Disease of pituitary gland. Diabetes mellitus.

Disease of thyroid glands, suprarenal glands

The endocrine system consists of a number of organized glands, groups of cells, and dispersed solitary cells that con­trol the functional balance of internal organs by means of chemical messengers called hormones. Organized endocrine glands include the pituitary, the thyroid and parathyroid, the adrenal cortex and medulla, and the endocrine pancreas. In addition, sex organs such as the ovary and testis produce cer­tain hormones.


Endocrine function responds to feedback control. Because the nervous system "supervises" the endocrine organs, partic­ularly the hypothalamus, it is more appropriate to speak of the neuroendocrine system. In fact, almost all neuroendocrine stimuli exert feedback control, so one could speak of, for ex­ample, a neuroendocrine-immunologic axis. All such actions and reactions follow a circadian rhythm, controlled by light, which is the subject of the science of chronobiology.


I The thyroid gland, which responds with peripheral feed­back control to the hypothalamus and pituitary, is the key en­docrine organ controlling energy metabolism (carbohydrate and lipid catabolism, stimulation of protein synthesis). It acts primarily through the effects of 2 hormones, thyroxin (tetraiodothyronine; T4) and triiodothyronine (T3), which bind to receptors on various peripheral cells and stimulate their metabolic activities. These hormones are coupled to tyroglobulin and are stored in follicular colloids. Proteolytic enzvmes release T4 and T3 and make it available in the pe­riphery as active hormones. This process is accompanied morphologically by signs of follicular activation such as paraepithelial resorptive vacuoles in the colloid, epithelial swelling (cuboidal size), and proliferation (focal stratification to form Sanderson cushions and papillae).


        In most people, 4 separate parathyroid glands lie in close proximity to the posterior part of the thyroid gland. Their hor-|mone, parathyroid hormone (PTH), controls the calcium bal­ance of the body as it responds to feedback mechanisms independently of hypothalamic-hypophysial supervision. One third of the normal parathyroid gland consists of fat tissue, and me balance contains the pale PTH-producing chief cells and pink oxyphilic cells. Any increase in weight above the normal 130 mg or replacement of fat tissue by glandular cells indicates hyperplasia hyperfunction. Hyperparathyroidism independent of feedback control (i.e., autonomous) usually is caused by ade-

nomas or carcinomas of the gland. Hypoparathyroidism (lack of PTH) is rare, usually follows surgical resection of the glands in thyroidectomies, and causes severe hypocalcemia. Familial autosomal recessive forms of hypoparathyroidism may oc­casionally occur as part of a multiglandular deficiency or in combination with T-cell immune deficiency (, DiGeorge syndrome). The ionized serum calcium level provides the stim­ulus for PTH secretion. PTH stabilizes the serum calcium level by inhibiting renal tubular phosphate reabsorption and cal­cium/phosphate absorption in the bone and by enhancing cal­cium absorption in the intestines.


The adrenal cortex is composed of 3 microscopically identi­fiable zones, each of which engages in the production of dif­ferent hormones: the zona glomerulosa (outer zone), the zona fasciculata (intermediate zone), and the zona reticularis (inner zone adjacent to adrenal medulla). The latter 2 zones re­spond to stimulation by hypophyseal corticotropin, whereas the zona glomerulosa functions independently of it. This zone produces the hormone aldosterone in response to increases in potassium levels and angiotensin or decreases in atrial natri­uretic peptide or somatostatin. The 2 inner zones produce glu­cocorticoids and androgens in response to corticotropins. Increased functional activity in either zone is associated with microscopic hyperplasia, adenoma, or carcinoma; decreased functional activity is associated with atrophy (e.g., in malnutri­tion), necrosis (e.g., in septicemia, tuberculosis, or viral infec­tion), or autoimmune adrenalitis.


The major organs of the sympathetic neuroendocrine sys­tem are the adrenal medulla and less compact collections of neuroendocrine cells in paraganglia, including the carotid body and the organ of Zuckerkandl. All consist of chromaf­fin cells (which have an affinity to chromium salts and stain dark on oxidation), which produce the catecholamines epi­nephrine and norepinephrine. Several tumors of chromaffin catecholamine-producing cells, such as pheochromocytoma and paragangliomas, exaggerate the physiologic functions of the organs. In addition, ganglionic cells in these regions may give rise to neuroblastomas. Approximately 10% of pheochromocytomas are part of a familial syndrome called multiple endocrine neoplasia (MEN). Several forms of MEN are autosomal dominant diseases with mutations on chromo­somes 10 and 11. Patients with an identified adenoma or car­cinoma at one of these organ sites and their families must therefore be screened for other endocrine abnormalities.


The endocrine pancreas consists of the islets of Langerhans. These are composite fabrication sites composed of different cells that produce and secrete se as well as cells that produce substance P, human pancreas polypeptide, or gastrin (G cells). Consequently, pancreatic en­docrine adenomas or carcinomas (e.g., gastrinoma, vasoactive intestinal polypeptide-secreting tumor IVIPoma], somato statinoma, and others) can affect multiple endocrine activities. This chapter focuses only on the more common types of] hyperinsulinism and hypoinsulinism (diabetes mellitus).

veral hormones. The greatest proportion (60-70%) are insulin-producing (3 cells; a cells (15-20%) produce the "insulin antagonist" glucagon. There are several clones of 5 cells (e.g., D cells, D1 cells) which se­crete somatostatin or vasoactive intestinal polypeptide (VIP)

The pituitary gland controls the functional activity of peripheral en­docrine tissues by secreting a large number of hormones, including thyroid-stimulating hormone (TSH), corticotropin (adrenocorti­cotropic hormone IACTH]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), interstitial cell-stimulating hormone (ICSH), luteotropic hormone or prolactin (LTH), somatotropic hormone (STH), and melanocyte-stimulating hormone (MSH). Hypothalamic damage from viral or other infections, granuloma-

tous diseases (e.g., sarcoidosis), degenerative disorders, or tumor metastases has pathologic effects on the function of other periph­eral tissues and endocrine organs. Such relations exist in obesity or anorexia nervosa, hypogonadism (e.g., pubertas tarda, sterility, amenorrhea), and certain rare polysymptomatic syndromes (Prader-Labhart-Willi syndrome, Laurence-Moon-Bardet-Biedl syndrome).

Acidophilic or chromophobe adenomas may secrete excessive so­matotropin (growth hormone [GH]), which produces gigantism in prepubertal children or acromegaly in postpubertal individuals. Ex­posure to excessive GH before epiphyseal closure leads to sym­metric giant growth. After symphyseal fusion, excessive GH causes asymmetrical growth affecting the nose, the chin, the hands, and the toes. Persons with acromegaly show hyperostosis, car-

diomegaly and visceromegaly, thickened skin, and other endocrine abnormalities. Clinical features include arthralgia, muscle weak­ness, neuropathy, and hypertension in approximately one third of patients. Patients are at high risk for cardiovascular and respiratory failure and cerebrovascular death unless the adenoma is removed by surgery or radiation.

