Addison biermer anemia symptoms. Pernicious anemia (Addison-Biermer disease, B12 deficiency anemia)

Other name: pernicious anemia, B 12-deficiency anemia, megaloblastic anemia

A disease caused by impaired hematopoiesis due to a lack of vitamin B12 in the body.

Eye symptoms. The retina is pale or gray, retinal hemorrhages are possible, partial atrophy optic nerves. Central scotoma with a significant decrease in vision, which is quickly restored under the influence of vitamin B 12 therapy, and subicteric sclera are typical.

General manifestations. Characterized by symptoms of damage to the gastrointestinal tract, hematopoietic tissue and nervous system.

Weakness, shortness of breath, fatigue, and dyspeptic disorders appear. With an exacerbation of the disease, pale skin with a lemon-yellow tint, Gunter's glossitis are characteristic; at first, inflammatory processes are more pronounced ("scalded" tongue), later - atrophic ("varnished" tongue). Inflammatory-atrophic changes often spread to the mucous membrane of the gums, cheeks, pharynx, and esophagus.

The liver is enlarged, the spleen is dense. Patients are prone to obesity. A gastric abnormality is detected, and there is no intrinsic gastric factor Castle in the gastric juice. Gastroscopy reveals nested or total atrophy of the gastric mucosa.

From the central nervous system, tabetic symptoms and symptoms of spinal paralysis are possible. Occurs frequently asthenic syndrome, at severe forms illness is sometimes observed hypochondriacal syndrome. At rapid development anemia leading to a lack of oxygen and cerebral ischemia, pernicious coma may occur with loss of consciousness, areflexia, collapse, hypothermia, shortness of breath, vomiting, and involuntary urination.

Hyperchromic anemia with a decrease in the number of red blood cells is noted in the blood. Characterized by an increase in red blood cells to 12-15 microns in diameter and their saturation with hemoglobin; color index is 1.4-1.8. The amount of vitamin B 12 in the blood is reduced.

Leading factor in the etiology of the disease- endogenous deficiency of vitamin B 12, resulting from a violation of its absorption due to a decrease or complete cessation of the production of the internal gastric factor Castle, necessary for the binding and adsorption of vitamin B 12.

Cases of family diseases indicate the role genetic factor. Presumably the pathological gene is localized in the autosome and is characterized by incomplete dominance.

Differentiate with anemia due to folic acid deficiency, as well as due to vitamin B12 deficiency of other origins.

The first description of the disease belongs to J. S. Combe (1822), who called it “severe primary anemia.” English doctor Th. Addison in 1855 described a disease called "idiopathic anemia", and the Swiss physician Anton Biermer (1827-1892) - in 1872 under the name "progressive pernicious anemia".

The disease, described by Addison in 1855 and Biermer in 1868, became known among doctors as pernicious anemia, that is, a fatal, malignant disease. Only in 1926, in connection with the discovery of hepatic therapy for pernicious anemia, the idea that had prevailed for a century about the absolute incurability of this disease was refuted.

Clinic. People over 40 years of age usually get sick. The clinical picture of the disease consists of the following triad: 1) disturbances from digestive tract; 2) disorders of the hematopoietic system; 3) disorders of the nervous system.

Symptoms of the disease develop unnoticed. Already many years before the pronounced picture of malignant anemia, gastric achylia is detected, and in rare cases, changes in the nervous system are noted.

At the onset of the disease, increasing physical and mental weakness appears. Patients quickly get tired, complain of dizziness, headaches, tinnitus, “flying spots” in the eyes, as well as shortness of breath, palpitations at the slightest physical exertion, drowsiness during the day and insomnia at night. Then dyspeptic symptoms (anorexia, diarrhea) occur, and patients consult a doctor already in a state of significant anemia.

Other patients initially experience pain and a burning sensation in the tongue, and they turn to specialists in oral diseases. In these cases, one examination of the tongue, revealing signs of typical glossitis, is sufficient to make the correct diagnosis; the latter is supported by the anemic appearance of the patient and the characteristic blood picture. The symptom of glossitis is very pathognomonic, although not strictly specific for Addison-Biermer disease.

Relatively rarely, according to various authors, in 1-2% of cases, pernicious anemia begins with symptoms of angina pectoris provoked by myocardial anoxemia. Sometimes the disease begins as a nervous disease. Patients are concerned about paresthesia - a feeling of crawling, numbness in the distal parts of the extremities or radicular pain.

The appearance of the patient during an exacerbation of the disease is characterized by severe pallor of the skin with a lemon-yellow tint. The sclera is subicteric. Often the integument and mucous membranes are more icteric than pale. Brown pigmentation in the form of a “butterfly” is sometimes observed on the face - on the wings of the nose and above the cheek bones. The face is puffy, and swelling in the ankles and feet is quite common. Patients are usually not emaciated; on the contrary, they are well nourished and prone to obesity. The liver is almost always enlarged, sometimes reaching significant sizes, insensitive, and soft in consistency. The spleen has a denser consistency and is usually difficult to palpate; splenomegaly is rarely observed.

The classic symptom - Hunter's glossitis - is expressed in the appearance of bright red areas of inflammation on the tongue, very sensitive to food intake and medications, especially acidic ones, causing the patient a burning sensation and pain. Areas of inflammation are most often localized along the edges and at the tip of the tongue, but sometimes they involve the entire tongue (“scalded tongue”). Aphthous rashes and sometimes cracks are often observed on the tongue. Such changes can spread to the gums, buccal mucosa, soft palate, and in rare cases, on the mucous membrane of the pharynx and esophagus. Subsequently, the inflammatory phenomena subside and the papillae of the tongue atrophy. The tongue becomes smooth and shiny (“varnished tongue”).

Patients have a capricious appetite. Sometimes there is an aversion to food, especially meat. Patients complain of a feeling of heaviness in the epigastric region, usually after eating.

X-rays often reveal smoothness of the folds of the gastric mucosa and accelerated evacuation.

Gastroscopy reveals nested, less often total atrophy of the gastric mucosa. A characteristic symptom is the presence of so-called pearlescent plaques - shiny, mirror-like areas of mucosal atrophy, localized mainly in the folds of the gastric mucosa.

Analysis of gastric contents usually reveals achylia and increased mucus content. In rare cases, free hydrochloric acid and pepsin are contained in small quantities. Since the introduction to clinical practice tests with histamine, cases of pernicious anemia with preserved free hydrochloric acid in the gastric juice began to occur more often.

The Singer test - a rat-reticulocyte reaction, as a rule, gives a negative result: the gastric juice of a patient with pernicious anemia, when administered subcutaneously to a rat, does not cause an increase in the number of reticulocytes in it, which indicates the absence of internal factor(gastromucoprotein). Glandular mucoprotein is not detected even with special research methods.

The histological structure of the gastric mucosa obtained by biopsy is characterized by thinning of the glandular layer and a decrease in the glands themselves. The chief and parietal cells are atrophic and replaced by mucous cells.

These changes are most pronounced in the fundus, but can also affect the entire stomach. Conventionally, three degrees of mucosal atrophy are distinguished: in the first degree, simple achlorhydria is noted, in the second, the disappearance of pepsin, in the third, complete achylia, including the absence of gastromucoprotein secretion. With pernicious anemia, the third degree of atrophy is usually observed, but there are exceptions.

Gastric achylia, as a rule, persists during remission, thereby acquiring a certain diagnostic value during this period. Glossitis may disappear during remission; its appearance portends an exacerbation of the disease.

The enzymatic activity of the intestinal glands, as well as the pancreas, is reduced.

During periods of exacerbation of the disease, enteritis with abundant, intensely colored feces is sometimes observed, which is caused by an increased content of stercobilin - up to 1500 mg in daily quantities.

