Fructose metabolic disorders

Palyza V, Bockova M. Poruchy metabolismu fruktozy a infuze. [Fructose metabolism disorders and infusions.] Vnitr Lek 1992 38(8) 814-21. 

Steinmann B, Gitzelmann R, Van den Berghe G (2001) Disorders of fructose metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, pp 1489-1520... 

Endogenous hepatosis comprises endogenous metabolic disorders of the liver cell as a rule, the terminology used in this context refers to the accumulated substances (e. g. glycogenosis), the harmful substrate (e.g. fructose-1 phosphate) or the enzyme defect (e.g. apantitrypsin deficiency). 

Fructose may appear in the urine after eating fruits, honey, and syrups, but has no significance in these circumstances. Three disorders of fructose metabolism, inherited as autosomal recessive traits, produce fructosuria. 

Biochemical basis of disorder Because of a genetic disorder, the hepatic aldolase B enzyme is defective, and functions normally in glycolysis but not in fructose metabolism. Glucose production is inhibited by elevated fructose 1-phosphate. When fructose is ingested, severe hypoglycemia results. 

More than 50% of the adult population are estimated to be unable to absorb fructose in high doses (50 g), and more than 10% cannot completely absorb 25 g fructose. These individuals, like those with other disorders of fructose metabolism, must avoid fruits and other foods containing high concentrations of fructose. 

Carbohydrate metabolism disorders like hereditary fructose intolerance and galactosemia result in acute, leading to chronic, liver damage through depletion of available ATP (by depleting the total phosphate pool) as well as aberrant glycosylation [1, 2]. Gluconeogenic defects like pyruvate carboxylase or 1,6-fructose-bis-phosphatase deficiency... 

Disorders of fructose metabolism are usually recognized during infancy or childhood when the ingestion of fructose or sucrose-containing foods results in vomiting, growth failure and/or hepatomegaly. 

Van den Berghe G (2000) Disorders of fructose metabolism. In Inborn metabolic diseases, Fernandes J, Saudubray J-M, van den Berghe G (eds). Springer-Verlag Berlin Heidelberg New York, 3rd edition 110-116. 

Some inherited metabolic disorders are extremely damaging while the effects of others are so mild that they can hardly be called diseases. For example, alkaptonurics are usually quite healthy although in later life they are prone to a particular form of arthritis. Similarly the conditions of fructosuria and pentosuria, in which fructose and pentose sugars respectively appear in the urine, have no pathological consequences. At the other end of the scale is phenylketonuria in which the enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine, is lacking. In this condition phenylpyruvic acid and other intermediate products of phenylalanine metabolism accumulate in the blood and tissues and are so injurious to the central nervous system that, although physical development is essentially normal, there is severe mental retardation. 

Fructose-1,6-bisphosphatase deficiency, first describ ed by Baker and Winegrad in 1970, has now been reported in approximately 30 cases. It is more common in women and is inherited as an autosomal recessive disorder. Initial manifestations are not strikingly dissimilar from those of glucose-6-phosphatase deficiency. Neonatal hypoglycemia is a common presenting feature, associated with profound metabolic acidosis, irritability or coma, apneic spells, dyspnea, tachycardia, hypotonia and moderate hepatomegaly. Lactate, alanine, uric acid and ketone bodies are elevated in the blood and urine [11]. The enzyme is deficient in liver, kidney, jejunum and leukocytes. Muscle fructose-1,6-bisphosphatase activity is normal. 

DHAP is a glycolysis intermediate, whereas glyceraldehyde must be reduced by a mitochondrial enzyme, glyceraldehyde dehydrogenase, to glycerol, which is then subject to action by glycerol kinase in the liver. The aldolase seems to be the principal pathway of metabolizing fructose and depends on the initial phosphorylation step catalyzed by fructokinase, which produces fructose-l-phosphate. Fructokinase is defective in an inherited disorder, essential fructosuria. Fructose-l-phosphate aldolase is deficient in the hereditary disorder fructose intolerance. 