Basophil adenomas are uncommon, usually small, and located within the normal-sized gland. They may secrete corticotropins (corticotropic adenoma) or related peptides, such as lipotropin and endorphins. Crooke hyaline, homogeneous hyaline globules con­sisting of densely packed, keratin-positive paranuclear intermediate filaments, is characteristic of basophil adenomas. Crooke hyaline is seen when Cushing disease is caused by primary adrenal tumors or in prolonged corticotropin therapy. Clinical features of functioning

corticotropic adenomas are described as Cushing syndrome: truncal obesity with moon facies, systemic hypertension, muscle weakness (decreased muscle mass), hyperglycemia, and thirst. ()s-teoporosis, hirsutism (male-type hair distribution in females) and amenorrhea, mood swings, and depression are also charac teristk , The diagnosis is further confirmed by elevated free Cortisol in the 24-hour urine.


Chromophobe adenomas, the most common pituitary tumors, constitute approximately 15% of all intracranial tumors. They occur in both sexes, usually in later lite (sixth decade). Chromophobe ade­nomas, which may remain microscopic for long periods, most often compress the optic chiasm, causing subsequent bitemporal hemi­anopsia when they expand. Vision impairment is often the initial clinical sign. Functioning chromophobe adenomas produce a variety of hormones, including prolactin (lactotrophic adenomas i, so­matotropin (somatotropic adenomas), LH and FSH (gonadotropic adenomas), and, rarely, TSH (thyrotropic adenomas). Clinical fea­tures differ according to adenoma type with signs of hypogonadism and virilization, acromegaly, hypothyroidism, and others. Some adenomas produce more than 1 hormone including corticotropins.



Hypopituitarism refers to deficiencies in hormone production by the adenohypophysis (anterior lobe of pituitary) The lack of ho mone affects the function of peripheral endocrine tissues. Hypopituitarism is caused by destruction of the gland by tumor metastases, local tumors extending into the sella turcica, infiltrative processes such as infections (e.g., tuberculosis), meta­bolic disorders (e.g., hemochromatosis, Hand-Schiiller-Christian

disease), ischemic postpartum necrosis (Sheehan syndrome), hem­orrhagic infarction (pituitary apoplexy), or, rarely, hypophyseal atro­phy secondary to subarachnoid space herniation (empty sella syndrome). Symptoms develop slowly and occur when approxi­mately 75% of the adenohypophysis is lost. Hormone replacement is the therapy of choice. The underlying disease causing the hypopi­tuitarism determines the prognosis.

  Chromophobe Adenoma


Chromophobe adenomas, the most common pituitary tumors, constitute approximately 15% of all intracranial tumors. They occur in both sexes, usually in later lite (sixth decade). Chromophobe ade­nomas, which may remain microscopic for long periods, most often compress the optic chiasm, causing subsequent bitemporal hemi­anopsia when they expand. Vision impairment is often the initial clinical sign. Functioning chromophobe adenomas produce a variety of hormones, including prolactin (lactotrophic adenomas i, so­matotropin (somatotropic adenomas), LH and FSH (gonadotropic adenomas), and, rarely, TSH (thyrotropic adenomas). Clinical fea­tures differ according to adenoma type with signs of hypogonadism and virilization, acromegaly, hypothyroidism, and others. Some adenomas produce more than 1 hormone including corticotropins.

    Diabetes Insipidus

Deficient hormone release by the neurohypophysis (posterior lobe of pituitary) results in inadequate ADH availability. Diabetes in­sipidus, characterized by uncontrolled water diuresis, polyuria, and polydipsia (excessive thirst), ensues. Although patients consume large amounts of water daily, they may experience life-threatening dehydration. Diabetes insipidus is caused by a variety of processes

(head trauma, infection, neoplasm), but may cases develop without recognizable underlying disease. Craniopharyngioma, a dysonto­genetic tumor derived from displaced epithelium of the Rathke pouch, is one of the more common tumors that compresses and destroys the neurohypophysis


Physiology of Thyroid Hormones


In the thyroid follicular epithelial cells, iodide, which is absorbed in the gastrointestinal (Gl) tract, is oxidized to I,, which serves for the stepwise iodination of tyrosine. The combination of 2 molecules of diiodotyrosine produces T4 (L-thyroxin). The coupling of 1 mole­cule of monoiodotyrosine to 1 molecule of diiodotyrosine results in T3. T4 and T3 are the main thyroid hormones. They are coupled to thyroglobulin and are stored in follicular colloids. Proteolytic en­zymes release T4 and T3 into the circulation as active hormones

when stimulated. Proteolysis, the follicular epithelial resorption and release of the hormone by these cells, is accompanied morphologi­cally by such signs of follicular activation as paraepithelial resorp-tive vacuoles in the colloid and epithelial swelling (cuboidal size) and proliferation (focal stratification to form Sanderson cushions and papillae). Various steps in iodine/hormone metabolism can be blocked by chemicals, which thus can be used to treat thyroid functional aberrations.




Hyperthyroidism is associated pathologically with diffuse or nodu­lar goiter, Graves disease, thyroid adenoma and carcinomas, and certain forms of early thyroiditis. The etiology of Graves disease, the most common cause of hyperthyroidism, remains obscure. The diagnosis is confirmed by scintigraphic demonstration of increased T4, T3 uptake in the thyroid gland. Autoantibodies against follicular epithelial membranes, which may bind to the TSH receptor and thus contribute to thyroid stimulation, are frequently observed. The thyroid, which is grossly enlarged, firm, and red (struma parenchymatosa), shows histologically diffuse follicular activation and hyperplasia with resorption of colloid and eventual lympho­cytic infiltration. The clinical course is variable, with exacerbations, remissions, and final hypothyroidism after secondary chronic nonspecific thyroiditis.

Congenital Hypothyroidism and Myxedema

Hypothyroidism is characterized by a reduction of the physiologic thyroid function with respectively reduced thyroid hormone excre­tion. Congenital hypothyroidism is related to developmental defects and may occur endemically. In addition, there exists a spo­radic, intrauterine post-inflammatory or post-toxic hypothyroidism

with unresponsiveness of the thyroid gland to TSH stimuli and defi­cient thyroid hormone synthesis. Patients are of short stature, with thick yellowish skin and a characteristic facial expression. Eyelids are puffy, the nose is flat and thick, and the tongue is enlarged and protruding. The neck is short and thick. Adult hypothyroidism

Congenital Hypothyroidism and Myxedema


manifests as myxedema. Patients experience tiredness and lethargy. Their hair is dry and brittle, their skin is thickened (myxedema), and the face resembles to a certain extent that in cretinism. The heart rate is usually decreased, and some patients have psychotic  (myxedema madness). Laboratory tests show a decrease of T4 lev­els in the blood, whereas TSH is significantly increased.



