Means for the treatment of pernicious anemia. Pernicious anemia

Malignant anemia was described in 1885 by Addison in his book on bronze disease of the adrenal glands under the name of idiopathic anemia and by Birmer in 1872 under the name of progressive malignant anemia.
For a long time, this disease was referred to as "primary" anemia. believing that its cause lies deep in the body. Already in 1870, on the basis of pronounced cases of complete atrophy of the digestive tract, the cause of anemia was considered to be the insufficiency of the digestive function. However, for many years the prevailing opinion was that "anemia occurs due to damage to the bone marrow by intestinal toxins or as a result of an oral ("oral") focal infection. Botkin established the importance for individual cases of malignant anemia of invasion with a wide tapeworm, and he explained the very mechanism of anemization as a reflex disturbance of the activity of the hematopoietic center in the brain. Achilles of the stomach, constantly accompanying malignant anemia, attracted the attention of scientists. Achilia develops, apparently, not so much as a result of inflammatory gastritis, but rather from neurodystrophic influence, especially with a lack of vitamins and protein in food. The development of anemia is often preceded by liver disease (cholecystitis, cholecystohepatitis), which can disrupt metabolism and worsen gastric trophism. Apparently, as a result of a persistent metabolic disorder and a violation of the nervous regulation of gastric secretion, under the influence of adverse influences, multiple cases of malignant anemia can also occur in one family. As a result of the same reasons, due to damage to the stomach in the family of a patient with malignant anemia, there may be cases of chlorosis, or in the patient himself, signs of this disease appear, as it were, to replace chlorosis. In the patient himself, it is possible to establish achilia ten years before the development of typical anemia. The method of gastroscopy was able to detect in patients areas of regeneration of the parenchyma of the stomach during remissions, especially under the influence of replacement therapy and intensive fortification, which to a certain extent explains the undulating course of the disease and shows the dependence of the course of malignant anemia on environmental factors. The glandular tissue of the stomach can also undergo further pathological restructuring and give rise to polypous growths and cancerous degeneration. The works of recent years have clarified the mechanism of development of anemia and lesions of the central nervous system, depending on the violation of gastrointestinal digestion and nutrition, based on the great therapeutic value of the hepatic diet in malignant anemia.
It should be considered proven that in a healthy person, in the process of gastric digestion, in addition to the breakdown of proteins by pepsin, a special anti-anemic substance is formed, which is absorbed in the intestine, deposited, like glycogen, protein, in the liver and, as needed, is consumed in the bone marrow, ensuring normal maturation. erythrocytes. In patients with malignant anemia, this substance is not formed in the stomach, they do not have it in the liver either; therefore, hematopoiesis in the bone marrow does not go beyond megaloblasts and non-nuclear large erythrocytes (megalocytes), as in the fetus; with calf's liver or its extracts, patients receive this missing substance, which ensures the formation of normal normoblasts in the bone marrow, as well as non-nuclear erythrocytes.
Castle in 1928 made the following experiment, which proved the role of the stomach in hematopoiesis. When a patient with malignant anemia is fed meat digested in a thermostat with normal gastric juice, the blood composition quickly improves, while the gastric juice of a patient with malignant anemia does not have such an effect even with the addition of nepsin and hydrochloric acid. The active principle of meat, as well as those acting similarly to eggs, cereals, yeast, is probably close to the vitamins of the B complex. specific stomach enzyme) = heat-labile anti-anemic substance deposited in the liver.
A specific enzyme is produced in humans mainly by the fundic glands, and possibly only in trace amounts by other parts of the gastrointestinal tract. The chemical nature of the anti-anemic substance has not been elucidated, although in recent years a cobal-containing vitamin, vitamin B 12 , which is particularly active in this direction, has been isolated.
For the late stages of pernicious anemia, damage to the central nervous system is extremely characteristic in the form of degeneration of the posterior and lateral columns of the spinal cord, mainly in the cervical part; the development of this "funicular myelosis" is also associated with a digestive defect - underproduction in the stomach and intestines of a special substance, in the absence of which occurs, as in pellagra, demyelination and degeneration of the axial cylinders of the central neurons.
Severe anemia occurs with progressive atrophy of the stomach and intestines (malignant anemia in its own form and with sprue disease), after extensive resection of the stomach (“agastric” malignant anemia), with impaired absorption of the antianemic substance by the intestinal wall (gastrointestinal fistula, sprue) and increased its destruction inside the intestine (with stenosis of the small intestine, with infection with a wide tapeworm). Malignant anemia can be detected in pregnant women due to increased consumption of hematopoietic substance for hematopoiesis of the fetus, and finally, due to a lack of an external factor (appropriate vitamins) with prolonged malnutrition.
The closest mechanism for the development of anemia is presented in the following form. Defective erythrocytes released by the bone marrow, as well as pathological erythrocytes in hemolytic jaundice, are easily destroyed in the spleen and other places of accumulation of reticuloendothelial tissue. The number of erythrocytes progressively falls, despite hyperplasia of the active bone marrow.
The consequence of increased breakdown of erythrocytes is yellowness of patients, increased levels of indirect bilirubin in the blood, urobilin in feces and urine, however, in a much smaller amount than with hemolytic jaundice, due to a deeper violation of pigment metabolism with the formation of porphyrin and hematin. In the blood serum, the content of iron is increased, which is deposited in Kupffer cells and in the parenchyma on the periphery of the liver lobules, in the lungs, spleen, kidneys - homosiderosis of the organs, giving them a rusty tint. Anatomically characteristic is a crimson-red brain in the diaphysis of tubular bones, for example, the thigh, rich in megaloblasts, with scanty foci of formation of granular leukocytes and megakaryocytes. The same metaplasia can be in a mildly enlarged spleen. At autopsy, fatty degeneration of the liver, degeneration of the kidneys, hemorrhages in the serous membranes, retina, and brain are found.
During remission, megaloblasts are replaced by erythroblasts, normoblasts and ordinary erythrocytes, pathological hemolysis stops, the need for colossal hematopoiesis decreases, the bone marrow of the thigh acquires a normal fatty appearance, and the sternum punctate does not contain megaloblasts after several days of liver treatment.

