Errors of D-Fructose Metabolism

In most of the family relationships examined, the occurrence of HFI conforms to an autosomal, recessive inheritance best illustrated in a study with eight patients reported by Foresch and coworkers.72 However, a few families are known with an apparent, autosomal, dominant inheritance.151-153 These may be instances of pseudodominance, but real genetic and biochemical heterogeneity of the syndrome is also possible. A test to indicate the heterozygous state for HFI would be of value. 

Besides hypoglycemia, D-fructose-induced renal acidification in the HFI defect involves a lowered hydrogen-ion secretory capacity of the proximal nephron, as evidenced by a 20 to 30% diminution in renal-tubular (T) reabsorption of bicarbonate (THCO3) and simultaneous occurrence, and persistence throughout D-fructose administration, of impaired tubular reabsorption of phosphate, cc-amino nitrogen, and uric acid. This abnormality of renal metabolism affects the renal cortex, which contains aldolase B, but does not affect the renal medulla. Thus, the abnormality may result from accumulation of D-fructose 1-phosphate in the renal cortex. The intimate, biochemical mechanism for renal, tubular acidosis is still unknown.164 

Subcellular pathology in HFI patients is observed with the electron microscope two hours after injection of 50 g of D-fructose. In the jejunum, the brush-border region of the absorptive cells remains normal, but concentric arrays of smooth membranes are noted in supranuclear regions. In the liver, the changes are most elaborate and widespread. Concentric, and irregularly disposed, membranous arrays occur in the glycogen area of most hepatocytes, and are associated with marked rarefaction of the hyaloplasm. Many of the membranous formations resemble cytolysomes.165 The formation of the lesions is probably related to the intracellular accumulation of D-fructose 1-phosphate.165 

Symptoms of HFI in infants typically start after weaning,72 154 and, in some cases, weaning may be difficult to accomplish because of aversion to sweetened food. Many infants with HFI die of the disease, because they are unable to select their food.166 In older patients, the dietary history of aversion to sugar, sugar-containing foods, fruits, and berries is almost diagnostic. Confirmation of diagnosis is obtained by 

The molecular basis of HFI involves the deficiency of normal D-fructose 1-phosphate aldolase activity, and low activity of D-fructose 1,6-bisphosphate aldolase in liver, intestine, and renal cortex. Accumulated D-fructose 1-phosphate leads to a diminution of liver-glycogen phosphorylase activity, causing severe hypoglycemia. An accumulation of D-fructose 1-phosphate produces renal acidification and subcellular pathology of the jejunum and liver. 

---