Goiter (struma) refers to an enlargement (usually nodular) of the thyroid related to either hyperthyroidism or hypothyroidism. Goiter in combination with hyperthyroidism, as is seen in Plummer syn­drome (toxic goiter), is usually autonomous but not cancerous. Goiter can be caused by low dietary intake of iodine but is usually caused by increased levels of TSH in response to a defect in hor­mone synthesis in the thyroid gland. Patients with goiter usually re­main asymptomatic except for progressive swelling of the neck

with potential airway obstruction and dysphagia or compression of the recurrent nerve with hoarseness. Microscopically, there is dif­fuse or nodular crowding of enlarged follicles. In time, regressive changes with chronic reactive inflammation  fibrosis develop. Focal intrafollicular hemorrhage and siderosis and follicle rupture with signs of colloid resorption and foreign body granulomatous reaction may occur.



There are several forms of primary thyroiditis . The thy­roid gland is usually enlarged (except in Riedel thyroiditis, in which the gland is small to undetectable) and tender with radiating pain. Regional lymph nodes are enlarged, suggesting an inflammatory disease. Patients may be euthyroid with eventual hyperthyroidism related to follicle destruction (hashitoxicosis in Hashimoto disease) but eventually have hypothyroidism. Thyroid autoantibodies and cytotoxic T lymphocytes often can be shown.

Thyroiditis (continued)

autoimmune thyroiditis are part of systemic autoimmune disorders such as collagen-vascular diseases. Consequently, careful examina­tion of the patient with primary thyroiditis is recommended. The nature of the autoimmune process usually determines the prognosis of the thyroiditis

Thyroid Adenomas and carcinoma


Autonomous proliferative diseases of the thyroid consist of adeno­mas (benign) and carcinomas (malignant), either of which may be hormone-producing tumors. Adenomas (usually autonomous nodules in a nodular goiter) show signs of hyperthyroidism, tachy­cardia, shortness of breath, nervousness, weight loss, and emo­tional instability, although they are usually less pronounced than in Graves disease. Iodine uptake is increased in the adenoma

(scintigram), and blood iodine is moderately increased (protein-bound as well as butanol-extractable forms). Certain forms of ade­noma are difficult to distinguish from well-differentiated follicular carcinoma (atypical adenoma with cellular atypia, mitoses, or even vascular invasion); therefore, adenomas should be removed and studied histologically.

   Thyroid adenomas and Carcinoma (continued)

The 4 major types of thyroid carcinomas differ histolog­ically, in their routes of metastasis, and in their prognosis. Papillary, follicular, and anaplastic carcinomas are derived from follicular epithelial cells. Medullary carcinoma is an endocrine tumor from calcitonin-producing interstitial C cells. This tumor may occur in combination with other related endocrine tumors forming familial MEN syndromes, such as MEN-2 with associated pheochromo-

(\ toma. The clinical features of such tumors are determined by the combination of different neoplasms. Medullary carcinoma may show symptoms of carcinoids (flushing, watery diarrhea), Cushing syndrome, hyperparathyroidism (HPPT), and episodic hyperten­sion. The life expectancy of patients with MEN is generally shorter than that of patients with solitary medullary carcinoma



There are 2 major forms of hyperparathyroidism (HPPT), primary and secondary, as well as combinations of the two. Eighty-four per­cent of primary HPPT (autonomous HPPT) is caused by parathyroid adenomas, 12% is caused by hyperplasia, and 4% is caused by parathyroid carcinomas. Secondary HPPT follows chronic renal in­sufficiency (renal rickets, renal osteodystrophy) with hyperphos­phatemia and decreased ionized serum calcium. Parathyroid glands

show diffuse or nodular hyperplasia. Long-standing secondary HPPT may be complicated by development of autonomous adenomas, thus adding a form of primary HPPT. Clinical features of HPPT are variable combinations of serum hypercalcemia with calcium de­posits (kidney stones, Gl mucosa, blood vessels, soft tissues, etc) and enhanced bone resorption (osteitis cystica fibrosa, dissecting fibroosteoclasia).





Hypoparathyroidism, the lack of PTH, is a rare ( ondition that may follow surgical resection of parathyroid glands in thyroidectomy. It causes severe hypocalcemia with paresthesias, muscle spasms, and seizures. There are occasional familial autosomal recessive forms of hypothyroidism that occur as part of a multiglandular deficiency or in combination with T-cell immune deficiency (DiGeorge syn­drome). The ionized serum calcium level provides the stimulus for PTH secretion. PTH stabilizes the serum calcium level by inhibiting renal tubular phosphate resorption and calcium/phos­phate absorption in the bone. In addition, calcium absorption in the intestines may be enhanced. Calcitonin or thyrocalcitonin of thyroid interstitial C cells counteracts calcium absorption by decreasing the serum calcium level.

Anatomy and Hyperplasia

The adrenal cortex is composed of the zona glomerulosa (outer zone), the zona fasciculata (intermediate zone), and the zona reticularis (inner zone adjacent to adrenal medulla). The 2 inner zones respond to stimulation by hypophyseal corticotropin. The outer zone functions independently of corticotropin. This zone pro­duces the hormone aldosterone in response to potassium and an­giotensin (T) or atrial natriuretic peptide and somatostatin (I). The inner zones produce glucocorticoids and androgens in response to

corticotropins. Increased functional activity may be caused by hy­perplasia, adenoma or carcinoma, and decreased functional activity by atrophy (e.g., in malnutrition), necrosis (e.g., in septicemia, tuberculosis, viral infection), or autoimmune adrenalitis. Hyperpla­sia of glucocorticoid-producing parts results in Cushing disease as caused by excessive corticotropin stimulation. Corticotropin-i dependent forms of Cushing syndrome occur in autonomous cortical adenomas or carcinomas.


Adrenogenital Syndrome

Adrenogenital syndrome (congenital and adult forms) is caused by a form of adrenal cortical hyperplasia or tumors with excessive production of 17-ketosteroids (dehydro-epiandrosterone, etio-cholanolone, and androsterone). In addition to androgen abnor­malities, the syndrome may be complicated by alterations in sodium metabolism, glucocorticoid deficiency, or both. Clinically, there are signs of masculinization in females (hirsutism, clitoral hypertrophy, oligomenorrhea) and precocious puberty and enlarge­ment of genitalia in males. Some forms of congenital adrenal corti­cal hyperplasia occur with androgen deficiency and cause pseudohermaphroditism in males. Ninety-five percent of patients with congenital adrenal hyperplasia show defects in 21-hydroxy­lase, which results from mutations on chromosome 6



Adrenal cortical adenomas that simulate structures of the zona glomerulosa cause primary hyperaldosteronism (Conn syndrome).

