Pathophysiology of Diabetes€¦ · Common Thyroid Disorders • Hypothyroidism: clinical syndrome that results from a deficiency of thyroid hormone • Hyperthyroidism: or thyrotoxicosis

Pathophysiology of Thyroid Disorders

PHCL 415Hadeel Alkofide

April 2010

1

Learning Objectives

• Understand the pathophysiology of hyperthyroidism & hypothyroidism

• Describe the signs & symptoms of hyperthyroidism & hypothyroidism

• Outline the changes seen in thyroid function tests (free and total triiodothyronine [T3] & thyroxine [T4], force-time integral [FTI] & thyroid-stimulating hormone [TSH]) & the radioactive iodine uptake (RAIU) scan in hyperthyroidism & hypothyroidism

2

Outline

• Introduction

• Epidemiology

• Causes/Classification

• Pathophysiology

• Manifestations (signs & symptoms)

• Diagnosis

3

Introduction

4

Introduction

• Thyroid Physiology

• The difference between T3 & T4

• Common thyroid disorders

5

Thyroid Physiology

• The thyroid gland synthesizes the hormones thyroxine (T4) & triiodothyronine (T3), iodine-containing amino acids that regulate the body's metabolic rate

• Adequate levels of thyroid hormone are necessary:

Infants for normal development of the CNS

Children for normal skeletal growth & maturation

Adults for normal function of multiple organ systems

6

Thyroid Physiology

• Triiodothyronine (T3) & thyroxine (T4) are the two biologically active thyroid hormones produced by the thyroid gland in response to hormones released by the pituitary & hypothalamus

• The hypothalamic thyrotropin-releasing hormone (TRH) stimulates release of thyroid-stimulating hormone [TSH]) from the pituitary in response to low circulating levels of thyroid hormone

7

Thyroid Physiology

• TSH promotes hormone synthesis & release by increasing thyroid activity

• When sufficient synthesis has occurred, high circulating thyroid hormone levels block further production by inhibiting TSH release

• As the serum concentrations of thyroid hormone decrease, the hypothalamic-pituitary centers again become responsive by releasing TRH & TSH

8

Thyroid Physiology

• T3 is 4 times more potent than T4, but its serum concentration is lower

• T4 is the major circulating hormone secreted by the thyroid

• About 80% of the total daily T3 production results from the peripheral conversion of T4 to T3 through deiodination of T4

• Certain drugs & diseases can modify the conversion rate of T4 to T3 and decrease the serum T3 levels

9

Thyroid Physiology

• T3 & T4 exist in the circulation in free (active) & protein-bound (inactive) forms

• About 99.97% of circulating T4 is bound, only 0.03% exists as the free form

• This affinity for plasma proteins accounts for T4's slow metabolic degradation & long half-life of 7 days

• In contrast, T3 is considerably less strongly bound to plasma proteins

• The lower protein-binding affinity of T3 accounts for its threefold greater potency & shorter half-life of 1.5 days

10

Thyroid Physiology

Common Thyroid Disorders

• Hypothyroidism: clinical syndrome that results from a deficiency of thyroid hormone

• Hyperthyroidism: or thyrotoxicosis is the hypermetabolic syndrome that occurs when the production of thyroid hormone is excessive

• Goiter: Diffuse thyroid enlargement most commonly results from prolonged stimulation by TSH

• Thyroid nodules & neoplasms

12

Epidemiology

13

Epidemiology

• General

• Hypothyroidism

• Hyperthyroidism

14

Epidemiology

• Thyroid disease is common, affecting approximately 5% to 15% of the general population

• Females are 3-4 times more likely than males to develop any type of thyroid disease

15

Hypothyroidism

• The prevalence of hypothyroidism is 1.4% to 2% in females and 0.1% to 0.2% in males

• The incidence increases in persons older than 60 years to 6% of women & 2.5% of men

• Hypothyroidism can be caused by either primary (thyroid gland) or secondary (hypothalamic-pituitary) malfunction

