Odessa National Medical University Department of Normal and

Odessa National Medical University Department of Normal and Pathological Clinical Anatomy Lecture on the topic: Hypothalamic-pituitary disorders. Pathology of the adrenal glands. Pathology of the thyroid gland. Pathology of the endocrine system of the pancreas.

Diseases of endocrine glands § Morphologic changes in endocrine glands are represented by: § dystrophic; § atrophic; § hyperplastic; § hypoplastic processes; § sclerosis; § structural reorganization; § formation of tumors. § The most frequent endocrine pathologies are diabetes mellitus and diseases of thyroid gland

Diseases of hypophysis § Appear in tumors of the gland, autoimmune affection, inflammation, necrosis (ischemic infarction) or develop because of impairments of hypothalamus and other parts of CNS. Because of this in some cases we may use the term «cerebro-hypophysal diseases» .

§ § § § Among them important are: acromegalia hypophysal nanism cerebro-hypophysal cachexy disease of Icenko - Cushing adiposogenital dystrophy diabetes insipidus tumors of hypophysis

Acromegalia § Causes of development are hypothalamohypophysal impairments or somatotropic adenoma, rarely - adenocarcinoma of anterior part of hypophysis. Abundant quantity of somatotropic hormone stimulates growth of tissue, mostly of mesenchimal origin (connective, cartilage, bone), and also parenchyma and stroma of internal organs (heart, liver, kidneys, etc).

§ In children and young people giantism develops. Acromegalia is followed by changes of other endocrine glands: goiter, atrophy of insular apparatus of pancreas, hyperplasia of thymus and epiphysis, of cortex of adrenal glands, atrophy of sex glands.

Patient with acromegalia

Hypophysal nanism § Can be found in congenital underdevelopment of hypophysis or its destruction in infancy (inflammation, necrosis). Patients demonstrate common underdevelopment while having proportional constitution, sexual organs are usually underdeveloped.

Cerebro-hypophysal cachexy § Also known as Simmonds’s disease. It is characterized by progressive cachexy, atrophy of internal organs, decreased function of sex glangs. It is observed in young women, often after delivery. In anterior part of hypophysis there areas of necrosis, as a result of embolism of vessels, or scars after necrosis. In some cases destruction of anterior part of hypophysis is connected to syphilitic, tuberculous, or tumor process. In this disease, besides affection of hypophysis, there are dystrophic or inflammative changes in diencephalon.

Disease of Icenko-Cushing § May be caused by hypothalamic impairments or development of adenocorticotropic adenoma, rarely - adenocarcinoma of anterior part of hypophysis. Because of hypersecretion of ACTH develops bilateral hyperplasia of cortex of adrenal glands with abudant production of glucocorticoids, which play a leading part in pathogenesis of the disease. The disease is often observed in women, its manifestations are progressing obesity of upper type (face and trunk), arterial hypertension, steroid diabetes mellitus and secondary dysfunction of ovaries.

§ There is also osteoporosis with spontaneous fractures of bones, hypertrichosis and hirsutism; red-blue striae of skin of thighs and stomach. Often the disease is accompanied by nephrolitiasis and chronic pyelonephritis.

Adiposogenital dystrophy § Also known as Babinskiy - Frelih’s disease. It is based on pathologic changes in hypophysis and hypothalamus, which appear because of tumor or neuroinfection. For this disease typical are progressive obesity, underdevelopment of sexual organs and decreased function of sex glands. Adiposogenital dystrophy is sometimes followed by hypothyreosis, decreased function of cortex of adrenal glands, and diabetes insipidus.

Diabetes insipidus § Develops after damage of posterior part of hypophysis (by tumor, inflammation, or trauma). Along with impairment of posterior part of hypophysis there are constantly seen changes of diencephalon. Diabetes insipidus is caused by decrease of funtion of antidiuretic hormone and ability of the kidneys to concentrate urine, which is followed by excretion of significant quantities of urine (polyuria) and increased thirst. Loss of liquid and impairment of mineral metabolism cause severe consequences of diabetes insipidus.