Excessive aldosterone secretion causes potassium depletion (in­creased potassium loss from kidneys and other exocrine glands), sodium retention, decreased plasma renin activity, and hyperten-

sion. Secondary hyperaldosteronisms in response to stimulation by the renin-angiotensin mechanisms show increased plasma renin ac­tivity. Adenomas in primary hyperaldosteronism usually remain small (less than 6 g) and can be difficult to identify clinically. Pa­tients experience a metabolic alkalosis and muscle weakness.

Acute Adrenal Cortical Insufficiency

Acute adrenal cortical insufficiency (adrenal crisis, Waterhouse-Friderichsen syndrome) follows the acute necrosis and hemor­rhage of the adrenal cortex secondary to bacterial septicemia, usually meningococcal septicemia, and sometimes Pseudomonas, pneumococci, and Haemophilus influenzae. Bacterial toxins (endo­toxins) are thought to cause diffuse vascular damage with intravascular coagulation and hemorrhage, which destroy large parts of the adrenal cortex. Other conditions that may be associated with simi­lar adrenal hemorrhage and necrosis are birth trauma, treatment with anticoagulants, and almost all causes of disseminated intra­vascular coagulation (DIC). The resulting acute adrenal crisis is attributed primarily to the sudden loss of glucocorticoids.

Chronic Adrenal Cortical Insufficiency,


Chronic adrenal cortical insufficiency, Addison disease, is a clinical syndrome characterized by progressive weakness and fatigue, hy­potension, weight loss, skin and mucosal hyperpigmentation, and abdominal problems. Laboratory test results show hypokalemia, hy­ponatremia and volume depletion (decrease in mineralocorticoids such as aldosterone), and, occasionally, hypoglycemia (decrease in glucocorticoids). Patients without adequate replacement therapy die in coma. The underlying disease is a progressive shrinking (col­lapse) of the adrenal cortex secondary to epithelial atrophy and chronic inflammation (lymphocytic or granulomatous). In approxi­mately two thirds of cases, autoimmune adrenalitis is responsible foi these changes. Other cases are associated with infections (tubercu­losis, fungal) or tumor metastases. Sarcoidosis, amyloidosis, and he­mochromatosis are less frequent causes.



The adrenal medulla consists of typical chromaffin cells (affinity to chromium salts with dark staining on oxidation), which produce the catecholamines epinephrine (80% in the adrenal medulla) and nor­epinephrine. Tumors of chromaffin, catecholamine-producing cells, include pheochromocytoma and paragangliomas. Pheochromocy-tomas, smooth yellowish-tan nodules or large hemorrhagic masses of several kilograms, may be bilateral. Nests of amphophilic chro­maffin cells with a finely granular, silver-stainable cytoplasm are

seen microscopically. Approximately 10%) of pheochromocytomas are found in extraadrenal locations. Clinical features are headaches, intermittent hypertension, palpitation, and sweating. Approximately 10% of pheochromocytomas are part of a familial syndrome called multiple endocrine neoplasia, autosomal dominant diseases with mutations on chromosomes 10 and 11, such as 11 q 1 i (MEN type I) and 10q1.2 (MEN types II and III).



The endocrine pancreas consists of the islets of Langerhans, which are composed of insulin-producing (} cells (60-70%), a cells (15-20%), which produce the "insulin-antagonist" glucagon, several clones of 8 cells (e.g., D cells, D1 cells), which secrete somatostatin or VIP, and other substances. Hyperinsulinism caused by (3-cell adenomas or carcinomas constitutes 75% of pancreatic endocrine neoplasms. Clinical features are spontaneous hypoglycemia with

hunger, tremor, perspiration, confusion, anxiety, convulsions, and coma. In nesidioblastosis, which occurs in rare cases of reactive hy­poglycemia, pancreatic P cells are hypertrophic and increased in number. Islet cell carcinomas (10% of insulin-producing tumors) are less well demarcated, metastasize early, preferentially to the liver, and generally are associated with a poor prognosis.

Insulin-Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM, type 1) is a complex disorder of carbohydrate, lipid, and protein metabolism caused by hypoinsulinism and multiorgan disease. In IDDM, the progressive destruction of P cells in pancreatic islets usually begins before the age of 20 years. Microscopically, pancreatic islets show scattered lymphocytic infiltration (predominance of cytotoxic CD8' T lympho­cytes and anti-islet cell antibodies in up to 80%) with loss of (3 cells


and mild fibrosis. Besides genetic predisposition, virus infections sue li as cox sackievirus are considered the initiating events for IDDM. The metabolic disturbance is characterized by hyperglycemia with mobi­lization of fat and protein, negative nitrogen balance, and acidosis. Polyuria leads to loss of electrolytes and dehydration, mobilization of fat and proteins, weight loss, and hunger.

especially hyperglycemia, cause a number of complications and secondary diseases, including progressive microangiopathy with diabetic retinopathy, renal glomerular nephrosclerosis (Kimmelstiel-Wilson disease), peripheral neuropathy, ulcus cruris, and gangrene. Many patients have severe hypertensive cardiovascular disease, which is the leading cause of mortality in this population.



Pregnancy and Puerperal Period Diseases. Pre- and Perinatal Life Diseases.

Neurohumoral changes during pregnancy can determine anomalies in embryonal development and pregnancy course. The following pathologies refer to the pregnancy period: early and late gestosis, extrauterine pregnancy, spontaneous abortion, preterm delivery, hydatidiform mole, chorioepithelioma, placental polyp, puerperal infection.

Pregnancy toxicoses (gestoses). Among the early gestoses  the most frequently occur the following ones: sickness of pregnancy, excessive sickness of pregnancy, allergic reactions, hyperptyalism and others. Early gestoses occur on the 1st-3d month of pregnancy and are determined by excessive irritation of the nerve centers and cerebral cortex depression or jump of estrogen and progesterone concentration in the blood.

To the late gestoses are referred edema of pregnant, nephropathy, preeclampsia and eclampsia. They occur and declare themselves more frequently from the 32th-34th week of pregnancy. In the studies they are also called “EPH-gestosis” – edema, proteinuria, hypertension or preeclampsia.

Eclampsia is one of the pregnancy toxicoses which develops in the second half of pregnancy, childbirth and puerperal period. Clinically eclampsia is determined by the renal and liver insufficiency, major epilepsy with syncope.

Etiology and pathogenesis. Autointoxication with products which are secreted by  fetal tissues and excrements is considered to be the cause of eclampsia. Eclampsia appears on the background of renal insufficiency, endocrine balance disturbance (hypophysis hyperfunctioning, adrenal and in-thyroid glands insufficiency). Allergic eclampsia theory is worth mentioning according to that the pregnant female’s organism is sensitized by the fetus and excremental albuminous products.