• Primary hypothyroidism is more common than secondary causes

16

Hyperthyroidism

• Hyperthyroidism affects about 2% of females & about 0.1% of males

• The prevalence of hyperthyroidism in older patients varies between 0.5% & 2.3%

17

Causes

18

Hypothyroidism

Etiologic Classification Pathogenetic Mechanism

CongenitalAplasia or hypoplasia of thyroid gland

Defects in hormone biosynthesis or action

Acquired

Hashimoto's thyroiditis Autoimmune destruction

Severe iodine deficiency Diminished hormone synthesis, release

Lymphocytic thyroiditis Diminished hormone synthesis, release

Thyroid ablation

Diminished hormone synthesis, release

Thyroid surgery131 I radiation treatment of hyperthyroidism

External beam radiation therapy of head & neck cancer

19

Causes

Hypothyroidism


Acquired

Drugs

Diminished hormone synthesis, release

Iodine, inorganic

Iodine, organic (amiodarone)

Thioamides (propylthiouracil,methimazole)

Potassium perchlorate

Thiocyanate

Lithium

Amiodarone

20

Causes

Hypothyroidism


Acquired

Hypopituitarism Deficient TSH secretion

Hypothalamic disease Deficient TRH secretion

21

Causes

Hypothyroidism

• Hashimoto's thyroiditis, an autoimmune disorder, is the most common cause of primary hypothyroidism & appears to have a strong genetic

22

Causes

Hyperthyroidism


Thyroid hormone overproduction

Graves' diseaseThyroid-stimulating hormone receptor-stimulating antibody (TSH-R [stim] Ab)

Toxic multinodular goiter Autonomous hyperfunction

Follicular adenoma Autonomous hyperfunction

Pituitary adenoma TSH hypersecretion (rare)

Pituitary insensitivity Resistance to thyroid hormone (rare)

Hypothalamic disease Excess TRH production

Germ cell tumors: choriocarcinoma, hydatidiform mole

Human chorionic gonadotropin stimulation

23

Causes

Hyperthyroidism


Thyroid gland destruction

Lymphocytic thyroiditis Release of stored hormone

Granulomatous (subacute) thyroiditis Release of stored hormone

Hashimoto's thyroiditis Transient release of stored hormone

Drug effect

Thyrotoxicosis medicamentosa, thyrotoxicosis factitia

Ingestion of excessive exogenous thyroid hormone

Amiodarone Excess iodine &/or thyroiditis

Interferon alpha Thyroiditis

24

Causes

Hyperthyroidism

• Graves' disease is the most common cause of hyperthyroidism

• Toxic autonomous nodular goiters, both multi- and uninodular, account for a large proportion of the remaining causes

25

Causes

Pathophysiology

26

Pathophysiology

• Hypothyroidism

Hashimoto's Thyroiditis

• Hypothyroidism

Graves' Disease

27

Hypothyroidism

• Hypothyroidism is characterized by abnormally low serum T4 & T3 levels

• Free thyroxine levels are always depressed

• The serum TSH level is elevated in hypothyroidism (except in cases of pituitary or hypothalamic disease)

28

Pathophysiology


• In the early stages of Hashimoto's thyroiditis, the gland is diffusely enlarged, firm, rubbery, & nodular

• As the disease progresses, the gland becomes smaller

• In the late stages, the gland is atrophic & fibrotic, weighing as little as 10–20 g

• Microscopically, there is destruction of thyroid follicles & lymphocytic infiltration with lymphoid follicles

29

Pathophysiology


• Autoimmune disease

• The pathogenesis of Hashimoto's thyroiditis results from an impaired immune surveillance, causing dysfunction of normal “suppressor” T lymphocytes & excessive production of thyroid antibodies by plasma cells

30

Pathophysiology


• The destruction of thyroid cells by circulating thyroid antibodies produces an underlying defect or block in the intrathyroidal, organo-binding of iodide

• As a result, inactive hormones or insufficient amounts of active hormones are synthesized, & this eventually produces hypothyroidism

31

Pathophysiology


• The clinical presentation of Hashimoto's thyroiditis can be variable, depending on the time of diagnosis:

The typical presentation is hypothyroidism & goiter (thyroid gland enlargement)

Patients can present with hypothyroidism & no goiter

Euthyroidism & goiter

Rarely (<5%) with hyperthyroidism (Hashi-toxicosis)

32

Pathophysiology

Hyperthyroidism

• Whatever the cause of hyperthyroidism, serum thyroid hormones are elevated

• Both the free thyroxine (FT4) & the free thyroxine index (FT4I) are elevated

• In 5–10% of patients, T4 secretion is normal while T3 levels are high (so-called T3 toxicosis)