clinical picture. Patients complain of gradually increasing general weakness, shortness of breath, palpitations, dizziness, pain in the heart, often swelling of the legs or general swelling, fever. At first glance, the doctor's attention is attracted by the general appearance of the patient: in front of him is an elderly man who looks older than his years, or a woman 30-40-50 years old, often graying early with bloodless mucous membranes and skin of a pale lemon-yellow hue; patients are not very emaciated, often even full. On the face, trunk, hands, pigmented spots (chloasma) and areas of depigmentation (vitiligo), wen. Patients often come with a diagnosis of heart disease, cardiosclerosis, angina pectoris or stomach cancer. With a detailed questioning, it is possible to find out that the patient has had burning pains in the tongue from spicy food for the last few months, periodically diarrhea, and when examining gastric juice, achilia has long been established; that before, for example, towards the end of last winter, the pallor of the patient attracted the attention of others, and a blood test established anemia; lately, the patient's fingertips have become numb and there is a crawling and tingling sensation in the hands and feet (paresthesia). In history, often, especially in women, attacks of hepatic colic, cholecystohepatitis.
Edema can reach the degree of anasarca with ascites, hydrothorax, edematous pads on the back of the hands, on the lower back and sacrum, sometimes swelling is limited to the shins, puffiness of the face. With very severe anemia, a few petechiae are found on the skin and minor hemorrhages in the mucous membranes. With pressure, soreness of the sternum (sternalgia), ribs.
The cardiovascular system presents the usual changes for severe anemia: increased cardiac activity with increased pulsation of the carotid and other arteries with an increase in pulse pressure; sharp systolic murmur at all orifices of the heart from vortex movements of blood with reduced, often two times against the norm, viscosity, with a sharp acceleration of blood flow. Those conditions cause a murmur audible on the bulb of the jugular vein, better on the right. This continuous whirring noise increases with inhalation, when the venous blood rushes with even greater force into the chest. The mass of blood is only slightly reduced: the loss of erythrocyte mass is replenished, as in general with anemia, by an increase in the liquid part of the blood. The acceleration of blood flow and other adaptive mechanisms of blood circulation provide a more or less normal respiratory function of the blood; this must be seen as an explanation for the amazing fact that patients with severe malignant anemia are still often capable of hard physical work. Edemas are, as a rule, “protein-free” in nature, that is, they are associated with a low content of protein in the blood serum. With prolonged anemia on the basis of anoxemia, fatty degeneration of organs develops, including the “tiger heart”. In this case, there may be signs of true circulatory insufficiency with an expansion of the cavities of the heart, an increase in venous pressure, a slowdown in blood flow, etc. In severe anemia, attacks of angina pectoris of a functional apoxemic nature may begin, which stop later along with an improvement in the composition of the blood. Of course, in elderly patients one has to reckon with the possibility of angina pectoris on the basis of coronary sclerosis.
On the part of the digestive organs, the tongue is characteristic - clean, bright red, smooth, devoid of papillae, atrophic, sometimes covered with aphthous vesicles or superficial sores (glossitis). Burning pain in the tongue is sometimes the main complaint of patients. The same burning pains can be in the esophagus due to a similar esophagitis. Dyspeptic complaints from the stomach are uncharacteristic, although due to the atrophic process, the secretion of hydrochloric acid cannot be caused by a subcutaneous injection of 0.5 mg of histamine, i.e. there is histamine-resistant achilia (The absence of a hematopoietic enzyme in the patient's gastric juice can be proved by biological tests: 1) repeated feeding another patient with undoubted pernicious anemia in the stage of exacerbation of meat, each time subjected to digestion in a thermostat with the gastric juice of the patient under study, does not cause remission; 2) subcutaneous administration of neutralized gastric juice of the patient to rats, unlike normal juice, does not cause an increase in the number of reticulocytes (the so-called rat-reticulocyte test). With extreme degrees of anemization, there may be persistent vomiting, making it impossible to ingest the liver. Periodically advancing diarrhea is in the nature of enteritis, accompanied by swelling, rumbling, pain near the navel.
The liver during exacerbations is usually enlarged; often sensitivity in the gallbladder and other signs of cholecysto-hepatitis.
A slight enlargement of the spleen is noted in most untreated cases.
From the side of the central nervous system, signs of damage to the predominantly posterior columns of the spinal cord are found - a decrease and absence of reflexes, ataxia, a significant violation of deep sensitivity while maintaining superficial ("pseudotabes"); the lateral columns are also affected to a lesser extent, and spastic phenomena predominate and often, disorders of superficial sensitivity are detected early. More often, spinal cord lesions are mixed, with a predominance of the posterior columnar type. Flaccid or spastic paralysis of the lower extremities develops, later the sphincters of the bladder and rectum are disturbed. Less commonly observed are degenerative processes in the brain with a varied picture of general asthenia, psychosis, and peripheral neuritis. Patients often complain of memory impairment, irritability.
When the number of erythrocytes falls to 2,000,000 or below, there is almost always a significant fever of one or another, usually of the wrong type, simulating malaria, typhoid fever, sepsis and other infectious diseases. An increase in temperature can reach 39-40 ° and is apparently associated with a sharp breakdown of the blood or rejuvenation of the bone marrow; this aseptic "anemic" fever quickly stops with an improvement in the composition of the blood.
The most characteristic blood changes are as follows. There is a high color index, greater than one, which depends on the presence of large macrocytic erythrocytes that are excessively stained with hemoglobin (hyperchromia), which creates a misleading impression of a good blood composition on a cursory examination of the smear (as opposed to iron deficiency anemia, in which the erythrocytes remain completely unstained in the center ). So, at 40% hemoglobin, 1,500,000 red blood cells (30% of the norm) are often determined, i.e., the color indicator is 1.3. The color index remains high for a long time and with a significant improvement in red blood, without falling, as a rule, and in remissions below 0.7-0.8, which is in sharp contrast to the low color index of patients with chlorosis. On the part of white blood, leukopenia is characteristic with polysegmented neutrophils - five-, seven-lobed, etc. - the so-called shift to the right in the neutrophilic series.

Careful examination of a stained smear reveals a variety of other cellular forms: pathognomonic megaloblasts with a characteristic sieve-like structure of the nucleus (“like raindrops in sand”) and often basophilic protoplasm; megalocytes - non-nuclear erythrocytes - giants over 12 r. diameter; poikilocytes (erythrocytes of the most bizarre shape - in the form of a tennis racket, tape); fragments of erythrocytes, polychromatophiles, erythrocytes with basophilic puncture, with Cabot rings, Jolly bodies, neutrophilic myelocytes, etc.

An increase in the number of reticulocytes, eosinophils, platelets indicates the restoration of normal bone marrow hematopoiesis and is a good indicator of the onset of remission. Liver therapy naturally causes a steep rise in the number of reticulocytes on the 7-10th day with a slower subsequent decline. Following the peak of reticulocytes from the 10-14th day of treatment, a constant long-term rise in the number of erythrocytes and hemoglobin occurs, which continues after the fall of reticulocytosis. The number of eosinophils in the treatment of raw liver remains extremely high for a long time, reaching 50-60% of all leukocytes; liver extracts give only moderate eosinophilia.

Turning, complications and outcomes. The onset of the disease is gradual. Obviously, at least half a year or a year passes before the blood drops to those low figures at which the patient usually goes to the doctor. A significant deterioration in the condition is often preceded by attacks of glossitis with diarrhea, as in other diseases of insufficiency, or an accidental acute infection.
Prior to the introduction of hepatic therapy, the disease fully justified its name as pernicious (“fatal”) and progressive. True, even without treatment, the disease gave one or two, rarely three characteristic remissions lasting from 2-3 months to 1 year, yet leading to death usually after 1-3 years, as an exception, after 7-10 years. Treatment with the liver significantly changed the course of the disease, making it possible to immediately induce remission at the first attack and maintain this state of practical health and full working capacity, apparently for an indefinitely long time, at least up to 10-15 years. However, the disease remains serious due to the often late recognition of many complications (pyelitis, cholecystitis, protein-free edema) and especially due to the difficulty of long-term liver replacement treatment; in the end, however, the disease leads to severe damage to the spinal cord with paralysis, urinary infection (urosepsis), pneumonia, and death.

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A severe attack, not recognized and not treated in a timely manner, can lead to a kind of coma - coma perniciosum, when in patients with a hemoglobin amount of about 10% (hard to determine exactly), general edema, jaundice, hypothermia, circulatory disorders, there is a sharp lethargy, drowsiness, even complete loss of consciousness, and it is possible to get the patient out of this dangerous state only by urgent measures: drop blood transfusion, parenteral administration of active hepatic drugs in a large dose, cardiovascular agents, oxygen therapy.
A completely different picture is presented by patients in a state of remission, when, in the complete absence of complaints, neither the appearance of the patient and the study of individual organs (normal color of the skin and mucous membranes, an undischarged spleen and liver), nor a blood test (normal number of erythrocytes and hemoglobin; the most persistent morphological changes are macrocytosis with hyperchromia and leuko-neutropenia, but they, apparently, can disappear; even punctate of the sternum reveals normoblastic bone marrow). But this well-being is under constant threat from the remaining disturbed activity of the nervous system and digestive tract: attacks of diarrhea, exacerbation of glossitis, the development of polyposis and stomach cancer, and most importantly, nervous symptoms can progress. Even with a normal blood composition, the patient can become a severe invalid, bedridden due to paraplegia, etc. Ignoring liver therapy can also lead to a relapse of anemia.

Pernicious-like macrocytic a blood picture without other classic signs of malignant anemia can cause diseases such as cirrhosis of the liver, malaria, acute leukemia, etc. Chronic leukemia, especially lymphatic, is sometimes combined with pernicious anemia - actually "leukanemia". With family hemolytic jaundice, anemia is hyperchromic, but at the same time microcytic in nature; this disease is distinguished by a peculiar, well-defined clinical picture.

