Special Pathology 2 страница

character. The total amount of juice produced during the study is usually significantly diminished; the pepsin content of the juice is very low or it cannot be determined at all (achylia). Usually achlorhydria develops many years before the first symptoms of anaemia develop.

Elevated temperature is a common symptom of vitamin B₁₂ (folic acid) deficiency anaemia; the temperature is usually subfebrile.

Blood plasma contains slightly increased amounts of free bilirubin due to increased haemolysis of the red cells, especially megalocytes; the plasma iron content increased to 30-45 mmol/1 (170-200 ^g/ml).

The blood picture (Plate 31) is characterized by a sharp decrease in the quantity of erythrocytes (to 0.80 x 10¹² per 1 1) at a comparatively high haemoglobin saturation. Despite the decreased total haemoglobin content of the blood, the colour index remains high (1.2-1.5). Red blood cells dif­fer in size (anisocytosis), with prevalence of large erythrocytes (macrocytes). Especially large slightly oval and intensely red megalocytes appear (in many cases megaloblasts are also seen). The volume of each cell increases. Many erythrocytes are oval, or they have the shape of a sickle and other shapes (poikilocytosis). Megalocytes often have remnants of the nucleus or its envelope in the form of Jolly bodies or Cabot rings. The con­tent of reticulocytes is not high. The number of reticulocytes sharply in­creases (reticulocytic crisis) during vitamin B₁₂ therapy to indicate the beginning remission. Blood leucocytes decrease mostly at the expense of neutrophils. Eosinopenia, relative lymphocytosis, and thrombocytopenia are observed. Large neutrophils with polysegmented nuclei also occur.

The quality of erythroid precursors in a specimen of bone marrow sharply increases, by 3-4 times compared with the number of leucopoietic cells (the proportion being reverse in physiological conditions). Megaloblasts are observed in varying amounts among the erythroid precur­sors; in grave cases they are found in prevailing quantity. Both erythropoiesis and leucopoiesis are disordered. Megakaryocytes are also large, with a multi-lobed nucleus: thrombocyte separation is disordered.

Course. If untreated, the disease progresses. Before Minot and Murphy proposed their effective treatment of the disease, patients rarely survived more than 3 years. At the terminal period, many patients developed coma (coma perniciosum) with loss of consciousness, arephlexia, decreased arterial pressure and temperature, vomiting and involuntary urination.

At the present time the patient recovers from the Addison-Biermer anaemia if treated properly and if adequate prophylactic measures against relapses of the disease are taken.

Treatment. Vitamin B₁₂ is given. In most cases treatment begins with moderate doses of the vitamin (100—300; tg) which is given once a day in­tramuscularly or subcutaneously. Considerable shifts in the bone marrow

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punctate toward normalization of erythropoiesis are observed already in 24 hours after the first dose of the vitamin is given. Cells produced by division and differentiation of juvenile forms are very much like the cells produced at the corresponding stages of normal erythropoiesis. Erythropoiesis nor­malizes completely in 2 or 3 days. In 5 to 6 days of the therapy, the newly formed erythrocytes enter the blood vessels in considerable amounts: the reticulocytic crisis occurs. The number of reticulocytes in the peripheral blood increases to 20-30 per cent and then gradually decreases. General weakness lessens, work capacity is regained, and gastric secretion nor­malizes in certain cases.

Signs of funicular myelosis are eliminated much slower and do not always disappear completely. After the blood picture normalizes and the symptoms of the disease markedly subside, the patient is given maintenance therapy with small doses of vitamin B₁₂ (100 ng weekly, or 2-3 times a month). This therapy should be maintained for the rest of the patient's life. Clinical blood counts should be done periodically. The treat­ment ensures adequate subjective condition of the patient, his work capaci­ty is regained, and relapses of the disease are prevented.

