Pathology of the endocrine system. Markéta Hermanová Masaryk University, Medical Faculty nPituitary gland n nThyroid n nParathyrois n nAdrenal gland n nEndocrine pancreas n Posterior lobe of pituitary gland Pathological basis of endocrine signs and symptoms Sign or symptom Pathological basis Hormone excess (hyperfunction) Endocrine gland hyperplasia cause by increased trophic stimulus to secretion Functioning neoplasm of endocrine gland Hormone deficiency (hypofunction) Endocrine gland atrophy due to loss of trophic stimulus to secretion Destruction of endocrine gland by inflammation, ischamia or non-functioing tumor Diffuse enlargement of gland Inflammatory cell infiltration Hyperplasia Pituitary nAdenohypophysis nHypofunction/partial or panhypopituitarism -Due to destruction by tumor or compression, Rathke's cleft cyst; due to hypothalamic reasons -Due to inflammation (autoimmune); due to genetic abnormalities of hormone synthesis -Due to ischaemic necrosis, radiation damage or surgical ablation -Leads to secondary hypofunction of adenohypophyseal dependent endocrine glands n (atrophy of gonads, hypothyreosis, hypocorticalism,…) n nHyperfunction/hyperpituitarism -in adenomas, carcinomas, hyperplasias, due to hypothalamic reasons n n Adenoma type Clinical picture Prolactinoma Commonest type, produces galactorrhoea and menstrual disturbances GH-secreting Produces gigantism in children and acromegaly in adults ACTH-secreting Produces Cushing syndrome Others Exceptionally rare (TSH-, FSH-, LH- secreting) Plurihormonal Hormonally non-functioning Adenomas of the adenohypophysis Association with MEN-1 syndrome! Cushing syndrome Neurohypophysis nAntidiuretic hormone (ADH) nADH deficiency – diabetes insipidus (DI) -Due to hypothalamus damage (trauma, tumor, inflammation.. due to hypothalamic reasons) -Polyuria, polydipsia -In peripheral forms of DI the renal tubules insensitive to ADH - nExcess ADH -Usually due to ectopic production by tumors (neuroendocrine carcinomas of the lung) n nOxytocin n Hypothalamic suprasellar tumors nGliomas n nCraniopharyngeoma -usually benign, malignisation rare; from the Rathke´s cleft epithelial rests -children (5-15 years; endocrinopathies) + 2nd peak in 6th decase -solid, cystic or multilocular - - Adrenals nMedulla -Production of catecholamins (adrenalin, noradrenalin) n nTumors: -Pheochromocytoma •symptoms due to excess catecholamine secretion (secondary hypertension with ↑risk of cerebral bleeding), sweating) •Adrenal or extraadrenal, uni or bilateral, assoc. with MEB 2A and 2B (10 %) •10 % with malignant biological behavior • -Neuroblastoma n(tumor of children, malignant) -Ganglioneuroblastoma, ganglioneuroma n n n n Extraadrenal system of chromaffine paraganglia paraganglia Adrenals nCortex nProduction of glucocorticoids,mineralocorticoids, sex steroids nHyperfunction: nCushing syndrome n(excess secretion of ACTH, tumors of adrenals, treatment by steroids nConn´s syndrome n(overproduction of mineralocorticoids: retention of water, hypertension, muscular weakness, arrhythmias) n nHypofunction nCaused by autoimmune adrenalitis, tbc, necrosis of adrenals in sepsis, destruction by tumors,… nWeight loss, lethargy, hypotension, pigmentation, hyponatraemia n n n n n n n n n n n Thyroid nHyperthyroidism nSyndrome due to excess T3 and T4 nVery rarely due to excess TSH nCaused by Grave´disease/thyreoiditis, in which the thyroid stimulating autoantibodies are produced nRarely due to functioning adenoma or toxic nodular goiter n nHypothyroidism (myxoedema) nSyndrome due to insufficient circulating T3 and T4 nIf congenital , causes cretenism nCommonest cause is Hashimoto´s