Disorder of chromoprotein metabolism: causes, symptoms, diagnosis, treatment

The disruption of chromoprotein metabolism concerns both exogenous and endogenous pigments. Endogenous pigments (chromoproteins) are divided into three types: hemoglobinogenic, proteinogenic and lipidogenic. Disturbances consist in decreasing or increasing the amount of pigments formed in the norm, or the appearance of pigments formed in pathological conditions.

Distinguish between local and general disorders of pigments, primary, mostly genetically conditioned, and secondary, associated with various pathological processes.

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

Ferritin is an iron protein containing up to 23% of iron bound to a protein. Normally ferritin is 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. In pathological conditions, the amount of ferritin in tissues can increase, for example, in hemosiderosis.

Hemosiderin is formed during the cleavage of heme, is a ferritin polymer. It is a colloidal iron hydroxide bound to proteins, mucopolysaccharides and cell lipids. Hemosiderin is always formed intracellularly in sideroblasts - mesenchymal cells, in siderosomes of which hemosiderin granules are synthesized. When hemosiderin appears in the intercellular substance, he undergoes phagocytosis by siderophages. The presence of hemosiderin in the tissues is determined by the Perls reaction. Based on the results of this reaction, it is possible to distinguish hemosiderin from hemomelanin, melanin and lipofuscin. In abnormal conditions, excessive formation of hemosiderin (hemosiderosis) is observed. General hemosiderosis develops with intravascular destruction of erythrocytes (intravascular hemolysis), diseases of the organs of hematopoiesis, intoxications and some infections (influenza, anthrax, plague). Local hemosiderosis occurs with extravascular rupture of erythrocytes (extravascular hemolysis), for example, in foci of small and large hemorrhages.

In the skin hemosiderosis is observed quite often (with chronic capillaritis, chronic venous insufficiency, etc.). Clinically characterized by the appearance mainly on the lower extremities of point hemorrhages, pigmentation, less often - telangiectasias.

Hemochromatosis can be primary (idiopathic) and secondary. The changes have much in common with hemosiderosis. Primary hemochromatosis belongs to thesaurismosis, it is inherited mainly in the autosomal recessive type, is caused by a defect of enzymes that ensure the absorption of iron in the small intestine. Increased absorption of food iron leads to its accumulation in large quantities in various organs and tissues. In this case, the classic triad of symptoms includes skin pigmentation, liver cirrhosis and diabetes mellitus. It is indicated the possibility of a primary heart attack. The skin is bronze in color, which is caused by the increase in the amount of melanin, the most pronounced pigmentation on the open parts of the body. The same pattern can be observed with secondary hemochromatosis. Histologically, there is an increase in melanin in the cells of the basal layer of the epidermis, and in the dermis - the deposition of hemosiderin in the perivascular cells and around the sweat glands.

Porphyrins are the precursors of heme hemoglobin, they do not contain iron. In small amounts are found and normal (in urine, blood and tissues), have the ability to increase the sensitivity of the body to light. When the metabolism of porphyrins is disturbed, porphyrins develop, characterized by an increase in the number 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) distinguish erythropoietic and hepatic forms of porphyria. Among the erythropoietic forms, there are congenital erythropoietic porphyria of the Ponter, erythropoietic protoporphyria, and among the hepatitides - late cutaneous porphyria, porphyria mixed, hereditary coproporphyria, and acute intermittent porphyria, which occurs without skin changes.

Congenital erythropoietic porphyria of Gunther is a very rare form of porphyria, inherited by autosomal recessive type, is caused by a defect of uroporphyrinogen III co-synthase, which leads to excessive formation of uroporphyrinogen I. A high sensitivity to light is associated with photodynamic action of porphyrins. Immediately after the birth of the child under the influence of sunlight appears erythema and bubbles are formed. Infection and ulceration in lesions lead to severe deformation of the face and hands, scleroderm-like changes. Often find hypertrichosis, eversion of the eyelids, keratitis. Teeth are painted red.

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

Erythropoietic protoporphyria is less severe, inherited autosomally dominant, due to a defect in the enzyme ferrochelatase, which leads to the accumulation of protoporphyrin in the bone marrow, erythrocytes, plasma, liver and skin. The disease manifests itself in the infancy or early childhood, when under the influence of light there is a burning sensation, tingling, pain, erythema mainly on the face and hands, pronounced edema, purpura, vesiculation, rarely - blisters. Over time, the skin becomes dense, reddish-brown in color, cicatricial changes appear. Possible impaired liver function up to rapidly progressive severe decompensation.