AUTO-IMMUNE HAEMOLYTIC ANAEMIA

Aetiology and pathogenesis. The pathogenesis of acquired auto-immune haemolytic anaemia (anaemia haemolytica chronica) is underlain mainly by the immunopathological shifts, which are manifested by the production of antibodies to own erythrocytes (autoag-glutinins). This condition may be caused by acute infections, poisoning, medicamentous in­toxications, especially severe forms of malignant lymphomas and collagenosis, and by some other factors. These antibodies belong to the immunoglobulin fraction and are incomplete or " weak" antibodies. Erythrocyte-bound antibodies do not cause agglutination in the blood vessels but block erythrocytes to promote their deposition in the reticulohistiocytic system (mostly in the venous sinuses of the spleen) and their capture and destruction by macrophages.

Sometimes auto-immune haemolytic anaemia is associated with the appearance of cold an­tibodies which are bound (together with the complement) to erythrocytes. Their action is manifested in the peripheral parts of the body (finger tips, ears) in overcooling. In addition to auto-agglutinins, autohaemolysins are also found in some patients. The disease may proceed in them with signs of both extra- and intravascular haemolysis.

Clinical picture. The disease develops either gradually and incidiously or acutely with a haemolytic crisis. The main complaints of the patient are weakness, dizziness, fatigue, and slightly elevated temperature. All these symptoms intensify during the haemolytic crises. Skin itching is absent. The skin is pallid with a slightly icteric hue. Applying pressure to the sternum and its percussion are painful. Palpation reveals enlarged and consolidated spleen; the liver is enlarged only slightly.

The blood erythrocyte and haemoglobin content is low, while the colour index remains normal. Erythrocytes vary in size, shape, and colour (poikilocytosis, anisocytosis, anisochromia). The average size of the erythrocytes is slightly smaller than normal (microcytosis). As distinct from congenital haemolytic anaemia, the erythrocytes of healthy individuals, as well as of patients with acquired anaemia, are less intensely coloured in the cen-

tre than by the periphery, which depends on their form (planocytes). The number of reticulocytes is high; reticulocytosis is especially marked in considerable anaemization and after the haemolytic crisis. The osmotic resistance of erythrocytes is not substantially changed. The blood serum of patients is yellowish. Study of the blood confirms increased con­tent of unbound bilirubin on which the colour depends. Hypergammaglobulinaemia is also determined. The iron content of the serum is increased. Iron is liberated in large amounts dur­ing haemolysis of erythrocytes. Owing to increased liberation of bilirubin, bile obtained by duodenal probing is very dark. The urine and faeces of the patient are darker than normal; daily excretion of stercobilin with faeces and of urobilin with urine is increased. Study of specimens of bone marrow indicates more or less significant intensification of erythropoiesis.

Both cell-bound (blocking) antibodies and those found in the free state in the plasma (con-glutinins) are revealed in the blood of patients with auto-immune haemolytic anaemia. Coombs' test is used to reveal them. A direct Coombs' test is used to reveal cell-bound (block­ing) antibodies. A suspension of the patient's erythrocytes washed in isotonic sodium chloride solution is added to the serum of a rabbit immunized by human blood globulins. Erythrocytes agglutinate if anti-erythrocytic antibodies are present on their surface. Erythrocytes of in­dividuals without acquired haemolytic anaemia are not agglutinated. Conglutinins in the serum of patients are revealed by adding erythrocytes of a healthy individual (donor) in order to absorb the antibodies on them. The cells are washed and carried through the test as des­cribed above. This is the indirect Coombs's test.

Course. The course of the disease is usually undulant. The disease is exacerbated by infec­tions, big doses of some medicines, e.g. salicylates, and by some other transient factors. In grave and long-standing cases, the patient's bone marrow may be exhausted and anaemia becomes hyporegenerative. In some cases the activity of the bone marrow may also be in­hibited by the production of auto-antibodies to erythroblastic precursors. Formation of the pigment stones in the gall bladder is a complication of the disease. Thrombophlebitis, and thrombosis of the splenic vein are other possible complications.

Treatment. Corticosteroids inhibit the production of antierythrocytic auto-antibodies. Blood transfusion should be carried out in rare cases because it can markedly enhance haemolysis.

MYELOPLASTIC SYNDROME (PANMYELOPHTHISIS)

The myeloplastic syndrome or panmyelophthisis is a large group of conditions of various aetiology and pathogenesis, whose main clinical symptoms are determined by the inhibition of blood formation in the bone marrow. Congenital (genetically determined) and acquired forms of myeloid aplasia are distinguished by the origin, and acute and chronic forms—by the course of the disease. There are also forms characterized by incomplete inhibition of the regenerative capacity of the bone marrow (hypoplasia), and complete functional inhibition (aplasia).