thyreoiditis (=autoimmune thyreoiditis) n Causes of thyreotoxicosis nPrimary associated with hyperthyreoidism -Diffuse toxic hyperplasia (m. Graves-Basedow) -Hyperfunctional (toxic) nodulat goiter -Hyperfunctional (toxic) adenoma -Hyperfunctional thyreoidal carcinoma -Iodine induced hyperthyreoidismus -Neonatal thyreotoxicosis (of mothers with m. G-B) - nSecondary associated with hypertyreoidismem -TSH producing pituitary adenoma -TRH overproduction n nWithout association with hyperthyreoidism -Subacute granulomatous thyreoiditis -Chronic lymphocytic thyreoiditis -Struma ovarii (mature ovarial teratoma) n - - n Hypothyreoidismus: A) congenital - cretenismus (endemic (in iodine defficiency); sporadic (due to enzymatic defect) B) aquiered – myxoedema nClinical signs of cretenism: -Impaired physical growth and mental development, hypomimic face, tongue protrusion, umbilical hernia n nClinical signs of myxoedema -Accumulation of mucosubstances in corium (and viscerally) -Hypercholesteroĺaemia, accelerated AS -Dry cold skin, gruff voice, muscle weakness, prone to hypotermia, dry hair, brittle nails, oligo –amenorea, obesity, psychic disorders - depression,…. -Coma with hypothermia, circulaton failure - nCauses -Primary -Developmental (dysgenesis: mutation in genes for TSH-receptor, TTF) -Genetically caused resistence to thyreoidal hormones -Surgical ablation, radiation -Autoimmunne thyreoiditis -Iodine deficiency -Congenital biosynthetical defect (dyshormonogenetic goiter) -Drugs – thyreostatic -Secundary and tertiary (hypothalamic anf hypophyseal reasons) n M. Graves-Basedow (diffuse parenchymatous toxic (hyperfunctional) goitre) nF˃M, 2nd to 4th decade, genetically predisposed nAutoimmune disease: stimulating autoantibodies against TSH receptor nHyperthyreoidism+infiltrative ophtalmopathy-exophthalmos (T cells, oedema, GAGs, adipocytes) +(pretibial myxoedema) nDiffuse hypertrophy and hyperplasia n„too many follicular cells and too little colloid“ nSurgical removal or radioiodine ablation n n Thyroiditis nChronic autoimmune lymphocytic thyroiditis (Hashimoto´s) -F:M = 10:1 -Genetic predisposition -CD8+ cytotoxic T cells mediated cell death; cytokines mediated cell death -Autoantibodies against TSH receptor, thyreoglobulin, peroxidase – antibody-dependent cell-mediated cytotoxicity (ADCC) -Enlarged thyroid, lymphoplasmocytic infiltrate, lymphatic follicles, oncocytic transformation of thyreocytes, fibrotisation -Often assoc. with other autoimmune diseases -Increased risk of malignant lymphoma (MALToma) and carcinom of the thyroid - Thyroiditis nSubacute granulomatous thyroiditis (de Quervainova) -F:M = 3-5:1 -virus-induced host tisuue damage? cytotoxic T lymphocytes -Painfully enlarged thyroid, fever, fairly abrupt onset -Focal disruptions nad necroses of follicules, granulocytic and granulomatous reactions, fibrotisation) - -Chronic sclerosing thyroiditis (Riedl´s) -Fibrotising inflammation involving thyroid and also surrounding tissues and organs (stenosis of trachea, paresis of n. recurrens, hypothyroidism) -Systemic connective tissue disease (IgG4 assoc.?), fibrotising Hashimoto´s thyroiditis?, idiopathic fibrosis? n nSubacute lymphocytic thyroiditis (often post partum thyroiditis) n Chronic autoimmune lymphocytic thyroiditis (Hashimoto´s thyroiditis) CLPT folikly ŠŽ Sclerosing lesions associated with IgG4 nAutoimmune pancreatitia nSclerosing cholangitis nLymphoplasmocytic sclerosing cholecystitis nSclerosing sialoadenitis nIdiopathic retroperitoneal fibrosis (M. Ormond) nInflammatory pseudotumor of the liver, lung, pituitary gland nTubulointerstitial nephritis assoc. with IgG4 