Tumors of hypophysis § In most cases tumors of hypophysis are hormonally active

Normal hypophysis in low magnification. Adenohypophysis is on the right, neurohypophysis is on the left

Microadenoma in anterior lobe of hypophysis, low magnification

Adenoma of anterior lobe of hypophysis, high magnification

Diseases of thyroid gland § § Diseases of thyroid gland include: goiter (hyperplasia) thyreoiditis tumors

Goiter § Goiter - increase of gland, caused by hyperplasia § Depending on the reason goiter may be: § a) congenital, i. e. caused by genetic defects (fermentopathies) of metabolism of thyreoid hormones (synthesis, secretion, transport, reception) § b) caused by deficiency of iodine in food § c) caused by autoimmune mechanisms § d) physiologic (during puberty and during pregnancy) § e) cause unrevealed

§ § Function of thyroid gland in goiter may: stay normal (euthyreoid, non-toxic, simple goiter) increase (hyperthyreoid, toxic goiter) decrease (hypothyreoid goiter): in adults is followed by development of myxedema, in children - by cretinism § Myxedema is followed by drowse, chill, slowness, increase of body mass, edema of face, eye-lids, hands, dryness of skin, loss of hair

Morphologic classification of goiter § § By macroscopic picture: nodular goiter diffuse goiter mixed goiter § by microscopic organization: § colloid goiter: macrofollicular, microfollicular, macromicrofollicular § parenchymatous goiter

Normal thyroid gland

Thyroid gland in nodular goiter. Gland is increaded, nodular, its weight is more than 30 g

Normal thyroid gland, microscopically

Thyoid gland in nodular goiter. Follicles are increased, with flattened epithelium, non-active

§ Most frequent types of goiter: § 1) Congenital goiter § typical is nodular or diffuse (rarely) hyperplasia § has solid-trabecular (parenchymatous goiter) or microfollicular structure § is followed by hypothyreosis

§ 2) Endemic goiter (nodular non-toxic goiter) § develops in dwellers of certain geographic regions § is connected to lack of iodine in food § deficiency of iodine causes decrease of synthesis of hormones of thyroid gland, increase of synthesis of thyreotropic hormone (TTH) and development of hyperplasia. Significant quantities of colloid are accumulated inside of dilated follicles, which leads to atrophy of epithelium. Insufficient function of follicular epithelium is compensated by increase of mass of the gland

§ Function is normally euthyreoid, hypothyreosis may develop. § Macroscopic picture: nodular goiter: gland is enlarged, its mass may reach up to 250 g, dense in consistence, nodular surface; on section there are cavities that vary in size, filled with brown-yellow colloid contents. § Microscopic picture: consists of round follicles, many of which are cystously dilated, filled with oxyphilic thick colloid that is colored into crimson color by Pas-reaction. Epithelium in follicles and cysts is thickened.

§ 3) Sporadic goiter § cause is unknown § develops without connection to endemic regionas, but is morphologically identic to endemic goiter § macroscopic picture: nodular goiter § microscopic picture: has macro- or microfollicular structure § functions of gland are usually not changed, but hypothyreosis or (rarely) hyperthyreosis may be noticed sometimes

§ 4) Diffuse toxic goiter (Graves’s disease) § The most freqient cause of hyperthyreosis (thyreotoxicosis) § autoimmune disease connected to appearance of thyreoid-stimulating immunoglobuline and immunoglobuline of growth of thyreoid gland Ig. G-autoantibodies, which react with various domens of receptors of follicular epithelium for thyreotropic hormone, which, from one hand, leads to increase of synthesis of thyreoid hormones, and from the other - to proliferation of epithelium and increase of the gland § more often develops in young women

