Endocrinology Module PDF

🧪 Endocrinology Module Cellular and Systematic Pathology Date @October 31, 2024 Lecturer Dr Steven Patterson Week Week6-7 OVERVIEW Classification of endocrine disorders...

🧪 Endocrinology Module Cellular and Systematic Pathology Date @October 31, 2024 Lecturer Dr Steven Patterson Week Week6-7 OVERVIEW Classification of endocrine disorders Signs/symptoms of endocrine pathology Specific endocrine glands: physiology and related pathologies Pituitary Gland Thyroid Parathyroid glands Adrenal Glands Endocrine pancreas Common clinical problems associated with endocrine disease PITUITARY GLAND Hormones Endocrinology 1  Classification of endocrine disorders Several processes can disturb normal endocrine activity: impaired synthesis or release of hormones abnormal interactions between hormones and target tissues abnormal responses of target organs Endocrine diseases classified as: underproduction or overproduction of hormones and their resulting biochemical and clinical consequences diseases associated with the development of mass lesions Non-functional Functional Endocrinology 2  The study of endocrine diseases requires integration of: Morphologic findings Biochemical measurements Hormone levels Levels of regulators of endocrine hormones Measurement of other metabolites Common symptoms of endocrine disorders Pituitary gland Endocrinology 3  Two morphologically & functionally distinct regions: anterior pituitary ~75-80% posterior pituitary Endocrinology 4  Development of pituitary Endocrinology 5  Anterior pituitary 6 distinct cell type - can be identified by immunostaining with specific anti- hormone antibodies CELL TYPE HORMONE PRODUCT TARGET ORGANS Corticotrophs Adenocorticotrophic hormone (ACTH) Adrenal cortex Thyrotrophs Thyroid-stimulating hormone (TSH) Thyroid gland Follicle-stimulating hormone (FSH) & Gonadotrophs Ovaries, Testes Luteinising hormone (LH) Somatotrophs Growth hormone (GH) Multiple targets Lactotrophs Prolactin (PL) Breast tissue Chromophobes Unknown n/a Image below shows a normal pituitary stained for GH - about 50% of the cells are somatotrophs Endocrinology 6  REGULATION OF ANTERIOR PITUITARY FUNCTIONS - ANTERIOR PITUITARY HORMONES ACTH (39 aa peptide) – fragment derived from POMC (proopioomelanocortin) Levels highest early morning Increases hyperplasia in adrenal cortex Increases glucocorticoid secretion Endocrinology 7  No effect on mineralocorticoids GH (191 aa protein) Increased cellular protein synthesis Increased lipolysis Increased plasma glucose Growth/cell proliferation FSH/LH (glycoproteins) Females: FSH - Graffian follicle maturation – oestrogen secretion – endometrial proliferation LH – post ovulation follicle cell progesterone secretion Males: LH – intersistial cells of Leydig produce testosterone FSH – spermatogenesis Prolactin lactation TSH thyroid follicular cells proliferation synthesis and secretion of thyroxine (T4) and tri-iodothyronine (T3) Pituitary disease Hypopituitarism: Arising from deficiency of trophic hormones Hyperpituitarism: Arising from excess secretion of trophic hormones Endocrinology 8  Local mass effects: Among the earliest changes referable to mass effect are radiographic abnormalities of the sella turcica, including sellar expansion, bony erosion, and disruption of the diaphragma sella. Hypopituitarism Anterior pituitary hypofunction Quite uncommon due to reserve capacity Most cases - destruction by tumour or extrinsic compression: Adenomas, Craniopharyngiomas Rathkes Cleft cysts Ischaemic necrosis Loss of function due to hypothalamic and pituitary stalk damage Leads to secondary hypofunction of pituitary hormone-dependent endocrine glands E.g. adrenal, thyroid, gonads Pituitary disorders Endocrinology 9  Apoplexy is bleeding into the pituitary gland. Infections can include meningitis, tuberculosis and some mycobacterial infections linked to abscess formation Pituitary adenomas usually benign most common 35-60 years Endocrinology 10  Approx 48% of pituitary adenomas are macroadenomas and around 30% of adenomas are non-functional. Some prolactinomas may be rapid growing aggressive tumours which can cause significant clinical impact and results in serious adverse effects. Most common cause of hyperpituitarism Dysregulation of control from hypothalamus may also cause hyperpituitarism TYPES OF ADENOMA Prolactinoma (~53%) Infertility, galactorrhea hypogonadism