A plastic anemia (aleukia), as well as acute leukemia are often misdiagnosed as "acute pernicious anemia". Both diseases have a very similar clinical picture, which differs, however, significantly from pernicious anemia; there are also significant hematological differences.

cancer anemia, for example, in gastric cancer, it is usually easy to differentiate from malignant anemia by a low color index, neutrophilia with a normal or elevated white blood cell count, the presence of persistent gastric complaints, and most importantly, by a defect in gastric filling on an x-ray. X-ray examination, on the other hand, makes it possible to recognize polyposis of the stomach, often also giving severe anemia.
It should, however, be noted that in case of malignant anemia, swelling of the gastric mucosa can give an x-ray picture similar to a filling defect, and most importantly, with a long course, malignant anemia can lead to true gastric neoplasm. This combination can be recognized, in addition to a stable x-ray picture, by a continuous worsening of the patient's condition with a sharp cachexia, unusual for malignant anemia, a positive blood symptom - blood in the stool, in vomit, leukocytosis (and thrombocytosis). In isolated early cases, such patients underwent a radical operation to remove the tumor, and they recovered with liver replacement therapy.
For malignant anemia, other severe hypochromic anemias are often incorrectly mistaken, except for cancer, such as: anemia with prolonged hemorrhoidal bleeding, with chronic azotemia nephritis (anemia of the brights). According to the first impression (pale face, swelling of the eyelids and other signs of sclerotic cachexia), an elderly patient with atherosclerosis, as well as patients with edematous disease or lipoid-nephrotic syndrome, can be mistaken for a patient with pernicious anemia, but with these diseases, red blood is almost not affected .
Due to the presence of fever, along with swelling of the spleen, leukopenia, anemia, pernicious anemia is sometimes misdiagnosed as malaria (bright large basophilic puncture and Kebot rings in erythrocytes are often mistaken for the stage of development of malarial plasmodium), typhoid fever (diarrhea contributes to the misdiagnosis, leukopenia, etc.), sepsis-endocarditis lenta (heart murmurs, arterial pulsation, enlarged spleen, etc.).
Finally, often a significant damage to the spinal cord in malignant anemia leads to an erroneous diagnosis of the actual nervous suffering, especially the dorsal tabes (tabes dorsalis), multiple sclerosis, tumors of the spinal cord, polyneuritis; this mistake is even easier to make if after treatment with the liver only an erased anemic syndrome remains. There are known forms of funicular myelosis due to insufficiency of gastrointestinal digestion without anemia at all. In contrast to the dorsal tabes in malignant anemia, the cerebrospinal fluid remains normal, pupillary reactions, as a rule, persist, motor muscle strength is sharply disturbed, and shooting pains are unusual. The difference from multiple sclerosis is the older age of patients, the absence of eye symptoms and damage to the optic nerve, the absence of deep reflexes, the violation of sphincters only in the later stages of the disease.

Prevention. It should be remembered that every patient with persistent achilia, as well as after extensive resection of the stomach, may develop severe anemia, therefore, in such persons, it is necessary to systematically monitor the general condition and blood composition (hyperchromia, macrocytosis, etc.), provide them with a complete diet, and if necessary, apply early treatment of anemic syndrome and other measures. Thus, it will be possible to reduce the number of patients with malignant anemia, who first visit a doctor with severe anemia (often with a red blood cell count of about 2,000,000), requiring hospitalization and leading to long-term disability. The general correct hygienic regimen, the protection of the nervous system from difficult experiences are also of undoubted importance in the prevention of the disease.

Treatment. The treatment of malignant anemia is aimed primarily at regulating the general regimen, improving the neurotrophic regulation of the digestive organs and other systems, eliminating various foci of irritation (infectious diseases, inflammation of the gallbladder, etc.), providing good nutrition, especially substances that are most closely related to trophic - the gastrointestinal tract, hematopoietic organs and the nervous system (separate fractions of vitamin Bb, autoclaved yeast, etc.). During an exacerbation of the disease, bed rest is necessary. The food is varied, sufficient, always with a normal amount of high-grade proteins - meat, eggs, milk; the same principle of nutrition is observed in extreme degrees of anemia and the presence of diarrhea - meat soufflé, beaten egg whites, freshly grated cottage cheese, yogurt, etc.
The liver is both a food and the best remedy; the usual dose of it is 200 g per day. Fresh liver (veal, bovine) is washed in warm water, cleaned of connective tissue fibers, passed through a meat grinder and given raw or lightly scalded on the outside with boiling water on a sieve, with any seasonings, depending on the taste of the patient - with salt, onion, pepper, garlic, as well as in the form of sandwiches, sweet dishes, etc. At the first time, when the treatment of malignant anemia with the liver was proposed (1926), it was considered necessary to prescribe a special diet, poor in fats and rich in fruits. Soon, however, it became clear that treatment with the liver is valid with any diet, although it is advisable to provide the patient with a complete protein diet. The addition of hydrochloric acid is desirable, as with any achilia. Raw liver does not pose a danger in relation to helminthic invasion; often developing very high eosinophilia is a consequence of the intake of raw liver as such. Diarrhea is not a contraindication to raw liver treatment, on the contrary, with such treatment, it usually stops soon.
The various oral liver concentrates—liquid, dried powder—are practically of lesser value; they do not always satisfy the taste of patients, and most importantly, they are not always sufficiently active; one of the best is liver extract, given at a dose of about 2 tablespoons per day. The therapeutic effect is also possessed by "gastrocrine", a dried pig stomach, containing, in addition to the internal factor, formed in pigs mainly by the pyloric glands, also external - from the muscular layers of the stomach.
Fresh veal liver is a reliable carrier of an antianemic substance; in addition, it is rich in vitamins, iron, copper. If the patient refuses to take the liver orally, as well as in a severe, life-threatening condition and, of course, with a sharp violation of intestinal absorption, parenteral administration of liver preparations should be preferred.
Active injectable drugs, for example, Soviet campolon, gepalon, hepatia, are administered intramuscularly, usually at 1-2 ml, and in the most severe cases up to 5-8 ml per day (the so-called "campolon shock" treatment) until the onset of a clear remission. In the future, a rapid increase in red blood to normal numbers is provided, which requires at least 2-4 intramuscular injections of 1-2 ml of the active drug per week or daily intake of raw liver. In cases of moderate severity (when the number of erythrocytes is about 1,500,000 and hemoglobin is about 40%), the patient's well-being improves significantly by the end of the first week of treatment. On the 7-10th day, a peak of reticulocytosis is noted, followed by an increase in the number of erythrocytes and hemoglobin, which occurs the more vigorously, the lower the initial numbers were. Having achieved a stable remission in the treatment of raw liver, they often take a break for several weeks, and in the treatment of injections they are content with 1-2 injections per week or even more rare.
In cases of apparent invalidity of hepatic therapy, the misdiagnosis of malignant anemia or insufficient liver dosage is more common. So, with infectious complications - pyelitis, pneumonia, as well as in some less treatable patients, a double dose of 400 g of raw liver per day may be required. In these cases, as well as with extreme anemia, an additional drop blood transfusion is indicated repeatedly, 100-150 ml or more, or, better, erythrocyte mass (suspension) of 100-200 ml.
Recently, it has been recommended to use vitamin B12 treatment, which is already active in very small doses and, moreover, has a good effect on blood restoration and, if given in a timely manner, apparently prevents damage to the nervous system. (Another anti-anemic vitamin, folic acid, does not prevent neurological manifestations of the disease and is therefore now considered less indicated in malignant anemia.)
To prevent and improve nerve damage, a valuable adjunct to liver treatment, especially in the treatment of liver injections, is the systematic administration of vitamin B 1 (thiamine under the skin or inside, yeast autoclaved in a thermostat together with gastric juice); with spastic paralysis, motor-mechanotherapy is carried out, training in movements, walking, as in tabes, etc.
Arsenic currently does not find supporters in the treatment of malignant anemia; iron is indicated especially in the presence of iron deficiency anemia.
In cases of symptomatic and malignant anemia - with a wide tapeworm, pregnancy, agastric anomia, etc. - also, first of all, energetic treatment is carried out with raw liver or injections of appropriate drugs (injections are required for sprue, gastrocolic fistula, when absorption from the intestine is obviously extremely reduced), blood transfusion. In this way, it is possible to bring pregnant women to normal delivery, with an invasion with a wide tapeworm, significantly improve the composition of the blood and the entire clinical picture, followed by fern treatment, which is contraindicated in patients with a serious condition due to its general toxic effect and liver damage caused by it; with gastrocolic fistula, with stenosis of the small intestine, early surgical intervention is indicated, until severe cachexia occurs.

Pernicious anemia
Chronic diseases / anemia due to insufficient absorption of vitamin B 12

It occurs in adults as a result of gastric atrophy (cannot absorb vitamin B12). The wall cells in the stomach that produce the intrinsic factor necessary for the absorption of vitamin B12 and, if destroyed, lead to a lack of this very important vitamin.

The name of pernicious anemia has remained since the time when this type of anemia was fatal and has retained the name for historical reasons.