Due to anemia, an anoxic state of the body develops, which primarily affects the circulatory and respiratory systems. Functional myocardial failure in pernicious anemia is caused by impaired nutrition of the heart muscle and its fatty degeneration.

The electrocardiogram shows symptoms of myocardial ischemia - a negative T wave in all leads, low voltage, widening of the ventricular complex. During the period of remission, the electrocardiogram takes on a normal appearance.

The temperature during the period of relapse often rises to 38°C or higher, but is more often subfebrile. The increase in temperature is mainly associated with the process of increased breakdown of red blood cells.

Changes in the nervous system are very important in diagnostic and prognostic terms. The pathomorphological basis of the nervous syndrome is degeneration and sclerosis of the posterior and lateral columns spinal cord, or the so-called funicular myelosis. The clinical picture of this syndrome consists of combinations of spastic spinal paralysis and tabetic symptoms. The first include: spastic paraparesis with increased reflexes, clonus and pathological reflexes of Babinsky, Rossolimo, Bekhterev, Oppenheim. Symptoms simulating tabes dorsalis (“pseudotabes”) include: paresthesia (crawling sensation, numbness of the distal extremities), girdle pain, hypotension and decreased reflexes up to areflexia, impaired vibration and deep sensitivity, sensory ataxia and dysfunction pelvic organs.

Sometimes the symptoms of the lesion dominate pyramid paths or posterior columns of the spinal cord; in the latter case, a picture is created that resembles a tabes. In the most severe, rare forms of the disease, cachexia develops with paralysis, complete loss of deep sensitivity, areflexia, trophic disorders and disorders of the pelvic organs (our observation). More often we see patients with initial symptoms of funicular myelosis, expressed in paresthesia, radicular pain, mild disturbances of deep sensitivity, unsure gait and a slight increase in tendon reflexes.

Less commonly observed are lesions of the cranial nerves, mainly the visual, auditory and olfactory nerves, resulting in corresponding symptoms from the sensory organs (loss of smell, decreased hearing and vision). A characteristic symptom is central scotoma, accompanied by loss of vision and quickly disappearing under the influence of treatment with vitamin B12 (S. M. Ryse). In patients with pernicious anemia, peripheral neuron damage also occurs. This form, designated as polyneuritic, is caused by degenerative changes in various nerves - sciatic, median, ulnar, etc. or individual nerve branches.

Mental disorders are also observed: delusions, hallucinations, sometimes psychotic phenomena with depressive or manic moods; Dementia is more common in old age.

During a period of severe relapse of the disease, coma(coma perniciosum) - loss of consciousness, drop in temperature and blood pressure, shortness of breath, vomiting, areflexia, involuntary urination. There is no strict relationship between the development of comatose symptoms and a drop in red blood counts. Sometimes patients with 10 units of hemoglobin in the blood do not fall into a coma, but sometimes coma develops with 20 units or more of hemoglobin. In the pathogenesis of pernicious coma, the main role is played by the rapid pace of anemia, leading to severe ischemia and hypoxia of the centers of the brain, in particular the region of the third ventricle (A. F. Korovnikov).

A picture of blood. At the center of the clinical picture of the disease are changes in the hematopoietic system, leading to the development of severe anemia (Fig. 42).

The result of impaired bone marrow hematopoiesis is a kind of anemia, which during the period of relapse of the disease reaches an extremely high degree: observations are known when (with a favorable outcome!) hemoglobin decreased to 8 units (1.3 g%), and the number of red blood cells - to 140,000.

No matter how low hemoglobin decreases, the number of red blood cells drops even lower, as a result of which the color index always exceeds one, in severe cases reaching 1.4-1.8.

The morphological substrate of hyperchromia is large, hemoglobin-rich erythrocytes - macrocytes and megalocytes. The latter, reaching a diameter of 12-14 microns and more, are the end product of megaloblastic hematopoiesis. The apex of the erythrocytometric curve is shifted to the right from normal.

The volume of a megalocyte is 165 µm3 or more, i.e. 2 times the volume of a normocyte; Accordingly, the hemoglobin content in each individual megalocyte is significantly higher than normal. Megalocytes are somewhat oval or elliptical in shape; they are intensely colored and do not show central clearing (Tables 19, 20).

During the period of relapse, degenerative forms of erythrocytes are observed - basophilically punctured erythrocytes, schizocytes, poikilocytes and microcytes, erythrocytes with preserved remnants of the nucleus in the form of Jolly bodies, Cabot rings, etc., as well as nuclear forms - erythroblasts (megaloblasts). More often these are orthochromic forms with a small pyknotic nucleus (incorrectly designated “normoblasts”), less often - polychromatophilic and basophilic megaloblasts with a nucleus of a typical structure.

The number of reticulocytes during an exacerbation is sharply reduced.

The appearance of reticulocytes in the blood in large quantities portends an imminent remission.

Changes in white blood are no less characteristic of pernicious anemia. During a relapse of pernicious anemia, leukopenia (up to 1500 or less), neutropenia, eosinopenia or aneosinophilia, abasophilia and monopenia are observed. Among the cells of the neutrophil series, a “shift to the right” is noted with the appearance of peculiar giant polysegmented forms containing up to 8-10 nuclear segments. Along with a shift of neutrophils to the right, a shift to the left is also observed with the appearance of metamyelocytes and myelocytes. Among monocytes there are young forms - monoblasts. Lymphocytes in pernicious anemia do not change, but their percentage is increased (relative lymphocytosis).

The number of blood platelets during an exacerbation is slightly reduced. In some cases, thrombocytopenia is observed - up to 30,000 or less. Platelets may be atypical in size; their diameter reaches 6 microns or more (so-called megaplatelet); Degenerative forms also occur. Thrombocytopenia in pernicious anemia is usually not accompanied by hemorrhagic syndrome. Only in rare cases are bleeding phenomena observed.

Bone marrow hematopoiesis. The picture of bone marrow hematopoiesis in pernicious anemia is very dynamic (Fig. 43, a, b; Tables 21, 22).

During the period of exacerbation of the disease, bone marrow punctate macroscopically appears abundant, bright red, which contrasts with the pale watery looking peripheral blood. Total number of nucleated elements bone marrow(myelokaryocytes) increased. The ratio between leukocytes and erythroblasts leuco/erythro instead of 3:1-4:1 normally becomes equal to 1:2 and even 1:3; therefore, there is an absolute predominance of erythroblasts.

In severe cases, in untreated patients, with pernicious coma, erythropoiesis occurs entirely according to the megaloblastic type. There are also so-called reticulomegaloblasts - cells reticular type irregular shape, with a wide pale blue protoplasm and a core of a delicate cellular structure, located somewhat eccentrically. Apparently, megaloblasts in pernicious anemia can originate from both hemocytoblasts (via the erythroblast stage) and from reticular cells (return to embryonic angioblastic erythropoiesis).

The quantitative relationships between megaloblasts of different degrees of maturity (or different “ages”) are very variable. The predominance of promegaloblasts and basophilic megaloblasts in the sternal punctate creates a picture of “blue” bone marrow. In contrast, the predominance of fully hemoglobinized, oxyphilic megaloblasts gives the impression of “red” bone marrow.

A characteristic feature of megaloblastic cells is the early hemoglobinization of their cytoplasm while the delicate structure of the nucleus is still preserved. The biological feature of megaloblasts is anaplasia, i.e. loss by a cell of its inherent ability for normal, differentiating development and eventual transformation into an erythrocyte. Only a small part of megaloblasts mature to the final stage of their development and turn into anucleate megalocytes.

