Basic Mechanism of Endocrine Disorders Qi Hongyan

Content  Describe the endocrine system and the process of negative feedback in regulation of hormones production and secretion.  Discuss the pathogenesis of hyperthyroidism, hypothyroidism and diabetes mellitus.

Endocrine System Endocrine system uses chemical substances called Hormone as a means of regulating and integrating body functions. It participates in the regulation of digestion, use, and storage of nutrients; growth and development; electrolyte and water metabolism; and reproductive functions.

Endocrine System

Regulation of endocrine system Nerve system Endocrine system Immuno system

Historical retrospect 1 、 Gland Endocrinology ( ) 2 、 Tissue Endocrinology 、 Molecular Endocrinology

Hormones Hormones generally are thought of as chmical messengers that are transported in body fluids. They are highly specialized organic molecules produced by endocrine organs that exert their action on specific target cells.

Classifications of Hormones  Steroid hormones : estrogen, androstenedione, testosterone…  Peptides or proteins : PTH, insulin, oxytocin, GH, FSH, ACTH…  Amine and amino acids derivatives: TH, dopanime…

Relationship of free and carrier-bound hormones Endocrine cell Free hormone Carrier-bound hormone Hormone receptor Biological effects

Activation mechanism of Hormones Carol mattson porth Pathophysiology 7th edition

Activation mechanism of Hormones Carol mattson porth Pathophysiology 7th edition

Hypothalamus and hypophysis  Thyrotropin releasing hormone (TRH)  Corticotropin releasing hormone (CRH)  Growth hormone releasing hormone (GHRH)  Somatostatin as inhibiting hormone (e.g. GH)  Gonadotropin releasing hormone (GnRH)

Pituitary gland (Hypophysis)  Anterior lobe (Adenohypophysis)  Glandular cells (originate from Rathke’s pouch)  Secretes six important peptide hormones  Posterior lobe (Neurohypophysis)  Glial-type cells (neural origin)  Secretes two important peptide hormones Hypothalamus and hypophysis

Hormones of hypophysis Adenohypophysis  Somatotropes – human growth hormone (hGH)  Corticotropes – adrenocorticotropin (ACTH)  Thyrotropes – Thyroid stimulating hormone (TSH)  Gonadotropes – gonadotropic hormones  Luteinizing hormone (LH)  Follicle stimulating hormone (FSH)  Lactotropes – prolactin (PRL) Neurohypophysis  Antidiuretic hormone （ ADH ）  oxytocin

Regulation of endocrine system HypothalamusHypophysisGlandHormone TRHTSHThyroidT3/T4 CRHACTHAdrenalcortisol GHRH/GIHGH GnRHFSH/LHOvarian Testis E2 、 AD 、 Testosterone DAPRL ADH OXYTOCIN

Regulation of endocrine system Hypothalamus Pituitary Endocrine glands Hormone

Endocrine Dysfunction Hypofunction: defects of gland, defects of enzyme for the hormone synthesis, inflammation, neoplastic growth, defects of receptor… Hyperfunction: excessive hormone production Primary ： defects of target gland responsible for producing the hormone Secondary ： alteration of regulation for producing the hormone Tertiary:hypotalamic dysfunction

Regulation of cortisol secretion  Hypothalamus (CRH) regulates the secretion of ACTH secretion, which increases in stress  ACTH acts through the second messenger cAMP  It controls the rate limiting step of converting cholesterol to pregnenolone  Circadian rhythm – more in early morning & low in midnight

Hyperadrenalism – Cushing’s syndrome  Mobilization of fat from lower parts of body & extra deposition in upper portions – buffalo torso  Moon face  Striae – due to tearing of subcutaneous tissue, by diminished collagen fibers  Increased blood glucose level  Muscle weakness  Loss of protein synthesis in lymphoid tissue suppresses immune system

Hyperadrenalism – Cushing’s syndrome

Regulation of GH secretion Carol mattson porth Pathophysiology 7th edition

Growth hormone  Control of GH  Stress, exercise nutrition, sleep  Somatostatin (SS) inhibits  GH causes inhibition of glucose uptake and utilization, increased a.a. uptake and protein synthesis

Gigantism  Excessive GH during childhood  Growth plate stimulation  Tumor of somatotrophs Robert Wardlow 8’ 11”.