Due to lack of vitamin B12 can cause a number of diseases and conditions, but anemia only includes those caused by atrophic gastritis and loss of parietal cell function.
Dr. Addison first described the disease and before 1920 people died from this disease one to three years after diagnosis. Doctors have investigated this anemia so that patients consume more raw liver and juice in large quantities. And so they deservedly received the Nobel Prize in 1934, incurable diseases!

We are very grateful for the progress, as well as the fact that we do not eat raw liver, but have solved the lack of this vitamin with pills or injections!
Vitamin B 12 cannot be created/synthesized by the human or animal body in such a way that it must be supplied with food. It is essential for the proper functioning of the brain and nervous system, it is involved in the metabolism of every cell in the body.

Most people get their vitamin B12 from meat (especially liver), fish, shellfish, and dairy products.

The genetic variant of pernicious anemia is an autoimmune disease, with a definitive genetic predisposition. Antibodies are found in 90% of people with pernicious anemia, and currently only 5% of people in the general population.
Classic pernicious anemia caused by a lack of intrinsic factors synthesized in the parietal cells of the stomach, not absorption of vitamin B12, the result: megaloblastic anemia.
Any disease or condition can lead to vitamin B12 deficiency malabsorption and anemia is observed (although not always), a neurological condition.

Periodicity:
The most widespread in the North European population. English, Scandinavian, Irish, Scottish, aged 40-70 years of age.

Problem:
weight loss, fever
Anemia is quite tolerable, even when hemoglobin is very low (40-50), MCV (mean corpuscular volume) is high: more than 100 UGL
About 50% of patients have a very smooth tongue, without papillae (glositis)
Changes in character and personality
Disrupted thyroid function
Diarrhea
Paresthesias: tingling in the arms/legs
The most difficult: neurological disorders: balance problems, gait problems, muscle weakness. In an elderly person with signs of dementia, a lack of vitamin B12 is detected and memory problems, hallucinations, and irritability may occur.

Diagnosis:

Laboratory tests: complete blood count, peripheral blood, levels of vitamin B12, folic acid, methylmalonic acid and homocysteine ​​in the blood
testing the patient's ability to absorb vitamin B12.

Presence of antibodies and intrinsic factors in the blood.

THERAPY:
As you probably guessed, the therapy is to replace vitamin B12. Vitamin B12 does not exist in nature, but is synthesized and applied to patients in the form of tablets, transdermal, nasal or injection (IM, subcutaneous).
Today there are pills that contain high doses of vitamin B12: 500-1000 mcg, so that there is a sufficient amount of vitamin B12 cells in the body.

Is there any doubt, anyway, to provide replacement therapy in the form of injections!
Famous people with pernicious anemia
Alexander Graham Bell
Annie Oakley: 1925. died of pernicious anemia at age 65

Pernicious anemia is one of the blood diseases with a well-studied cause. All disorders in hematopoiesis are caused by a lack of vitamin B 12, therefore another name for the disease is B 12 deficiency anemia.

In the 19th century, anemia was considered progressive and malignant. At that time, it proceeded hard, with a fatal outcome.

Another name for the names of the clinicians who studied it is Addison-Birmer disease (in the UK - Addison, in Germany - Birmer). To the lack of vitamin B 12 they added a concomitant low acidity of gastric juice.

The role of vitamin B 12 in hematopoiesis

Vitamin B 12 "works" in the body not alone, but together with other elements. Most associated with folic acid (vitamin B 9). As a result of their joint activity, protein complexes are formed in the nuclei of cells of all tissues, which are responsible for maturation and division.

Under the influence of the B 12 + B 9 complex, erythrocytes in the bone marrow mature from the cells of the erythroid germ. In a deficient state, the production of normal erythrocytes slows down, and synthesis reaches only the stage of megalocytes. But these cells are unable to bind hemoglobin and carry oxygen. In addition, their lifespan is very short.

Vitamin B stores are stored in humans in the liver. It is believed that they are enough for an adult for a period of one to five years. The need for vitamin B 12 is 5 mcg per day, and B 9 - from 500 to 700 mcg. Stocks of folic acid are barely enough for six months. Gradual "shortage" leads to a violation of the production of red blood cells, the development of the disease.

Why does a vitamin deficiency occur?

The reasons may be:

• alimentary (depending on the composition of the food);
• caused by diseases of the stomach with impaired absorption of the vitamin.

To maintain the level of vitamin B 12, you need to eat meat, liver, kidneys, chicken eggs. Folic acid is found in significant amounts in vegetables (spinach), yeast, and dairy products. Deficiency in intake is observed in vegetarians, alcoholics, starving people, in people who have undergone the removal of part of the stomach. If it is impossible to eat on their own, the patient is given nutrient mixtures intravenously. They should have enough vitamin B 12.

In the stomach, the vitamin binds and is protected from breakdown by food enzymes by a special glycoprotein. With atrophy of the gastric mucosa and duodenum in the elderly or with chronic gastritis, peptic ulcer disease, glycoprotein is not produced and vitamins are lost.

Through the intestinal mucosa, the complex of glycoprotein molecules with vitamin B 12 enters the bloodstream and is transported by transcobalamins, which are formed by macrophages and leukocytes. Therefore, with leukocytosis, the vitamin accumulates in larger quantities. The process of absorption of substances from the intestine (malabsorption) is disturbed in congenital and acquired pathologies: Crohn's disease, sprue, celiac disease, intestinal lymphoma.

Pernicious anemia occurs during pregnancy, in patients with psoriasis and special types of dermatitis. In this case, the body needs an increased need for the vitamin, and anemia is the result of insufficient compensation.

Clinical manifestations

For pernicious anemia, gradual development is typical.

Initial symptoms:

• general weakness;
• dizziness;
• increased fatigue;
• tachycardia;
• shortness of breath on exertion.

The pronounced clinical picture includes:

• yellowing of the skin and sclera (lighter than with hepatitis);
• pain and inflammation of the tongue (glossitis);
• dull pain or a feeling of heaviness on the left in the hypochondrium due to an increase in the spleen (rarely the liver).

The disease is characterized by a cyclic course with periods of exacerbations and remissions. With each exacerbation, the symptoms worsen.

Picture of inflammation of the tongue (glossitis)

Damage to the nervous system

With pernicious anemia, unlike other types of anemia, damage occurs to the myeloid sheath of the nerve pathways (funicular myelosis).

It shows up:

• impaired sensitivity in the arms and legs, numbness;
• pain in the limbs;
• feeling of "tingling";
• increasing weakness in the muscles to the degree of atrophy;
• unsteady gait.

If left untreated, damage to the spinal cord and its roots occurs. In this case, the pathology spreads from the legs above. First, a violation of deep sensitivity is recorded, then hearing and smell are reduced.

In severe cases develops:

• exhaustion,
• loss of reflexes
• limb paralysis,
• memory loss.

Visual and auditory hallucinations, delusions are possible.

Anemia and pregnancy

Pernicious anemia can occur in the second half of pregnancy. The general symptoms of anemia (dizziness, weakness, tachycardia, shortness of breath, pallor) are accompanied by a slight decrease in the sensitivity of the fingers, and indigestion.

Pregnant women should have regular blood tests in order to suspect symptoms early.

With advanced forms of B 12 deficiency anemia, the risk of abortion is increased due to placental abruption, premature birth, and stillbirth.

Treatment of a woman leads to a complete recovery.

Why do children get sick?

In childhood, the disease often develops in families with hereditary pathology of the stomach or intestines. This leads to impaired absorption of vitamins. Less often, the reason lies in the non-compliance of the nursing mother with the regimen and diet.

Hereditary manifestations are found already from the age of three months. More complete symptoms are formed by the age of three.

The child has:

• pallor with a lemon tint;
• dry, flaky skin;
• tongue inflammation;
• lack of weight due to loss of appetite;
• frequent diarrhea.

Children with pernicious anemia are more prone to infections and often get sick. Possible developmental delay.

Diagnostics

The diagnosis is made by comparing the clinical manifestations and the blood picture. When deciphering a blood test, the following are noted:

• decrease in the number of red blood cells;
• increased color index;
• changes in the size and shape of erythrocyte cells;
• the presence of megaloblasts, erythrocytes with the remains of the nucleus;
• decrease in the number of reticulocytes;
• shift of the leukocyte formula to the left;
• decrease in the number of platelets.

Treatment

Therapy for pernicious anemia begins with the appointment of a balanced diet. To compensate for the necessary need for vitamins B 12 and B 9, beef meat (tongue, heart), rabbit, chicken eggs, seafood, cottage cheese and dairy products, legumes should be provided in the daily diet. Fatty foods will have to be limited, as it slows down blood formation.