A histological examination of the skin reveals a thickening of the epidermis, and in the dermis, especially in its upper part, there is a deposition of homogeneous, eosinophilic, Schick-positive, diastase-resistant masses that surround the vessels in the form of couplings and bulbous expansions of the papillae of the dermis. Numerous vessels with narrow lumens look like wide, homogeneous cords. In their walls and subepidermal sections, mucoid substances are detected. There are lipid deposits, as well as neutral mucopolysaccharides and glycosaminoglycans.

Electron microscopy revealed that hyaline strands consist of multi-row basal membranes of vessels and small-fibrillar material, in which it is possible to distinguish individual collagen fibrils. Research by FG Schnait et al. (1975) showed that the endothelium of the vessels is primarily damaged, up to the destruction of endotheliocytes, and in the perivascular regions there are red blood cells and cellular detritus that participate in the synthesis of hyaline.

Late skin porphyria is usually a non-hereditary form of porphyria, caused mainly by damage to the liver with subsequent disruption of porphyrin metabolism. The primary defect is the deficiency of uroporphyrinogen III-decarboxylase, but it is manifested under the influence of adverse factors, especially hepatotoxic (alcohol, lead, heavy metals, arsenic, etc.). There are reports of the development of late cutaneous porphyria in patients with renal insufficiency treated with hemodialysis after prolonged use of estrogens, tetracycline, antidiabetic agents, anti-tuberculosis and sulfonamide drugs. Sometimes this condition is observed in liver cancer. Laboratoryally, there is an increase in the isolation of uroporphyrins and (to a lesser extent) coproporphyrins with urine. Most often, men between the ages of 40 and 60 are ill. The main clinical symptoms are the formation of blisters and scars after insolation or trauma. Hypertrichosis is often observed. There may be hyperpigmentation, scleroderm-like changes. A combination of scleroderm-like and sclerovitiligenic manifestations with eye damage is described. Bubbles usually intense, their contents serous, rarely serous-hemorrhagic. Opening bubbles quickly become covered with serous-hemorrhagic crusts, after the rejection of which surface scars remain. At the rear of the hands, epidermal cysts are often formed in the form of small white nodules. 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 the symptoms of acute intermittent porphyria, and skin manifestations are identical with those of late cutaneous porphyria. The disease is inherited autosomal dominantly. The primary defect is a decrease in the activity of the enzyme protoporphyrinogen oxidase. There are data on the structural changes in ferrochelatase. During attacks in the urine, the amount of copro- and uroporphyrin, 5-aminolevulinic acid and porphobilinogen was increased, urine and feces had X-porphyrin peptides, which is of diagnostic importance, in feces - proto- and co-proporphyrins. Provoke an attack of infection, drugs, especially barbiturates, sulfonamides, griseofulvin, tranquilizers and estrogens.

Similar in the clinical picture, hereditary coproporphyria, differing in the primary defect (insufficiency of coproporphyrinogen oxidase) and excretion of coproporphyrin with urine and feces.

With very rare hepatoerythropoietic porphyria, laboratory parameters of porphyrin metabolism disturbance are similar to those observed with late cutaneous porphyria, but there is an increase in the level of protoporphyrin in erythrocytes. The reason for the violation of porphyrin metabolism has not yet been clarified. E.N. Edler et al. (1981) found a decrease in the activity of uroporphyrinogenecarboxylase and suggested that patients with hepatoerythropoietic porphyria are homozygous for the gene that causes late cutaneous porphyria in the heterozygous state. Clinically manifested photosensitivity in early childhood, bladder rashes, scarring with mutations, hypertrichosis and sclerodermiform changes, persistent dyschromia. Liver damage and anemia are common.

Pathomorphology of the skin in all types of porphyria is characterized by the appearance of subepidermal blisters. Infiltration under the bladder consists mainly of poorly differentiated fibroblasts. In the dermis there are deposits of hyaline, similar in appearance to those with colloid milium. With congenital erythropoietic porphyria, hytherin Gunther is identified in the upper part of the dermis and thickened capillary walls, with erythropoietic protoporphyria - around the capillaries of the upper third of the dermis. Histochemically, in the walls of vessels with late cutaneous porphyria, SHIC-positive diastasis-resistant substances are detected, and immunofluorescence is detected by immunoglobulins, mainly IgG. Electron microscopy revealed the reduplication of the basal membrane of the vessels and the presence of masses of the fungal matter around them. Based on this, the authors concluded that the primary changes in late porphyria of skin develop in capillary vessels in the papilla of the dermis. In the histogenesis of late cutaneous porphyria, in addition to damage to the liver by exogenous substances, the role of disturbance in the immune system plays a role.