Various clinicohaematological variants of myeloid hypo- and aplasia are differentiated by partial (in one direction) or total (in all directions) inhibition of the regenerative capacity of the bone marrow. Most specific forms are hypo- and aplastic anaemia (in which the erythropoietic function of the bone marrow is inhibited in the first instance), agranulocytosis (inhibition of the granulocytopoietic function of the bone marrow), and also pan­myelophthisis in which the regenerative function of the bone marrow is inhibited in all direc­tions (the production of erythrocytes, granulocytes and thrombocytes is deranged more or less uniformly).

Hypo- and aplastic conditions of the bone marrow (especially hypoplastic anaemia) should not be mistaken for the hyporegenerative conditions which develop for example in chronic

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posthaemorrhagic anaemia, grave haemolytic anaemia, and in some other conditions. As distinct from hypoplastic anaemia, a sufficiently large amount of the erythroid precursors are preserved in the bone marrow of patients with hyporegenerative anaemia; the course of the disease is not steady; if the cause of the bone marrow exhaustion is removed, its function is restored. The myeloplastic conditions do not also include cases where the decreased content of the formed elements (erythrocytes, neutrophils, thrombocytes) in the peripheral blood is ex­plained by their increased destruction in the spleen (hypersplenism) which occurs when the spleen is significantly enlarged (e.g. in cirrhosis of the liver) because the activity of the bone marrow is not decreased in these conditions but is, on the contrary, increased. Cytopenia due to metaplasia of the bone marrow (in malignant lymphomas and leucosis) and due to displace­ment of myeloproliferative tissue (in multiple myeloma, multiple metastases of cancer, etc.) does not belong to this group either.

Aetiology and pathogenesis. The aetiological factors of myeloid hypo- and aplasia are varied. These may be endogenous factors, e.g. thymus hypofunction, hereditary predisposi­tion, etc. But the exogenous factors are as a rule decisive. Among them the most important are (a) chemical poisoning, e.g. with benzene, tetraethyl lead; (b) prolonged and uncontrollable medication with some drugs, e.g. amidopyrin, butadion, cytostatic preparations (embichin, TEPA, 6-mercaptopuHne), methylthiouracyl, sulpha drugs, some antibiotics (chloram-phenicol), or increased sensitivity to them; (c) infectious and toxic effects (tuberculosis, sepsis, syphilis); (d) vegetable food that may, under certain conditions, contain toxic substances (wheathered corn, etc.); (e) ionizing radiation (radioactive substance, X-rays, etc.). It is be­lieved that the above factors act mainly by inhibiting the nucleoproteid enzymes to slow down the mitotic cell division.

A special importance is now attached to auto-aggressive mechanism in the development of some forms of myeloid hypoplasia. This mechanism consists in production of antibodies to own blood and bone marrow cells. It is possible however that the auto-antibodies are not the triggering mechanism of the disease, and their production is only secondary to the changes in the cells. Causes of myeloid aplasia remain unknown in some cases.

Pathological anatomy. Pronounced anaemia of organs, dystrophic changes and traces of multiple haemorrhage in them are revealed in classical cases. The territory of red bone mar­row is markedly contracted due to its replacement by fat tissue.

Clinical picture. The clinical picture of the disease varies depending on the prevailing direction of the inhibition of the bone marrow function. But the most characteristic symptoms are caused by anaemization, haemorrhagic diathesis, necrotization of tissues, and secondary infection (e.g. in agranulocytosis). As the disease progresses, certain changes can be seen in the clinical picture: a certain syndrome may dominate during the initial stage of the disease but later other syndromes join to indicate the total inhibition of the regenerative capacity of the bone marrow. If the disease develops gradually and remains unnoticed by the patient his first complaints are weakness, dyspnoea, rapid unmotivated fatigue, and decreased work capacity. Haemorrhagic signs are possible in thrombocytopenia: nasal bleeding, multiple ec-chymoses on the skin caused by the slightest injuries and sometimes spontaneously, gastro­intestinal and uterine haemorrhages. Fever is also characteristic.