Cellular anaplasia in malignant anemia has features in common with cellular anaplasia in malignant neoplasms and leukemia. Morphological similarity with blastoma cells is especially evident in polymorphonuclear, “monstrous” megaloblasts. Comparative study of morphological and biological features megaloblasts in malignant anemia, hemocytoblasts in leukemia and cancer cells in malignant neoplasms led us to think about the possible commonality of pathogenetic mechanisms in these diseases. There is reason to think that both leukemia and malignant neoplasms, like malignant anemia, arise under conditions of a deficiency of specific factors necessary for normal development cells.

Megaloblasts are a morphological expression of a peculiar “dystrophy” of the red nuclear cell, which “lacks” a specific maturation factor - vitamin B 12. Not all cells of the red row are anaplastic to the same extent; - some of the cells appear as if in the form of transitional cells between normo- and megaloblasts; these are the so-called macronormoblasts. These cells, which present particular difficulties for differentiation, are usually found in initial stage remission. As remission progresses, normoblasts come to the fore, and cells of the megaloblastic series recede into the background and completely disappear.

Leukopoiesis during an exacerbation is characterized by a delay in the maturation of granulocytes and the presence of giant metamyelocytes and polymorphonuclear neutrophils, the size of which is 2 times larger than that of normal neutrophils.

Similar changes - impaired ripening and pronounced nuclear polymorphism - are also observed in giant cells of the bone marrow. Both in immature megakaryocytes and in “overripe”, polymorphic forms, the processes of formation and release of platelets are disrupted. Megaloblastosis, polysegmented neutrophils and megakaryocyte changes are dependent on the same cause. This reason is a deficiency of a specific hematopoietic factor - vitamin B12.

Bone marrow hematopoiesis in the stage of hematological remission, in the absence of anemic syndrome, occurs according to the normal (normoblastic) type.

Increased breakdown of erythrocytes, or erythrorrhexis, occurs throughout the reticulohistiocytic system, including in the bone marrow itself, where some of the hemoglobin-containing erythromegaloblasts undergo the process of karyo- and cytorexis, which results in the formation of erythrocyte fragments - schizocytes. The latter partly enter the blood, partly are captured by phagocytic reticular cells - macrophages. Along with the phenomena of erythrophagy, significant accumulations of iron-containing pigment - hemosiderin, derived from the hemoglobin of destroyed red blood cells, are found in the organs.

Increased breakdown of erythrocytes does not give grounds to classify pernicious anemia as a hemolytic anemia (as was assumed by older authors), since erythrorrhexis occurring in the bone marrow itself is caused by defective hematopoiesis and is secondary in nature.

The main signs of increased breakdown of erythrocytes in pernicious anemia are icteric coloration of the integument and mucous membranes, enlarged liver and spleen, intensely colored golden blood serum with an increased content of “indirect” bilirubin, the constant presence of urobilin in the urine and pleiochromia of bile and feces with a significant increase in the content of stercobilin in kale.

Pathological anatomy. Thanks to the successes of modern therapy, pernicious anemia in the section is now very rare. When autopsying a corpse, one notices the anemia of all organs while maintaining fatty tissue. Fatty infiltration of the myocardium (“tiger heart”), kidneys, and liver is noted, and central fatty necrosis of the lobules is also found in the latter.

In the liver, spleen, bone marrow, lymph nodes, especially retroperitoneal ones, a significant deposition of fine-grained yellow-brown pigment - hemosiderin, which gives a positive reaction to iron, is determined. Hemosiderosis is more pronounced in Kupffer cells along the periphery of the hepatic lobules, while in the spleen and bone marrow hemosiderosis is much less pronounced, and sometimes does not occur at all (contrary to what is observed with true hemolytic anemia). A lot of iron is deposited in the convoluted tubules of the kidneys.

Changes in the digestive organs are very characteristic. The tongue papillae are atrophic. Similar changes can be observed in the mucous membrane of the pharynx and esophagus. In the stomach, atrophy of the mucous membrane and its glands is detected - anadenia. A similar atrophic process occurs in the intestines.

In the central nervous system, mainly in the posterior and lateral columns of the spinal cord, degenerative changes are noted, referred to as combined sclerosis or funicular myelosis. Less commonly, ischemic foci with necrotic softening are found in the spinal cord nerve tissue. Necrosis and foci of glial proliferation in the cerebral cortex have been described.

A typical sign of pernicious anemia is crimson-red, juicy bone marrow, which sharply contrasts with the general pallor of the integument and anemia of all organs. Red bone marrow is found not only in flat bones and epiphyses of long bones, but also in the diaphysis of the latter. Along with bone marrow hyperplasia, extramedullary foci of hematopoiesis (accumulation of erythroblasts and megaloblasts) are observed in the splenic pulp, liver and lymph nodes. Reticulo-histiocytic elements in the hematopoietic organs and extramedullary foci of hematopoiesis exhibit the phenomena of erythrophagocytosis.

The possibility of the transition of pernicious anemia to an aplastic state, recognized by previous authors, is currently denied. Sectional findings of red bone marrow indicate that hematopoiesis persists until the last moment of the patient’s life. The lethal outcome does not occur due to anatomical aplasia of the hematopoietic organ, but due to the fact that functionally defective megaloblastic hematopoiesis is not able to provide vital processes for the body oxygen breathing the necessary minimum of red blood cells.

Etiology and pathogenesis. Since Biermer identified “pernicious” anemia as an independent disease, the attention of clinicians and pathologists has been attracted by the fact that with this disease gastric achylia is constantly observed (which, according to recent data, turned out to be histamine-resistant), and atrophy of the gastric mucosa is found in sections ( anadenia ventriculi). Naturally, there was a desire to establish a connection between the state of the digestive tract and the development of anemia.

According to modern ideas, pernicious anemic syndrome should be considered as a manifestation of endogenous B12 vitamin deficiency.

The direct mechanism of anemia in Addison-Biermer disease is that due to vitamin B12 deficiency, the metabolism of nucleoproteins is disrupted, which leads to a disorder of mitotic processes in hematopoietic cells, in particular in bone marrow erythroblasts. The slow pace of megaloblastic erythropoiesis is caused by both a slowdown in mitotic processes and a reduction in the number of mitoses themselves: instead of three mitoses characteristic of normoblastic erythropoiesis, megaloblastic erythropoiesis occurs with one mitosis. This means that while one pronormoblast produces 8 red blood cells, one promegaloblast produces only 2 red blood cells.

The disintegration of many hemoglobinized megaloblasts that did not have time to “denucleate” and turn into erythrocytes, along with their slow differentiation (“abortion of erythropoiesis”) is the main reason leading to the fact that the processes of hematopoiesis do not compensate for the processes of blood destruction and anemia develops, accompanied by an increased accumulation of unused products hemoglobin breakdown.

The latter is confirmed by data from determining the iron cycle (using radioactive isotopes), as well as increased excretion of blood pigments - urobilin, etc.

In connection with the indisputably established “deficient” endogenous vitamin deficiency nature of pernicious anemia, the previously dominant views on the significance of increased breakdown of red blood cells in this disease have undergone a radical revision.

As is known, pernicious anemia was classified as a hemolytic anemia, and megaloblastic erythropoiesis was considered as a response of the bone marrow to increased breakdown of red blood cells. However, the hemolytic theory has not been confirmed either in experiment, or in the clinic, or in medical practice. Not a single experimenter was able to obtain pictures of pernicious anemia when animals were poisoned with a hemolytic nucleus. Anemia of the hemolytic type, neither in experiment nor in the clinic, is accompanied by a megaloblastic reaction of the bone marrow. Finally, attempts to treat pernicious anemia by splenectomy to reduce the breakdown of red blood cells have also been unsuccessful.

