Glycogenoses

The activity of many enzymes of glycogenolysis( enzymes involved in the decomposition of glycogen) in the fetal liver is much lower than in adults, whereas the activity of the amyloglucosidase enzyme( under the influence of which further glycogen degradation occurs with the formation of glucose) approaches that of adults. This explains the high potential ability of the fetus to mobilize glucose from glycogen.

The structure of glycogen in the form of an open branched structure makes it readily available for enzymes, so that glycogen in the muscles is a ready source for immediate energy supply. In the liver, which uses primarily fatty acids as an energy substrate, glycogen is split, providing an uninterrupted supply of brain glucose and red blood cells. This difference emphasizes the central role of the liver in maintaining a constant level( homeostasis) of glucose at the body level.

Among the disorders of carbohydrate metabolism, which are characterized by an increase in the liver( hepatomegaly) and a decrease in blood glucose( hypoglycemia), include

glycogenosis IA type( also known as glucose-6-phosphatase defect, Girke's disease).

The cause of a variety of symptoms that occur with glycogenase I A type is the deficiency of the multifunctional enzyme glucose-6-phosphatase, which acts at the last stage of glucose formation( gluconeogenesis).This enzyme provides the formation of more than 90% of glucose released in the liver;therefore, he plays a central role in the normal homeostasis of glucose. In the decay of glycogen or as a result of glucose synthesis, glucose-6-phosphate forms, splitting off part of the molecule from which it converts glucose into the bloodstream.

Permanent symptoms of Girke's disease are hypoglycemia and low levels of insulin.

The pseudoglycogenosis I is isolated, in which the defect does not concern glucose-6-phosphatase, but the glucose-6-phosphate transfer systems.

The clinical picture of Girke's disease is characterized by hypotrophy( weight loss), combined with liver enlargement( hepatomegaly), hypoglycemia, and other biochemical changes in the body. Often there is an increase in kidneys, which may accompany the release of glucose in the urine( glucosuria).Sometimes the release of ketone bodies with urine( ketonuria) is detected, however, the development of a severe condition, such as ketoacidosis, is not characteristic. Quite often develop complications such as prolonged bleeding, characterized by a violation of the function of thrombocytes. At an older age, xanthomas develop. Sick children have a characteristic face, reminiscent of a Chinese doll.

The diagnosis is based on the presence of a triad of disorders, such as hypoglycemia, hyperlactatemia and hyperuricemia.

Determination of the activity of a key enzyme in a material taken from a hepatic tissue biopsy helps confirm the diagnosis and choose the right treatment. The latter involves limiting food products containing lactose and sucrose, from which an additional amount of glucose-6-phosphate is formed.

Glycogenosis II type ( also called maltase maltose deficiency, Pompe disease) is described by Pompe in 1932.

Symptoms of the disease appear already at the beginning of the first year of life in the form of a bad weight gain, increased excitability, hypotension, respiratory depression with cyanosis,increasing the language;develops cardiomegaly( an increase in the size of the heart).As a rule, such pathology from the side of the cardiovascular system is revealed by roentgenology( the globular shape of the heart is characteristic) and with ultrasound examination of the heart.

The disease progresses rapidly, the treatment of this disease, in most cases leading to death, is only symptomatic. There are descriptions of a lighter version of the pathology, manifested in the older age, in which only striated muscle is affected.

Based on glycogenosis type III ( Cory's disease, Forbes disease) lies the defect of the enzyme amylo-1,6-glucosidase. In the absence of the above enzyme, there is no complete cleavage of glycogen.

The clinical picture consists of augmentation of the liver, muscle weakness and other disorders, fasting hypoglycaemia, as well as a puppet person, as with Girke's disease. The kidneys do not increase, but sometimes they notice an increase in the spleen and xanthoma.

The results of a laboratory study are similar to those of type I glycogenase. Optimal therapeutic effect gives a protein-rich diet with frequent meals. In infancy and during the course of infectious diseases, night feeding is important. The prognosis is relatively favorable, much more favorable than with Girke's disease.

Glycogenosis IV type ( amylopectinosis, Andersen's disease) is a rare severe form of glycogen storage disease that develops as a result of the deficiency of the enzyme amylo-1,4,1,6-transglucosidase. When this enzyme is deficient, a structurally altered glycogen is formed.

For Andersen's disease, cirrhosis of the liver with jaundice and liver failure, which develops in infancy, is typical. Glycogen is also deposited in the heart, kidneys, spleen, lymph nodes, skeletal muscles;as a result of the latter, muscular weakness is often noted, which may precede severe impairment of liver function.

Treatment of the disease is only symptomatic.

Glycogenosis V type ( myophosphorylase deficiency, Mc-Ardl's disease) was first described in 1951. This disease was detected in a patient with muscle aches after minor physical exertion, while at rest there were no symptoms. In this disease there is a deficiency of the enzyme( muscle phosphorylase).This enzyme differs from hepatic phosphorylase, so the liver is not affected in the case of Mc-Ardl's disease, and glycogen is deposited excessively in muscles, which after physical exertion breaks down, and so the soreness noted before by the patients passes.

The first signs of the disease, as a rule, develop at the end of the second - the beginning of the third decade of life. Sometimes it is episodic myoglobinuria, especially after intense physical exertion. The diagnosis is based on the definition of increased activity of muscle enzymes in the blood serum after physical stress( such as lactate dehydrogenase, aldolase, creatine phosphokinase) and the determination of myoglobin in the urine. Increase in the concentration of lactic acid in the blood serum is not observed, since the energy requirements of the muscles are satisfied by fatty acids, and not by glucose.

