Chromoprotein metabolism disorder: causes, symptoms, diagnosis, treatment

Disturbances in the metabolism of chromoproteins affect both exogenous and endogenous pigments. Endogenous pigments (chromoproteins) are divided into three types: hemoglobinogenic, proteinogenic, and lipidogenic. Disturbances consist of a decrease or increase in the amount of pigments formed under normal conditions, or the appearance of pigments formed under pathological conditions.

A distinction is made between local and general pigment disorders, primary, mostly genetically determined, and secondary, associated with various pathological processes.

Hemoglobinogenic pigmentations develop due to the appearance of hemoglobin derivatives in tissues. Hemoglobin consists of the protein globin and a prosthetic part - heme, which is based on a protoporphyrin ring associated with iron. As a result of the physiological breakdown of erythrocytes and hemoglobin in mononuclear phagocytes, pigments are formed: ferritin, hemosiderin and bilirubin.

Ferritin is an iron protein containing up to 23% of iron bound to protein. Normally, ferritin is found in large quantities in the liver, spleen, bone marrow and lymph nodes, where its metabolism is associated with the synthesis of hemosiderin, hemoglobin and cytochromes. Under pathological conditions, the amount of ferritin in tissues can increase, for example, in hemosiderosis.

Hemosiderin is formed by the breakdown of heme and is a polymer of ferritin. It is a colloidal iron hydroxide associated with proteins, mucopolysaccharides and lipids of cells. Hemosiderin is always formed intracellularly in sideroblasts - mesenchymal cells, in the siderosomes of which hemosiderin granules are synthesized. When hemosiderin appears in the intercellular substance, it is phagocytized by siderophages. The presence of hemosiderin in tissues is determined using the Perls reaction. Based on the results of this reaction, hemosiderin can be distinguished from hemomelanin, melanin and lipofuscin. In pathological conditions, excessive formation of hemosiderin (hemosiderosis) is observed. General hemosiderosis develops with intravascular destruction of red blood cells (intravascular hemolysis), with diseases of the hematopoietic organs, intoxications and some infections (flu, anthrax, plague). Local hemosiderosis occurs with extravascular destruction of red blood cells (extravascular hemolysis), for example, in the foci of small and large hemorrhages.

In the skin, hemosiderosis is observed quite often (with chronic capillary disease, chronic venous insufficiency, etc.). Clinically, it is characterized by the appearance of pinpoint hemorrhages, pigmentation, and, less often, telangiectasias, mainly on the lower extremities.

Hemochromatosis can be primary (idiopathic) and secondary. The changes have much in common with hemosiderosis. Primary hemochromatosis is a thesaurismoses, inherited mainly in an autosomal recessive manner, caused by a defect in enzymes that ensure iron absorption in the small intestine. Increased absorption of dietary iron leads to its accumulation in large quantities in various organs and tissues. The classic triad of symptoms includes skin pigmentation, liver cirrhosis, and diabetes mellitus. The possibility of predominant heart damage is indicated. The skin is bronze in color, which is due to an increase in the amount of melanin, with pigmentation most pronounced on exposed parts of the body. The same picture can be observed in secondary hemochromatosis. Histologically, an increase in the melanin content in the cells of the basal layer of the epidermis is noted, and in the dermis - hemosiderin deposition in perivascular elements and around the sweat glands.

Porphyrins are precursors of hemoglobin heme, they do not contain iron. They are found in small quantities in the norm (in urine, blood and tissues), and have the ability to increase the body's sensitivity to light. When porphyrin metabolism is disrupted, porphyrias occur, characterized by an increase in the amount of porphyrins in the blood, urine and feces, as well as a sharp increase in the sensitivity of the skin to ultraviolet rays.

LC Harber and S. Bickar (1981) differentiate erythropoietic and hepatic forms of porphyria. Among the erythropoietic forms, there are congenital erythropoietic porphyria of Ponter, erythropoietic protoporphyria, and among the hepatic forms, there are late cutaneous porphyria, mixed porphyria, hereditary coproporphyria, and also acute intermittent porphyria, which occurs without skin changes.

Congenital erythropoietic porphyria of Gunther is a very rare form of porphyria, inherited in an autosomal recessive manner, caused by a defect in uroporphyrinogen III-co-synthase, which leads to excessive formation of uroporphyrinogen I. Characterized by high sensitivity to light associated with the photodynamic action of porphyrins. Immediately after birth, erythema appears and blisters form under the influence of sunlight. Infection and ulceration in the lesions lead to severe deformation of the face and hands, scleroderma-like changes. Hypertrichosis, eversion of the eyelids, keratitis are often found. The teeth are colored red.

Histological examination of the skin reveals subepidermal blisters, and fluorescent deposits can be seen in the fibrous substances.

Erythropoietic protoporphyria is less severe, is inherited in an autosomal dominant manner, and is caused by a defect in the enzyme ferrochelatase, which leads to the accumulation of protoporphyrin in the bone marrow, erythrocytes, blood plasma, liver, and skin. The disease manifests itself in infancy or early childhood, when exposure to light causes a burning sensation, tingling, pain, erythema mainly on the face and hands, severe edema, purpura, vesiculation, and, less commonly, blisters. Over time, the skin becomes dense, reddish-brown in color, and cicatricial changes appear. Liver dysfunction may occur, including rapidly progressing severe decompensation.