Anatomical pathology.  At the time of the partition jaundice, edemas, full-blown changes in liver and kidneys. Liver is enlarged, striped in looks – on the yellow background (fatty degeneration) there are numerous flat subcapsular hemorrhages. The surface of the incision is pale, clayey, with numerous hemorrhages. With the help of the microscope hemorrhages, necroses in the peripheric sites of particles, fibrinogenous small venous thrombosis, albuminous and fatty degeneration of the hepatocytes.

Kidneys are enlarged, slack, crust layer is pale, gummy, a little thickened, cerebral one is sharply plethoric.




DIC by the eclampsia

Fatty hepatosis by the eclampsia



With the help of histology dystrophy and tubule epithelium necrosis, excrement cells embolism of the vas capillares glomerulares, fibrinoid necrosis of the capillary walls, stroma hemorrhages, sometimes a picture of mesangium glomerulonephritis with laying the immune complexes on the basic membrane and mesangium cells proliferation are detected. In the serious cases necrotic nephrosis  with acute renal insufficiency develops.

Numerous hemorrhages combined with small venous thrombosis as well as necrotic and dystrophic changes apart from liver and kidneys are detected in the celebral, lungs, heart tissue, serous membranes. In the placenta changes are found which are the consequence of its ischemia: intensive deciduocellular nodi formation, thickening of the basic trophoblast membrane, cytotrophoblast hyperplasia, infarctions. Premature placenta exfoliation is often observed. Infants are born premature with the features of hypoxia and intrauterine  fetal hypotrophy, sometimes intrauterine fetal death occurs. Parturient women die of liver-renal insufficiency and hemorrhages to the vital organs.

Extrauterine pregnancy is characterized by the fetus development outside the uterine cavity – in the tube (tubal pregnancy), in the ovary (ovarian pregnancy) or in the abdominal cavity (abdominal pregnancy). Development of the extrauterine pregnancy is determined by abnormality of the uterine tubes permeability (chronic inflammation, congenital luminal narrowing, tumors) which make fertilized ovum translocation from ampullar tube part to the uterine cavity difficult.

Tubal pregnancy can be ampullar which develops in the abdominal tube part, interstitial – in the part of the tube located in the uterus wall depth, and isthmic – in the place of the anatomic tube constriction. If the tube breaks along the lower rib in the consequence of the fetal egg growth then the latter falls between the uterine ligament folia and interligament pregnancy develops.

During the tubal pregnancy in the mucous tube, on the place of the fetal egg attachment and in the endometrium decidual reaction appears – appearance of big cells rich in glycogen. The fetus is attached to the endometrium with chorion. As the wall of the tube is thin, the choria grow through the endometrium, muscular layer reaches the serous membrane. The wall becomes friable and the fetus is torn away (2nd-3d pregnancy months) – it is called maldeveloped tubal pregnancy. The tube rapture is accompanied with the hemorrhage into abdominal cavity which can result in the woman’s death. Sometimes a thrombus tampons the rapture hole (masked rapture); if the latter drops out, recurring hemorrhages are possible.

If the torn-away egg is left in the tube lumen – incomplete tubal abortion. In the cases it dies and its membranes are impregnated with blood – it’s a blood mole, and if the fetus falls into the abdominal cavity through the ampullar tube part, a complete tubal abortion comes. Reimplantation is possible in this case, the development of the secondary abdominal pregnancy. The fetus dies more often, embalm (papyraceous fetus) and limes (lithopedion), or resolves. When the histologic study of the tube extracted by means of the operation, pregnancy features are displayed – chorionic villi, decidual cells. Decidual reaction in the endometrium takes place, the uterus enlarges a little.



Dystrophic changes in the chorionic villi



Miscarriage (spontaneous abortion) is a spontaneous fetus wastage and fetus excretion out of the endometrium before the 28th week from the conception moment. Abortion before 14th week is considered early, from 14th to 28th weeks – the late one. Miscarriage between the 28th and the 38th week is called preterm delivery. At the time of the fetus wastage the whole fetal egg (fetus and membranes) is excreted out of the endometrium. The latter can be intact or torn. During the preterm delivery the fetus is born first and then the membranes and placenta (afterbirth). Histologically chorionic villi, decidual cells and fetuc membranes are detected among the grumes.

The abortion very often comes after the fetus has died as a result of incomplete immersion of the fetus egg into the endometrium as a result of its incompetence. The latter was mainly determined by the atrophy resulted from previous abortions, inflammation. Separation and extrusion of the fetus egg is often caused by the early fetal death when the mother has different diseases (syphilis, serious infections, intoxications, avitaminoses). Miscarriage also develops along with congenital maldevelopment which are incompatible with life. It remains a mystery how the mother’s organism detects the deformities of the embryo.

According to the data of the embryologists Svyetlov P.G., Dyban A.P., the fetal death more frequently comes during a certain period of gestation. For the human embryo such periods of special sensitivity to the pathogenic agents are implantation which coincide with the 15th day of gestation and placentation – every 3th-6th week. These periods of the most fetus sensitivity to the influence of the disturbing agents are called the first and the second critical periods. But the embryo death in most cases doesn’t come right after the damage but after some time for the first critical period – the 4th week of gestation, for the second one – the 8th-11th week of gestation.

Artificial abortion is carried out according to the medical indication or the undesirable pregnancy. If such abortion is either carried out outside the medical establishments in insanitation which can lead to sepsis and criminal investigation or is not registered as surgical operation and it is called criminal. It is proved that embryo is very troubled before the artificial abortion, his heart beating speeding up; it contracts as if trying to become less, unnoticed, hides in the most remote corner. He reacts to the abortion as to death which is coming closer. The abortion complications are: sterility, hemorrhages, sepsis.

Trophoblastic tumor includes hydatidiform mole, invasive hydatidiform mole, chorioncarcinoma, trophoblastoma of the placental site. The source of the disease is placental tissues. It is more often found among the pregnant in the age before 16 or after 35 years.

Hydatidiform mole (mola hydatiosa) is a hydropic and cystic degeneration of the placental chorionic villi during gestation. The number of villi increases they become large in the shape of moles filled with transparent liquid and resemble a bunch of grapes. The disease manifests itself through vaginal hemorrhages, sometimes with elimination of the hydatidiform villi during the first term. The uterus is enlarged and extremely high level of chorionic gonadotrophin is displayed. The fetus dies. The trophoblast proliferates, lytic activity rises which leads to the growing of the villi into the deep layers of the uterus (moimetrium), sometimes to the serous membrane (chorioadenoma destruens). In such cases  urinal hemorrhages are observed a few weeks after the ablation of hydatidiform mole. Along with it lung, vagina metastases are found which can disappear especially after the chemotherapy course. If the villi have grown into the veins, tissue placental pulmonary embolism occurs. Hydatidiform mole can be complicated with chorioepithelioma. The cause of hydatidiform mole is unknown, it is often connected with follicular ovary cyst and perhaps appears on the background of the harmonic dysfunction of the rest. Cystic transformation of the placental villi with formation of hydatidiform mole can be also determined by domination of the father’s chromosomes in the embryonic karyotype.