• Total serum T4 & T3 levels are not always definitive because of variations in concentrations of thyroid hormone–binding proteins

33

Pathophysiology

Graves' Disease

• Graves' disease is the most common cause of hyperthyroidism

• The thyroid gland is symmetrically enlarged

• The gland may double or triple in weight

• Microscopically, the follicular epithelial cells are columnar in appearance and increased in number & size

34

Pathophysiology

Graves' Disease

• Graves' disease is an autoimmune disorder

• Characterized by one or more of the following features:

Hyperthyroidism

Diffuse goiter

Ophthalmopathy (exophthalmos)

Dermopathy (pretibial myxedema)

Acropachy (thickening of fingers or toes)

35

Pathophysiology

Graves' Disease

• The production of excessive quantities of thyroid hormone is attributed to a circulating IgG or thyroid receptor antibody (TRAb), which has a TSH-like ability to stimulate hormone synthesis

• The peak incidence of Graves' disease occurs in the third or fourth decade of life, the duration of the disease is unknown, & its clinical course is characterized by remission & relapse

36

Pathophysiology

Graves' Disease

• Patients with hyperthyroidism from Graves' disease may later develop hypothyroidism by one of several mechanisms

1. Thyroid ablation by surgery or 131 I radiation treatment

2. Autoimmune thyroiditis, leading to thyroid destruction

3. Development of antibodies that block TSH stimulation (TSH-R [block] Ab)

37

Pathophysiology

Manifestations

38

Clinical Manifestations

• Hypothyroidism

Symptoms

Signs

Long term complication (Myxedema Coma)

• Hyperthyroidism

Symptoms

Signs

Thyroid storm39

Manifestations

Hypothyroidism

Symptoms

Slow thinking

Lethargy, decreased vigor

Dry skin; thickened hair; hair loss; broken nails

Diminished food intake; weight gain

Constipation

Menorrhagia; diminished libido

Cold intolerance

40

Manifestations

Hypothyroidism

Signs

Round puffy face; slow speech; hoarseness

Hypokinesia; generalized muscle weakness; delayed relaxation of deep tendon reflexes

Cold, dry, thick, scaling skin; dry, coarse, brittle hair; dry, longitudinally ridged nails

Periorbital edema

Ascites; pericardial effusion; ankle edema

Mental depression

Anemia

Decreased metabolic rate41

Manifestations

Hypothyroidism

Signs

Bradycardia (↓ HR)

Hypertension

Goiter (primary hypothyroidism)

Thickening of tongue

Thinning of outer eyebrows

Yellowing of skin

42

Manifestations

Hypothyroidism

43

Manifestations

Myxedema Coma

• The end stage of long-standing, uncorrected hypothyroidism

• The classic features are hypothermia, delayed DTRs, & may reach to coma

• Other predominant features include hypoxia, carbon dioxide retention, severe hypoglycemia, hyponatremia, & paranoid psychosis

Hypothyroidism

44

Manifestations

Myxedema Coma

• Precipitating factors include cold weather or hypothermia, stress (e.g., surgery, infection, trauma), coexisting disease states such as MI, diabetes, hypoglycemia, or fluid & electrolyte abnormalities (especially hyponatremia), & medications such as sedatives, narcotic analgesics, antidepressants, & other respiratory depressants & diuretics

• Mortality rates of 60% to 70% despite treatment

Hyperthyroidism

Symptoms

Alertness, nervousness, irritability, tremors

Poor concentration

Muscular weakness, fatigability

Palpitations

Voracious appetite, weight loss

Hyperdefecation (increased frequency of bowel movements)

Heat intolerance

45

Manifestations

Hyperthyroidism

Signs

Hyperkinesia, rapid speech

Proximal muscle (quadriceps) weakness, fine tremor

Fine, moist skin; fine, abundant hair; onycholysis

Lid lag, stare, chemosis, periorbital edema, proptosis

Accentuated first heart sound, tachycardia, atrial fibrillation (resistant to digitalis), widened pulse pressure, dyspnea

Increased metabolic rate

46

Manifestations

Hyperthyroidism

47

Manifestations

Thyroid Storm

• The clinical manifestations of thyroid storm include acute onset of high fever, hyperglycemia & involvement of the following organ systems:

Cardiovascular (tachycardia, pulmonary edema, hypertension, shock)