GH-secreting (~12%) Gigantism (children) Acromegaly (adults) ACTH-secreting (~4%) Cushing’s syndrome Others rare Plasma prolactin level is proportional to the tumor mass: 50 to 300 ng/mL in microprolactinomas and 200 to 5000 ng/mL in macroprolactinomas (normal range, 2–23 ng/mL) MORPHOLOGY OF ADENOMAS Soft, well-circumscribed lesion usually confined to the sella turcica Relatively uniform, polygonal cells arranged in sheets/cords Endocrinology 11  Little supporting connective tissue (reticulin), accounting for the soft, gelatinous consistency Chromophobe adenoma – seem inactive but may be prolactin secreting Basophil adenoma – ACTH producing Eosinophil adenoma – GH secreting Microadenoma – small but usually prolactin Shown above on the left is a prolactinoma, and on the right is a GH-secreting adenoma. Genetic factors GENE GENE Mechanism Pituitary tumour Gain of Loss of function function GNAS (Gsα) Activating mutation GH adenomas Protein Kinase Inactivating mutation GH/prolactin A of PRKAR1A adenomas Cyclin D1 overexpression Aggressive adenomas HRAS Activating mutation Pituitary carcinoma Inactivating mutation GH/prolactin/ACTH Menin (TSP) MEN1 adenomas Endocrinology 12  Inactivating mutation CDKN1B (p27/KIP1) ACTH adenomas CDKN1B Aryl hydrocarbon receptor interacting Mutation of AIP GH adenomas protein (AIP) Methylation of RB Retinoblastoma protein Aggressive adenomas gene promoter Treatment Prolactinomas - dopamine agonists like bromocriptine Others - transsphenoidal resection Posterior pituitary Endocrinology 13  Cells called pituicytes. Do not synthesize hormones – only stores and releases them: Oxytocin Antidiuretic hormone (ADH) Neurosecretory cells in the supra-optic and paraventricular nuclei of the hypothalamus give rise to modified nerve fibres which carry these hormones into the posterior pituitary ADH disorders Posterior pituitary tumours extremely rare Diabetes Insipidus: (polyuria with polydipsia) Lack of ADH (trauma or hypothalamic damage) Excess ADH: (hyponatremia & cerebral oedema) head trauma, meningitis, bronchial carcinoma, neuroendocrine cell tumours THYROID AND PARATHYROID Learning outcomes Be able to describe and reflect on the normal structure/function of endocrine organs and their hormones Be able to critically evaluate the possible consequences leading to abnormal hormone secretion from endocrine organs and the identification of changes at the cellular level Endocrinology 14  Be able to judge what consequence insufficient, or raised hormone levels will have on the various organs/tissues throughout the body Understand possible feedback interactions caused by hormones Thyroid gland Two lobes connected by thin isthmus Lobes divided by thin fibrous septae into lobules composed of ~ 20 to 40 evenly dispersed follicles Follicular cells cuboidal epithelial cells lining follicles which contain thyroglobulin synthesize iodinated amino acids, thyroxine (T4) and tri-iodothyronine (T3) C-cells (parafollicular): sparsely scattered throughout the gland calcitonin (peptide hormone involved in calcium metabolism) Endocrinology 15  Total hormone concentration Thyroxine (T4): 60-150nmol/L Triiodothyronine (T3): 1.0-2.0 nmol/L TBG and free hormone Increases in TBG concentration will reduce free T4/T3 Drugs may displace T3/T4 from TBG (e.g. salicylates, phenytoin (Dilantin)) Free T3/T4 level modulates TRH & TSH release to restore balance ACTIONS OF T3/T4 Basal metabolic rate Glucose, protein and lipid metabolism altered Cytochrome oxidase Na+,K+-ATPases badrenergic receptor expression: Endocrinology 16  Cardiovascular Skeletal muscle Nervous system Clinical thyroid disease 1. Secretory malfunction 2. Swelling of entire gland 3. Solitary masses HYPERSECRETORY MALFUNCTIONS GRAVES THYROIDITIS Endocrinology 17  Accounts for 85% of thyrotoxicosis cases An 'organ-specific' autoimmune disease Auto-antibody (IgG class) binds to follicular cells and mimics action of TSH. Long-acting thyroid stimulator (LATS) 'stimulatory hypersensitivity‘ Depresses blood TSH levels ~ STRUCTURE OF THYROID IN GRAVES DISEASE ~ HYPOSECRETORY MALFUNCTIONS Endocrinology 18  HASHIMOTOS THYROIDITIS May be initial thyroid enlargement and thyrotoxicosis, but proceeds to thyroid atrophy and fibrosis Organ specific autoimmune disease Gland appears firm, fleshy and pale Histologically: Densely infiltrated by lymphocytes and plasma cells, with lymphoid follicle