§ Clinical manifestations - goiter, exophtalm, tachicardia, nervousness, decrease of body mass, hyperhidrosis § macroscopic picture: significant (in 2 -3 times) diffuse increase of the gland (diffuse hyperplasia), the tissue is succulent, homogenous in color, gray-red § microscopic picture: there are follicles of various size and irregular «star-shape» . Epithelium is high, proliferating, forms papillae. Colloid in the follicles is liquid, vacuolized. In stroma there accumulations of lymphoid elements

Diffusely enlarged thyroid gland in Graves’s disease, low magnification. Note the prominent folds of hyperplastic epithelium

Diffusely enlarged thyroid gland in Graves’s disease, high magnification. Note the prominent folds of hyperplastic epithelium, colorless vacuoles in the colloid

§ Because of thyreotoxicosis develops thyreotoxic heart, for which typical are: hypertrophia, serous edema and lymphoid infiltration of stroma, and also edema of cardiomyocytes. In the end develops diffuse interstitial sclerosis § In liver develops serous edema, sometimes ending with fibrosis (thyreotoxic fibrosis of liver) § Death in diffuse toxic goiter may be caused by cardiac insufficiency, exhaustion, acute adrenal insufficiency (during operation of removal of goiter)

Thyreoditis § By etiology thyreoiditis may be: § a) infectious (nonspecific, connected to bacteria and fungi, tuberculous) § b) autoimmune (thyreoiditis of Hashimoto) § c) caused by physical factors: radiation, traumatic § d) unknown etiology: § subacute (giant-cell granulomatous) de Quervain’s thyreoiditis § fibrous thyreoiditis (Ridel’s struma)

§ § By clinical course thyreoiditis may be acute subacute chronic

Acute thyreoiditis § Infectious by nature; often caused by staphylococcus, streptococcus, and gram-negative microorganisms § typical is infiltration by polymoroph-nuclear leucocytes, dystrophic and necrotic changes

Subacute (granulomatous) De Quervain’s thyreoiditis § Etiology unknown § Often affects women of middle age § Macroscopic picture: the gland is enlarged (2 times and more), dense, not joined with adjacent tissues § microscopic picture: there is granulomatosis with giant foreing body cells (in cytoplasm colloid may be found)

Chronic thyreoiditis § Hashimoto’s thyreoiditis (autoimmune thyreoiditis, lymphomatous struma) § classified as chronic thyreoiditis § one of the most common causes of hypothyreosis § more often affects women

§ autoimmune disease, caused by several antithyreoid autoantibodies (the most important are antibodies to thyreoglobulin and microsomes of follicular epithelium) § may be combined with other autoimmune diseases (diabetes mellitus of 1 st type, Sjogren’s disease, pernicious anemia, etc) § Typical is slow development with steady enlargement of thyroid gland long euthyreoid period

§ Microscopic picture: in the gland there is thick lymphocytal infiltration, forming follicles with light centers; epithelial follicles are atrophied. § Finally thyroid gland is decreased in sized and sclerocized, which is followed by development of hypothyreosis and myxedema

Hashimoto’s thyreoiditis, low magnification

Hashimoto’s thyreoiditis, high magnification

§ 2) Riedel’s thyreoiditis (Riedel’s struma) § Etiology and pathogenesis unknown § characterized by substitution of glandular tissue by fibrous tissue § thyroid gland is very dense ( «iron goiter» ), joined with adjacent tissues § compression of trachea may lead to breathing impairments § is followed by hypothyreosis

Diseases of parathyroid glands § The most important is syndrome of hyperfunction of parathyroid glands hyperparathyreosis, morphologically manifested by hyperplasia or tumor of these glands; also possible is hyperparathyreosis of immune genesis.

§ There are primary and secondary hyperplasia of parathyroid glands. Primary hyperplasia, often adenoma of the gland, leads to development of parathyroid osteodystrophy. Secondary hyperplasia of glands develops as reactive compensatory state because of accumulation of lime in the organism in primary destruction of bones (metastasis of cancer, multiple myeloma, rickets) and renal diseases (chronic renal insufficiency).