nInterstitial pneumonia assoc. With IgG4 nSclerosing prostatitis nSclerosing thyreoiditis n -M>F; immunosuppressive therapy response (steroids) -Imitation of neoplastic lesions -Sclerosing lesions with lymphoplasmocytic infiltrates, irregular fibrotisation, obliterative phlebitis, IgG4+ plasma cells. -Increased risk of malignant lymphoma Goitre (enlargement of the whole gland) nParenchymatous goitre vs colloid goitre nDiffuse vs nodular goitre nHypofunctional vs hyperfunctional vs eufunctional n nAetiology nIodine deficiency, due to endemic goitre or food faddism nRare inherited enzyme defects in T3 and T4 synthesis nDrugs that induce hypothyroidism Thyroid tumors nBenign -Follicular adenoma - nMalignant -Carcinoma -Lymphoma n (lymphoma (usually non-Hodgkin´s lymphomas of B-cell type, variable prognosis) n n Carcinoma of the thyroid Type Proportion of all cases (%) Typical age range Mode of spread Prognosis Papillary 60-70 Children, young adults Lymphatic, to lymph nodes Excellent Follicular 20-25 Young-middle age Haematogenous, to bones Good Anaplastic 10-15 Elderly Aggressive local extension Very poor Medullary 5-10 Usually elderly, also familial case (MEN sy) Local, lymphatic, haematogenous Variable, more aggressive in familial cases Papillary carcinoma of the thyroid Thyroid_papillary_carcinoma_histopatholgy_(1) Thyroid_papillary_carcinoma_histopathology_(2) Papillary carcinoma of the thyroid Renata FNAB Medullary carcinoma of the thyroid 18-9f Amyloid deposits Parathyroid Secondary hyperparathyreoidsm: a physiological response to hypocalcaemia (e.g. in malabsorption, renal failure) Primary MEN 1, MEN 2 Clinical signs of hyperparathyreoidismu hyperparathyreoidismus Pathological fracture and brown pseudotumor WHO-Bone Tumours_03 WHO-Bone Tumours_04 Hypoparathyreoidism nCauses hypocalcaemia nTetany (spasm of the skeletal muscle) nConvulsions nParaesthesiae nPsychiatric disturbances nRarely cataracts and brittle nails n nCaused by: nRemoval of or damage of the glands during thyreoidectomy nIdiopathic, autoimmune (also as a part of polyendocrine syndrome) nCongenital hypoplasia or aplasia (Di George syndroma) nCongenital deficiencies Other causes of hypocalcaemia: chronic renal failure, vitamin D deficiency, excess loss during lactation Pseudohyperthyreoidism: -Insensitivity of peripheral tissues to PTH -Usually genetically caused Endocrine pancreas: islet cell tumors – neuroendocrine neoplasias nLess common than pancreatic adenocarcinoma (1-2 % of pancreatic tumors) n nPresent with endocrine effects and can be malignant: -Insulinoma: hypoglycaemia due to hypersecretion of insulin -Glucagonoma: secondary diabetes and skin rash -Gastrinoma: hypersecretion of gastric acid due to gastrin action resulting in severe peptic ulcerations -….others (somatostatinoma, VIPoma, serotoninoma, with ectopic hormonal production (ACTH, calcitonin) -Non-functional -Microadenoma (˂0,5 cm) n n n Islet cell tumor and gastrinomas may occur as a part of inherited MEN (multiple endocrine neoplasia) syndrome. Neuroendocrine neoplasias – tumors of the endocrine pancreas nNeuroendocrine tumor (NET) -Non-functional pancreatic NET (NET G1, G2) -NET G1 -NET G2 -NET G3 (from WHO 2019) - nNeuroendocrine carcinoma (NEC) -Large cell type NEC -Small cell type NEC n n n Neuroendocrine neoplasia of the pancreas. _pancreas-islet-cell-tumor-malignant Neuroendocrine neoplasia of the pancreas. Amyloid deposits in insulinoma FNAB cytology of neuroendocrine neoplasia of the pancreas. NE tumor 357606 Multiple endocrine neoplasia (MEN) syndromes Diabetes mellitus (group of metabolic disorders sharing the common sign– hyperglycemia) nType 