Inspection of the patient reveals pallor; signs of resolving subcutaneous haemorrhages can be seen as bluish-purple spots, which later turn brown, and finally yellow. The skin is moist, its turgor is slightly decreased. The tourniquet and pinch tests are positive in pronounced thrombocytopenia. Changes in the heart, lungs, kidneys and the gastro-intestinal tract are usually not pathognomonic, but haemorrhages into various organs and internal and external haemorrhages are possible in the haemorrhagic syndrome. The lymph nodes, the liver and the spleen are usually not enlarged.

The blood picture shows various degrees and directions of changes in the regenerative capacity of the bone marrow. Hypo- and aplastic anaemia are characterized by markedly

decreased erythrocyte counts (to 1 x 10¹² per 1 1 and below). As a rule, erythropenia is at­tended by more or less pronounced leuco- and thrombocytopenia. The number of reticulocytes decreases considerably.

Neutropenia is most pronounced in agranulocytosis: the number of leucocytes decreases to 1.5 X 10⁹-1 x 10⁹ and even to 0.2 x 10⁹ per 1 1. The number of granulocytes decreases in the first instance. Their percentage content does not exceed 15-5 of the total number of leucocytes. This accounts for relative lymphocytosis and monocytosis although the absolute content of these cell forms usually remains unaltered or decreases only insignificantly. Younger forms of neutrophil leucocytes (stab neutrophils) are practically absent from the peripheral blood. Eosinophils cannot be revealed either. Some pathological changes in the nuclei and cytoplasm of neutrophils are seen: pyknosis of the nuclei and toxic granulation of the cytoplasm. Anaemia and thrombocytopenia are not pronounced during the initial period but later they become more pronounced.

In certain cases, anaemia, leucopenia and thrombocytopenia develop almost simultaneously which corresponds to the clinical picture of panmyelophthisis. When the number of thrombocytes falls below 30 x 10⁹ per 1 1, the haemorrhagic syndrome develops.

The sternal punctate is not substantially changed during the early stages of the disease. The number of erythroid or myeloid precursors may be relatively decreased. In marked cases, the sternal punctate can contain only meagre quantity of cell elements (with prevalence of the reticular and plasma cells). Since the course of marrow aplasia is not uniform, sternal punc­tate may occasionally contain portions of bone marrow in which the changes are only in­significant. This may mislead a physician in his assessments of the disease gravity. A more correct and accurate picture of marrow haemopoiesis gives trepanobiopsy of the iliac bone by which histological preparations of the bone marrow can be obtained.

Course. Acute, subacute, and chronic forms are distinguished. The acute disease may have a fulminant course: cases were reported in which patients died in two days. The course of the forms with inhibited leucopoiesis is usually more rapid than that with the prevalent inhibition of erythropoiesis. This to a certain degree depends on a different life span of white and red blood cells.

The prognosis of the congenital and genuine myeloid aplasia is quite unfavourable. The disease progresses and the patient dies in a certain period of time. The progress of the myelotoxic form of the disease, e.g. caused by overdosage of amidopyrin, butadion or cytostatics, can often be arrested if the intake of these preparations is discontinued in due time. The patient may thus recover. The frequent cause of death in agranulocytosis is sepsis.

Treatment. The patient must be taken to hospital. In order to act on the auto-immune mechanism of the disease, corticosteroids (e.g. prednisolone) are given. If anaemization is pronounced, repeated transfusions of blood and erythrocytic mass are indicated. Blood and specially prepared leucocytic and platelet mass are transfused to patients with leucopenia and thrombocytopenia. In order to stimulate leucopoiesis, sodium nucleate, pentoxyl, and anabolic steroid hormones are given. Large doses of vitamins (especially of vitamin B, ₂) are indicated in all cases. Antibiotics are given in septic complications. Bone marrow transplanta­tion is now used to treat myeloid aplasia.

Haemoblastosis

Haemoblastosis is proliferation of the haemopoietic tissue; it can be diffuse and focal.

