THYROID DISORDERS AND TYPE 2 DIABETES MELLITUS FOCUS: PATHOPHYSIOLOGY

LEVEL OF COMPETENCIES
Hyperthyroidism Hypothyroidism NIDDM (without complication) IDDM Complication acute and chronic Hypoglycemia

3A 1 4 3A 3A (3B) 3B 3B

Adrenal cortex failure

SUGESTED BOOKS READING

S Melmed; KSP Palonsky; PR Larsen; and HM Kronenberg (Eds). Williams Textbook of Endocrinology 12th ed. 2011. Elsevier, Saunders CR Kahn; GL King; AC Moses; GC Weir; AM Jacobson; and RJ Smith (eds.). Joslins Diabetes Mellitus 14th ed. 2005. One Joslin Place Boston Buku Ajar Ilmu Penyakit Dalam

THYROID DISORDERS
The function?

The histology? The etiology?

INTRODUCTION
The terms of hyper- and hypothyroidism are related to the function of thyroid gland Thyrotoxicosis is clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones The function of thyroid gland is synthesis of thyroid hormones: T4 (tetraiodothyronine/ thyroxine) and T3 (triiodothyronine)

LABORATORY EXAMINATION OF THYROID FUNCTION

The function of the thyroid gland may be evaluated in many different ways: 1. test of thyroid hormones in blood, 2. evaluation of the hypothalamic-pituitary-thyroid axis, 3. assessment of iodine metabolism (bisa uptake, bisa ekskresi), 4. estimation of gland size, 5. thyroid biopsy 6. observation on peripheral tissue, and 7. measurement of thyroid autoantibodies (Greenspan, 2004) TSH (thyroid stimulating hormone), T4 (thyroxine), T3 (triiodothyronine)

PHYSIOLOGIC EFFECTS OF THYROID HORMONES

Effects on fetal development (brain development, skeletal maturation) Effects on oxygen consumption, heat production, and free radical formation Cardiovascular effects (positive inotropic and chronotropic effects) Sympathetic effects (sensitivity to cathecolamine is markedly increased) Pulmonary effects Hematopoietic effects (increased production of erythropoietin) Gastrointestinal effects (stimulated gut motility) Skeletal effects (stimulated bone turnover, bone resorption Neuromuscular effects Effects on lipid and carbohydrate metabolism Endocrine effects

THYROID HORMONES REGULATION

THYROID HORMONE SYNTHESIS

Trapping of iodide, diffusion and transport to colloid Oxidation iodine and iodination of tyrosine residues in thyroglobulin Coupling of iodotyrosine molecules within thyroglobulin Proteolysis of thyroglobulin Deiodination of iodotyrosine (MIT/DIT) form iodine to recyle

THYROTROPIN (TSH) LEVEL

High

Primary Hypofunctio n

Subclinical Hypofunction

Secondary Hyperfunctio n

Normal

Normal range

Low

Pituitary Failure

Subclinical Hyperfunction

Primary Hyperfunctio n

Low

Normal

High

THYROID HORMONE LEVEL

ETIOLOGIES OF HYPERTHYROIDISM

Graves disease Toxic multinodular goiter / Toxic adenoma (autonomy) De Quervains (acute/subacute) thyroiditis (thyrotoxicosis, eventually hypothyroid) Silent/painless thryroiditis (autoimmune, eg, graves, postpartum) Postpartum thyroiditis Hashimotos thyroiditis (Ig involved can be stimulatory or inhibitory) Thyrotoxicosis factitia (hypothyroid, kemudian diberi hormone replacement, dose berlebihan hyperthyroid) Thyrotoxicosis due to pregnancy and trophoblastic disease (HCG homologous w/ TSH) Iodide-induced thyrotoxicosis (eg: amiodarone) Hyperthyroidism due to inappropiate TSH secretion Congenital Metastatic thyroid carcinoma (widely spread, usually involving bone; follicular cell found in bones) Struma ovarii

ETIOLOGIES OF HYPOTHYROIDISM

Primary hypothyroidism: primary idiopathic hypothyroidism, postablative/surgery/ therapeutic irradiation, sporadic athyreotic hypothyroidism (agenesis/dysgenesis), endemic cretinism, unresponsiveness to TSH Goitrous: Hashimotos thyroiditis, Reidels struma (thyroiditis yg terjadi sclerosing --> follicular cell fibrosis), endemic iodine deficiency, antithyroid drugs, inherited defect of hormone synthesis Transient: thyroid hormon treatment withdrawal, removal of the gland, DeQuervains thyroiditis (thyrotoxicosis (-) feedback transient hypothyroid), postpartum thyroiditis, postablative treatment for Gravesdisease Secondary hypothyroidism (hypophysis) Tertiary hypothyroidism (hypothalamic) Peripheral tissue resistance to thyroid hormone action