formation. Colloid is reduced Follicular cells enlarge, develop eosinophilic granular cytoplasm due to proliferation of mitochondria Hürthle cells or oncocytes Aids in biopsy diagnosis Endocrinology 19  The above image shows densely infiltrated lymphocytes and plasma cells, with lymphoid follicle formation. ~ PATHOGENESIS OF HASHIMOTO THYROIDITIS ~ Endocrinology 20  MYXOEDEMA Endocrinology 21  SWELLING OF THE THYROID GLAND (GOITRE) Thyroid enlargement w/o hyperthyroidism IODINE DEFICIENCY 1. Colloid goitre No epithelial hyperplasia Follicles accumulate large volumes of colloid These coalesce to form colloid-filled cysts. Haemorrhage, fibrosis and dystrophic calcification. The thyroid may be diffusely enlarged or multinodular. 2. arenchymatous goitre Epithelial hyperplasia Loss of stored colloid eventually less active areas appear compressed by the hyperplastic areas. Tracts of fibrosis may separate these areas multinodular goitre Endocrinology 22  SOLITARY MASSES Diagnosis – T3, T4, TSH, fine needle aspiration (FNAB) Usually benign Follicular adenoma Malignant tumours rare but include: Papillary adenocarcinoma Follicular adenocarcinoma Anaplastic carcinoma Lymphoma Follicular adenoma Solid nodule with fibrous capsule May compress adjacent gland Central haemorrhage and cystic change Endocrinology 23  Occasional thyrotoxicosis Papillary adenocarcinoma ~ 85% of primary thyroid malignancies Slow growing non-encapsulated fibrous mass Follicular cell nuclei large with central clear area ‘Orphan Annie’ nuclei Psammoma bodies concentric lamellated calcified structures Metastasises via lymphatic system Endocrinology 24  The image above shows cell nuclei with central clear area. Follicular adenocarcinoma Slowly enlarging painless nodules Endocrinology 25  Larger lesions may penetrate the capsule and infiltrate into the adjacent neck Nuclei lack the features typical of papillary carcinoma Psammoma bodies not present Anaplastic (undifferentiated) carcinoma Usually older individuals (65yrs) 2:1 Female:Male Derived from follicular cells Giant cells (may be multinucleated) Spindle cells Rapid growing infiltrative mass Mortality rate almost 100% The image above shows giant multinucleated cells as well as spindle cells. Endocrinology 26  Lymphoma Mostly B-cell non-Hodgkin’s lymphoma Hashimoto thyroiditis Usually derived from mucosa associated lymphoid tissue MALT B-cell lymphocyte infiltration through follicular epithelium Endocrinology 27  Parathyroid glands CHIEF CELLS Light to dark pink H&E staining depend on glycogen content Polygonal (12-20 um) Central round nuclei Store and secrete PTH OXYPHIL CELLS Single or clusters Larger than chief cells Acidophilic cytoplasm Packed with mitochondria Few or no secretory granules Endocrinology 28  Parathyroid gland stromal fat increases to about 30% by age 25 PTH and calcium metabolism Endocrinology 29  PTH release not under control of trophic hormones, but controlled by blood calcium levels Feedback regulation Parathyroid hormone 84 amino acid polypeptide regulation of bone metabolism and plasma calcium levels Decrease in plasma ionized calcium stimulates synthesis and secretion of PTH Daily calcium fix: Endocrinology 30  Actions of PTH PTH activates 1ahydroxylase in the kidney which increase the formation of 1,25 (OH)2 vitamin D3 (Calcitriol) Calcitriol enhances intestinal absorption of calcium and bone turnover Endocrinology 31  Disease of parathyroid glands 1. Hyperparathyroidism → hypercalcaemia primary e.g. adenoma, hyperplasia secondary - usually due to physiological hypocalcaemia 2. Hypoparathyroidism 3. Tumours → hypocalcaemia PRIMARY HYPERPARATHYROIDISM Secretory Adenoma (85-95%): mostly sporadic but some familial Hyperplasia (5-10%) Carcinoma (1%) common condition ~ 0.1% of the population usually post-menopausal females (4:1 - female:male) Asymptomatic or symptomatic Malignancy (breast, lung, kidney)– PTHrp CLINCIAL HYPERCALCAEMIA Nephrolithiasis (renal stones) and renal Kidneys Polyuria/polydipsia dysfunction Bone pain due to Bone osteoporosis or osteitis fibrosa cystica fractures Constipation, nausea, peptic Intestine Decreased smooth muscle activity ulcers, pancreatitis, and gallstones. Endocrinology 32  depression, Central Nervous Depression of neuronal membrane lethargy, and system excitability eventually seizures weakness and Muscle Due to effects on nerves fatigue calcification of aortic and