Increased excretion of pigments in pernicious anemia is explained not so much by the destruction of newly formed red blood cells in the circulating blood, but by the disintegration of hemoglobin-containing megaloblasts and megalocytes even before their release into the peripheral blood, i.e. in the bone marrow and foci of extramedullary hematopoiesis. This assumption is confirmed by the fact that we discovered increased erythrophagocytosis in the bone marrow of patients with pernicious anemia. The increased iron content in the blood serum noted during the period of relapse of pernicious anemia is mainly explained by impaired iron utilization, since during the period of remission the blood iron content returns to normal levels.

In addition to increased deposition in tissues of iron-containing pigment - hemosiderin and high content in the blood, duodenal juice, urine and feces of iron-free pigments (bilirubin, urobilin), in patients with pernicious anemia, an increased amount of porphyrin and small amounts of hematin are found in the blood serum, urine and bone marrow. Porphyrinemia and hematinemia are explained by insufficient utilization of blood pigments hematopoietic organs, as a result of which these pigments circulate in the blood and are excreted from the body in the urine.

Megaloblasts (megalocytes) in pernicious anemia, as well as embryonic megaloblasts (megalocytes), are extremely rich in porphyrin and cannot be full oxygen carriers to the same extent as normal red blood cells. This conclusion is consistent with the established fact of increased oxygen consumption by megaloblastic bone marrow.

The B12-avitaminosis theory of the genesis of pernicious anemia, generally accepted by modern hematology and clinics, does not exclude the role of additional factors contributing to the development of anemia, in particular the qualitative inferiority of macromegalocytes and their “fragments” - poikilocytes, schizocytes and the “fragility” of their presence in the peripheral blood. According to the observations of a number of authors, 50% of red blood cells transfused from a patient with pernicious anemia to a healthy recipient remain in the latter’s blood for 10-12 to 18-30 days. The maximum lifespan of erythrocytes during the period of exacerbation of pernicious anemia ranges from 27 to 75 days, therefore, 2-4 times less than normal. Finally, the weakly expressed hemolytic properties of the plasma of patients with pernicious anemia are of some (by no means primary) importance, proven by observations of erythrocytes from healthy donors transfused to patients with pernicious anemia and subjected to accelerated decay in the blood of recipients (Hamilton and co-workers, Yu. M. Bala).

The pathogenesis of funicular myelosis, as well as pernicious anemic syndrome, is associated with atrophic changes in the gastric mucosa, leading to deficiency vitamin complex IN.

Clinical observations that have established the beneficial effect of using vitamin B12 in the treatment of funicular myelosis allow us to recognize nervous syndrome with Birmer's disease (along with anemic syndrome) a manifestation of B12-vitamin deficiency in the body.

The question of the etiology of Addison-Birmer disease should still be considered unresolved.

According to modern views, Addison-Biermer disease is a disease characterized by congenital inferiority of the glandular apparatus of the fundus of the stomach, which is revealed with age in the form of premature involution of glands producing gastromucoprotein, necessary for the assimilation of vitamin B12.

We are not talking about atrophic gastritis (gastritis atrophicans), but about gastric atrophy (atrophia gastrica). The morphological substrate of this peculiar dystrophic process is nested, rarely diffuse atrophy, affecting mainly the fundic glands of the fundus of the stomach (anadenia ventriculi). These changes, which create “pearl spots” known to pathologists of the last century, are detected intravitally during gastroscopic examination (see above) or by biopsy of the gastric mucosa.

The concept of the autoimmune genesis of gastric atrophy in pernicious anemia, put forward by a number of authors (Taylor, 1959; Roitt and co-workers, 1964), is worthy of attention. This concept is supported by the detection in the blood serum of most patients with pernicious anemia of specific antibodies to the parietal and chief cells of the gastric glands that temporarily disappear under the influence of corticosteroids, as well as immunofluorescence data showing the presence of antibodies fixed in the cytoplasm of the parietal cells.

It is believed that autoantibodies against gastric cells play a pathogenetic role in the development of atrophy of the gastric mucosa and subsequent disorders of its secretory function.

By microscopic examination biopsied gastric mucosa, significant lymphoid infiltration was found in the latter, which is considered as evidence of the participation of immunocompetent cells in unleashing organ-specific autoimmune inflammatory process with subsequent atrophy of the gastric mucosa.

In this regard, the frequency of combinations characteristic of Birmer's pernicious anemia deserves attention histological picture atrophy and lymphoid infiltration of the gastric mucosa with Hashimoto's lymphoid thyroiditis. Moreover, deceased patients with Birmer's anemia often show (at autopsy) signs of thyroiditis.

The immunological commonality of Biermer's anemia and Hashimoto's thyroiditis is supported by the fact that antithyroid antibodies were detected in the blood of patients with Biermer's anemia, and, on the other hand, antibodies against parietal cells of the gastric mucosa in patients with thyroid disease. According to Irvine et al (1965), antibodies against gastric parietal cells are found in 25% of patients with Hashimoto's thyroiditis (antithyroid antibodies in these same patients are found in 70% of cases).

The results of studies of relatives of patients with Birmer's anemia are also of interest: according to various authors, antibodies against the lining cells of the gastric mucosa and against the cells of the thyroid gland, as well as a violation of the secretory and adsorption (in relation to vitamin B 12) functions of the stomach, are observed in no less than 20 % of relatives of patients with Birmer's pernicious anemia.

According to the latest research Conducted using the radiodiffusion method on 19 patients with pernicious anemia, a group of American researchers established the existence in the blood serum of all patients of antibodies that either “blocked” the intrinsic factor or bound both the intrinsic factor (IF) and the CF+B12 complex.

Anti-HF antibodies have also been found in the gastric juice and saliva of patients with Birmer's anemia.

Antibodies are also found in the blood of infants (up to 3 weeks of age) born from mothers with pernicious anemia who contained anti-HF antibodies in their blood.

In childhood forms of B12-deficiency anemia, occurring with intact gastric mucosa, but with impaired production of internal factor (see below), antibodies to the latter (anti-HF antibodies) are detected in approximately 40% of cases.

Antibodies are not detected in childhood pernicious anemia, which occurs due to impaired absorption of vitamin B 12 at the intestinal level.

In light of the above data, the profound pathogenesis of B12 deficiency anemia Birmera appears as an autoimmune conflict.

Schematically, the occurrence of neuroanemic (B12-deficiency) syndrome in Addison-Biermer disease can be represented in the following way.

The question of the relationship between pernicious anemia and gastric cancer requires special consideration. This question has long attracted the attention of researchers. Since the first descriptions of malignant anemia, it has been known that this disease is often combined with malignant neoplasms of the stomach.

According to US statistics (cited by Wintrobe), stomach cancer occurs in 12.3% (in 36 cases out of 293) of those who died from malignant anemia over the age of 45 years. According to summary data collected by A.V. Melnikov and N.S. Timofeev, the incidence of stomach cancer in patients with malignant anemia, established on the basis of clinical, radiological and sectional materials, is 2.5%, i.e. approximately 8 times more than in the general population (0.3%). The incidence of stomach cancer in patients with pernicious anemia, according to the same authors, is 2-4 times higher than that of stomach cancer in people of the same age who do not suffer from anemia.

Noteworthy is the increase in cases of stomach cancer in patients with pernicious anemia in last years, which should be explained by the prolongation of the life of patients (due to effective Bia therapy) and the progressive restructuring of the gastric mucosa. In most cases, these are patients with pernicious anemia who develop stomach cancer. One should not, however, lose sight of the possibility that gastric cancer itself sometimes gives a picture of pernicious anemia. At the same time, it is not necessary, as some authors suggested, that the cancer should strike the fundic part of the stomach, although the localization of the tumor in this part is certainly of “aggravating” significance. According to S. A. Reinberg, out of 20 patients with a combination of stomach cancer and pernicious anemia, only 4 had the tumor localized in the cardial and subcardial regions; in 5, a tumor was found in the antrum, in 11 - in the body of the stomach. A pernicious anemic blood picture can develop at any location of gastric cancer, accompanied by diffuse atrophy of the mucosa involving the glands of the fundus of the stomach. There are cases when the developed pernicious anemic blood picture was the only symptom of stomach cancer (a similar case has been described by us)1.