Cyanocobalamin must not be mixed in the same syringe with other medicines

Be sure to prescribe therapy for diseases of the stomach and intestines.

In order to compensate for the lack of vitamins, a large dose of Cyanocobalamin is administered intravenously. Feeling better after a few days.
The course of treatment lasts up to a month or more, depending on the achievement of stable normalization of blood test results and the severity of the patient's condition. Then the medicine is administered for another six months once a week.

Preparations from liver extracts (Campolon and Antianemin) are administered intramuscularly daily.

Inside, folic acid tablets are prescribed.

Currently, the disease belongs to rare varieties of anemia. This is facilitated by simple diagnosis and affordable treatment.

Pernicious anemia shares symptoms with other types of anemia, but the diagnosis is based on very precise clinical data. Consider the features and methods of treatment of this type of anemia.

Features of pernicious anemia

pernicious anemia is a progressive disease, i.e. it gradually intensifies. Associated with deficiency of a particular vitamin B12 or cobalamin important for the formation and maturation of red blood cells in the blood.

In addition, the accelerated destruction of erythrocytes provokes increased bilirubin levels, a substance that is formed as a result of the catabolism of hemoglobin.

Pernicious anemia is quite common in the elderly, due to the reduced functionality of the gastrointestinal tract, which loses the ability to effectively absorb many vitamins, including B12.

More rarely, megaloblastic anemia affects children, in which, as we will see later, it is most often associated with genetic causes or malnutrition.

Symptoms of megaloblastic anemia

The symptoms of pernicious anemia are due to the low efficiency of transporting oxygen to the tissues and, therefore, are common to all other types of anemia.

In particular:

• pallor associated with reduced blood flow to the skin
• fatigue and apathy caused by muscle hypoxia
• tachycardia, due to the heart's attempt to compensate for the reduced oxygen supply
• dizziness, confusion and memory loss, due to the fact that vitamin B12 is a cofactor important for the functioning of nerve cells, and the deficiency of which leads to neurological changes.

How is pernicious anemia diagnosed?

Diagnostic research in the direction of pernicious anemia includes, first of all, a general blood test, which confirms the diagnosis if:

• the number of red blood cells is less than 3 million per mm 3
• there is a decrease in serum iron levels
• vitamin B12 test below control values ​​- 200 - 900 pg / ml
• reduced ferritin level, i.e. iron reserves
• the average volume of erythrocytes is increased, since immature erythrocytes are large

Other tests used for diagnosing pernicious anemia:

• indirect bilirubin level which is elevated in pernicious anemia
• gastrin level, - a hormone that is present in the gastric mucosa and is necessary for the absorption of vitamin B12
• alkaline phosphatase level, which allows you to evaluate the activity of white blood cells to identify autoimmune causes of the disease

A decrease in the level of red blood cells and iron has a negative prognosis if not corrected, as it can lead to significant complications, especially when the nervous system is stressed: cobalamin deficiency for a long time can lead to irreversible nerve damage.

Causes of pernicious anemia

Normally, vitamin B12, found in animal products, binds to Factor Castle, which is secreted by the gastric mucosa and has the task of facilitating the absorption of cobalamin in the intestine.

In this way, vitamin B12 deficiency may result from:

• insufficient intake of animal food (vegetarian diet): Vitamin B12 is naturally found only in animal products, so a vegetarian diet (without the use of nutritional supplements) inevitably leads to vitamin B12 deficiency.
• Intrinsic factor deficiency caused by damage to the gastric mucosa. Cancer of the stomach, alcohol, infection of the stomach with helycobacter bacteria, or Birmer's disease (an autoimmune disease in which antibodies attack and destroy the stomach's own lining, causing it to atrophy) can damage the stomach walls.
• Malabsorption in the intestine, as in the case of Crohn's disease, in which intestinal cells lose their ability to absorb vitamin B12.
• Congenital intrinsic factor deficiency, a rare genetic pathology in which the synthesis of the Castle factor is disrupted. The disease is present from birth and manifests itself in children up to the fifth year.

Therapy for macrocytic anemia: nutritional supplements and diets

In the case of pernicious anemia, therapy consists in administering to the patient:

• vitamin B12 tablets to compensate for its deficiency;
• gland to restore the level of this mineral in the blood;
• folic acid, which stimulates the synthesis and production of red blood cells.

In case of malabsorption of vitamin B12 or gastric atrophy, vitamin B12 is given by injection or nasal spray.

An important role in the prevention and treatment of pernicious anemia plays food. Cobalamin can be found in foods such as:

• liver
• egg yolk

and to a lesser extent:

• mature cheeses
• spirulina algae

A varied and balanced diet provides the right amount of vitamin B12, but vegetarian diets, and even more so vegan ones, require the appropriate integration of this important vitamin in order not to risk and face the consequences of 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. It usually affects people over 40 years of age. The clinical picture of the disease consists of the following triad: 1) disorders of the digestive tract; 2) violations of the hematopoietic system; 3) disorders of the nervous system.

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

At the beginning of the disease, there is an increasing physical and mental weakness. Patients quickly get tired, complain of dizziness, headaches, tinnitus, "flying flies" in the eyes, as well as shortness of breath, palpitations at the slightest physical exertion, drowsiness during the day and nighttime insomnia. Then dyspeptic symptoms (anorexia, diarrhea) join, and patients go to the doctor already in a state of significant anemia.

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

Relatively rarely, according to various authors in 1-2% of cases, pernicious anemia begins with 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 extremities or pain of a radicular nature.

The appearance of the patient during the period of exacerbation of the disease is characterized by a sharp pallor of the skin with a lemon-yellow tint. The sclera are 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 zygomatic bones. The face is puffy, swelling in the area of ​​the ankles and feet is quite often noted. Patients are not usually emaciated; on the contrary, they are well-fed and prone to obesity. The liver is almost always enlarged, sometimes reaching a significant size, insensitive, soft consistency. The spleen is more dense, 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, which are very sensitive to food and medicines, especially acidic ones, causing the patient to feel a burning sensation and pain. Areas of inflammation are more often localized along the edges and at the tip of the tongue, but sometimes they capture the entire tongue ("scalded tongue"). Often there are aphthous rashes on the tongue, sometimes cracks. Such changes can spread to the gums, buccal mucosa, soft palate, and in rare cases, to the mucosa of the pharynx and esophagus. In the future, the inflammatory phenomena subside and the papillae of the tongue atrophy. The tongue becomes smooth and shiny ("varnished tongue").

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

X-ray often determine the 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 mother-of-pearl plaques - shiny mirror areas of mucosal atrophy, localized mainly on the folds of the gastric mucosa.

The analysis of gastric contents, as a rule, reveals achilia and increased mucus content. In rare cases, free hydrochloric acid and pepsin are contained in a small amount. Since the introduction of the histamine test into clinical practice, cases of pernicious anemia with preserved free hydrochloric acid in the gastric juice have become more common.

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, which indicates the absence of an internal factor (gastromucoprotein). The ferruterous mucoprotein is not found also at special methods of research.

The histological structure of the gastric mucosa, obtained by biopsy, is characterized by a 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 involve 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 secretion of gastromucoprotein. 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 in 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 is sometimes observed with abundant, intensely colored stools, which is due to an increased content of stercobilin - up to 1500 mg per day.

In connection with anemia, an anoxic state of the body develops, which primarily affects the system of the circulatory and respiratory organs. Functional myocardial insufficiency in pernicious anemia is caused by impaired nutrition of the heart muscle and its fatty degeneration.

On the electrocardiogram, symptoms of myocardial ischemia can be noted - a negative T wave in all leads, low voltage, widening of the ventricular complex. During remission, the electrocardiogram becomes normal.

The temperature during the period of relapse often rises to 38 ° and higher figures, but more often it is subfebrile. The increase in temperature is mainly due to the process of enhanced breakdown of red blood cells.

Changes in the nervous system are very important in diagnostic and prognostic terms. The pathological basis of the nervous syndrome is degeneration and sclerosis of the posterior and lateral columns of the 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 former include: spastic paraparesis with increased reflexes, clonus and pathological reflexes of Babinsky, Rossolimo, Bekhterev, Oppenheim. Symptoms that mimic dorsal tabes (“pseudotabes”) include: paresthesias (a feeling of crawling, numbness of the distal extremities), girdle pain, hypotension and a decrease in reflexes up to areflexia, impaired vibrational and deep sensitivity, sensory ataxia and dysfunction of the pelvic organs .

