basic mechanism of endocrine disorders qi hongyan
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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 ( 1850-1950)
2 、 Tissue Endocrinology 1950-
3 、 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
Hypothalamus Hypophysis Gland Hormone
TRH TSH Thyroid T3/T4
CRH ACTH Adrenal cortisol
GHRH/GIH GH
GnRH FSH/LH Ovarian
Testis
E2 、 AD 、 Testosterone
DA PRL
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
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
DIABETESINSIPIDUS
Endocrine Dysfunction
Thyroid Functionand 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 (T4)
• Triiodotyrosine (T3)
The Thyroid Produces and Secretes 2 Metabolic Hormones
Two principal hormones Thyroxine (T4 ) and triiodothyronine (T3)
• 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 T4 and T3
Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism
Biosynthesis of T4 and T3
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 T4 and T3
Proteolysis of Tg with release of T4 and T3 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
Iodide Active Transport is Mediated by the Sodium-Iodide Symporter (NIS)
NIS is a membrane protein that mediates active iodide uptake by the thyroid It functions as a I- concentrating mechanism that
enables I- to enter the thyroid for hormone biosynthesis
NIS confers basal cell membranes of thyroid follicular cells with the ability to effect “iodide trapping” by an active transport mechanism
Specialized system assures that adequate dietary I- accumulates in the follicles and becomes available for T4 and T3 biosynthesis
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 T3
or T4
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 H2O2 as the oxidant to activate I- to
hypoiodate (OI-), the iodinating species
Proteolysis of Tg With Release ofT4 and T3
T4 and T3 are synthesized and stored within the Tg
molecule Proteolysis is an essential step for releasing the
hormones To liberate T4 and T3, Tg is resorbed into the follicular cells
in the form of colloid droplets, which fuse with lysosomes to form phagolysosomes
Tg is then hydrolyzed to T4 and T3, which are then secreted into the circulation
T4: A Prohormone for T3
T4 is biologically inactive in target tissues until converted to T3
Activation occurs with 5' deiodination of the outer ring of T4
T3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects
Carriers for Circulating Thyroid Hormones
More than 99% of circulating T4 and T3 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% T4; 0.3% T3)
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 + TR1 TR2
Heart: TRß1 e TRß2 + TR1
Liver: TRß1 e TRß2
Kindy: TR1 + TRß1 e TRß2
Hypothalamus- hypophysis: TRß1 e TRß2
Muscle: TR1
Gonad: TR1
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
T3
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;900:65-76.
Glinoer D. Trends Endocrinol Metab. 1998; 9:403-411.
Glinoer D. Endocr Rev. 1997;18:404-433.
Thyroid Hormone is Critical for Normal Bone Growth and Development
T3 is an important regulator of skeletal maturation at the growth plate T3 regulates the expression of factors and other
contributors to linear growth directly in the growth plate
T3 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 T3) regulate rate of
overall body metabolism T3 increases basal metabolic rate
Calorigenic effects T3 increases oxygen consumption by most peripheral
tissues
Increases body heat production
Metabolic Effects of T3
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; 2000.
Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.
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)
Tiredness
Forgetfulness/Slower Thinking
Moodiness/ Irritability
Depression
Inability to Concentrate
Thinning Hair/Hair Loss
Loss of Body Hair
Dry, Patchy Skin
Weight Gain
Cold Intolerance
Elevated Cholesterol
Family History of Thyroid Disease or
Diabetes
Muscle Weakness/
Cramps
Constipation
Infertility
Menstrual Irregularities/
Heavy Period
Slower Heartbeat
Difficulty Swallowing
Persistent Dry or Sore Throat
Hoarseness/
Deepening of Voice
Enlarged Thyroid (Goiter)
Puffy Eyes
Clinical Features of Hypothyroidism
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 ipertiroidismo50-75% of patients associated with ipertiroidismo,
Graves ophthalmopethy
Graves ophthalmopethy
Graves Disease
T3
Na/K-ATP 酶 UCP metabolism NervesCardiovasculargastro digestion
Producing CalorieReduce body weight
Nervousness/Tremor
Mental Disturbances/ Irritability
Difficulty Sleeping
Bulging Eyes/Unblinking Stare/ Vision
Changes
Enlarged Thyroid (Goiter)
Menstrual Irregularities/
Light Period
Frequent Bowel Movements
Warm, Moist Palms
First-Trimester Miscarriage/
Excessive Vomiting in Pregnancy
Hoarseness/
Deepening of Voice
Persistent Dry or Sore Throat
Difficulty Swallowing
Palpitations/
Tachycardia
Impaired Fertility
Weight Loss or Gain
Heat Intolerance
Increased Sweating
Family History of
Thyroid Disease
or Diabetes
Signs and Symptoms of Hyperthyroidism
Sudden Paralysis
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/100000 Mortality is 0,4-0,8/100000 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
NNRET-PTC
15%15%
40%40%BRAF
RAS
20%20%
PCPC
PCPC
PCPC
FCFC ACAC
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
Insulin acts through a tyrosine kinase receptor
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
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 differencesFamilial clusteringHigh concordance rate in twinsSpecific genetic markersHigher 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
VirusesCoxaschie BMumpsRubellaReoviruses
Nutrition & dietary factorsCow’s milk proteinContaminated 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 CysIRS-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
Clinic features of diabetes
principal Polyuria Polydipsia Polyphagia Weight loss in spite of polyphagia
others Hyperglycemia Glucosuria Ketosis Acidosis
COMPLICATIONS OF DIABETES
Acute complicationsDiabetes ketoacidosishypoglycemia
Chronic complicationsRetinopathy NeuropathyNephropathyIschemic heart disease & strokeDiabetic foot ulcersMacrovascular complicationInfection
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 Secretagoguesa ) Sulphonylurea group b) Non Sulphonylurea Insulin Secretagogues
2. Insulin sensitizersa ) Metforminb) Thiazolidinedione
3. Digestive enzyme inhibitor-Glucosidase inhibitor : Acarbose
Insulin