Signs suspicious in terms of development cancerous tumor stomach in a patient with pernicious anemia, one should consider, firstly, a change in the type of anemia from hyperchromic to normohypochromic, secondly, the patient’s developing refractoriness to vitamin B12 therapy, thirdly, the appearance of new symptoms that are uncharacteristic of pernicious anemia as such: disappearance appetite, weight loss. The appearance of these symptoms obliges the doctor to immediately examine the patient in the direction of possible gastric blastoma.

It should be emphasized that even a negative result of an X-ray examination of the stomach cannot guarantee the absence of a tumor.

Therefore, in the presence of even just clinical and hematological symptoms that inspire reasonable suspicion of the development of blastoma, it is necessary to consider it indicated surgery- exploratory laparotomy.

Forecast. Liver therapy, proposed in 1926, and modern treatment with vitamin B i2 radically changed the course of the disease, which had lost its “malignancy”. Now death malignant anemia, which occurs during oxygen starvation of the body (anoxia) in a coma, is very rare. Although not all symptoms of the disease disappear during remission, nevertheless, persistent blood remission, which occurs as a result of systematic use of antianemic drugs, is actually tantamount to practical recovery. There are cases of complete and final recovery, especially for those patients who have not yet developed a nervous syndrome.

Treatment. For the first time, Minot and Murphy (1926) reported the cure of 45 patients with malignant anemia using special diet rich in raw veal liver. The most active was low-fat calf liver, minced twice and prescribed to the patient 200 g per day 2 hours before meals.

A great achievement in the treatment of pernicious anemia has been the production of effective liver extracts. Of the parenterally administered liver extracts, the most famous was the Soviet campolon, extracted from the liver. cattle and available in ampoules of 2 ml. In connection with reports of the antianemic role of cobalt, liver concentrates enriched with cobalt were created. A similar Soviet drug, antianemin, was successfully used in domestic clinics to treat patients with pernicious anemia. The dosage of antianemin is from 2 to 4 ml into the muscle daily until hematological remission is obtained. Practice has shown that a single administration of a massive dose of Campolon in 12-20 ml (the so-called “Campolon blow”) is equivalent in effect full course injections of the same drug, 2 ml daily.

According to modern research, the specificity of the action of liver drugs in pernicious anemia is due to the content of hematopoietic vitamin (B12) in them. Therefore, the basis for the standardization of antianemic drugs is the quantitative content of vitamin B12 in micrograms or gammas per 1 ml. Campolon of various series contains from 1.3 to 6 μg/ml, antianemin - 0.6 μg/ml of vitamin B12.

In connection with the production of synthetic folic acid, the latter was used to treat pernicious anemia. Prescribed per os or parenterally in a dose of 30-60 mg or more (maximum up to 120-150 mg pro die), folic acid causes pernicious anemia in the patient rapid attack remission. However negative property folic acid is that it leads to increased consumption of tissue vitamin B12. According to some data, folic acid does not prevent the development of funicular myelosis, and with long-term use even promotes it. Therefore, folic acid has not been used for Addison-Biermer anemia.

Currently, due to the introduction of vitamin B12 into widespread practice, the above remedies in the treatment of pernicious anemia, which were used for 25 years (1925-1950), have lost their significance.

The best pathogenetic effect in the treatment of pernicious anemia is achieved from parenteral (intramuscular, subcutaneous) use of vitamin B12. A distinction should be made between saturation therapy, or “impact therapy”, carried out during an exacerbation, and “maintenance therapy”, carried out during a period of remission.

Saturation therapy. Initially, based on the daily human need for vitamin B12, which was determined to be 2-3 mcg, it was proposed to administer relatively small doses of vitamin B12 - 15? daily or 30? in 1-2 days. At the same time, it was believed that the introduction large doses impractical due to the fact that most of what is received is in excess of 30? Vitamin B12 is excreted from the body in urine. Subsequent studies, however, showed that the B12-binding capacity of plasma (depending mainly on the content of β-globulin) and the degree of utilization of vitamin B12 vary depending on the body's need for vitamin B12, in other words, on the degree of vitamin B12 deficiency in tissues . The normal content of vitamin B12 in the latter, according to Ungley, is 1000-2000? (0.1-0.2 g), of which half comes from the liver.

According to Mollin and Ross, with severe B12 deficiency in the body, clinically manifested by the picture of funicular myelosis, after an injection of 1000? Vitamin B12 is retained in the body by 200-300?.

Clinical experience has shown that although small doses of vitamin B12 practically lead to clinical improvement and restoration of normal (or near normal) blood counts, they are still insufficient to restore tissue reserves of vitamin B12. Undersaturation of the body with vitamin B12 manifests itself in the known inferiority of clinical and hematological remission (preservation residual effects glossitis and especially neurological phenomena, macrocytosis of erythrocytes), and in the tendency to early relapses of the disease. For the reasons stated above, the use of small doses of vitamin B12 is considered inappropriate. In order to eliminate vitamin B12 deficiency during the period of exacerbation of pernicious anemia, it is currently proposed to use average amounts of 100-200? and large ones - 500-1000? - doses of vitamin B12.

In practice, as a regimen for exacerbation of pernicious anemia, we can recommend injections of vitamin B12 at 100-200? daily during the first week (before the onset of reticulocyte crisis) and every other day thereafter until the onset of hematological remission. On average, with a course of treatment lasting 3-4 weeks, the course dose of vitamin B12 is 1500-3000?.

For funicular myelosis, more massive (shock) doses of vitamin B12 are indicated - 500-1000? daily or every other day for 10 days, and then 1-2 times a week until a lasting therapeutic effect is obtained - the disappearance of all neurological symptoms.

Positive results - a pronounced improvement in 11 out of 12 patients with funicular myelosis (and in 8 patients with restoration of ability to work) - were obtained by L. I. Yavorkovsky with endolubic administration of vitamin B12 in a dose of 15-200 MCG at intervals of 4-10 days, for a total of a course treatment up to 840 mcg. Considering the possibility of complications, even severe meningeal syndrome(headache, nausea, neck stiffness, fever), the indication for endolubic administration of vitamin B12 should be limited to exclusively severe cases of funicular myelosis. Other methods of treating funicular myelosis used in the recent past: spinal diathermy, raw pork stomach in large doses (300-400 g per day), vitamin B1 50-100 mg per day - have now lost their significance, with the exception of vitamin B1 , recommended for neurological disorders, especially in the so-called polyneuritic form.

The duration of treatment with vitamin B12 for funicular myelosis is usually 2 months. The course dose of vitamin B12 is from 10,000 to 25,000?.

Chevallier recommended to obtain a stable remission to carry out long-term treatment vitamin B12 in massive doses (500-1000? per day) until the highest red blood counts are obtained (hemoglobin - 100 units, red blood cells - over 5,000,000).

In connection with the long-term use of massive doses of vitamin B12, the question of the possibility of hypervitaminosis B12 arises. This issue is resolved negatively due to the rapid removal of vitamin B12 from the body. Accumulated rich clinical experience confirms the virtual absence of signs of oversaturation of the body with vitamin B12, even with prolonged use.