mitral valves in Heart heart Ischaemia of skin Blood vessels calcification and organs (calciphylaxis) ADENOMA PTH adenoma-induced hypercalcaemia affects normal PT tissue due to feedback inhibition SPORADIC ADENOMAS Cyclin D1 (CDK1) gene inversions (cell cycle regulator) 10% and 20% of adenomas have this clonal genetic defect inversion on chromosome 11 results in relocation of the cyclin D1 gene (normally on 11q), so that it is positioned adjacent to the 5'-flanking region of the PTH gene (on 11p). Increases cellular proliferation. Endocrinology 33  cyclin D1 is also overexpressed in approximately 40% of parathyroid adenomas not linked to inversion Multiple endocrine neoplasia-1 (MEN-1) mutation MEN1 gene on chromosome 11q13 is a tumor suppressor gene 20% to 30% of parathyroid tumors not associated with the MEN-1 syndrome have mutations in both copies of the MEN1 gene FAMILIAL ADENOMAS Multiple endocrine neoplasia-1 (MEN-1) MEN1 gene on chromosome 11q13 is a tumor suppressor gene Multiple endocrine neoplasia-2 (MEN-2) caused by activating mutations in the tyrosine kinase receptor, (RET), on chromosome 10q. Familial hypocalciuric hypercalcemia autosomal-dominant disorder Inactivating mutations in the parathyroid calcium-sensing receptor gene (CASR) on chromosome 3q decreased sensitivity to extracellular calcium SECONDARY HYPERPARATHYROIDISM Due to chronic hypocalcemia Renal failure most common cause Inadequate dietary intake of calcium Malabsorption and steatorrhea Vitamin D deficiency Chronic renal insufficiency Endocrinology 34  decreased phosphate excretion (hyperphosphatemia) elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity. loss of renal substance reduces the availability of α-1-hydroxylase Less active vitamin D produced Reduces intestinal absorption of calcium Lower suppressive effects of vitamin D on parathyroid growth and PTH secretion CVD risk very high due to high levels of phosphate in Chronic kidney disease Induce differentiation of vascular smooth muscle cells into osteoblast like cells and increase VSMC necrotic cell death and calcification of the artery wall HYPOPARATHYROIDISM Plasma PTH decreases Plasma calcium decreases Plasma phosphate increases Causes: Surgery : thyroidectomy, treatment of primary hyperparathyroidism. Autoimmune Autosomal-dominant hypoparathyroidism: gain-of-function mutations in the calcium-sensing receptor (CASR) gene. -Familial isolated hypoparathyroidism (FIH): rare condition Absence of parathyroid glands: can occur in conjunction with other malformations such as thymic aplasia (DiGeorge syndrome). Endocrinology 35  CLINICAL HYPOCALCAEMIA Tetany (spasm of the skeletal muscles) Convulsions Paraesthesiae (tingling of extremeties) Psychiatric disturbances Cardiovascular: conduction defect that produces a characteristic prolongation of the QT interval in the electrocardiogram. rarely, cataracts and brittle nails Signs of hypocalcaemia: Chvostek's Sign of Hypocalcemia https://www.youtube.com/watch?v=2tV4J2DxjNM Trousseau Sign of Hypocalcaemia https://www.youtube.com/watch?v=Ry5Rh3wO8Sw PARATHYROID TUMOURS Endocrinology 36  Commonest are adenomas benign neoplasms of one type of parathyroid cell small ( 11.1 mmol/l a fasting plasma glucose concentration > 7.0 mmol/l (repeated) Oral glucose tolerance test (OGTT): individual consumes 75g anhydrous glucose solution. Glucose measured at 2 h and if > 11.1 mmol/l then confirms diabetes HbA1c of >48mmol/mol (high risk (prediabetes) 43 – 48 mmol/mol) Prediabetes - Fasting glucose 5.6-6.9 mmol/l Type 1 diabetes Autoimmune disease which destroys insulin producing pancreatic beta cells Driven by CD8+ cytotoxic T-cells Development of at least 2 autoantibodies insulin, GAD, ZnT8, ICA69, etc Genetic and environmental factors Higher concordance rates in monozygotic (40%) vs dizygotic twins Genetic factors: Certain HLA types (up to 50%) notably HLA-DR4, especially if HLA-B8 or - DR3 is also present. HLA overexpression which presents autoantigens to immune cells Viral infection Enteroviruses, Coxsackie B virus and mumps are elevated in some patients Endocrinology 40  Reduced exocrine pancreatic mass compared to age/sex/BMI matched controls HISTOLOGICAL PROGRESSION OF T1D WITHIN HUMAN PANCREATIC ISLET Endocrinology 41  HOW ARE ISLETS PRODUCED AND WHAT GOES WRONG IN T1D? Islets are separated from exocrine pancreas by a layer of extracellular matrix (ECM) made up of