14. Pathology of the endocrine glands PATHOLOGY OF ENDOCRINE SYSTEM ENDOCRINE SYSTEM • Function: maintenance of homeostasis through secretion of hormones • Hormones: signalling molecules secreted into the bloodstream, transported to and act on distant target organs by binding to specific receptors • Components of endocrine system: o Endocrine organs (glands) – entire parenchyma o Group of endocrine cells – e.g. islets of Langerhans, ovary, testis o Isolated endocrine cells – in GI tract Endocrine diseases may manifest as: • Hormone overproduction o Primary overproduction by gland o Secodary to excessive trophic hormone • Hormone underproduction o Primary underproduction by gland (e.g. due to inflammation, post surgery) o Secondary to insufficient trophic hormones • Altered tissue responses to hormones o Target organ hormone resistance (insulin resistance in type 2 diabetes) • Tumors of endocrine glands DISEASES OF THE PITUITARY GLAND DISEASES OF THE ANTERIOR PITUITARY PITUITARY ADENOMAS • Benign neoplasms derived from the epithelial cells of the adenohypophysis • Mainly sporadic, rarely associated with MEN1 syndrome (see below) • Types: o Functional – 80% ▪ With clinical manifestations of hormone excess (↑ blood hormone) → hyperpituitarism o Nonfunctional (silent) – 20% ▪ Without the clinical manifestations of hormonal excess ▪ Usually grow larger (few symptoms) → destruction of nontumorous parenchyma → hypopituitarism + local mass effects • Size: o Microadenomas - <10 mm o Macroadenomas – >10 mm LOCAL MASS EFFECT • Larger, predominantly nonfuctional adenomas may compress or even infiltrate adjacent structures: cavernous sinus, hypothalamus, sphenoid bone (sella turcica), optic chiasm o Infiltrative spread is not a sign of malignancy • Enlargement of the sella turcica + optic chiasm compression → visual field abnormalities (bitemporal hemianopia) • Increased intracranial pressure (headache, nausea, vomiting) – especially in sudden pituitary apoplexy • Hypopituitarism due to the destruction of the nontumorous parenchyma HISTOLOGY OF PITUITARY ADENOMAS LM: • Both nonfunctional and functional adenomas are usually composed of a single cell type (acidophilic, basophilic or chromophobic cells); cells are monomorphous 1 13. Pathology of the endocrine glands • Functioning adenomas produce a single hormone • Hormone produced by the tumor cells can be detected by immunohistochemistry, this classifies the tumors into multiple subtypes: Prolactinomas (lactotroph cell adenomas) - prolactin Somatotroph – growth hormone (GH) Corticotroph - ACTH Gonadotroph – FSH/LH Thyrotroph - TSH EM: • Numerous membrane-bound secretory granules in the cytoplasm FUNCTIONAL ADENOMAS AND HYPERPITUITARISM Prolactinoma • Most common functional pituitary tumor • Most are macroadenomas • Dg: PRL (prolactin) immunostaining Clinical features • Amenorrhea • Galactorrhea • Loss of libido • Infertility Dg: • Easily made in women of reproductive age (because of absence of menstruation) • In older women and men the tumor may reach a considerable size before discovery (no recognizable endocrine symptoms) Somatotroph cell adenoma • 2nd most common functional pituitary adenoma • Macroadenomas, which may become large since the clinical symptoms are mild • Clinical features and consequences: o Local mass effect o Excess GH with associated acromegaly and gigantism • Gigantism o GH effect before the closure of the epiphyses o Generalized increase in body size with long arms and legs • Acromegaly o Increased GH levels only after the closures of the epiphyses o Enlargement of head, hands, feet, jaw, tongue and soft tissues Corticotroph adenomas Morphology • Basophilic or chromophobe cells, ACTH positive • Microadenomas (mostly) • Chromophobic tumors are often larger and cause local mass effect Clinical features • Usually in young females; excess production of ACTH → Hypercortisolism (Cushing syndrome) o If hypercortisolism is caused by excess ACTH production by a pituitary adenoma, we call it Cushing disease Rare adenomas • Thyrotroph (TSH producing) adenomas → rare cause of hyperthyroidism • Gonadotroph (LH and FSH) adenomas → menstrual disturbances and decreased libido/impotence; local mass effects Pituitary carcinomas • Very rare, mostly nonfunctional • Diagnostic feature: metastasis HYPOPITUITARISM • Hypopituitarism is decreased pituitary hormone secretion resulting from the diseases of the hypothalamus or of the pituitary • At least 75% of the anterior pituitary parenchyma should be destroyed. • Symptoms vary, depending on which pituitary hormones are deficient and how severe the deficiency is • Panhypopituitarism – all trophic hormones are undersecreted Causes • Compression / infiltration o Large adenomas o Metastases o Empty sella syndrome • Ischaemia or