§ Parathyroid or fibrous osteodystrophy is based on impairments of metabolism of calcium and phosphorus because of hyperproduction of parathormone by adenoma of the glands. This hormone causes mobilization of mineral salts from bone tissue; processes of resorbtion of bone prevail over new-forming of bone, in which case mainly osteoid tissue is formed, deep reorganization of bone occurs

§ Hypoparathyreosis may be connected to autoimmunization which leads to death of the glands. Sometimes it develops after accidental removal of the glands in operations on goiter, it is followed by tetany.

Tumors of parathyroid glands § Adenoma of parathyroid glands develops from main cells. Atypic cells with hyperchromic nuclei form acinus, trabecules, cysts with papillary overgrowth. Tumor is hormonally active, followed by hyperparathyreosis, which is the base of fibrous osteodystrophy. § Cancer of parathyroid glands is found rarely and does not have any specific morphologic features.

Normal parathyroid gland

Hyperplasia of parathyroid gland

Adenoma of parathyroid gland

Cancer of parathyroid gland. On the left - low magnification, on the right - high magnification

Diabetes mellitus § Diabetes mellitus is a disease caused by absolute or relative insufficiency of insulin. This leads to heavy impairments of all kinds of metabolism, first of all - carbohydrate and lipid metabolism.

Classification of diabetes mellitus § § § By etiology there are: 1) primary (idiopathic), which may be: a) insulin-dependant (in young people) b) insulin-nondependant (in adults) 2) secondary

Insulin-dependant diabetes mellitus § Usually develops in patients under 30 years old § Is found much less frequently than diabetes mellitus of 2 nd type § Mechanism of impairment of -cells is connected to autoantibodies; in islets of Langerhans of the pancreas, develops immune inflammation - insulitis

§ In development of the disease important are hereditary dysposition and viral infection (which starts autoimmune process) § Disease is caused by absolute insufficiency of insulin: § Without administration of insulin develop such states as hyperglycemia, polyuria, decrease of body weight, ketoacidosis, and coma, leading to death.

Islet of Langerhans, normal microscopic picture

Insulitis of islet of Langerhans in a patient with diabetes mellitus. The presence of the lymphocytic infiltrates in this edematous islet suggests an autoimmune mechanism for this process.

Insulin-nondependant diabetes mellitus (diabetes of adults) § Much more frequent than insulindependant diabetes § Usually develops in middle age § Development is caused by increase of resistance of cells to insulin, which is caused by decreased quantity of cellular receptors to insulin, or impairment of transformation of proinsulin into insulin, decreased sensitivity of -cells to insulin, or impaired function of intracellular transport proteins

§ In development important are hereditary dysposition and common obesity § Concentration of insulin in plasm is normal, often increased § Hyperglycemia is usually corrected by diet, administration of antidiabetic preparations, administration of insulin is not required § Ketoacidosis is not typical

This islet of Langerhans demonstrates pink hyalinization (with deposition of amyloid) in many of the islet cells. This change is common in the islets of patients with type II diabetes mellitus.

Secondary diabetes mellitus § Develops secondarily in various diseases of pancreas: § idiopathic hemochromatosis (“bronze diabetes”) § pancreatitis § cancer § Also may develop in Cushing’s syndrome, acromegaly, pregnancy, etc.

Morphology of diabetes mellitus § Morphologic picture consists not only of changes of pancreas itself, but also other organs because of metabolic impairments. The most important of them is diabetic angiopathy.