Sometimes symptoms of damage to the pyramidal tracts or posterior columns of the spinal cord dominate; in the latter case, a picture resembling tabes is created. In the most severe, rare forms of the disease, cachexia develops with paralysis, complete loss of deep sensitivity, areflexia, trophic disorders, and dysfunction of the pelvic organs (our observation). More often it is necessary to see patients with the initial symptoms of funicular myelosis, expressed in paresthesia, radicular pain, mild violations of deep sensitivity, unsteady gait and a slight increase in tendon reflexes.

Damage to the cranial nerves, mainly visual, auditory and olfactory, is less common, and therefore there are corresponding symptoms from the senses (loss of smell, decreased hearing and vision). A characteristic symptom is a central scotoma, accompanied by loss of vision and quickly disappearing under the influence of vitamin B12 treatment (S. M. Ryse). In patients with pernicious anemia, damage to the peripheral neuron also occurs. This form, referred to as polyneuritic, is due to degenerative changes in various nerves - the sciatic, median, ulnar, etc., or individual nerve branches.

Mental disorders are also observed: delusional ideas, hallucinations, sometimes psychotic phenomena with depressive or manic moods; dementia is more common in older people.

During a period of severe relapse of the disease, a coma (coma perniciosum) may occur - 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 the fall in the quantitative indicators of red blood. Sometimes patients with 10 units of hemoglobin in the blood do not fall into a coma, sometimes a coma develops with 20 units or more of hemoglobin. In the pathogenesis of pernicious coma, the main role is played by the rapid rate of anemia, leading to severe ischemia and hypoxia of the centers of the brain, in particular the region of the third ventricle (AF Korovnikov).

Rice. 42. Hematopoiesis and blood destruction in pernicious B12 (folic) deficiency anemia.

Blood picture. In 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: there are observations when (with a favorable outcome!) Hemoglobin decreased to 8 units (1.3 g%), and the number of red blood cells - up to 140,000.

No matter how low hemoglobin decreases, the number of red blood cells falls 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 the normal one.

The volume of a megalocyte is 165 microns 3 and 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, they do not show a 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 pycnotic nucleus (incorrectly designated as "normoblasts"), less often - polychromatophilic and basophilic megaloblasts with a nucleus of a typical structure.

The number of reticulocytes during the period of exacerbation is sharply reduced.

The appearance of reticulocytes in the blood in large numbers portends a close remission.

Changes in white blood are no less characteristic of pernicious anemia. During a recurrence of pernicious anemia, leukopenia (up to 1500 or less), neutropenia, eosinopenia or aneosinophilia, abasophilia and monopenia are observed. Among the cells of the neutrophilic series, a "shift to the right" is noted with the appearance of peculiar giant polysegmentonuclear forms containing up to 8-10 nuclear segments. Along with the shift of neutrophils to the right, there is also a shift to the left 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).

Tab. 19. pernicious anemia. Blood picture in severe relapse of the disease. In the field of view, megaloblasts of various generations, megalocytes, erythrocytes with nuclear derivatives (Caebot rings, Jolly bodies) and basophilic puncture, a characteristic polysegmentonuclear neutrophil are visible.

Tab. 20. pernicious anemia. Blood picture in remission. Macroanisocytosis of erythrocytes, polysegmentonuclear neutrophil.

The number of platelets during the period of exacerbation is somewhat reduced. In some cases, thrombocytopenia is noted - up to 30,000 or less. Platelets may be atypical in size; their diameter reaches 6 microns or more (the so-called megaplatelets); there are also degenerative forms. Thrombocytopenia in pernicious anemia, as a rule, is not accompanied by hemorrhagic syndrome. Only in rare cases, bleeding phenomena are observed.

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

In the period of exacerbation of the disease, bone marrow punctate macroscopically appears to be abundant, bright red, which contrasts with the pale, watery appearance of peripheral blood. The total number of nucleated elements of the bone marrow (myelokaryocytes) is increased. The ratio between leukocytes and erythroblasts leuko/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.

Rice. 43. Hematopoiesis in pernicious anemia.

a - bone marrow punctate of a patient with pernicious anemia before treatment. Erythropoiesis is performed according to the megaloblastic type; b - bone marrow punctate of the same patient on the 4th day of treatment with a liver extract (orally). Erythropoiesis is performed according to the macronormoblastic type.

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

The quantitative ratios 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. On the contrary, the predominance of fully hemoglobinized, oxyphilic megaloblasts gives the impression of "red" bone marrow.

A characteristic feature of the cells of the megaloblastic series is the early hemoglobinization of their cytoplasm with the delicate structure of the nucleus still preserved. The biological feature of megaloblasts is anaplasia, i.e. loss by the cell of its inherent ability for normal, differentiating development and final transformation into an erythrocyte. Only an insignificant part of megaloblasts matures to the final stage of their development and turns into nuclear-free megalocytes.

Tab. 21. Megaloblasts in the bone marrow in pernicious anemia (color microphoto).

Tab. 22. Pernicious anemia in the advanced stage of the disease (bone marrow puncture).

Below at 7 o'clock - a promyelocyte, at 5 o'clock - a characteristic hypersegmentonuclear neutrophil. All other cells are megaloblasts in various phases of development, ranging from a basophilic promegaloblast with nucleoli (at 6 o'clock) to an orthochromic megaloblast with a pycnotic nucleus (at 11 o'clock). Among megaloblasts, mitoses with the formation of two- and three-nuclear cells.

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. A comparative study of the morphological and biological features of megaloblasts in malignant anemia, hemocytoblasts in leukemia, and cancer cells in malignant neoplasms led us to the idea of ​​a possible commonality of pathogenetic mechanisms in these diseases. There are reasons to think that both leukemias and malignant neoplasms, like malignant anemia, arise under conditions of a deficiency of specific factors necessary for the normal development of cells that is created in the body.

Megaloblasts are a morphological expression of a kind of "dystrophy" of the red nuclear cell, which "lacks" a specific maturation factor - vitamin B 12. Not all cells of the red row are equally anaplastic; 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 special difficulties for differentiation, are usually found in the initial stage of 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 those of normal neutrophils.

Similar changes - a violation of aging and a pronounced polymorphism of the nuclei - are also noted in the giant cells of the bone marrow. Both in immature megakaryocytes and in "overripe", polymorphic forms, the processes of formation and detachment of platelets are impaired. Megaloblastosis, polysegmentonuclear neutrophils and changes in megakaryocytes are dependent on the same cause. This reason is the insufficiency of a specific hematopoietic factor - vitamin B12.

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

Increased breakdown of erythrocytes, or erythrorhexis, takes place throughout the reticulohistiocytic system, including in the bone marrow itself, where part of the hemoglobin-containing erythromegaloblasts undergoes the process of karyo- and cytorhexis, which results in the formation of fragments of erythrocytes - schizocytes. The latter partly enter the bloodstream, partly are captured by phagocytic reticular cells - macrophages. Along with the phenomena of erythrophagy, significant accumulations of an iron-containing pigment, hemosiderin, originating from the hemoglobin of destroyed erythrocytes, are found in the organs.

The increased breakdown of erythrocytes does not give grounds to attribute pernicious anemia to the category of hemolytic anemia (as was allowed by the old authors), since erythrorrhexis, which occurs in the bone marrow itself, is due to defective hematopoiesis and is secondary.

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 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 feces.

Pathological anatomy. Thanks to the advances in modern therapy, pernicious anemia in the section is now very rare. At autopsy, anemia of all organs is striking, while maintaining fatty tissue. There is fatty infiltration of the myocardium ("tiger heart"), kidneys, liver, in the latter, central fatty necrosis of the lobules is also found.

In the liver, spleen, bone marrow, lymph nodes, especially retroperitoneal, there is a significant deposition of a fine-grained yellow-brown pigment - hemosiderin, which gives a positive reaction to iron. 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 it does not occur (in contrast 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 papillae of the tongue are atrophic. Similar changes can be observed on the part of the mucous membrane of the pharynx and esophagus. In the stomach, atrophy of the mucosa and its glands is found - anadenia. A similar atrophic process exists 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 often in the spinal cord there are ischemic foci with necrotic softening of the nervous tissue. Necrosis and foci of glial growth in the cerebral cortex are described.