Treatment consists in limiting severe physical exertion. The prognosis is generally relatively favorable, in severe cases the disease leads to disability.

Glycogenosis VI type ( insufficiency of the hepatic phosphorylase complex, Hers disease) is characterized by a mutation of the structural gene encoding the activity of the enzyme of hepatic phosphorylase and adhered to the 14th chromosome.

Clinical manifestations are less pronounced than with glycogenases of types I and III.Mark hepatomegaly, a slight slowdown in growth rates, ie, compared with other glycogenases is an easy variant of the disease of accumulation of glycogen. Hypoglycemia is not typical. Sometimes the level of enzymes of transaminases is increased.

To confirm the diagnosis, it is necessary to investigate the activity of the enzyme system in peripheral blood leukocytes or in biopsy liver tissue.

The basis of treatment is a diet with high protein content( 15-20% of total calories), as well as frequent meals. Fats should account for 30-35% of calories, carbohydrates are recommended in the form of starch and glucose. At adolescence, the size of the liver decreases. Dietotherapy prevents possible hypoglycemia. The prognosis for life is good, mental development does not suffer.

Glycogenosis VII type ( a violation of the function of the enzyme muscle phosphofructokinase).This type of glycogenosis is reminiscent of McDurdl's disease in that intense physical stress causes an increase in lactic acid levels in the blood, muscle pain and destruction can occur, accompanied by the release of myoglobin protein( myoglobinuria), the main structural protein of muscle tissue, in the urine.

Treatment consists in limiting physical activity, preventing the appearance of clinical symptoms.

Glycogenosis VIII type is characterized by a deficiency of the enzyme of hepatic phosphorylase, kinase;Inherited in adhesion to the X chromosome. Clinical manifestations correspond to those in type VI glycogenesis.

Other inherent disorders of carbohydrate metabolism, often leading to liver enlargement, include hereditary fructose sugar intolerance, as well as galactosemia( developing as a result of the deficiency of the galactosophosphate-uridyltransferase enzyme).

Liver enlargement is usually due to fatty degeneration resulting from the reaction of the hepatic tissue to the accumulation of excessive amounts of toxic intermediates of fructose metabolism.

In liver disorders, when the concentration of bile acids in the intestinal cavity falls below the critical level due to the cessation of bile excretion into the duodenum, assimilation of dietary fats is sharply reduced, and steatorea( the release of large amounts of fat) develops a second time.

Bile is synthesized by the liver and is collected in the gallbladder, one of the main functions of which is bile concentration by removing a portion of water from it. The release of bile from the gallbladder during digestion is due to the substance cholecystokinin, while hepatocrinin stimulates the formation of bile by the liver. Both these hormones are secreted by the upper parts of the small intestine in response to food ingestion there. Bile acids, inherently steroids, are important end products of cholesterol metabolism, which are removed from the blood by the liver and used for the synthesis process. However, it should be noted that cholesterol itself is also present in the bile. Bile acids are not released in free form into the lumen of the intestine, but bind to the liver with other substances, such as amino acids( glycine and taurine), and in the form of complex bound compounds are secreted with bile. Such binding increases the solubility of bile acids, which facilitate the process of formation in the aqueous medium of substances containing cholesterol and phospholipids.

Bile acid binding affects their absorption in the jejunum, so that their concentration in the upper part of the small intestine is maintained above the critical level.

Since bile has an alkaline reaction, conjugated bile acids are usually neutralized by reaction with sodium and potassium, forming bile salts. The resulting compounds have an emulsifying effect on the contents of the intestine, thereby helping to digest fat by forming micelles. In addition, alkaline bile, due to the effect on the pH of intestinal contents, activates a number of pancreatic enzymes.

After absorption of dietary fats conjugated bile acids in the terminal part of the ileum come back to the liver and are removed again with bile. This circulation occurs after each meal, with about 90-95% of bile acids released during each cycle being reabsorbed. Those bile acids, which are not absorbed in the ileum, are exposed to the intestinal bacterial flora, with the formation of secondary bile acids. It should be noted that it is important that the ratio of these acids is stable( choleln - 50%, chenodeoxycholic - 30%, deoxycholic - 15%, lithocholic - 5%), a violation of this equilibrium leads to cholelithiasis.

In newborns, the production of bile acids is approximately twice lower than in adults, hence their concentration in the intestine is also lower. This circumstance prevents the formation of micelles and the complete absorption of dietary fats. As a result, a large loss of bile acids with feces is accompanied by insufficient absorption in the intestine. In premature infants the concentration of bile acids in the intestine is much lower than the critical level required for the formation of micelles. Thus, the inferiority of the processes of formation and circulation of bile in newborns is manifested by significant losses of bile acids with feces, a violation of digestion of edible fats and fat-soluble vitamins, and a tendency to stagnate bile( cholestasis).Disorders of bile acid synthesis are observed in liver cirrhosis, some forms of xanthomatosis, cholestasis, enzyme deficiency( cholesterol-12-a-hydroxylase), enterohepatic circulation disorders and absorption disorders in premature and immature children, after ileal resection, in cystic fibrosis,with the syndrome of the contaminated small intestine.