Abnormalities of GH secretion  Gigantism

 GH late in life  Causes excessive growth of flat bones Acromegaly Rondo Hatton

 Acromegaly Abnormalities of GH secretion

GH deficiency: nanism

NEUROHYPOPHYSIS ADH or vasopressin  Supraoptic nucleus  Increased water reabsorption in kidney  Vasoconstriction in high dose

Thyroid Function and Disease

Anatomy of the Thyroid Gland

Follicles: the Functional Units of the Thyroid Gland Follicles Are the Sites Where Key Thyroid Elements Function: Thyroglobulin (Tg) Tyrosine Iodine Thyroxine (T 4 ) Triiodotyrosine (T 3 )

The Thyroid Produces and Secretes 2 Metabolic Hormones  Two principal hormones  Thyroxine (T 4 ) and triiodothyronine (T 3 ) Required for homeostasis of all cells Influence cell differentiation, growth, and metabolism Considered the major metabolic hormones because they target virtually every tissue

Thyroid-Stimulating Hormone (TSH)  Regulates thyroid hormone production, secretion, and thyroid growth  Is regulated by the negative feedback action of T 4 and T 3

Biosynthesis of T 4 and T 3 The process includes  Dietary iodine (I) ingestion  Active transport and uptake of iodide (I - ) by thyroid gland  Oxidation of I - and iodination of thyroglobulin (Tg) tyrosine residues  Coupling of iodotyrosine residues (MIT and DIT) to form T 4 and T 3  Proteolysis of Tg with release of T 4 and T 3 into the circulation

Iodine Sources  Available through certain foods (eg, seafood), iodized salt, or dietary supplements, as a trace mineral  The recommended minimum intake is 150  g/day

Active Transport and I - Uptake by the Thyroid  Dietary iodine reaches the circulation as iodide anion (I - )  The thyroid gland transports I - to the sites of hormone synthesis  I - accumulation in the thyroid is an active transport process that is stimulated by TSH

Oxidation of I - and Iodination of Thyroglobulin (Tg) Tyrosyl Residues  I - must be oxidized to be able to iodinate tyrosyl residues of Tg  Iodination of the tyrosyl residues then forms monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are then coupled to form either T 3 or T 4  Both reactions are catalyzed by TPO

Thyroperoxidase (TPO)  TPO catalyzes the oxidation steps involved in I - activation, iodination of Tg tyrosyl residues, and coupling of iodotyrosyl residues  TPO has binding sites for I - and tyrosine  TPO uses H 2 O 2 as the oxidant to activate I - to hypoiodate (OI - ), the iodinating species

T 4 : A Prohormone for T 3  T 4 is biologically inactive in target tissues until converted to T 3  Activation occurs with 5' deiodination of the outer ring of T 4  T 3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects

Carriers for Circulating Thyroid Hormones  More than 99% of circulating T 4 and T 3 is bound to plasma carrier proteins  Thyroxine-binding globulin (TBG), binds about 75%  Transthyretin (TTR), also called thyroxine-binding prealbumin (TBPA), binds about 10%-15%  Albumin binds about 7%  High-density lipoproteins (HDL), binds about 3%  Carrier proteins can be affected by physiologic changes, drugs, and disease

Free Hormone Concept  Only unbound (free) hormone has metabolic activity and physiologic effects  Free hormone is a percentage of total hormone in plasma (about 0.03% T 4 ; 0.3% T 3 )  Total hormone concentration  Normally is kept proportional to the concentration of carrier proteins  Is kept appropriate to maintain a constant free hormone level

TR  ch 17 TR  ch 3

SNC: TRß1 e TRß2 + TR  1 TR  2 Heart: TRß1 e TRß2 + TR  1 Liver: TRß1 e TRß2 Kindy: TR  1 + TRß1 e TRß2 Hypothalamus- hypophysis: TRß1 e TRß2 Muscle: TR  1 Gonad: TR  1 Distribution of TH receptors