Oral administration of vitamin B12 is effective in combination with the simultaneous administration of gastric antianemic factor - gastromucoprotein. Favorable results were obtained in the treatment of patients with pernicious anemia by oral administration of tablet preparations containing vitamin B12 in combination with gastromucoprotein.

In particular, positive results were noted when using domestic drug mucovit (the drug was produced in tablets containing 0.2 g of gastromucoprotein from the mucous membrane of the pyloric region of the lower stomach and 200 or 500 mcg of vitamin B12).

In recent years, there have been reports of positive results in treating patients with pernicious anemia with vitamin B12 administered orally in a dose of at least 300? per day without internal factor. In this case, one can count on the fact that the absorption of even 10% of the administered vitamin B12, i.e. approximately 30?, is quite sufficient to ensure the onset of hematological remission.

It is also proposed to administer vitamin B12 in other ways: sublingually and intranasally - in the form of drops or by spraying - at a dose of 100-200 mcg daily until the onset of hematological remission, followed by maintenance therapy 1-3 times a week.

According to our observations, transformation of hematopoiesis occurs within the first 24 hours after the injection of vitamin B12, and the final normalization of bone marrow hematopoiesis is completed 48-72 hours after the administration of vitamin B12.

The possibility of transforming the megaloblastic type of hematopoiesis into a normoblastic one is decided in the light of the unitary theory from the point of view of the genesis of erythroblasts of both types from a single parent cell. As a result of the onset of saturation of the bone marrow with the “erythrocyte maturation factor” (vitamin B12, folinic acid), the direction of development of basophilic erythroblasts changes. The latter, in the process of differentiating division, turn into cells of the normoblastic series.

Already 24 hours after the injection of vitamin B12, radical changes occur in hematopoiesis, expressed in the massive division of basophilic erythroblasts and megaloblasts with the differentiation of the latter into new forms of erythroblasts - mainly meso- and microgeneration. The only sign indicating the “megaloblastic past” of these cells is the disproportion between the high degree of hemoglobinization of the cytoplasm and the nucleus, which still retains its loose structure. As the cell matures, the dissociation in the development of the nucleus and cytoplasm is smoothed out. The closer a cell is to final maturation, the more it approaches a normoblast. Further development of these cells - their denuclearization, final hemoglobinization and transformation into erythrocytes - occurs according to the normoblastic type, at an accelerated pace.

On the part of granulopoiesis, there is an increased regeneration of granulocytes, especially eosinophils, among which there is a sharp shift to the left with the appearance of a significant number of eosinophilic promyelocytes and myelocytes. On the contrary, among neutrophils there is a shift to the right with an absolute predominance of mature forms. The most important is the disappearance of polysegmented neutrophils characteristic of pernicious anemia. During the same period, restoration of the normal morphophysiology of giant bone marrow cells and the normal process of platelet formation is observed.

Reticulocyte crisis occurs on the 5-6th day.

Hematological remission is determined by the following indicators: 1) the onset of a reticulocyte reaction; 2) normalization of bone marrow hematopoiesis; 3) normalization of peripheral blood; 4) restoration of normal levels of vitamin B12 in the blood.

The reticulocyte response, expressed graphically as a curve, in turn depends on the degree of anemia (it is inversely proportional to the initial number of red blood cells) and the speed of the bone marrow response. The faster the curve rises, the slower its decline, which is sometimes interrupted by a second rise (especially with irregular treatment).

Isaacs and Friedeman proposed a formula by which in each individual case one can calculate the maximum percentage of reticulocytes expected under the influence of treatment:

Where R is the expected maximum percentage of reticulocytes; En is the initial number of red blood cells in millions.

Example. The number of red blood cells on the day of initiation of therapy was 2,500,000.

The immediate effect of vitamin B12 therapy in the sense of replenishing the peripheral blood with newly formed red blood cells begins to be felt only from the 5-6th day after the administration of the antianemic drug. The percentage of hemoglobin increases more slowly than the number of red blood cells, so the color indicator in the remission stage usually decreases and becomes less than one (Fig. 44). In parallel with the cessation of megaloblastic erythropoiesis and the restoration of a normal blood picture, the symptoms of increased breakdown of red blood cells also decrease: the yellowness of the integument disappears, the liver and spleen are reduced to normal sizes, the amount of pigments in the blood serum, bile, urine and feces decreases.

Clinical remission is expressed in the disappearance of all pathological symptoms, including anemic, dyspeptic, neurological and ocular. The exception is histamine-resistant achylia, which usually persists during remission.

Improvement in general condition: increased strength, disappearance of diarrhea, drop in temperature - usually occurs before the disappearance of anemic symptoms. Glossitis is eliminated somewhat more slowly. In rare cases, restoration of gastric secretion is also noted. Nervous phenomena are reduced to some extent: paresthesia and even ataxia disappear, deep sensitivity is restored, and the mental state improves. In severe forms, nervous phenomena are hardly reversible, which is associated with degenerative changes in nervous tissue. The effectiveness of vitamin B12 therapy has a known limit, after which the increase in blood counts stops. Due to the faster increase in the number of red blood cells compared to the increase in hemoglobin, the color indicator decreases to 0.9-0.8, and sometimes lower, anemia becomes hypochromic. It seems that vitamin B12 therapy, while promoting the maximum use of iron to build red blood cell hemoglobin, leads to the depletion of its reserves in the body. The development of hypochromic anemia in this period is also favored by reduced absorption of dietary iron due to achylia. Therefore, during this period of illness, it is advisable to switch to treatment with iron preparations - Ferrum hydrogenio reductum 3 g per day (must be washed down with hydrochloric acid) or hemostimulin. An indication for the administration of iron to patients with pernicious anemia may be a decrease in plasma iron from elevated (up to 200-300?%) during the period of exacerbation of figures to subnormal during the period of remission. Indicator useful action iron during this period is an increase in the utilization of radioactive iron (Fe59) from 20-40% (before treatment) to normal (after treatment with vitamin B12).

The issue of using blood transfusions for pernicious anemia is decided in each case according to the indications. An absolute indication is pernicious coma, which poses a threat to the patient’s life due to increasing hypoxemia.

Despite the brilliant achievements in the treatment of pernicious anemia, the problem of its final cure still remains unresolved. Even in remission with normal indicators blood, characteristic changes in erythrocytes (aniso-poikilocytosis, single macrocytes) and a shift of neutrophils to the right can be detected. Examination of gastric juice reveals in most cases permanent achylia. Changes in the nervous system can progress even in the absence of anemia.

With the cessation of the administration of vitamin B12 (in one form or another), there is a threat of relapse of the disease. Clinical observations show that relapses of the disease usually occur within 3 to 8 months after cessation of treatment.

In rare cases, relapses of the disease occur after several years. Thus, in a 60-year-old patient we observed, a relapse occurred only 7 (!) years after the complete cessation of vitamin B12 intake.

Maintenance therapy consists of prescribing a preventive (anti-relapse) intake of vitamin B12. In this case, one should proceed from the fact that a person’s daily need for it is, according to the observations of various authors, from 3 to 5?. Based on these data, it can be recommended to administer 100 ? to the patient 2-3 times a month in order to prevent recurrence of pernicious anemia. or weekly 50 vitamin B12 injections.

As maintenance therapy in a state of complete clinical and hematological remission and for the prevention of relapses, oral drugs - mucovit with or without intrinsic factor (see above) can also be recommended.

Prevention. Prevention of exacerbations of pernicious anemia comes down to the systematic administration of vitamin B12. The timing and dosage are set individually (see above).

ANEMIA-B12-DEFICIENCY (ADDISON-BIRMER ANEMIA)- formation of mega loblasts in the bone marrow, destruction of red blood cells inside the bone marrow. changes in the nervous system in the form of funicular myelosis.

