Intracellular carbohydrate change

Carbohydrates are divided into 3 groups:

1) polysaccharides (glycogen);

2) mucopolysaccarides;

3) glycoproteides (mucin, mucoid).

There are several special reactions for identification of these carbohydrates, PAS or SHIK reaction and carmine according to Best are used for identification polysaccharides (glycogen) and mucopolysaccarides. Polysaccharides and mucopolysaccarides are stained dark pink or red.

Staining according to Haile — for identification glycoproteides. Glycoproteides are stained blue.

Glycogen metabolism disturbance is significant in the human pathology. It is known that glucose which enters the organism with the food polymerizes to glycogen which accumulates in the liver and muscles and is called labile glycogen.

Glycogen in the nervous cells, endothelium, connective tissue, cartilages and other cells is called stable glycogen.

Disturbance of glycogen amount manifests with:

• increase or reduction in the amount in the tissues where it is present under normal conditions;

• its appearance in the areas where it is not present under normal conditions.

Glycogen metabolism disturbance occurs in diabetes mellitus. (See Endocrine pathology). In this disease insulin insufficiency causes glucosuria and hyperglycemia. Glycogen amount in the tissues reduces sharply (e.g. in the liver) which causes its fat infiltration (fatty liver degeneration). Glucosuria causes changes in the kidneys. Glycogen infiltration of the tubular epithelium develops (we observe glycogen in the cells and lumens). In the glomeruli, microangiopathy develops due to their increased permeability for sugar and protein. It's called intercapillary (diabetic) glomerulonecrosis.

Storage diseases

There are a lot of diseases which are due to hereditary factors and connected with metabolism disturbance. Those diseases are called storage diseases or enzymopathy.

A few general comments can be made about all storage diseases:

1. All the storage diseases occur as a result of autosomal recessive, or sex-(X)linked recessive genetic transmission.

2. Most of the storage diseases are lysosomal storage diseases. Out of the glycogen storage diseases, only type II (Pompe's disease) is due to lysosomal enzyme deficiency.

According to the type of metabolism disturbance storage diseases have been classified into proteinoses, lipidoses and glucogenoses. The type of proteinoses, lipidoses and glucogenoses depends on the defect in the enzyme.

The most frequent of them are described in the above diagrams.


Disease Enzyme Organs in which pathologic proteins accumulate
Cystinosis - Liver, kidney, spleen, eyes, skin
Tyrosinosis Tyrosine-aminotransferase Liver, kidney, bones
Phenylpyruvic oligophrenia Phenylalanines-hydroxylase Central nervous system, muscles, skin, blood, urine

Cystinosisis a rare metabolic disease with an autosomal recessive inheritance. It is characterized by deposition of an extraordinary amount of cystine in different organs of the body, particularly the kidneys. In children, cystinosis is the most common cause of proximal renal tubular acidosis as seen in Fanconi syndrome. Deposition of cystine may also occur in brain, bones, liver, lymph nodes, fibroblasts, leukocytes, cornea, conjunctiva, thyroid, pancreas and intestines. Depending on the degree of involvement, there are different types of cystinosis: infantile (nephropathic), adolescent (intermediate) and adult (benign) type (Schneider JA, Katz B, Melles RB., 1990).

Nephropathic cystinosis is transmitted as an autosomal recessive trait with an incidence of 1 in 200 000 live births. The actual defect is located at the levl of lysosomal transportation. The infantile or nephropathic cystinosis involves many organs and systems particularly kidneys which are the first to get involved leading to renal insufficiency. In adolescent type nephropathy is mild and renal involvement progresses very slowly. In the adult type renal involvement is not seen. Recently the disease is classified into two types: nephropathic cystinosis and non-nephropathic cystinosis. The nephropathic type is progressive, starting with symptoms between 6 and 18 months of age whereas non-nephropathic type is found in childhood at the age of A—5 years and in adolescent 12—15 years.

The extrarenal signs of cystinosis are numerous and are caused by intracellular accumulation of cystine in various organs, which continues even after renal replacement therapy. The most prominent features are rickets and growth retardation. Despite intensive supplementation with fluids, electrolytes, vitamins and calories, it is not possible to achieve a normal growth rate. The eyes are involved early extensively. Patchy retinal depigmentation, sparkling crystal in the cornea and abundant crystals in the conjunctiva are observed.