Changes of pancreas § Macroscopically: pancreas is decreased in size, dense, on section represented by rows of whitish connective tissue and overgrowth of fatty tissue - lipomatosis (typical for diabetes of 2 nd type)

§ Microscopically: § 1) for diabetes of 1 st type typical are numerous small islets with sclerosis and lymphocytal infiltration (insulitis); quantity of -cells is decreased, they are degranulated § 2) for diabetes of 2 nd type typical are sclerosis (hyalinosis) and amyloidosis of islets (accumulation of amylin - islets’ amyloid polypeptid), -cells are small, degranulated; surviving islets may be hypertrophic

Diabetic angiopathy § Is represented by macro- and microangiopathy. § 1) Diabetic macroangiopathy: § has the morphology of atherosclerosis, which occurs in vessels of elastic and muscular-elastic types. Diabetes mellitus is risk factor for development of atherosclerosis. § Atherosclerotis complications in diabetes mellitus develop in much younger age.

§ 2) Diabetic microangiopathy § Develops in arterioles and capillaries because of plasmatic impregnation and represented by hyalinosis, often with proliferation of endotelium and peritelium § Has generalized character: it is found in kindeys, retina, skin, skeletal muscles, pancreas, brain, peripheral nervous system, etc.

§ In kidneys develops diabetic glomerulosclerosis, which is clinically manifested by syndrome of Kimmelstiel Wilson, which runs with high proteinuria, edemas, arterial hypertension, finally develops uremia

§ Macroscopically: § kidneys are decreased in size, dense, smallgranular § § § Microscopically: there are two forms: a) in nodular form in mesangium of glomeruli appear focal accumulation of eosinophilic hyaline masses; § b) in diffuse form there is diffuse thickening of basal membranes of glomerules’ capillaries and widening of mesangium. Process is better seen in PAS-reaction

Complications of diabetes mellitus § Possible is development of diabetic coma § Because of macro- and microangiopathy often develops gangrene of lower extremities and other complications § Chronic renal insufficiency in progressing of diabetic glomerulosclerosis § Typical are infectious complications: purulent pyodermia, furunculosis, purulent pyelonephritis, septicopyemia, bronchopneumonia, candidosis, tuberculosis

Diseases of adrenal glands § Addison’s disease, or bronze disease: is caused by two-sided affection of mainly cortical substance of adrenal glands and elimination (acorticism) or decrease (hypoadrenocorticisim) of production of its hormones. Most often causes of bronze disease are metastasis of tumor into both adrenal glands, their autoimmune impairment (primary Addison’s disease), amyloidosis (epinephropatic amiloidosis), hemorrhages, necrosis because of thrombosis of vessels, tuberculosis.

§ In some cases the disease is caused by impairments of hypothalamo-hypophysal system (decreased secretion of ACTH or corticotropin-releasing-factor) or has hereditary character. § In Addison’s disease there is hyperpigmentation of skin (melanodermia) and mucous membranes because of hyperproduction of ACTH and melanostimulating hormone, atrophy of myocardium, decreased lumen of aorta and magistral vessels.

§ Also there is adaptive hyperplasia of cells of islet apparatus of pancreas (hyperglycemia ), atrophy of mucous membrane of stomach, as well as hyperplasia of lymphoid tissue and thymus. § Death in Addison’s disease is caused by acute adrenal insufficiency, cachexy (suprarenal cachexy) or insufficiency of cardio-vascular system.

Normal adrenal tissue

Atrophy of adrenal tissue in Addison’s disease

Tumors of adrenal glands § Adrenocortical adenoma - benign tumor of cortical substance: § light-cell § dark-cell § Adrenocortical cancer - malignant tumor of cortical substance § Feochromocytoma - benign tumor of medullar substance § Malignant feochromocytoma - malignant tumor of medullar substance

Adrenocortical adenoma, low magnification

Cancer of adrenal gland, low magnification

Feochromocytoma, low magnification

Feochromocytoma, high magnification

Syndrome of multiple endocrine neoplasia § Syndrome of multiple endocrine neoplasia (MEN) includes genetic diseases which are inherited by autosomal-dominant type and manifest as multiple tumors or hyperplasia of various endocrine glands.