Etiology and pathogenesis

One of the most important moments The biological effect of vitamin B12 is its activation of folic acid; vitamin B12 promotes the formation of folic acid derivatives, folates, which are directly necessary for bone marrow hematopoiesis. With a deficiency of vitamin B12 and folate, DNA synthesis is disrupted, which in turn leads to impaired cell division, an increase in their size and qualitative inferiority. The cells of the erythroblastic lineage are most significantly affected: instead of erythroblasts, large cells are found in the bone marrow embryonic hematopoiesis- megaloblasts, they are not able to “mature” into a full-fledged red blood cell, that is, they cannot tolerate hemoglobin and oxygen. The average lifespan of megalocytes is approximately 3 times less than that of “normal” red blood cells. With a lack of the second coenzyme vitamin B12 - internal factor - another mechanism for the development of anemia occurs - a violation of fat metabolism occurs with the accumulation of methylmalonic acid, which is toxic to the nervous system. As a result, funicular myelosis occurs - a disorder of hematopoiesis in the bone marrow and the development of anemia. B12-deficiency anemia also develops as a result of impaired absorption of the vitamin in the gastrointestinal tract due to atrophic gastritis or as a result of congenital insufficiency of the glandular apparatus of the stomach, while the gastric juice lacks gastromucoprotein, which is directly involved in the breakdown and absorption of B12 and its coenzymes.

Clinic

The disease begins unnoticed, weakness gradually progresses, palpitations, dizziness and shortness of breath appear, especially during physical exertion, sudden movements, working ability decreases, appetite worsens, and nausea is possible. Often the first complaint with which patients consult a doctor is a burning sensation of the tongue, its cause is a characteristic of this disease atrophic glossitis. As a consequence of dystrophic changes in the nervous system, skin anesthesia and paresthesia occur; in severe cases, gait disturbance (spastic paraparesis) is often observed, and functional disorders may be observed. Bladder and rectum, sleep is disturbed, emotional instability and depression appear. When examining a patient, pay attention to the pallor of the skin and mucous membranes (usually with a yellowish tint due to the increased breakdown of megalocytes and the formation of bilirubin from the released hemoglobin), puffiness of the face; A bright red, shiny, smooth tongue is very characteristic (due to severe atrophy of the papillae) - a “polished” tongue. Atrophic gastritis is very characteristic. Often, when tapping flat and some tubular bones, pain is noted - a sign of bone marrow hyperplasia. A common symptom B12 deficiency anemia is a low-grade fever.

Diagnostics

In the peripheral blood, a sharp decrease in the number of red blood cells is determined (up to 0.8 X 1012), the color index remains high - 1.2-1.5. Red blood cells are unequal in size (anisocytosis), large red blood cells predominate - macrocytes, many red blood cells have an oval, racket, crescent and other shape (poikilocytosis).

In the bone marrow aspirate, the number of red lineage cells is sharply increased, 3-4 times more than the cells of the leukocyte lineage (normally, the opposite ratio). In the blood plasma there is an increase in the content of free bilirubin and iron (up to 30-45 mmol/l).

Treatment

Vitamin B12 is prescribed. Treatment begins with the introduction of 100-300 mcg of the vitamin subcutaneously or intramuscularly once a day. On the 2-3rd day of therapy, erythropoiesis is completely normalized, and on the 5-6th day, newly formed full-fledged red blood cells begin to enter the bloodstream in required quantity, the patients’ well-being is gradually returning to normal. After the blood picture is restored, they switch to maintenance therapy - the introduction of vitamin B12 in a dose of 50-100 mcg, which is carried out throughout the patient’s life. For disorders of the nervous system, neurotropic drugs are used at the first stage.

Forecast

Favorable with adequate therapy. Without treatment, the disease progresses and can lead to the death of the patient.

Addison-Beermer disease is common chronic illness human, characterized from the blood system by megaloblastic hematopoiesis, progressive anemia, from the digestive organs - gastric achylia, and from the nervous system - the phenomena of funicular myelosis in the form of damage to the lateral and posterior columns of the spinal cord.

On hematological examination we find hyperchromic anemia, megaloblastic bone marrow hematopoiesis and increased hemolysis.

The basis of this disease is a violation of the absorption of vitamin B12 from the gastrointestinal tract.

History of the study. The clinical picture of pernicious anemia was first described in England by Addison in 1855. In 1868, Birmer in Germany gave a fairly complete clinical picture this disease, distinguishing it from other forms of anemia. Ehrlich presented the basic hematological characteristics of the disease. The British call it Addison's disease, the Germans call it Biermer or Biermer-Ehrlich disease.

Before the advent of effective treatment methods, the disease was malignant and progressive; deteriorated uncontrollably general state sick. This corresponded to the name of the disease - anaemia perniciosa progressiva, i.e. progressive malignant anemia.

This name is currently essentially unjustified: the disease does not progress with appropriate treatment, it has ceased to be malignant. But even today Addison-Birmer disease is often called anemia perniciosa in all countries.

As stated above, Ehrlich gave the main hematological characteristic of this disease - megaloblastic bone marrow hematopoiesis. Lichtenstein described a neuroanemic syndrome in this type of anemia. Fenwick drew attention to the atrophy of the gastric mucosa, and Faber emphasized the persistence of gastric achylia.

The introduction into practice of liver treatment was of great importance in the study of the pathogenesis and clinical picture of pernicious anemia. The American physiologist Whipple, repeating heavy bloodletting on dogs, caused them to develop persistent anemia. By testing various methods of treating this experimental anemia, he showed that the best results were obtained by giving these dogs large quantities of fresh liver.

In 1926-1927 Based on these studies, Whipple Minot and Murphy, using the liver diet in humans for anemia of various types, obtained excellent results for pernicious anemia.

In 1928-1929 Castle proved that for normal hematopoiesis, an extrinsic factor contained in meat and an intrinsic factor contained in normal gastric juice are necessary.

In 1948, vitamin B12 was isolated from the liver, and later from Streptomyces griseus. West used it for Addison-Biermer's disease. Vitamin B12 is an antipernicious liver factor and an extrinsic food factor.

Since 1926, since the work of Minot and Murphy, the era of descriptive study of pernicious anemia has ended. Conditions were created for an in-depth study of the pathogenesis of this disease, and new ways of studying hematology were opened.

Etiology. Addison-Biermer disease is a disease that has certain characteristics - clinical, hematological and histopathological. Its pathogenesis has been sufficiently elucidated. The etiology remains currently unknown. It is called “cryptogenic”, “idiopathic”, “constitutional”. These terms express our ignorance of the true cause of the disease. However, they separate Addison-Birmer disease from a group of other megaloblastic anemias for which the cause is known.

These include pernicious-like symptomatic megaloblastic anemia: 1) with helminthic infestation, 2) with sprue, 3) with pregnancy, 4) with some organic lesions of the stomach (stomach cancer, total resections).

The onset and development of Addison-Birmer disease is associated with age. This is a disease of mature and elderly people. It is extremely rare before the age of 20. Starting from 21-30 years, the incidence of pernicious anemia gradually increases, reaching its greatest height at the ages of 41-50 and 51-60 years. These two age groups account for more than half of the patients. In women, the onset of the disease can often be associated with the onset of menopause.

Hereditary predisposition is of known importance. Addison-Biermer disease has been observed in members of the same family. This cannot be explained only by identical living conditions: these are blood relatives. Bremer gives a family tree: out of 16 family members, blood relatives, 7 suffer from anemia, 5 of them have proven anemia perniciosa. Interestingly, among the latter two are twins.

Cases of Addison-Biermer's disease and essential hypochromic disease have been observed in the same family. iron deficiency anemia. You can think about constitutional, hereditary bone marrow deficiency. But it can be assumed that the primary, general condition is the gastrointestinal tract: achylia in Biermer's disease and gastroenterogenic iron deficiency anemia.