Biological Role of Thyroid Hormones (THs) THs initiate or sustain differentiation and growth, they are essential for childhood growth and for neural development and maturation and function of the CNS THs stimulate oxygen consumption by mitochondria, mitochondrial protein synthesis and mitochondrogenesis  THs stimulate Metabolic Activities in Most Tissues exerting calorigenic effetcs, stimulate lypolisis and metabolism of cholesterol  THs Influences Cardiovascular Hemodynamics  THs influence the Female Reproductive System

Thyroid Hormone Plays a Major Role in Growth and Development  Thyroid hormone initiates or sustains differentiation and growth  Stimulates formation of proteins, which exert trophic effects on tissues  Is essential for normal brain development  Essential for childhood growth  Untreated congenital hypothyroidism or chronic hypothyroidism during childhood can result in incomplete development and mental retardation

Thyroid Hormones and the Central Nervous System (CNS)  Thyroid hormones are essential for neural development and maturation and function of the CNS  Decreased thyroid hormone concentrations may lead to alterations in cognitive function  Patients with hypothyroidism may develop impairment of attention, slowed motor function, and poor memory  Thyroid-replacement therapy may improve cognitive function when hypothyroidism is present

Thyroid Hormone Influences Cardiovascular Hemodynamics Thyroid hormone Mediated Thermogenesis (Peripheral Tissues) Release Metabolic Endproducts Local Vasodilatation Decreased Systemic Vascular Resistance Decreased Diastolic Blood Pressure Cardiac Chronotropy and Inotropy Increased Cardiac Output Elevated Blood Volume T3T3 Laragh JH, et al. Endocrine Mechanisms in Hypertension. Vol. 2. New York, NY: Raven Press;1989.

Thyroid Hormone Influences the Female Reproductive System  Normal thyroid hormone function is important for reproductive function  Hypothyroidism may be associated with menstrual disorders, infertility, risk of miscarriage, and other complications of pregnancy Doufas AG, et al. Ann N Y Acad Sci. 2000;900: Glinoer D. Trends Endocrinol Metab. 1998; 9: Glinoer D. Endocr Rev. 1997;18:

Thyroid Hormone is Critical for Normal Bone Growth and Development  T 3 is an important regulator of skeletal maturation at the growth plate  T 3 regulates the expression of factors and other contributors to linear growth directly in the growth plate  T 3 also may participate in osteoblast differentiation and proliferation, and chondrocyte maturation leading to bone ossification

Thyroid Hormones Stimulate Metabolic Activities in Most Tissues  Thyroid hormones (specifically T 3 ) regulate rate of overall body metabolism  T 3 increases basal metabolic rate  Calorigenic effects  T 3 increases oxygen consumption by most peripheral tissues  Increases body heat production

Metabolic Effects of T 3  Stimulates lipolysis and release of free fatty acids and glycerol  Stimulates metabolism of cholesterol to bile acids  Facilitates rapid removal of LDL from plasma  Generally stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation

Overview of Thyroid Disease States  Hypothyroidism  Hyperthyroidism

Overview of Thyroid Disease States Euthyroidism Primary Hypothyroidism Primary Hyperthyroidism hypothalamus hypophysis thyroid hypothalamus hypophysis thyroid hypothalamus hypophysis thyroid

Hypothyroidism  Hypothyroidism is a disorder with multiple causes in which the thyroid fails to secrete an adequate amount of thyroid hormone  The most common thyroid disorder  Usually caused by primary thyroid gland failure  Also may result from diminished stimulation of the thyroid gland by TSH

Hypothyroidism: Types  Primary hypothyroidism  From thyroid destruction  Central or secondary hypothyroidism  From deficient TSH secretion, generally due to sellar lesions such as pituitary tumor or craniopharyngioma  Infrequently is congenital  Central or tertiary hypothyroidism  From deficient TSH stimulation above level of pituitary—ie, lesions of pituitary stalk or hypothalamus  Is much less common than secondary hypothyroidism Bravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; Persani L, et al. J Clin Endocrinol Metab. 2000; 85:

Primary Hypothyroidism: Underlying Causes  Congenital hypothyroidism  Agenesis of thyroid  Defective thyroid hormone biosynthesis due to enzymatic defect  Thyroid tissue destruction as a result of  Chronic autoimmune (Hashimoto) thyroiditis  Radiation (usually radioactive iodine treatment for thyrotoxicosis)  Thyroidectomy  Other infiltrative diseases of thyroid (eg, hemochromatosis)  Drugs with antithyroid actions (eg, lithium, radiographic contrast agents, interferon alpha)

HYPOTHYROIDISM

Hyperthyroidism  Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues

Hyperthyroidism Underlying Causes  Signs and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone  Toxic diffuse goiter (Graves disease)  Toxic uninodular or multinodular goiter  Painful subacute thyroiditis  Silent thyroiditis  Toxic adenoma  Iodine and iodine-containing drugs and radiographic contrast agents  Trophoblastic disease, including hydatidiform mole  Exogenous thyroid hormone ingestion

Graves Disease  The most common cause of hyperthyroidism  Accounts for 60% to 90% of cases  Affects more females than males, especially in the reproductive age range  Graves disease is an autoimmune disorder possibly related to a defect in immune tolerance

Pathogenesis

 5-10% of patients without ipertiroidismo  50-75% of patients associated with ipertiroidismo, Graves ophthalmopethy

Graves Disease T3 Na/K-ATP 酶 UCPmetabolism Nerves Cardiovascular gastro digestion Producing Calorie Reduce body weight

Thyroid dysfunction

Thyroid Carcinoma  Incidence  Thyroid carcinoma occurs relatively infrequently compared to the common occurrence of benign thyroid disease  Thyroid cancers account for only 1% of cancers  The annual rate has increased nearly 11 new cases/year/  Mortality is 0,4-0,8/ inn men and women, respectively  Thyroid carcinomas  Papillary (80%)  Follicular (about 10%)  Medullary thyroid (5%-10%)  Anaplastic carcinoma (1%-2%)  Primary thyroid lymphomas (rare)  Metastatic from other primary sites (rare)

Molecular mechanism in papillary thyroid carcinoma N RET-PTC 15% 40% BRAF RAS 20% PC PC PC FCAC

Diabetes mellitus

PANCREATIC ISLET  Alpha cells (25%)  Glucagon  Beta cells (60%)  Insulin & amylin  Delta cells (10%)  Somatostatin

Control of insulin secretion  Increased blood glucose stimulates insulin secretion  Some amino acids (arginine & lysine) when present along with ↑ glucose stimulates insulin secretion  Hormones like glucagon, GH, cortisol etc act directly or indirectly to ↑ insulin secretion

Insulin and glucagon Carol mattson porth Pathophysiology 7th edition

FUNCTION OF INSULIN  Insulin being an anabolic hormone stimulates protein & fatty acids synthesis.  Insulin decreases blood sugar 1.By inhibiting hepatic glycogenolysis and gluconeogenesis. 2.By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue.

Metabolic effects of Insulin Effect of insulin on carbohydrate metabolism  Insulin promotes glucose uptake & metabolism in muscle cells, adipose tissues etc. by translocating the GLUT  Insulin promotes glucose uptake & storage in liver  Insulin inactivates liver phosphorylase which prevents glycogen break down  It ↑ activity of glucokinase, causing the phosphorylation of glucose & then glucose get trapped inside  It ↑ activity of enzymes for glycogen synthesis (glycogen synthase)  Insulin promotes conversion of excess glucose into fatty acids & inhibits gluconeogenesis in liver  The brain cells are permeable to glucose & can use glucose without the intermediation of insulin

Effect of insulin on fat metabolism  Since insulin ↑ utilization of glucose by most cells, causes ↓ utilization of fat, leading to fat storage  In liver cells excess glycogen prevents the further formation of glycogen & the glucose thus entering gets converted to pyruvate by glycolysis & forms the acetyl CoA which leads to the formation of fatty acids  On adipose tissue insulin inhibits the action of lipases, preventing the hydrolysis of fats  Glucose entered into adipose tissue gets converted to α–glycerol phosphate, which helps in the formation of triglycerides & thus the storage of fat.