Haemoblastosis is a disease of the whole blood system characteri­zed by (1) progressive cell hyperplasia in the haemopoietic organs with

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I,

pronounced prevalence of proliferation of certain cells (which deter­mine the morphological essence of the disease in each particular case) over their differentiation (maturation), and the loss of their typical mor­phological and functional properties; (2) substitution (metaplasia) of these pathological cells for normal cells of the haemopoietic organs; (3) develop­ment of pathological foci of haemopoiesis in various organs.

Haemoblastosis is a comparatively rare disease. Its mortality rate is 1.7-8.1 per 100 000 population. The share of leucosis among therapeutic cases is 1.5-2.6 per cent. However the incidence of haemoblastosis, especially of acute forms, has recently increased in all countries.

Aetiology and pathogenesis. Most authors regard haemoblastosis as tumours whose morphological basis are haemopoietic cells of various organs. This has been proved by numerous observations and experiments. For example, some factors can provoke the growth of tumours and haemoblastosis. These factors are cancerogenic substances (3, 4-benzpy-rene, methylcholanthrene, etc.) and radiation. There are common features in the character of tissue proliferation in haemoblastosis and tumours. Metabolic disorders in haemoblastosis-affected cells and tumour cells have been proved to be of the same type (anaerobic glycogenolysis prevails in them). Concurrence of haemoblastosis and tumour is not infrequent. Ad­ministration of an extract of tumour tissue to experimental animals causes haemoblastosis in some of them; and vice versa, administration of the bone marrow or lymph node punctates of haemoblastosis patients may provoke the growth of tumours.

There are two main theories explaining the aetiology of haemoblastosis and tumours. These are the virus and the genetic theory. At the present time more than 20 viruses have been isolated that can cause haemoblastosis in animals. Attempts at isolating the virus of the main forms of haemoblastosis in man end in failure. According to the genetic theory, haemoblastosis develops due to the congenital or acquired damage to the chromosome structures of low differentiated cells of the haemopoietic organs. A clone theory has been launched recently, according to which haemoblastosis arises due to primary chromosome mutation in one of the haemopoietic cells with its subsequent multiplication and formation of a clone of blast cells.

Nomenclature and classification of haemoblastosis. All types of haemoblastosis are designated in accordance with the name of cells which determine the cytomorphological essence of the disease. For example, acute myeloblastic leucosis, chronic erythromyelosis, lymphoid leucosis, etc. The traditional names of certain types of haemoblastosis describe the major syndrome of the disease, e.g. osteomyelosclerosis, macroglobuli-naemic haemoblastosis, etc. Certain types of haemoblastosis have a second

name (the name of the author who was the first to study or describe the disease), e.g. Waldenstrom disease, Cesaris disease, etc. Like other tumours, haemoblastoses can be benign and malignant.

More than 30 forms of haemoblastosis have been well studied. Recent advances in haematology have made it possible to improve the classifica­tion of the diseases.

The following two groups of haemoblastosis are distinguished: leucosis and haematosarcoma (malignant lymphoma).

Leucosis* is the disease of the haemopoietic cells with the primary locus of the tumour in the bone marrow. The release of tumour (leucosis) _ceu_s into the blood cause leukaemia as a symptom of the disease. The following forms of leucosis are distinguished.

1. Acute leucosis in which haemopoiesis is transformed at the expense
of low differentiated blast cells or precursor cells of the 3rd and even 2nd
series. Haemocytoblastosis is now absent from the modern classification
because it has been proved that the " youngest" cell of haemopoiesis is not
the haemocytoblast but three consecutive series of precursor cells. Various
forms of acute leucosis are differentiated mainly by the cytochemical
characteristics of leukaemic cells. In adult patients, acute myeloblastic
leucosis occurs in 60 per cent and lymphoblastic leucosis in 25-30 per cent
of cases. Other forms occur less frequently.

2. Chronic leucosis, in which haemopoiesis is transformed at the ex­
pense of more mature cells of differentiated haemopoiesis. Separate forms
are differentiated quite easily by cytomorphological signs of leukaemic
cells: chronic myeloid leucosis, chronic lymphoid leucosis, chronic
erythromyelosis, erythraemia, etc.