A typical sign of pernicious anemia is crimson-red juicy bone marrow, which contrasts sharply with the general pallor of the integument and anemia of all organs. Red bone marrow is found not only in the flat bones and epiphyses of tubular bones, but also in the diaphysis of the latter. Along with bone marrow hyperplasia, extramedullary foci of hematopoiesis (accumulation of erythroblasts and megaloblasts) in the splenic pulp, liver, and lymph nodes are noted. Reticulo-histiocytic elements in the hematopoietic organs and extramedullary foci of hematopoiesis reveal 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 is preserved until the last moment of the patient's life. The lethal outcome occurs not due to anatomical aplasia of the hematopoietic organ, but due to the fact that functionally defective megaloblastic hematopoiesis is not able to provide oxygen respiration processes vital for the body with the necessary minimum of erythrocytes.

Etiology and pathogenesis. Since Biermer singled out "pernicious" anemia as an independent disease, the attention of clinicians and pathologists has been attracted by the fact that gastric achylia (which, according to recent years, has turned out to be histamine-resistant) is constantly observed in this disease, and atrophy of the gastric mucosa is found on the section ( 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 concepts, pernicious anemic syndrome should be considered as a manifestation of endogenous B12 vitamin deficiency.

The direct mechanism of anemia in Addison-Birmer disease is that, due to vitamin B12 deficiency, nucleoprotein metabolism is disrupted, which leads to disruption of mitotic processes in hematopoietic cells, in particular in bone marrow erythroblasts. The slow rate of megaloblastic erythropoiesis is due to 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 proceeds with one mitosis. This means that while one pronormoblast produces 8 erythrocytes, one promegaloblast produces only 2 erythrocytes.

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

The latter is confirmed by the data on the determination of the iron circulation (with the help of radioactive isotopes), as well as the increased excretion of blood pigments - urobilin, etc.

In connection with the indisputably established "deficient" endogenous-avitaminous nature of pernicious anemia, the previously dominant views on the significance of increased breakdown of erythrocytes in this disease have undergone a radical revision.

As is known, pernicious anemia was classified as hemolytic anemia, and megaloblastic erythropoiesis was considered as a response of the bone marrow to an increased breakdown of erythrocytes. However, the hemolytic theory has not been confirmed either in the 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 the 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 failed.

The increased excretion of pigments in pernicious anemia is explained not so much by the destruction of newly formed erythrocytes in the circulating blood, but by the decay of hemoglobin-containing megaloblasts and megalocytes even before they enter the peripheral blood, i.e. in the bone marrow and foci of extramedullary hematopoiesis. This assumption is confirmed by the fact of increased erythrophagocytosis found by us in the bone marrow of patients with pernicious anemia. The increased content of iron in the blood serum noted during the period of recurrence of pernicious anemia is mainly explained by impaired utilization of iron, since during the period of remission the content of iron in the blood returns to normal values.

In addition to the increased deposition in the tissues of the iron-containing pigment - hemosiderin and the increased content of iron-free pigments (bilirubin, urobilin) ​​in the blood, duodenal juice, urine and feces, patients with pernicious anemia in the blood serum, urine and bone marrow have an increased amount of porphyrin and small amounts of hematin. Porphyrinemia and hematinemia are due to insufficient utilization of blood pigments by the 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-fledged oxygen carriers to the same extent as normal erythrocytes. This conclusion is consistent with the established fact of increased oxygen consumption by the megaloblastic bone marrow.

The B12-avitaminous theory of the genesis of pernicious anemia, generally recognized 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 stay in the peripheral blood. According to the observations of a number of authors, 50% of erythrocytes transfused from a patient with pernicious anemia to a healthy recipient stay in the blood of the latter from 10-12 to 18-30 days. The maximum lifespan of erythrocytes during an exacerbation of pernicious anemia is from 27 to 75 days, therefore, 2-4 times less than normal. Finally, the slightly pronounced hemolytic properties of the plasma of patients with pernicious anemia, which are proved by observations of erythrocytes from healthy donors transfused to patients with pernicious anemia and subjected to accelerated decay in the blood of recipients, are of some (by no means paramount) importance (Hamilton et al., 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 a deficiency of the vitamin B complex.

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

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

According to modern views, Addison-Birmer's 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 that produce gastromucoprotein necessary for the assimilation of vitamin B12.

This is not 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 in vivo during gastroscopic examination (see above) or by biopsy of the gastric mucosa.

Noteworthy is the concept put forward by a number of authors (Taylor, 1959; Roitt and colleagues, 1964) about the autoimmune genesis of gastric atrophy in pernicious anemia. This concept is supported by the detection in the blood serum of the majority of patients with pernicious anemia of specific antibodies that temporarily disappear under the influence of corticosteroids against the parietal and chief cells of the gastric glands, as well as immunofluorescence data showing the presence of antibodies fixed in the cytoplasm of 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 of the biopsied gastric mucosa, a significant lymphoid infiltration was found in the latter, which is considered as evidence of the participation of immunocompetent cells in unleashing an organ-specific autoimmune inflammatory process with subsequent atrophy of the gastric mucosa.

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

In favor of the immunological commonality of Birmer's anemia and Hashimoto's thyroiditis, the fact of detection of antithyroid antibodies in the blood of patients with Birmer's anemia, on the other hand, antibodies against parietal cells of the gastric mucosa in patients with thyroid lesions, speaks in favor of the immunological commonality. According to Irvine et al. (1965), antibodies against gastric parietal cells are found in 25% of patients with Hashimoto's thyroiditis (antithyroid antibodies are found in the same patients in 70% of cases).

Of interest are the results of studies of relatives of patients with Birmer's anemia: according to various authors, antibodies against parietal cells of the gastric mucosa and against 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 at least 20 % of relatives of patients with Birmer's pernicious anemia.

According to the latest studies conducted using the radiodiffusion method on 19 patients with pernicious anemia, a group of American researchers found the existence of antibodies in the blood serum of all patients, either “blocking” the intrinsic factor or binding both the intrinsic factor (IF) and the HF+ complex AT 12.

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 the blood.

In childhood forms of B12-deficiency anemia, occurring with intact gastric mucosa, but with impaired production of intrinsic factor (see below), antibodies against 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 the light of the above data, the deep pathogenesis of B12 deficiency anemia of Birmer appears as an autoimmune conflict.

Schematically, the occurrence of neuroanemic (B12-deficient) syndrome in Addison-Birmer disease can be represented as follows.

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 (cit. Wintrobe), gastric 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 the summary data collected by A. V. Melnikov and N. S. Timofeev, the frequency of gastric cancer in patients with malignant anemia, established on the basis of clinical, radiological and sectional materials, is 2.5%, i.e. about 8 times more than among the general population (0.3%). The frequency of gastric cancer in patients with pernicious anemia, according to the same authors, is 2-4 times higher than that of gastric cancer in people of the same age who do not suffer from anemia.

The increase in cases of gastric cancer in patients with pernicious anemia in recent years is noteworthy, which should be explained by the lengthening 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. However, one should not 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 affected the fundus of the stomach, although the localization of the tumor in this section is certainly "aggravating" significance. According to S. A. Reinberg, out of 20 patients with a combination of gastric cancer and pernicious anemia, only 4 had a tumor localized in the cardiac and subcardial regions; 5 had a tumor in the antrum, 11 - in the body of the stomach. A pernicious-anemic blood picture can develop at any localization of gastric cancer, accompanied by diffuse atrophy of the mucosa with involvement of the glands of the fundus of the stomach in the process. There are cases when the developed pernicious anemia blood picture was the only symptom of stomach cancer (a similar case was described by us) 1 .

Signs that are suspicious in terms of the development of a cancerous tumor of the stomach in a patient with pernicious anemia should be considered, firstly, a change in the type of anemia from hyperchromic to normohypochromic, secondly, the patient's refractoriness to vitamin B12 therapy, and thirdly, the appearance of new symptoms, uncharacteristic for pernicious anemia as such: loss of appetite, weight loss. The appearance of these symptoms obliges the doctor to immediately examine the patient in the direction of a 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 some clinical and hematological symptoms that inspire reasonable suspicions of the development of blastoma, it is necessary to consider surgical intervention - a trial laparotomy, as indicated.

Forecast. Hepatic therapy, proposed in 1926, and modern treatment with vitamin B i2 radically changed the course of the disease, which had lost its "malignancy". Now the fatal outcome of malignant anemia, which occurs with the phenomena of oxygen starvation of the body (anoxia) in a state of coma, is a rarity. Although not all symptoms of the disease disappear during remission, nevertheless, persistent blood remission, which occurs as a result of the systematic use of anti-anemic drugs, is actually tantamount to a practical recovery. There are known cases of complete and final recovery, especially those patients who have not yet had time to develop a nervous syndrome.