Chorioepithelioma (chorioncarcinoma) is a malignant tumor from the trophoblast epithelium. It develops of the remnants of placenta after abortions (25%), deliveries complicated by the hydatidiform mole (50%), clinically normal delivery (22%), ectopic pregnancy, especially with chorioadenoma destruens (invasive mole). Chorioncarcinoma can develop in the lungs as a result of placental embolism, in the ovary with teratogen, urinary bladder, partial septum of testis, testicles. Typical clynical symptom is the appearance of the metrorrhagias. The tumor is hormonally active, extremely malignant, accompanied with the uterus enlargement with evident decidual reaction in the endometrium.

Some time ago this tumor was called deciduoma, it was considered to originate from decidual tissue of the gravid uterus. In 1886 Nikiforov M.N. and Marshan proved that it develops of the chorionic villi epithelium. It looks like a variegated fluffy nodus in the myometrium, the vessels in the form of cavities. There are no stroma and own vessels. It feeds from blood which flows out the tissues, destroyed by it. It is of a dark-brown colour due to hematogenous pigments. It consists of the cyto- and syncytiotrophoblast cells – light epithelium Langhans cells, among which there are many gigantic cells with numerous mitoses; polymorphous dark syncytium cells are located at the periphery. It gives metastases to the lungs in the early period.

Placental pathology is classified due to localization and character of the pathologic process. Pathologic process can nestle on the basic membrane (deciduas basalis), intervillous lacuna, fetus part of placenta (villi, chorionic plate), umbilical cord, outplacental fetus membranes. Inflammatory processes and blood-circulation disorders are the most often found in the placenta. Disturbance of the villiferous tree are often found which lead to the placental hypoplasia, insufficient vascularization of the villi.

Infectional processes in the placenta appear as a result of penetration of the microorganisms (viruses, bacteria, protozoas, etc.) into the placenta. They distinguish: –   ascending way of infectioning – through the uterus and the cervix uteri which takes place along with early moving of waters and long-lasting anhydrous period; – hematogenic from the maternal blood-circulation; – descending through the uterus tubes. The inflammation can nestle in the decidual membranes, in the villi, in the  intervillous lacuna, chorionic and amniotic membranes, in the umbilical cord. Depending on the causative agent inflammatory cellular infiltration is presented by leukocytes, lymphocytes, plasma and gigantic cells, histiocytes, etc. Inflammatory processes in placenta can cause fetus, uterus infection, preterm delivery, anomalies of the following pregnancies.

Placental blastodisk anomalies manifest themselves through the change of form, appearance of the elevation or limbus which surround placenta. In such cases hemorrhages in placenta, preterm delivery or stillbirth are observed. According to the changes in the localization of the placenta attachment the following variants of anomalies are distinguished: marginal or central placental presentation relative to the cervix uteri internal fauces. Such anomalies can cause hemorrhages and lead to the fetal and mother’s death. Anomalies of exfoliation manifest themselves through adherences or early exfoliations which lead to the metrorrhagias.

Blood-circulation disorders in placenta manifest themselves through diffuse ischemia, diffuse hyperemia, hemorrhages, edema, perivilliferous fibrin deposition, thromboses, infarctions. Diffuse ischemia of placenta is observed with hemolytic anemia, posthemorrhagic conditions, intrauterine fetal death. Placental ischemia can cause anemia as well as the fetal death. Diffuse hyperemia of placenta takes place accompanied with mother’s hypoxic conditions, blood outflow derangements through the umbilical vein as a result of nodi formation in the umbilical cord. Hemorrhages from the placenta occur with early exfoliation, placental presentation. Placental edema develops At the time of hemolytic disease, nephropathies, infectious diseases. Thromboses develop during gestoses and cause infarctions formation. Perivilliferous fibrin deposition is observed at the periphery of placenta in the form of close daffodil bonfires with fibrosis and vessels obliteration.

Umbilical cord pathology manifests itself through the change of length (a short one – less than 40 cm, a long one – over 70 cm), places of attachment to placenta (central, eccentric, marginal, membranous), vessels hypoplasia, persistence with formation of the umbilical-intestinal fistula, persistence of the urachus with formation of the umbilical-urinary fistula.

Anomalies of the amnion development manifest themselves through enlargement (over 2 l) or diminution (less than 500 ml) of the amount of waters by the amniotic adhesions or amnionic constrictions.

The twins’ placentas distinguish depending on the kind of ovum fertilization: dizygotic twins have a dichorionic diamniotic placenta, monoovular twins have a monochorionic placenta. Anastomoses between the twins’ vessels is formed in the placenta. In case of unilateral direction of such anastomoses placental transfusion syndrome develops: one of the twins becomes a donor, another – a recipient. With this syndrome a twin-donor death rate is rather high.

Placental polyp develops in the endometrium from the remnants of placenta pieces after deliveries or abortions. Histologically it is made of villi, decidual tissue, fibrin clots which become organized. In the place where the polyp is attached connective tissue site is formed. Placental polyp slows down postnatal involution of uterus, contributes to development of endometritis, is accompanied by metrorrhagias.

Afterbirth infection of the uterus is the most often determined with streptococcosis, staphylococcosis, colon bacillus. Purulent endometritis (endometritis pyrylenta) occurs. Endometritis can develop before delivery (endometritis sub partum), during delivery (endometritis intra partum), and after delivery (endometritis post partum). Afterbirth infection more frequently occurs exogenously (nonobservance of the aseptics rules) or endogenously (antenatal endometritis). Endometritis very often causes uterine sepsis. Septical endometritis is of purulent, diphtheritic or suppurative character; endometrium surface is covered with taupe incrustation. Lymphangitis, phlebitis, thrombophlebitis develop. Metritis, perimetritis, pelvic peritonitis often develop.

Prenatal pathology

Prenantal (antenatal) pathology includes pathologic processes of the human embryo, beginning with fertilization and ending with delivery. Prenatal period lasts 280 days, or 40 weeks. The whole development from fertilization to delivery is called kinetogenesis which is preceded by progenesis – period of male and female sex cells (gametes) ripening before the fertilization. Kinetogenesis period is divided into three periods – blastogenesis, lasts from fertilization to the 15th day of pregnancy, when the fertilized ovum division takes place and it ends up with embryo- and trophoblast elimination;  embryogenesis – from the 16th to the 75th day of pregnancy when the main organogenesis takes place amnion and chorion are formed; fetogenesis – lasts from the 76th to the 280th day of pregnancy when differentiation and ripening of the fetal tissue take place, placenta is formed, ends up with delivery. Fetogenesis period can be divided into early fetal (from the 76th to the 180th day), at the end of this period fetus becomes viable, and late fetal (from the 181st to the 280th day), when the fetus becomes mature. Pathology which occurs during the kinetogenesis period is called kinetopathy and it is correspondingly divided into blastosis, embryopathy, early and late fetopathy.