Skin changes in metabolic disorders of amino acids are observed in pellagra, ochronic disease (alkaponuria), phenylketonuria, hyperthyrosinazemia.

Pellagra develops as a result of a deficiency in the body of nicotinic acid and its precursor amino acid tryptophan of endogenous or exogenous origin (prolonged starvation or inadequate nutrition with an excessive amount of carbohydrates, chronic diseases of the digestive tract, prolonged use of medications, especially antagonists of PP and B6 vitamins). Pellagra is manifested by a syndrome characterized by dermatitis, diarrhea, and dementia. Skin changes are usually the earliest symptom, gastrointestinal disorders and mental disorders occur in the more severe course of the disease. Skin changes are most pronounced on open parts of the body. The back part of the hands, wrists, forearms, face, occipital region of the neck, where sharply limited erythema appears, sometimes form a bubble, later the skin thickens, thickens, pigmented.

Pellagroide phenomena are observed in patients with Hartnup syndrome, which is a genetically determined violation of tryptophan metabolism, inherited by autosomal recessive type. In addition to skin changes, there are aminoaciduria, stomatitis, glossitis, diarrhea, cerebellar ataxia, less often - ocular pathology (nystagmus, diplopia, etc.), mental disorders.

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

Ochronosis (alkaponuria) is inherited by autosomal recessive type, develops due to a defect of homozygosinic acid oxidase, which causes accumulation of metabolites of the latter 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 area, as well as the progressive lesion of mainly large joints and spine.

Pathomorphology. In the dermis, as well as in macrophages, endotheliocytes, basal membrane, sweat glands, large extracellular deposits of a yellowish-brown pigment are found. As a result of inhibition of lysyl oxidase by homogentisic acid, significant changes in collagen fibers are observed.

Phenylketonuria is caused by insufficient activity of phenylalanine-4-hydroxylase, which blocks the conversion of phenylalanine into tyrosine, the main changes being the reduction of pigmentation of the skin, hair and iris. There may be eczema- and scleropodic changes, atypical dermatitis. The most severe manifestation of the disease is mental retardation. Histological changes of the skin correspond to clinical ones.

Tyrosinemia type II (the Richter-Hanhart syndrome) is inherited in an autosomal recessive type. The disease is caused by a failure of the hepatic tyrosine aminotransferase. The main symptoms are palmar-plantar surface limited keratoses, keratitis, and sometimes mental retardation. W. Zaeski et al. (1973) observed limited epidermolytic hyperkeratosis.

Proteinogenic pigments include melanin, adrenochrome and pigment of enterochromaffin cells. The most common, especially in the skin, is the pigment melanin. It is formed from tyrosine by tyrosinase. Melanin synthesis is carried out in melanocytes of the skin, retina of the eye, hair follicles, soft dura mater. Violation of melanogenesis leads to excessive formation of melanin either to a significant decrease in its content or to its complete disappearance - depigmentation.

Lipidogenic pigments (lipopigments) constitute a group of fat-pigment pigments. It includes 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 predominate, namely phospholipids. Electron microscopy revealed that lipofuscin consists of electron-lobate granules surrounded by a three-loop membrane that contains myelin-like structures and ferritin molecules. Lipofuscin is synthesized in a cell near the nucleus, where the primary pro-pigment granules are formed, which then enter the zone of the Golgi complex. These granules move to the peripheral parts of the cytoplasm of the cell and are absorbed by the lysosomes in which mature lipofuscin is formed. Lipofuscin in the skin most often appears with aging: it is detected in fibroblasts, macrophages, vessels, nervous formations and almost all cells of the epidermis.

In fibroblasts, lipofuscin has a peculiar structure. It consists of dense granules and droplets of fat, between which you can see the narrow tubular formations, perhaps, representing the cisterns of the endoplasmic reticulum. Their shape and size are variable, with age their number increases. The formation of lipofuscin granules is attributed by some authors to the participation of lysosomes in this process. Lipofuscin accumulates in cells with a sharp depletion of the body (cachexia), in old age (acquired lipofuscinosis).

To hereditary lipofuezinosis carry neuronal lipofuscinosis - thesaurismosis.

[1], [2], [3]