The previous assumption that Addison-Biermer disease can develop as a result of prolonged malnutrition, both quantitative and qualitative (lack of proteins, vitamins, in particular the B complex, vitamin C), was not justified. Observations abroad (China, Java, India), as well as the experience of the blockade, show that such malnutrition can cause anemia, but Addison-Birmer anemia in these conditions is no more common than usual, and even less common. According to autopsy reports, deaths from Birmer's disease in 1932-1935 were. 0.3-0.5% of autopsies, during the blockade (1942-1944) - 0.1-0.16%, and in 1945 - 0.07%. However, in the USA, megaloblastic anemia has been described in children fed with powdered milk.

Many authors deny any significance of working and living conditions in the occurrence of Addison-Biermer disease. A careful analysis of individual cases, however, tells a different story. Thus, American authors point to a high incidence of Addison-Birmer disease in people working with lead and lighting gas. Some authors associate the onset of the disease with chronic carbon monoxide poisoning.

It is interesting to note that Addison-Birmer disease is more frequent illness in northern latitudes. The further south you go, the less common it is. Incidence of Addison-Birmer disease per 100,000 population in northern states USA is 6.9, in the southern states - 2.4, in Norway - 9.18, in Italy - 2.3, in Ceylon - 3.3, in Chile - isolated cases. These statements have no general meaning.

Pathogenesis. The study of pathogenesis in recent years has been very fruitful and has led to significant changes in our views on the essence of the disease.

The first works in this direction belonged to the American scientists Minot and Murphy, who established an excellent therapeutic effect from the administration of raw liver. Subsequently it was shown that similar action have preparations obtained from the pork stomach, as well as specially prepared concentrated extracts from the liver. These studies established that the liver contains some substance that has therapeutic effect with Addison-Birmer disease.

In 1928-1929 A number of works by Castle appeared, creating a scheme for the pathogenesis of this disease that was generally accepted until recently. Castle showed that meat exposed to the digestive action of the gastric juice of healthy people, when administered orally to patients with pernicious anemia, causes an increase in the number of reticulocytes, and then hemoglobin and erythrocytes. Meat exposed to low-acid gastric juice had a similar effect. Meat without pre-treatment with gastric juice, as well as gastric juice alone, did not have a similar effect. In cases where meat was exposed to the gastric juice of patients with Addison-Birmer anemia, the content of red blood cells, reticulocytes and hemoglobin did not change.

From these experiments it was concluded that in the gastric juice of patients there is no special substance called “intrinsic” factor, which, in combination with the “external” factor found in food, forms a special substance necessary for normal hematopoiesis and called hemopoietin. In healthy people, the “internal” factor in the gastric juice is contained in sufficient quantities, therefore, during the processing of food by the gastric juice, the “external” and “internal” factors combine to form hematopoietin. The effect obtained when liver and its preparations are administered to patients is associated with the deposition of hemopoietin in the liver.

This concept of Addison-Birmer disease as a “deficiency disease” turned out to be fruitful and, in principle, has not changed to the present day. However, the discovery of vitamin B12 made significant adjustments to existing ideas and made it possible to clarify a number of issues.

As is known, in 1948, Ricks in the USA and Lester-Smith in England isolated crystalline vitamin B12 from the liver, containing cobalt - cyanocobalamin. This drug, already in doses of 1-3, had a noticeable effect when administered parenterally to patients with Addison-Biermer anemia. The use of large doses of the drug caused reverse development and symptoms of damage to the nervous system, which was not observed during treatment with Campolon.

Vitamin B12 taken orally (at least in usual doses) without the addition of an “intrinsic” factor in the form of extracts of the gastric mucosa did not have a therapeutic effect. In all its properties, vitamin B12 was identical to the antianemic factor contained in the liver and previously called hemopoietin.

These data served as the basis for the view that changes in hematopoiesis characteristic of Addison-Birmer disease, occurring in the megaloblastic type, as well as degenerative lesions of the spinal cord are the result of vitamin B12 deficiency.

Quantitative determination of vitamin B12 by microbiological methods made it possible to clearly establish that in Addison-Biermer disease its content in the blood is sharply reduced.

Intramuscular injection of several micrograms of vitamin B12 leads to a noticeable increase in its content in the blood and the rapid transformation of megaloblastic hematopoiesis into normoblastic.

In cases where vitamin B12 is administered orally in combination with the “intrinsic” factor in the form of preparations of the gastric mucosa, a clear therapeutic effect is observed.

Thus, the “internal” factor is not some substance that, when combined with the “external” one, forms hematopoietin, but its role is that it promotes the extraction and absorption of vitamin B12 from food.

The question of the nature of the “internal” factor remained unclear for a long time, until Glass and his colleagues showed by electrophoretic method that this factor belongs to the gastromucoproteins secreted by the stomach.

More intimate mechanisms of action of the internal factor still remain unclear. It, in all likelihood, enters into an unstable combination with vitamin B12, extracting it from food and promoting its absorption. It is less likely that gastromucoprotein acts on the intestinal wall

In Addison-Birmer disease, there is no “intrinsic” factor in the gastric contents; as a result of this, a sharp disturbance in the assimilation and absorption of vitamin B12 occurs and endogenous vitamin B12 deficiency develops, clinical manifestations which are changes in the blood, nervous system, etc.

The question of the place of production of the “internal” factor in humans can now be considered resolved, although for a long time it served as a reason for discussion. Thus, Meulengracht, based on experiments carried out on pig stomachs, believed that this factor is produced in the pyloric part of the stomach and the initial part of the duodenum.

However, Castle and Fox showed that the greatest therapeutic effect Preparations obtained from the fundic and cardiac parts of the human stomach are effective against Addison-Biermer disease.

Back in 1941, O. B. Makarevich and S. Ya. Rappoport established that extracts of the fundic part of the human stomach cause the greatest reticulocytosis when administered to rats.

Finally, histological studies of the stomachs of persons suffering from pernicious anemia showed that the most dramatic atrophic changes are observed not in the pyloric, but in the fundus of the stomach. Yu. M. Lazovsky and O. B. Makarevich also established that the replacement of megaloblastic hematopoiesis with normoblastic hematopoiesis in the human embryo occurs at approximately the same time when the glands of the fundus of the stomach are formed.

The “starter” theory proposed by Meulengracht, according to which the glands of the fundic part of the stomach secrete a special substance, which in turn stimulates the secretion of the “internal” factor by the pyloric glands, also did not come true.

The latter circumstance also explains why pernicious anemia so rarely develops after gastrectomy.

In Addison-Biermer disease, intrinsic factor is not produced in the stomach. This is not associated with achylia, since in the absence of hydrochloric acid this factor is determined in the gastric contents. In addition, as is known, in 2% of cases with Addison-Birmer disease, gastric secretion may persist.

It is generally accepted that the cause of impaired secretion of the “internal” factor - gastromucoprotein - in this disease is inflammatory and degenerative changes in the mucous membrane of the fundus of the stomach. This does not make it possible, however, to answer the main question about the root cause of these changes.

There are currently a number experimental work that disruption of the innervation of the stomach and the ventricles formed from it leads in dogs to a sharp decrease and even disappearance of the “internal” factor from the gastric juice.
Thus, the pathogenesis of Addison-Birmer disease boils down to the fact that as a result of a violation of neurotrophic influences and degenerative changes in the glands of the mucous membrane of the fundus of the stomach, the release of gastromucoprotein is disrupted. In this regard, the extraction and absorption of vitamin B12 from food is disrupted and endogenous vitamin B12 deficiency occurs.

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