 Insulin promotes protein synthesis & storage.  It inhibits the catabolism of proteins  Insulin stimulates transport of many of the amino acids (especially valine, leucine, isoleucine, tyrosine, & phenylalanine) into the cells  Insulin & growth hormone interact synergistically to promote growth – GH also cause the uptake of amino acids, but a different selection as from that of insulin Effect of insulin on protein metabolism & growth

DEFINITION The term diabetes mellitus describes a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.

DIABETES EPIDEMIOLOGY  Diabetes is the most common endocrine problem & is a major health hazard worldwide.  Incidence of diabetes is alarmingly increasing all over the globe.  5% of the general population are diagnosed with diabetes.

WHO CLASSIFICATION 2000  Is based on etiology not on type of treatment or age of the patient.  Type 1 Diabetes (idiopathic or autoimmune  -cell destruction)  Type 2 Diabetes (defects in insulin secretion or action)  Other specific types  Gestational diabetes

Carol mattson porth Pathophysiology 7th edition

TYPE 1 DIABETES: ETIOLOGY  Type 1 diabetes mellitus is an autoimmune disease.  It is triggered by environmental factors in genetically susceptible individuals.  Both humoral & cell-mediated immunity are stimulated.

GENETIC FACTORS  Evidence of genetics is shown in Ethnic differences Familial clustering High concordance rate in twins Specific genetic markers Higher incidence with genetic syndromes or chromosomal defects

AUTOIMMUNITY  Circulating antibodies against  -cells and insulin. ICA islet cell autoantibody IAA autoantibody to insulin GADA autoantibody to glutamic acid decarboxylase IA-2 autoantibody to tyrosine phosphatases IA-2

ENVIRONMENTAL SUSPECTS  Viruses Coxaschie B Mumps Rubella Reoviruses  Nutrition & dietary factors Cow’s milk protein Contaminated sea food Chemistry compounds or drugs

 Interaction of genetic and environmental factors that impair insulin secretion and produce insulin resistance  Impaired glucose uptake by skeletal muscle  Increased in hepatic gluconeogenesis TYPE 2 DIABETES: ETIOLOGY

GENETIC FACTORS Insulin resistance Mutation of insulin receptor substance IRS: IRS-1 mutation Ala 513 Pro 、 Gly 819 Arg 、 Gly 972 Arg 、 Arg 1221 Cys IRS-2 mutation Gly 1057 Asp Mutation of Glucose transporter GLUT4 Mutation of Insulin receptor Mutation of uncoupling protein UCP B cell defects  Mutation of glucokinase GCK  Mutation of GLUT2  Defects of mitochondrion  Defects of insulin synthesis  Mutant insulin  Abnormal amylin secretion

 Obesity  Assume of high caloric food  Stress  Age ecc. ENVIRONMENTAL SUSPECTS

Carol mattson porth Pathophysiology 7th edition

Clinic features of diabetes principal  Polyuria  Polydipsia  Polyphagia  Weight loss in spite of polyphagia others  Hyperglycemia  Glucosuria  Ketosis  Acidosis

COMPLICATIONS OF DIABETES Acute complications Diabetes ketoacidosis hypoglycemia Chronic complications Retinopathy Neuropathy Nephropathy Ischemic heart disease & stroke Diabetic foot ulcers Macrovascular complication Infection

DIET REGULATION  Regular meal plans with calorie exchange options are encouraged.  50-60% of required energy to be obtained from complex carbohydrates.  Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars.  Encouraged low salt, low saturated fats and high fiber diet.

Antidiabetic Agents 1. Insulin Secretagogues a ) Sulphonylurea group b) Non Sulphonylurea Insulin Secretagogues 2. Insulin sensitizers a ) Metformin b) Thiazolidinedione 3. Digestive enzyme inhibitor  -Glucosidase inhibitor ： Acarbose Insulin

Carol mattson porth Pathophysiology 7th edition