Histological examination of the skin reveals thickening of the epidermis, and in the dermis, especially in its upper part, there is a deposition of homogeneous, eosinophilic, PAS-positive, diastase-resistant masses that surround the vessels in the form of cuffs, and flask-shaped expansions of the dermal papillae. Numerous vessels with narrow lumens look like wide homogeneous strands. Mucoid substances are detected in their walls and subepidermal sections. There are lipid deposits, as well as neutral mucopolysaccharides and glycosaminoglycans.

Electron microscopy revealed that hyaline cords consist of multi-row vascular basement membranes and fine-fibrillar material in which individual collagen fibrils can be distinguished. Research by FG Schnait et al. (1975) showed that the vascular endothelium is primarily damaged, up to the destruction of endotheliocytes, and in the perivascular areas there are erythrocytes and cellular detritus, which participate in the synthesis of hyaline.

Porphyria cutanea tarda is a usually non-hereditary form of porphyria caused mainly by liver damage with subsequent disruption of porphyrin metabolism. The primary defect is uroporphyrinogen III decarboxylase deficiency, but it manifests itself under the influence of unfavorable factors, primarily hepatotoxic (alcohol, lead, heavy metals, arsenic, etc.). There are reports of the development of porphyria cutanea tarda in patients with renal failure treated with hemodialysis, after long-term use of estrogens, tetracycline, antidiabetic agents, anti-tuberculosis and sulfonamide drugs. Sometimes this condition is observed in liver cancer. Laboratory tests show an increase in the excretion of uroporphyrins and (to a lesser extent) coproporphyrins in the urine. Men aged 40 to 60 years are most often affected. The main clinical symptoms are the formation of blisters and scars after insolation or injury. Hypertrichosis is often observed. There may be hyperpigmentation, scleroderma-like changes. A combination of scleroderma-like and sclerovitiliginous manifestations with eye lesions has been described. The blisters are usually tense, their contents are serous, rarely serous-hemorrhagic. Opening blisters are quickly covered with serous-hemorrhagic crusts, after rejection of which superficial scars remain. Epidermal cysts in the form of small white nodules often form on the back of the hands. The presence of areas of hyperpigmentation and depigmentation gives the skin a mottled appearance.

Mixed porphyria is characterized by general symptoms (abdominal crises, neuropsychiatric disorders) similar to those of acute intermittent porphyria, and skin manifestations are identical to those in porphyria cutanea tarda. The disease is inherited in an autosomal dominant manner. The primary defect is a decrease in the activity of the enzyme protoporphyrinogen oxidase. There is evidence of structural changes in ferrochelatase. During attacks, the amount of copro- and uroporphyrin, 5-aminolevulinic acid and porphobilinogen is increased in the urine, X-porphyrin peptides are in the urine and feces, which is of diagnostic value, and proto- and coproporphyrins are in the feces. Attacks are provoked by infections, drugs, especially barbiturates, sulfamides, griseofulvin, tranquilizers and estrogens.

Hereditary coproporphyria has a similar clinical picture, differing in the primary defect (deficiency of coproporphyrinogen oxidase) and the excretion of coproporphyrin in urine and feces.

In very rare hepatoerythropoietic porphyria, laboratory indices of porphyrin metabolism disorders are similar to those observed in porphyria cutanea tarda, but there is an increase in the level of protoporphyrin in erythrocytes. The cause of the porphyrin metabolism disorder has not yet been determined. E.N. Edler et al. (1981) found a decrease in the activity of uroporphyrinogen decarboxylase and suggested that patients with hepatoerythropoietic porphyria are homozygotes for the gene causing porphyria cutanea tarda in the heterozygous state. Clinically, it is manifested by photosensitivity in early childhood, blistering rashes, scarring with mutilations, hypertrichosis and scderodermaform changes, and persistent dyschromia. Liver damage and anemia are often observed.

The pathomorphology of the skin in all types of porphyria is characterized by the appearance of subepidermal blisters. The infiltrate under the blister consists mainly of poorly differentiated fibroblasts. In the dermis, there are hyaline deposits, similar in appearance to those in colloid milium. In congenital erythropoietic porphyria, Gunther's hyaline is detected in the upper part of the dermis and thickened capillary walls, and in erythropoietic protoporphyria - around the capillaries of the upper third of the dermis. Histochemically, in late cutaneous porphyria, PAS-positive diastase-resistant substances are detected in the walls of blood vessels, and immunoglobulins, mainly IgG, are detected by the immunofluorescence method. Electron microscopy revealed reduplication of the basal membrane of the vessels and the presence of masses of delicate fibrillar substance around them. Based on this, the authors came to the conclusion that the primary changes in late cutaneous porphyria develop in the capillary vessels in the dermal papillae. In addition to liver damage by exogenous substances, immune system disorders play a role in the histogenesis of late cutaneous porphyria.