Phenylketonuria (PKU, phenylpyruvic oligophrenia)with its associated hyperphenylal-aninemia (HPA) and mental retardation, is a classic

genetic disease. The disorder is caused by a mutant allele at the phenylalanine hydroxylase (PAH) locus that results in lack of functional PAH, the liver enzyme required for hydroxylation of phenylalanine. The disease is environmental in that the clinical phenotype is produced by the presence in food of L-phenyl-alanine, an essential amino acid. Thus, combining dietary phenylalanine with lack of phenylalanine catabolism produces hyperphenylalaninemia, and this leads to mental retardation. Successful treatment requires control of the hyperphenylalaninemia. The relationship between hyperphenylalaninemia and brain dysfunction in PKU is indisputable, even though the proximate cause of the brain damage is unknown. Children born with even the most severe form of PKU can have normal cognitive development when dietary treatment begins in early infancy and the blood phenylalanine concentration is maintained at near normal or normal levels .

Woolf and Vulliamy in 1951 were the first to suggest that the levels of phenylalanine and the biochemical byproducts of hyperphenylalaninemia could be reduced by restricting the dietary intake of phenylalanine. Two years later, Bickel et al. followed this suggestion by constructing a phenylalanine-restricted diet and using it to treat a child with PKU who was mentally retarded. They demonstrated that the diet produced both a marked reduction in the blood phenylalanine concentration and improvement in behavior.

During the next few years, a number of infants known to be at risk for PKU were diagnosed and begun on the diet soon afterbirth. Follow-up studies of these infants indicated that, under these conditions, the diet could prevent mental retardation. This led to newborn screening for PKU which, by the mid-1960s, was routine throughout the United States and, by the early 1970s, was routine throughout most of the developed world. Over 150 million infants now have been screened, and over 10,000 have been detected with PKU and have been treated with diet.

Some important forms of lipidoses are described below.


Disease Enzyme Organs in which pathologic lipids accumulate
Gaucher disease -cerebrosid-lipidosis Glycocerebrosi-dase Liver, spleen, bone marrow, central nervous system
Niemann-Pick disease (sphingo-myelinlipido-sis) Sphingomyelinase Liver, spleen, bone marrow, central nervous system
Tay-Sachs disease (amaurotic idiopathy) Hexosaminidase Central nervous system, retina, spleen, liver
Normann-Landing disease (generalized gangliosidosis) B-galactosidase Central nervous system, nervous bands, liver, spleen, bone marrow, kidneys

Gaucher's Disease

This is an autosomal recessive disorder in which there is deficiency of lysosomal enzyme, gluco-cerebrosidase, which normally cleaves glucose from ceramide. This results in lysosomal accumulation of glucocerebroside (ceramide-glucose) in phagocytes of the body and sometimes in the neurons. The main sources of glucocerebroside in phagocytes are the membrane glycolipids of old leukocytes and erythrocytes, while the deposits in the neurons consist of gangliosides.

Clinically, there are 3 types of Gaucher's disease:

Type I or classic form is the adult form of the disease in which there is storage of glycocerebrosides in the phagocytes of the body, principally involving the spleen, liver, bone marrow and lymph nodes. This is the most common type comprising 80% of all cases of Gaucher's disease.

Type II is the infantile form in which there is progressive involvement of the central nervous system.

Type III is the juvenile form of the disease having features in between type I and type II, i.e. they have systemic involvement like in type I and progressive involvement of the CNS as in type II.

The clinical features depend upon the clinical subtype of Gaucher's disease. In addition to involvement of different organs and systems (splenomegaly, hepatomegaly, lymphadenopathy, bone marrow and

cerebral involvement), a few other features include pancytopenia, or thrombocytopenia secondary to hypersplenism, bone pains and pathologic fractures. Microscopically large number of characteristically distended and enlarged macrophages called Gaucher cells which are found in the spleen, liver, bone marrow and lymph nodes, and in the case of neuronal involvement, in the Virchow-Robin space. The cytoplasm of these cells is abundant, granular and fibrillar resembling crumpled tissue paper. They have mostly a single nucleus but occasionally may have two or three nuclei. Gaucher cells are positive with PAS, and Prussian-blue reaction indicating the nature of accumulated material as glycolipids admixed with haemosiderin. These cells often show erythro-phagocytosis and are rich in acid phosphatase.

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