JOD-BASEDOW PHENOMENON : low iodine intake hyperplasia n hypertrophy, some gain autonomy iodine supplementation hyperthyroid

SYNDROMES OF THYROID AUTOIMMUNITY

Graves disease: goiter, exophthalmus, and hyperthyroidsm (thyroid-stimulating antibodies) Hashimotos thyroiditis: goiter and euthyroidism or hypothyroidism (thyroid-stimulating hormone blocking antibodies/TSBAG) Primary thyroid failure (cell-destructive process) Antigen: antigen thyroglobulin (TG), antigen TSH-R, microsomal antigen (thyroid peroxidase/TPO)

ANTIBODIES TO TSH-R
TSI

(thyroid-stimulating immunoglobulin) (in Gravesdisease) Antibodies interfere with TSH binding (thyrotrophin-binding inhibitory immunoglobulin/TBII) Prevent the action of TSH (thyrotrophinstimulation blocking antibodies/TSBAb) (in Hashimotos thyroiditis) TSAb/TSI, TSBAb, and TBIAb are present in graves disease

TYPE 2 DIABETES MELLITUS

Definition of Diabetes Mellitus

Type 2 Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in:

Insulin resistance

IR

b-cell dysfunction

Macrovascular complication

Microvascular complication

(Expert Committee on the Diagnosis and Classification of Diabetes mellitus 2002)

NATURAL HISTORY OF TYPE 2 DIABETES

Severity of diabetes

Impaired glucose tolerance

Frank diabetes
Insulin resistance Hepatic glucose production

Endogenous insulin Postprandial blood glucose

Asymptomatic stage

Fasting blood glucose

Microvascular complications Macrovascular complications

Time Years to decades Typical diagnosis of diabetes

Ramlo-Halsted BA and Edelman SV. Primary Care. 1999;26:771-789.

MORE THAN 80% OF PATIENTS PROGRESSING TO T2DM ARE INSULIN RESISTANT

Insulin sensitive; low insulin secretion (16%)

Insulin sensitive; good insulin secretion (1%)

Insulin resistant; low insulin secretion (54%)

83%
Insulin resistant; good insulin secretion (29%)
Haffner SM, et al. Circulation 2000; 101:975980.

Glukosa

Insulin
Receptor Insulin

GLUT - 4

Auto phosphorilation
Prot Kinase B
Phosphoinositide Dependent-Kinase

p110 p85 IRS

PPARg + RXR

GLUT - 4

Atypical PK C

Phosphoisnositide-3 Kinase

GLUT - 4

GLUT - 4

mRNA
PPRE

transcription

Sel Otot

Dinding sel

Glukosa

Insulin
Receptor Insulin

Auto phosphorilation

PPARg

+ RXR

mRNA
PPRE

transcription

Sel Otot

Dinding sel

ISLET CELL DYSFUNCTION LEADS TO ABNORMAL INSULIN AND GLUCAGON DYNAMICS IN TYPE 2 DIABETES
360 330 300 270 240 110 80 120 90 60 30 0 Meal
22

Glucose (mg/dL)

Type 2 diabetes (n=12) Normal patients (n=11)

Insulin* (/mL) from beta cells

Glucagon (/mL) from alpha cells

140 130 120 110 100 90 Time (minutes)

60

60

120

180

240

*Insulin measured in 5 patients. Adapted with permission from Mller WA et al. N Engl J Med 1970;283:109115. Copyright 1970 Massachusetts Medical Society. All rights reserved.

INCRETINS MODULATE INSULIN AND GLUCAGON TO DECREASE BLOOD GLUCOSE DURING HYPERGLYCEMIA
Meal
23

Increased insulin (beta cells)

Muscle
Adipose tissue

Peripheral glucose uptake

GIP
Gut

Glucose Dependent

GLP-1

Pancreas
Glucose Dependent Decreased glucagon (alpha cells)

Physiologic Glucose Control

Liver

Glucose production

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Brubaker PL et al. Endocrinology 2004;145:26532659; Zander M et al. Lancet 2002;359:824930; Ahren B. Curr Diab Rep 2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Drucker DJ. Diabetes Care 2003;26:29292940.

Septicidal Septet

Impaired Insulin secretion

DeFronzo ADF 2006

Decreased Incretin effect

Increased lipolysis

Islet -cell

??
Hyperglycemia

Increase Glucagon secretion

Increased HGP

Decreased Glucose uptake

Neurotransmitter dysfunction

Septem = seven