haemorrhage o Sheehan syndrome o Pituitary apoplexy • Iatrogenic (medically-induced) 2 13. Pathology of the endocrine glands o Surgery o Irradiation Empty sella syndrome • There is a defect in the diaphragma sellae → the cerebrospinal fluid (CSF) and the arachnoid mater herniate into the sella → compression atrophy of pituitary gland Pituitary apoplexy • Sudden hemorrhage of an adenoma → Rapid increase of the size of the adenoma, • Clinical features: headache, neurological symptoms, hypopituitarism + death Ischemic necrosis of the pituitary Causes • Sheehan syndrome: postpartum necrosis of the anterior lobe; the sudden infarction is precipitated by obstetric hemorrhage during delivery or after delivery leading to shock • DIC • Shock of any origin Outcome: over time the necrosis is replaced by fibrous tissue → panhypopituitarism Clinical features of panhypopituitarism in Sheehan syndrome • Lactation failure • Secondary hypothyroidism Cold sensitivity, • Adrenocortical insufficiency Weakness, hypotension, hypoglycaemia Loss of pubic hair • Gonadotropin insufficiency Amenorrhoea, infertility, loss of libido THYROID GLAND Follicular epithelial cells Thyroid hormone synthesis • Actively uptake iodide (iodide concentration inside is 50x higher than in the plasma) and transport into the lumen of thyroid follicles; synthesize and secrete thyroglobulin (TG) into the lumen of thyroid follicles; tyroperoxidase present in the apical (colloid-facing) cell membranes fabricate triidothyronine and thyroxine (T3 and T4). • If thyroid hormones (THs) are needed, the follicular cells endocytose the colloid, digest T3 and T4 from TG and release T3 and T4 into the circulation. Regulation of thyroid hormone secretion • When TH levels decrease, the hypothalamus secretes TSH releasing hormone which alerts the pituitary to produce thyroid stimulating hormone (TSH); the thyroid responds by increasing the production of THs. The effects of thyroid hormones • Normal embryological development – nervous and skeletal system • Increase basal metabolic rate and heat production • Enhance the response to the sympatho-adrenergic system o Heart rate, contractility, etc. • Metabolic effects: glucose, cholesterol levels etc. Parafollicular cells • Secrete calcitonin, which helps control blood Ca level via blocking Ca resorption by osteoclasts Thyroid disorders • Frequent, particularly in women; many of them has autoimmune pathogenesis • Euthyroidism - normal thyroid function that occurs with normal serum levels of TSH and T3/T4 • • Disturbed thyroid function can manifest as: o Hyperthyroidism (thyrotoxicosis) o Hypothyroidism • Classification of thyroid diseases: o Autoimmune thyroid disease ▪ Graves-Basedow disease ▪ Autoimmune (Hashimoto) thyroiditis ▪ Subacute lymphocytic thyroiditis o Other forms of thyroiditis o Goiters (impaired thyoroid hormone synthesis) o Neoplasms Hyperthyroidism and thyrotoxicosis Thyrotoxicosis is a hypermetabolic state caused by increased levels of circulating triiodothyronine (T3) and thyroxine (T4). 3 13. Pathology of the endocrine glands Clinical features (for details see pathophysiology lecture): • Heart and circulation: increased cardiac output, increased cardiac contractility, increased peripheral oxygen requirements lead to tachycardia, cardiac hypertrophy, hypertension, and arrhythmias (particulary atrial fibrillation) • Sympathic nervous system overactivity: tremor, hyperactivity, inability to concentrate, anxiety, insomnia (inadequate or poor quality of sleep) • Skin: warm, moist and flushed to increase heat loss • Ocular changes: eyes are wide open and the frequency of winking is much slower than normally; ophtalmopathy (exophtalmus) only appears in Graves-Basedow disease! • GI tract: hypermotility, diarrhea; weight loss despite increased appetite Diagnosis is based predominantly on: clinical features, laboratory data, imaging +/- fine needle aspiration cytology (if needed) Diagnostic alterations in the blood • Primary hypethyroidism: o Decreased TSH (feedback inhibition) o Elevated T4 and T3 • Secondary hyperthyroidism: o Elevated TSH (TSH producing pituitary adenoma) o Elevated T4 and T3 Radioactive iodine, taken by the thyroid, has been used to o image the gland – thyroid scintigraphy ▪ ”hot nodules” – increased uptake ▪ ”cold nodules” – decreased uptake o applied in higher concentrations, the radiation destroys the follicular cells and this effect is used to treat hyperthyroidism or thyroid cancer Graves-Basedow disease • Autoimmune disorder with diffuse thyroid enlargement (diffuse hyperplasia) and ↑ thyroid hormone production Epidemiology • More common in women • Between 20-40 yrs of age • Most common cause of hyperthyroidism Etiology and pathogenesis In genetically susceptible individuals, autoantibodies to