1 -Immune mediated destruction of B cells -Autoimunne IDDM in genetically predisposed patients + environmental factors (viruses) nType 2 -Insulin rezistent, with relative or absolute insulin deficiency -Genetics; obesity, life style nGenetically caused defects of B cells functions -„maturity-onset diabetes of the young“ (mutations in different genes) -„mitochondrial diabetes“ (mutations in mtDNA; oxidative phosphorylation failures) nGenetically caused defects in insulin function n- Insulin gene, insulin receptor gene mutations, defects of proinsulin conversion nDisorders of exocrine pancreas -Chronic pancreatitis -Pancreatectomy -Pancreatic neoplasia -Cystic fibrosis -Haemochromatosis Diabetes mellitus (group of metabolic disorders sharing the common sign– hyperglycemia) nEndokrinopathies -Acromegaly -Cushing syndroma -Hyperthyreoidismus -Glucagonoma, feochromocytoma nInfections -CMV -Coxackie virus B nDrugs n- Glucocorticoids, hormones of thyroid, alpha interferon, proteases inhibitors, thiazids, phenytoin, … nGenetic syndromas assoc. with DM -Down syndroma -Klienefelter syndroma -Turner syndroma nGestational DM n Differences between types of diabetes mellitus (DM: abnormal metabolic state characterised by glucose intolerance due to inadequate insulin action) Features Type 1 (ketosis-prone, juvenile onset, insulin-dependent) Type 2 (not ketosis-prone, maturity onset, non-insulin-dependent) Age of onset Usually ˂20y Usually ˂40y Proportion of all cases ˂10 % ˃90% Type of onset Abrupt (acute or subacute) Gradual Etiological factors Possible viral/autoimmune, resulting in destruction of islet cells Obesity associated insulin resistence HLA asocciation Yes (=genetic predisposition in DM) No Insulin antibodies Yes No Body weight at onset Normal or thin, obesity uncommon Majority are obese (80%) Endogenous insulin production Decreased (little or none) Variable (above or below normal) Ketoacidosis May occur Rare Treatment Insulin, diet, exercise Diet, oral hypoglycemic agents, exercise, insulin, and weight control Risk factors for type 1 and type 2 diabetes mellitus Type 1 DM risk factors Type 1 DM in a first-degree relative (sibling or parents) Type 2 DM risk factors Positive family history Ethnic origin (black, native americans, hispanic, asian american, pacific islanders) Obesity Increasing age Habitual physical inactivity, sedentary lifestyle History of gestational DM Other clinical conditions assoc. with insulin resistence (e.g. polycystic ovary syndrome) History of vasular diseases Previously identified impaired fasting glucose or impaired glucose tolerance Hypertension HDL cholesterol level ˂35mg/dL and/or triglyceride level ≥250mg/dL Cigarette smoking Cardinal clinical signs of DM at diagnosis nPolyuria nPolydipsia nPolyphagia, excessive hunger (in type 1) nWeight loss (in type 1) nRecurrent blured vision nKetonuria (in type 1) nWeakness, fatigue, dizziness nOften asymptomatic (type 2) n Complications of diabetes Situation Complication Large blood vessels Accelerated arteriosclerosis leading to: -Myocardial infarction -Cerebrovascular diseases -Ischaemic limbs -Responsible for 80 % of adult diabetic death Small blood vessels Endothelial cells and basal lamina damage. Retinopathy (major cause of blindness), nephropathy Peripheral nerve Diabetic neuropathy (v.s. due to disease of small vessels supplying the nerves) Neutrophils Susceptibility to infection Pregnancy Pre-eclamptic toxaemia Large babies Neonatal hypoglycamia Skin Gangrene of extremities Soft tissue lesions (Granuloma annulare, necrobiosis lipoidica) Complications of diabetes. komplikace diabetu Thank you for your attention…