Skin changes due to metabolic disorders of amino acids are observed in pellagra, ochronosis (alkaptonuria), phenylketonuria, and hypertyrosinazemia.

Pellagra develops as a result of deficiency of nicotinic acid and its precursor amino acid tryptophan of endogenous or exogenous origin (prolonged starvation or poor nutrition with excessive carbohydrates, chronic gastrointestinal diseases, long-term use of drugs, especially antagonists of vitamins PP and B6). Pellagra manifests itself as a syndrome characterized by dermatitis, diarrhea, dementia. Skin changes are usually the earliest symptom, gastrointestinal disorders and mental disorders appear with a more severe course of the disease. Skin changes are most pronounced on exposed parts of the body. The back of the hands, wrists, forearms, face, occipital region of the neck are mainly affected, where sharply limited erythema appears, sometimes blisters form, later the skin thickens, thickens, pigments.

Pellagroid phenomena are observed in patients with Hartnup syndrome, which is a genetically determined disorder of tryptophan metabolism, inherited in an autosomal recessive manner. In addition to skin changes, aminoaciduria, stomatitis, glossitis, diarrhea, cerebellar ataxia, and, less commonly, eye pathology (nystagmus, diplopia, etc.), and mental disorders are observed.

Pathomorphology. In fresh lesions, there is an inflammatory infiltrate in the upper part of the dermis, sometimes accompanied by the appearance of subepidermal blisters. In long-standing lesions, moderate acanthosis, hyperkeratosis, and focal parakeratosis are observed. The amount of melanin in the epidermal cells is increased. In some cases, hyalinosis and fibrosis of the deep dermis may be observed. In the final stage of the process, hyperkeratosis and hyperpigmentation weaken, the epidermis atrophies, and fibrosis develops in the dermis.

Ochronosis (alkaptonuria) is inherited in an autosomal recessive manner and develops as a result of a defect in homogentisic acid oxidase, which causes accumulation of the latter's metabolites in various organs and tissues (articular cartilage, ears, nose, ligaments, tendons, sclera). Clinically, hyperpigmentation is observed, most pronounced on the face, in the armpits and sclera, as well as progressive damage mainly to large joints and the spine.

Pathomorphology. Large extracellular deposits of yellowish-brown pigment are found in the dermis, as well as in macrophages, endotheliocytes, basement membrane, and sweat glands. Significant changes in collagen fibers are observed as a result of inhibition of lysyl oxidase by homogentisic acid.

Phenylketonuria is caused by insufficient activity of phenylalanine-4-hydroxylase, which blocks the conversion of phenylalanine to tyrosine; the main changes are a decrease in pigmentation of the skin, hair, and iris. There may be eczema- and scleral-like changes, atypical dermatitis. The most severe manifestation of the disease is mental retardation. Histological changes in the skin correspond to clinical ones.

Tyrosinemia type II (Richner-Hanhart syndrome) is inherited in an autosomal recessive manner. The disease is caused by a deficiency of hepatic tyrosine aminotransferase. The main symptoms are palmoplantar superficial limited keratoses, keratitis, and sometimes mental retardation. W. Zaeski et al. (1973) observed limited epidermolytic hyperkeratosis.

Proteinogenic pigments include melanin, adrenochrome, and enterochromaffin cell pigment. The most common pigment, especially in the skin, is melanin. It is formed from tyrosine by tyrosinase. Melanin is synthesized in melanocytes of the skin, retina, hair follicles, and pia mater. Disruption of melanogenesis leads to excessive formation of melanin or to a significant decrease in its content or its complete disappearance - depigmentation.

Lipidogenic pigments (lipopigments) are a group of fat-protein pigments. They include lipofuscin, hemofusiin, ceroid and lipochromes. However, due to the fact that all these pigments have the same physical and chemical properties, they are considered varieties of one pigment - lipofuscin.

Lipofuscin is a glycoprotein in which fats, namely phospholipids, predominate. Electron microscopy revealed that lipofuscin consists of electron-particle granules surrounded by a three-contour membrane that contains myelin-like structures and ferritin molecules. Lipofuscin is synthesized in the cell near the nucleus, where primary granules of the propigment are formed, which then enter the Golgi complex area. These granules move to the peripheral parts of the cell cytoplasm and are absorbed by lysosomes, in which mature lipofuscin is formed. Lipofuscin in the skin most often appears with aging: it is detected in fibroblasts, macrophages, vessels, nerve formations and almost all epidermal cells.

In fibroblasts, lipofuscin has a unique structure. It consists of dense granules and fat droplets, between which narrow tubular formations can be seen, possibly representing cisterns of the endoplasmic reticulum. Their shape and size are variable, and their number increases with age. Some authors associate the formation of lipofuscin granules with the participation of lysosomes in this process. Lipofuscin accumulates in cells during severe exhaustion of the body (cachexia), in old age (acquired lipofuscinosis).

Hereditary lipofuscinoses include neuronal lipofuscinoses - thesaurismoses.

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