It should be remembered that differentiation between acute and chronic leucosis first of all depends on the cytomorphological sign (the degree of cell maturity) rather than on the clinical course of the disease, although both these signs coincide in most cases. Acute leucosis may continue for a year or even longer, while a patient with chronic leucosis may die within a few months. Therefore, the diagnosis, in addition to the definition of the type of leucosis (acute, chronic), should also determine its course. It is also important to remember that acute leucosis almost never transforms into the chronic form because it is characterized by anaplasia (the cells lose ability to further maturation) of the initial elements of haemopoiesis. Quite the reverse, chronic leucosis can be exacerbated with formation of non-differentiated elements (blasts) in the foci of haemopoiesis and in the

* Translator's note: the term " leukaemia" is generally used in western literature while " leucosis" is the accepted usage in the USSR. In view of the authors' preference we have re­tained their usage, while both terms are used more or less synonymously.

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peripheral blood. Exacerbations may be spontaneous or provoked by some causes of progressive anaplasia of leukaemic cells. Chronic leucosis in the stage of blast crisis is similar to acute leucosis.

Leucosis can have the following three variants: with considerable in­crease in the quantity of pathological cells in the peripheral blood (leukaemic form), with moderate increase in their number (subleukaemic form), and without appreciable leukaemic shift in the presence of normal or decreased quantity of white blood elements (aleukaemic form).

Leukaemic forms of leucosis are sometimes difficult to differentiate from leukaemoid reactions (extreme leucocytosis to 0.1 x 10¹² per 1 1 of blood) which are observed in some infectious diseases. In leukaemoid reac­tions, the leucocyte counts can be shifted to the left, to myeloblasts. But this leucocytosis in leukaemoid reactions is characterized by its potential reversibility (provided the causes are removed) and by preservation of the functional and morphological properties of leucocytes. Although leukaemic cells are called normal haemopoietic cells, in fact they cannot perform their usual function, and patients with leucosis have decreased im­munity. The cells cannot differentiate into more mature cells; they decom­pose at a quicker rate. It has been established that leukaemic cells have an inhibiting effect on normal haemopoiesis.

Leucosis is characterized by lability, pronounced ability to transforma­tion with exacerbation of the process (with the progress of anaplasia to less differentiated cells) and with involvement of other haemopoietic cells. Moreover, both morphological and clinical changeability of the process are characteristic. In some cases more or less long remissions can occur spon-s taneously or under certain effects (infectious disease, treatment). Remis­sions are then followed by exacerbations (to blast crisis).

Each type of leucosis is a static expression of the specific features of clinico-cytomorphological picture of the diseases and at the same time can also include certain elements of the dynamic process. This should be taken into consideration during establishing a diagnosis and in prescribing the appropriate therapy.

Haematosarcoma (malignant lymphoma, or regional tumours with their possible generalization) is also a tumour of haemopoietic cells but its localization is mostly extra-marrow and focal. Lymphogranulomatosis is the most common haemoblastosis. Paraproteinaemic haemoblastosis (mutliple myeloma, Waldenstrom's disease) is a special form arising from precursors of B lymphocytes and characterized by production of pathological globulins. Reticulosarcoma and some other diseases are also special forms of paraproteinaemic haemoblastosis.

Leucosis can also transform into some types of malignant lymphomas, except lymphogranulomatosis. The reverse process is also possible: ample

leukaemic cells appear in the blood and bone marrow in malignant lym­phomas, i.e. the blood picture and the course of the disease are similar to those observed in leucosis.

ACUTE LEUCOSIS

Acute leucosis is characterized by profuse proliferation of the youngest (blast) elements of blood with their subsequent disturbed differentiation and also with development of foci of pathological haemopoiesis in various organs. Lympho- and myeloblastic forms of the disease are common.

Acute leucosis occurs at any age, but men and women from 20 to 30 are mostly affected.

Pathological anatomy. The skin and the internal organs are anaemic. Mucosa (especially in the fauces and mouth) and often the skin are affected by necrotic ulcers and multiple haemorrhages. Haemorrhages into the internal organs also occur. Lymph nodes, the spleen and the liver are moderately enlarged. Histological studies of these organs and of the bone marrow show that they are as if " stuffed" with non-differentiated cells of blood (blasts).