The reasons for kinetopathy according to the latest data: 20% deformities (main kinetogenesis period pathology) are connected with gene mutations, 10% – with chromosome aberration, 10% – with the exogenous factors influence, 60% – of ambiguous etiology. German measles, rubeola, chickenpox, mononucleosis, parotitis, hepatitis, influenza, poliomyelitis, pale treponema, toxoplasmosis, tuberculosis microbacterium belong to the exogenous factors.

Apart from infection agents kinetopathies can be caused by radiation energy, some pharmaceutical preparations (tolidomide, cytostatic drugs), hormones, vitamins, alcohol, drugs, hypoxia.

Gametopathies. During protogenesis pathology of gametes may occur – gametopathies. They are manifested through nuclear substance and sex cells cytoplasm pathology. Nucleus changes are characterized by hereditary apparatus of gamete pathology. Gene, chromosome and genomic mutations are distinguished that are the cause of congenital maldevelopment (deformity). Deformities are not viable and end up with spontaneous abortion. Gamete cytoplasm pathology as a rule results in sterility (infertility).

 Blastopathies. They are the most frequently caused by chromosome aberrations accompanied with environmental influence (mother’s endocrine diseases, hypoxia, intoxications, etc.). To blastopathy belong: blastocyte implantation disturbance (extrauterine pregnancy), twin deformities, solitary deformities, placenta and  umbilical cord formation deformities. Twin deformities are connected with appearance of two or more independent growing centres during division. If centres of growth are in close location and have  common intermediate zone, than two conjoined twins develop. If the conjoined twins are identical, symmetrically developed, they are called diplopagus (from Gr. diplos – double, pagus – to connect), if the twins are asymmetrically developed, it is heteropagus. The twin lesser in size is called teratic parasite. Sometimes such twin is found in the body of the bigger one – “fetus in fetu”. In 1995 in the medical press was announced that a 43-year-old man had suddenly died in Nizhni Novgorod, in his thorax a dead fetus was found, its weight was 6,1 kg and sizes 32×26×18 cm. The body of the fetus was of ligneous density, yellow-red colour. Lungs and heart of the dead man were deformed, underdeveloped. The medical workers were surprised how this man had lived to the age of 43 with such deformation of thorax organs. A few years before it was reported that in China a fetus, extracted from the thorax of a 46-year-old man during the tumor ablation, began to grow. The doctors treated it as growth of the thorax tumor.

The degree of twins conjugation can be different – from minor conjoined superficial tissues to such degree when only heads and limbs are separated. To determine the localization of twins conjugation a word pagus was added to the anatomic name of the site of conjugation – craniopagus, thoracopagus, ischiopagus, etc.

Embryopathy is an embryonic period pathology from the 16th to the 75th day of pregnancy, during which the main organogenesis is completed. To the embryopathies belong mostly congenital maldevelopment – deformities. With the embryo’s development the ability to react to different pathogenic influences with disturbance of morphogenesis is gradually developed. This ability is called dysontogenesis. It was found out that different teratogenic agents can cause the same deformity. Along with it the same teratogenic agent can cause different deformities of development influencing during different periods of embryogenesis. There is a certain period of time for each organ during which under the influence of a teratogenic agent hypoplasia of this organ occurs. This period of time is called teratogenic termination period (from Lat. teratos – deformity and terminus – boundary). So, it is a certain period of time during which anlage and formation of different organs is performed and the influence of teratogenic factors in this period causes the disturbance of this process which results in deformities. Morphogenesis of different organs is carried out during different periods of embryogenesis and during this time the organs are the most  susceptible to the teratogenic agent effect. Teratogenic agents are the viruses – bacteria, toxins, alcohol, medicine, hormones, vitamins, penetrating radiation, etc.

Congenital maldevelopment is persistent morphologic changes of the organs which appeared as a result of the region’s or organism’s morphogenesis disturbance and they are beyond the measures of normal variations. To the congenital maldevelopment belong:

1)     absence of any organ or region – agenesia, aplasia;






2)     underdevelopment of an organ – hypoplasia;

Congenital defect of the upper jaw (cleft palate)


Congenital pathology of the bones`development



3)     excessive development – hyperplasia;

4)     change in forms: conjugated organs, arthrodesia or stenosis of apertures or canals, nonclosure of embryonic fissures – persistence, eversionectropion;



Congenital pathology of the upper extremity



Congenital encephalomalacia



5)     change in organs’ location – ectopia;

6)     persistence of embryonic (provisional) organs, more frequently of branchial arches or their remnants.

Apart from the pathology of organs their can be congenital maldevelopment with disturbance in differentiation of separate tissues of: skeletal muscles – congenital Oppenheim’s myopathy;

-         connective tissue – Marphan’s disease;

-         skin – ichthyosis congenita;

-         bones of cartilage genesis – congenital chondrodysplasia.

Congenital maldevelopment can be simple – when one organ is involved, complicated – a few organs of one system and numerous – organs of few systems.


Fetopathies are pathologies of the fetal period, from the 76th to the 280th day of pregnancy, during which the basic tissue differentiation of the organs is carried out. Two types of manifestations are typical: blood-circulation disorders, dystrophy and necroses, mutated immune reactions and compensatory and time-serving processes. Disturbances of tissue morphogenesis are typical of early fetopathies, reactive reactions – of the late ones. Fetus infection takes place in ascending way through genital organs and placenta and in a descending hematogenic way, mainly with either salpingitis or ovaritis. Morphologically infectional fetopathies manifest through generalization of the inflammatory process with numerous foci of reactive necroses, granuloma formation, hemorrhagic syndrome resulted from vasculitis, hemolytic jaundice, retention of foci of extramedullar hematosis, accidental involution (athrophy) of the retrosternal gland (thymus), general hypothrophy, prematurity. As a rule, such infants die during their first months of life. If they survive, persistent changes in the organs remain that cause disability. 

Noninfectious fetopathies can be early or late. To the early ones belong:  hypertrophic pylorostenosis, megacolon, megaurethra, agenesis, hypoplasia or hyperplasia of bile ductules, polycystic lung disease, polycystic renal disease, etc., to the late ones – hemolytic disease of the infants, fetal mucoviscidosis, endocardial fibroelastosis, diabetic and alcoholic fetopathy, etc.

Alcoholic fetopathy is characterized by small fetal weight, microcranium, microgyria, polygyria. Sizes of head and brain are diminished, gyri are narrow, numerous, sulci are deep. These changes are often combined with other congenital maldevelopmentmaldevelopment of brain, cardiovascular system, and urinary system. Such children are slow in their mental and physical development.  