Metabolic mutant. What are the likely consequences of a genetic disorder rendering fructose 1,6-bisphosphatase in liver less sensitive to regulation by fructose 2,6-bisphosphate ... 

Hereditary fructose intolerance is caused by an autosomal recessive hereditary defect of the enzyme fructose-l-phosphate aldolase. Whenever fructose is supplied, severe hypoglycaemia and functional disorders occur in the liver, kidneys and CNS. The prevalence is estimated at 1 20,000 births. As with galactose intolerance, the gene which codes aldolase B is also localized on chromosome 9. This enzyme defect causes fructose-l-phosphate to accumulate in the liver and tissue. The cleavage of fructose-1,6-biphosphate is only slightly compromised since the enzymes aldolase A and C are available for this process. The consumption of phosphate and ATP in the tissue results in various functional disorders (i.) inhibition of gluconeogenesis in the liver and kidneys, (2.) increase in lactate in the serum with metabolic acidosis, (3.) decrease in protein synthesis in the liver, and (4.) functional disorders of the proximal tubular cells with development of Fanconi s syndrome, (s. pp 593, 594) (193, 194, 196, 198)... 

Storage diseases Some of the genetic metabolic diseases require special dietary measures, e.g. (1.) disorders of the urea cycle are treated by means of a diet similar to that applied in encephalopathy (s. p. 594), (2.) Gierke s disease necessitates a high-carbohydrate diet (s. p. 595), (i.) Cori s disease is treated with formula diets and a starch diet (s. p. 596), (4.) galactosaemia requires a galactose-and lactose-free diet (s. p. 597), and (5.) in fructose intolerance, a fructose- and saccharose-free diet must be given, (s. p. 597)... 

The dangers of consuming HFCS are apparent for at least one group of people, those who lack the enzyme needed to metabolize fructose properly. Individuals with this genetic disorder may develop serious reactions if exposed to even a very small amount of fructose, reactions that include sweating, nausea, vomiting, confusion, abdominal pain, and, in extreme cases, convulsion and coma. Fortunately, this disorder is quite rare, affecting one person in about every twenty thousand individuals. For those with the disorder, however, care must be used in the kinds of sweeteners included in the diet. 

Intoxication disorders include urea cycle disorders, organic acidurias, aminoacidopathies, fatty acid oxidation disorders, and carbohydrate disorders such as galactosemia or hereditary fructose intolerance. In these disorders, a partial or complete lack of enzymatic activity causes the accumulation of substances proximal to the metabolic block in tissues and body fluids, where they act as toxins (Fig. 5.1). Treatment is based on limiting the substances that are the source of the toxic metabolites and introducing alternatives (e.g., drugs, procedures) that speed the elimination of those toxic metabolites. 

Previous observations in hereditary fructose intolerance also suggest that fructose-induced hyperuricemia cannot be attributed to increased levels of PP-ribose-P. The infusion of fructose produces hyperuricemia in this disorder despite a block in the further metabolism of fructose-l-P in these patients. 

This chapter deals with disorders of galactose, fructose and glycogen metabolism. The clinical presentations of these disorders can be mild or severe and life-threatening. The clinical features include failure to thrive, hepatomegaly, hypoglycemia, jaundice, metabolic acidosis, and myopathy including muscle pain and weakness. 

Glycerol kinase deficiency (GKD) is the only disorder of glycerol metabolism for which the biochemical defect is known and well-characterized [1]. Glycerol intolerance syndrome (GIS) is poorly characterized and appears to be associated, at least in part, with fructose-1,6-diphosphatase deficiency [2-5]. Among individuals with GKD, there are three distinct clinical phenotypes, the complex form (17.1.1) and two subtypes of the isolated form -symptomatic (juvenile, 17.1.2) and benign (adult, 17.1.3) [1]. 

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