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

A great achievement in the treatment of pernicious anemia has been the preparation of effective liver extracts. Of the parenterally administered liver extracts, the most famous was the Soviet campolone, extracted from the liver of cattle and produced in 2 ml ampoules. In connection with reports of the anti-anemic role of cobalt, liver concentrates enriched with cobalt have been created. A similar Soviet drug - antianemin - was successfully used in domestic clinics for the treatment of patients with pernicious anemia. Dosage of antianemin - from 2 to 4 ml per muscle daily until hematological remission is obtained. Practice has shown that a single injection of a massive dose of Campolone in 12-20 ml (the so-called "Campolon impact") is equivalent in effect to a full course of injections of the same drug, 2 ml daily.

According to modern studies, the specificity of the action of hepatic 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 gamma 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. Assigned per os or parenterally at a dose of 30-60 mg or more (up to a maximum of 120-150 mg pro die), folic acid causes a patient with pernicious anemia to quickly go into remission. However, the negative property of folic acid is that it leads to an increased consumption of tissue vitamin B12. According to some reports, folic acid does not prevent the development of funicular myelosis, and even contributes to it with prolonged use. Therefore, folic acid in Addison-Birmer anemia has not been used.

At present, 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 "shock 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 at 2-3 μg, it was proposed to administer relatively small doses of vitamin B12 - 15  daily or 30  every 1-2 days. At the same time, it was believed that the introduction of large doses is inappropriate due to the fact that most of the vitamin B12 obtained in excess of 30  is excreted from the body with urine. Subsequent studies, however, showed that plasma B12-binding capacity (depending mainly on the content of   -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 is in the liver.

According to Mollin and Ross, in severe B12-deficiency of the body, which manifests itself clinically as funicular myelosis, after an injection of 1000  vitamin B12, 200-300  .

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

In practice, as a scheme for exacerbation of pernicious anemia, it is possible to recommend injections of vitamin B12 at 100-200  daily during the first week (before the onset of a reticulocyte crisis) and then a day later until the onset of hematological remission. On average, with a course of treatment of 3-4 weeks, the course dose of vitamin B12 is 1500-3000  .

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

Positive results - a pronounced improvement in 11 out of 12 patients with funicular myelosis (moreover, in 8 patients with rehabilitation) - were obtained by L. I. Yavorkovsky with endolubial administration of vitamin B12 at a dose of 15-200 mcg With intervals of 4-10 days, total for the course of treatment up to 840 mcg . Given the possibility of complications, up to severe meningeal syndrome (headache, nausea, neck stiffness, fever), the indication for endolubal administration of vitamin B12 should be limited to extremely severe cases of funicular myelosis. Other methods used in the recent past for the treatment of funicular myelosis: diathermy of the spine, raw pork stomach in large doses (300-400 g per day), vitamin B1 at 50-100 mg per day - have now lost their value, 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. Heading dose of vitamin B12 - from 10,000 to 25,000  .

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

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

Oral use of vitamin B12 is effective in combination with the simultaneous intake of the gastric anti-anemic 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 the domestic drug mucovit (the drug was produced in tablets containing 0.2 g of gastromucoprotein from the mucous membrane of the pyloric part of the stomach and 200 or 500 μg of vitamin B12).

In recent years, there have been reports of positive results in the treatment of patients with pernicious anemia with vitamin B12, administered orally at a dose of at least 300  per day without intrinsic factor. At the same time, it can be expected that the absorption of even 10% of the administered vitamin B12, i.e., approximately 30  , quite enough 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, the 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 a 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 upcoming 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 in hematopoiesis occur, expressed in the mass division of basophilic erythroblasts and megaloblasts with the differentiation of the latter into new forms of erythroblasts - mainly meso- and microgenerations. The only sign pointing to the "megaloblastic past" of these cells is the disproportion between the high degree of hemoglobinization of the cytoplasm and the nucleus that still retains its loose structure. As the cell matures, the dissociation in the development of the nucleus and cytoplasm is smoothed out. The closer the cell is to final maturation, the more it approaches the normoblast. The further development of these cells - their denucleation, final hemoglobinization and transformation into erythrocytes - takes place according to the normoblastic type, at an accelerated pace.

On the part of granulopoiesis, there is an enhanced 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 polysegmentonuclear neutrophils characteristic of pernicious anemia. In the same period, there is a restoration of the normal morphophysiology of giant bone marrow cells and the normal process of platelet formation.

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 the normal content 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 response of the bone marrow. The faster the curve rises, the slower its decline, sometimes interrupted by a second rise (especially with irregular treatment).

Isaacs and Friedeman proposed a formula by which in each individual case it is possible to calculate the maximum percentage of reticulocytes expected under the influence of treatment:

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

Example. The number of erythrocytes on the day of the start of therapy was 2,500,000.

The immediate effect of vitamin B12 therapy in the sense of replenishing the peripheral blood with newly formed erythrocytes begins to affect only from the 5th-6th day after the administration of the antianemic drug. The percentage of hemoglobin increases more slowly than the number of erythrocytes, so the color indicator in remission 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 erythrocytes also decrease: the yellowness of the integument disappears, the liver and spleen shrink to normal sizes, the amount of pigments in the blood serum, bile, urine and feces decreases.

Rice. 44. Dynamics of blood parameters under the influence of vitamin B12.

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

Improving the general condition: a surge of strength, the disappearance of diarrhea, a drop in temperature - usually occurs before the disappearance of anemic symptoms. Glossitis is eliminated somewhat more slowly. In rare cases, there is also a restoration of gastric secretion. To some extent, nervous phenomena are reduced: paresthesia and even ataxia disappear, deep sensitivity is restored, and the state of the psyche improves. In severe forms, nervous phenomena are hardly reversible, which is associated with degenerative changes in the nervous tissue. The effectiveness of vitamin B12 therapy has a known limit, upon reaching which the growth of blood counts stops. Due to a faster increase in the number of red blood cells compared to an increase in hemoglobin, the color index decreases to 0.9-0.8, and sometimes even lower, anemia becomes hypochromic. It seems that vitamin B12 therapy, by facilitating the maximum use of iron to build erythrocyte hemoglobin, leads to the depletion of its reserves in the body. The development of hypochromic anemia in this period is also favored by the reduced absorption of dietary iron due to achilia. Therefore, during this period of the disease, it is advisable to switch to treatment with iron preparations - Ferrum hydrogenio reductum, 3 g per day (it is necessary to drink hydrochloric acid) or hemostimulin. An indication for the appointment of iron in patients with pernicious anemia can be a decrease in plasma iron from elevated (up to 200-300 %) during the period of exacerbation to subnormal numbers during remission. An indicator of the beneficial effect of iron during this period is an increase in the utilization of radioactive iron (Fe 59) from 20-40% (before treatment) to normal (after treatment with vitamin B12).

The question of the use of blood transfusions in pernicious anemia in each case is decided according to the indications. An unconditional indication is a pernicious coma, which poses a threat to the life of the patient 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 blood counts, characteristic changes in erythrocytes (aniso-poikilocytosis, single macrocytes) and a shift of neutrophils to the right can be detected. The study of gastric juice reveals in most cases permanent achilia. Changes in the nervous system can progress even in the absence of anemia.

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

In rare cases, relapses of the disease occur after a few years. So, 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 in prescribing a prophylactic (anti-relapse) intake of vitamin B12. In this case, one should proceed from the fact that the daily need for it of a person is, according to the observations of various authors, from 3 to 5 . Based on these data, it can be recommended to administer to the patient 2-3 times a month for 100  or weekly for 50 vitamin B12 in the form of injections in order to prevent the recurrence of pernicious anemia.

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

Prevention. Prevention of exacerbations of pernicious anemia is reduced to the systematic administration of vitamin B12. Terms and dosages are set individually (see above).

Considering the age characteristics (usually the elderly age of patients), as well as the existing pathomorphological substrate of the disease - atrophic gastritis, considered as a pre-cancer condition, it is necessary to exercise reasonable (not excessive!) Oncological alertness in relation to each patient with pernicious anemia. Patients with pernicious anemia are subject to dispensary observation with obligatory blood control and X-ray examination of the gastrointestinal tract at least once a year (if there is suspicion, more often).