructose are found in both the free fatty acid and glycerol moieties of plasma triglycerides. Fructose undergoes more rapid glycolysis in the liver than does glucose, because it bypasses the regulatory step catalyzed by phosphofructokinase (Figure-3). This allows fructose to flood the pathways in the liver. High fructose consumption can lead to excess pyruvate production, causing a buildup of glycolytic intermediates and Acetyl co A. Dihydroxyacetone phosphate (DHAP), the glycolytic intermediate, can be converted to glycerol 3-phosphate providing the glycerol backbone for the triglyceride molecule. Excess Acetyl co A is channeled towards fatty acid synthesis.
Triglycerides , thus synthesized are incorporated into very low density lipoproteins (VLDL), which are released from the liver destined toward peripheral tissues for storage in both fat and muscle cells. Excessive fatty acid and triglyceride levels form the basis for the development of the metabolic syndrome, hypertension, glucose intolerance and type 2 diabetes mellitus.
In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric over consumption. Thus, the increase in consumption of HFCS (High fructose corn syrup) has a temporal relation to the epidemic of obesity, and the over consumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity.
Figure-3- Hypertriglyceridemia upon excessive fructose consumption
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