basement membrane and interstitial matrix (like a wall/fort). ISLET MORPHOLOGY IN T1DM Insulitis – infiltration of lymphocytes (mainly CD8+ T-cells) Destruction of beta cells and islet atrophy Endocrinology 42  Immunostained for insulin (brown) and glucagon (red), and each image shows an individual islet. Evidence of immune cell infiltration (seen as small nucleated cells; black arrows) is observed around each of the islets. Diabetic ketoacidosis Caused by severe lack of insulin: Glucose unable to enter cells so body mimics starvation state Increased lipolysis in liver Excess acetyl-CoA converted to ketones (non-metabolisable in liver) Ketone enter plasma Excess of acidic ketones lower blood pH A diabetes emergency which can be fatal Endocrinology 43  Type 2 diabetes Endocrinology 44  Type 2 diabetes is the main type of diabetes (~90% of all cases) Associated with aging but increasingly common in children, adolescents and young adults with poorer prognosis if diagnosed earlier Obesity, sedentary behaviour and poor nutritional and lifestyle habits associated with increased risk of Type 2 diabetes Increased risk in women who have had gestational diabetes during pregnancy Potentially reversible in early stages with diet and lifestyle changes Obesity and insulin resistance Nonesterified fatty acids (NEFAs): inverse correlation between fasting NEFAs and insulin sensitivity. Ectopic lipid storage -triglycerides in muscle and liver and around organs Endocrinology 45  Fatty acid oxidation pathways overwhelmed leading to accumulation of diacylglycerol (DAG) & ceramide. DAG & ceramide activate serine/threonine kinases to impair insulin receptor signalling Due to lack of insulin response liver increases gluconeogenesis. Excess fatty acids compete with glucose for oxidation which causes inhibition of glycolytic enzymes further exacerbating glucose imbalance. Adipokines: Pro-hyperglycaemic adipokines (e.g., resistin, retinol binding protein 4 [RBP4]) Anti-hyperglycaemic adipokines (leptin, adiponectin) Leptin and adiponectin improve insulin sensitivity > enhancing AMPK – promotes fatty acid oxidation. Adiponectin - reduced in obesity. Inflammation: adipose tissue secretes pro-inflammatory cytokines in obesity (TNF, IL-6, and MCP-1) These induce insulin resistance by increasing cellular "stress," antagonizing insulin action on peripheral tissues Beta cell dysfucntion Hyperinsulinaemia Excess secretion increased proinsulin:insulin ratio Gradual beta cell dysfunction Loss of insulin secretion over time Cell damage increased due to: Endocrinology 46  Glucotoxicity Lipotoxicity Deposition of amyloid plaques replacing islets in 90% of individuals with chronic type 2 diabetes Endocrinology 47  Folli F, La Rosa S, Finzi G, et al. Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus. Diabetes Obes Metab. 2018;20(Suppl. 2):137–144. https://doi. org/10.1111/dom.13380 Advanced glycation endproducts (AGE) AGE formed by non-enzymatic glycosylation of proteins (e.g. HbA1c) due to hyperglycaemia AGE can bind to receptor called RAGE on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle: 1. Stimulates pro-inflammatory cytokines and growth factor release from intimal macrophages 2. Increases reactive oxygen species (ROS) in endothelial cells 3. Increases procoagulant activity on endothelial cells Endocrinology 48  4. Enhances proliferation of vascular smooth muscle cells and synthesis of extracellular matrix Cross linking of collagen – decreases elasticity Together these cause increased damage to endothelial cells lining blood vessels, promotes risk of blood clotting, promotes hypertension and accelerates and increases risk of atherosclerosis Polyol pathway disturbance Nerves, lenses, kidneys, blood vessels Hyperglycaemia raises intracellular glucose NADPH needed for glutathione reductase Decreased reduced glutathione (GSH) Increased sensitivity to oxidative stress Secondary complications of diabetes Endocrinology 49  Adrenal glands Cortex - rich in lipids, including cholesterol and fatty acids adrenocorticoids or corticosteroids hormones Glucocorticoids (mainly cortisol) zona fasciculata Mineralocorticoids (mainly aldosterone) zona glomerulosa Sex hormones or gonadocorticoids (mainly androgens) zona reticularis The inner region known as the medulla. chromaffin cells - produce and secrete catecholamines (epinephrine (~80%), norepinephrine (~20%) and dopamine (