Pathologies of the infants

Perinatal period (period “around delivery”) lasts from the 196th day of the intrauterine life of fetus (28 weeks of pregnancy) to the first week of the extrauterine independent life. Infant is a neonate which has begun to breathe by itself. Stillborn is a fetus which doesn’t breathe at the moment of birth and it could not be stimulated artificially although the heart beating can be observed during some time. Stillbirth and death of infants during the first seven days after delivery are called perinatal mortality. Perinatal period and corresponding pathology and mortality can be divided into antenatal (prenatal), intranatal (during the delivery), postnatal (postpartum) or neonatal.


Congenital pathology of the kidney



Features of prematurity: gestation duration is less than 38 weeks, the weight of fetus is less than 2500g, height – less than 45 cm, long, lanugo hair on the face, shoulders, back, soft auricles, underdeveloped nails, the boys’ testicles are not dropped into the gates and the girls’ pudendal fissure gapes because of the maldevelopment of vulvar lips, cranial bones are soft, foci of bones in the long cortical bones are absent.

Features of postmaturity: gestation duration is over 41 weeks, dryness, desquamation and partial maceration of skin, general hypothrophy, anemia, water, umbilical cord and membranes are imbued with meconium into bottle green because of hypoxia.

To the pathology of infants belong asphyxia, pneumopathies, birth trauma, hemorrhagic and hemolytic disease of infants.



Congenital pneumonia



Congenital pneumonia





Birth trauma is a mechanic injury of tissues and organs of the fetus during delivery. The causes which determine it are divided into three groups. The first group is those laid in the condition of fetus itself: fragility of tissues at prematurity or postmaturity, congenital maldevelopments which are accompanied by venous hyperemia, hemorrhagic syndrome, fetopathies, hypoxia. The second group is determined by pathologies in the mother’s maternal passages: rigidity of the maternal passages tissues, inclination of pelvis, contracted pelvis, tumors, olygoamnios, early pouring-out of the waters. The third group is those laid in the course of delivery – accelerated and prolonged labor.



Hemorrhagic disease of newborn



Morphology of the birth traumas.

Cephalic tumor appears in the part of head that adjoins the pelvic outlet. It is determined by disorders of blood-circulation and lymphokinesis. The tissues of the latter become dropsy, swollen, can suppurate.

Cephalohematoma is a hemorrhage under the cranial bones, it is always restricted to the one bone site. External hematoma is the most frequently found. It resolves slowly, undergoes organization and petrification. If there is a purulence, meningitis can develop.

Hemorrhage into the meninges and brain. Epidural, subarachnoid and intracerebral hemorrhages are distinguished. Epidural hemorrhages (internal cephalohematoma) are always massive. They can take place when there are traumas of cranial bones and dura mater of brain. Subdural hemorrhages most frequently occur along with laceration of tentorium of cerebellum, of crescent, they are as a rule massive and located on the surface of celebrum. Subarachnoid hemorrhages are mostly determined by rupture of small veins. Unlike asphyctic, traumatic subarachnoid hemorrhages are always massive.



Haemorrhage into the brain after the delivery


Intracerebral haemorrhage after the delivery




Intracerbral hemorrhages are caused by rupture of terminal veins, can lead to development of hematomas. Intraventricular hemorrhages are most frequently observed among the premature infants.

Spinal cord trauma is a result of injury of the spine mostly on the level of the IV cervical vertebra and is accompanied by development of descending subdural hemorrhages.

Among the skeleton bones clavicle is most frequently injured (fracture of clavicle). Paralyses of arms and diaphragm of the infants are determined by trauma of root of cervical plexus and brachial plexus. Rapture and hemorrhage into the nodding muscle results in torticollis. Among the internals liver and adrenal glands are most frequently injured.

Hemolytic disease of the infants develops with blood incompatibility between the mother and the fetus (mother is Rh-negative and child is Rh-positive). From the mother’s blood anti-Rh antibodies penetrate to the child’s blood and attack red blood cells. It develops during the second and the following gestations because immunization of the network (antibody titer) grows with gestation. Thee main types of disease are distinguished – edematous, anemic and jaundice diseases. Manifestation of their certain forms depends on the period and amount of penetration of the mother’s antibodies into the blood of fetus.

When early massive penetration of the antibodies takes place, in some cases early fetopathy develops and antenatal death of the 5-7-month-old fetus, in the others – chronic fetopathy in the form of heavy edematous form of the hemolytic disease with maldevelopment of the tissue ripening. Pathologoanatomic changes with the intrauterine fetal death manifest through maceration and autolysis. Maceration (from the lat. maceratio – maceration) is softening of the tissues by the water. Along with it edema of face and peeling of the epidermic tissue in big layers. Autolysis (from the gr. autolis – by oneself, lisis – dissolution) is an autodigestion, disintegration of tissues of the organism which takes place under aseptic conditions and effect of their own enzymes. Organs and tissues disintefrate till the formation of the uniform mass of the murrey colour. If it is chronic edematous form, the skin of the infant is pale, half-transparent, glossy, partly macerated, with solitary petechial hemorrhages. Hypodermic cellulose, cerebral tissue and cerebral membranes are sharply dropsical, in the body cavity is transsudate (hydrops factus universalis). Liver and spleen are greatly enlarged, retrosternal gland is atrophied. The heart is enlarged due to myocardium hyperplasia, lungs are diminished. With the help of the microscope foci of extramedullar hematosis with the dominance of erythroblasts (erythroblastosis) in the liver, spleen, lymph nodi, kidneys and petechial hemorrhages, dystrophic and necrobiotic changes in the internals.

During the later and moderate penetration of the mother’s antibodies into the blood of fetus anemic form of the hemolytic disease of the infants develops, it is more frequent observed with the premature infants. Paleness, slight pitting edemas are observed.  There is no icteritiousness. The internals are anemic. Liver and spleen are slightly enlarged, they contain microscopic displays of marked erythroblastosis.

Icteritous form seldom develops itrauterinally, because placenta is able to remove bilirubin from the organism of fetus. During the massive penetration of the antibodies at delivery time a heavy postnatal icterous form of the hemolytic disease of the infants develops (icterus neonatorum gravis). Jaundice appears at the end of the first or on the second day after delivery and grows quickly. Penetration of the indirect toxic bilirubin into the brain causes the damage of ganglionic cells till their very necrosis – bilirubinic encephalopathy. The changes develop mostly in the subcortical sections – hypostones, nuclei of the bottom of the diamond-shaped fossa, inferior olives, pale nucleus and nuclei of the cerebellum. Hypostones, nuclei of the bottom of the diamond-shaped fossa, inferior olives, pale nucleus and nuclei of the cerebellum are intensively coloured yellow – nuclear icterus. Erythroblastosis, hemosiderosis, biliarystases and thrombi, sometimes even  gallstones; in the kidneys – bilirubinic infarctions are observed in the liver. Spleen is enlarged, dense. Microscopically hemosiderosis and erythroblastosis are found in it.

The children who overcame hemolytic disease can have considerable defects in the development of the central nervous system (CNS) that results in mental deficiency.