CNS (tremor, emotional lability, confusion, psychosis, apathy, stupor, coma)

GI (diarrhea, abdominal pain, nausea & vomiting, liver enlargement, jaundice, elevations of bilirubin & PT)

Hyperthyroidism

48

Manifestations

Thyroid Storm

• Thyroid storm develops in about 2% to 8% of hyperthyroid patients

• The pathogenesis of thyroid storm is not well understood, but the condition can be described as an “exaggerated” or decompensated form of thyrotoxicosis

• Decompensated means failure of body systems to adequately resist the effects of thyrotoxicosis

Diagnosis

49

Diagnosis

• Thyroid Function Tests

• How to diagnose Hypothyroidism & Hyperthyroidism?

50

Diagnosis

Thyroid Function Tests

• The principal laboratory tests recommended in the initial evaluation of thyroid disorders are:

TSH

FT4

• Positive thyroid antibodies indicate an autoimmune thyroid etiology

• Other tests: total T3 (TT3), free T3 (FT3) or FT3 index (FT3I), RAIU & scan, TRAb, ultrasound, & FNA biopsy

51

Diagnosis

Thyroid Function Tests

• Free & Total Serum Hormone Levels

• Tests of the Hypothalamic-Pituitary-Thyroid Axis

• Tests of Gland Function

• Tests of Autoimmunity

52

Diagnosis

Free & Total Hormone Levels

Free Thyroxine, Free Thyroxine Index, Free Triiodothyronine, & Free Triiodothyronine Index

• The FT4 & FT3 are the most reliable tests for the evaluation of hormone concentrations

53

Diagnosis


Total Thyroxine & Total Triiodothyronine

• TT4 & TT3 measure both free & bound (total) serum T4 & T3

• Because the bound fraction is the major fraction measured, situations that change the hormone's affinity for TBG or the TBG level will influence the results

• E.g. falsely elevated levels of TT4 & TT3 are common in the euthyroid pregnant woman

• TT3 can be low in older patients & nonthyroidal illnesses because the peripheral conversion of T4 to T3 is decreased

54

Diagnosis


Total Thyroxine & Total Triiodothyronine

• Careful interpretation of these tests is necessary

• TT3 is particularly helpful in detecting early relapse of Graves' disease & in confirming the diagnosis of hyperthyroidism despite normal TT4 levels

• The TT3 is not a good indicator of hypothyroidism because TT3 can be normal

• Measurement of only the total hormone levels is less reliable than either the free hormone

55

Diagnosis

Tests of Hypothalamic-Pituitary-Thyroid Axis

Thyroid Stimulating Hormone (TSH)

• The serum TSH or thyrotropin is the most sensitive test to evaluate thyroid function

• TSH, secreted by the pituitary, is elevated in early or subclinical hypothyroidism (when thyroid hormone levels appear normal) & when thyroid hormone replacement therapy is inadequate

• TSH can be abnormal even if the FT4 remains within the normal range because the TSH is specific for each person's physiological set point

56

Diagnosis

Tests of Gland Function

Radioactive Iodine Uptake

• RAIU, a measure of iodine utilization by the gland, is an indirect measure of hormone synthesis

• It is elevated in hyperthyroidism & in early hypothyroidism

• A low or undetectable RAIU occurs in hypothyroidism, thyrotoxicosis factitia, & subacute thyroiditis

• RAIU is used to calculate the dose of RAI therapy for treatment of Graves' disease & to determine the activity of one or several nodules in a gland. The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism.

57

Diagnosis


Radioactive Iodine Uptake

• The RAIU is not necessary to diagnose classic Graves' disease or hypothyroidism

• A tracer dose of 131I is administered, & the radioactivity of the gland is measured at 5 & 24 hours after ingestion

• It is necessary to measure both the 5- & 24-hour RAIU so that patient with rapid turnover of iodine will not be missed

• In some hyperthyroid patients, the 5-hour uptake is elevated, but the 24-hour uptake can fall to normal or subnormal levels

58

Diagnosis


Imaging Study

Thyroid Scan

• A scan of the gland is performed simultaneously with the RAIU

• The scan provides information concerning gland size & shape, & identifies hypermetabolic (“hot”) & hypometabolic (“cold”) areas

59

Diagnosis


Thyroid Ultrasound

• A thyroid ultrasound can provide information about gland size & number of clinically palpable or nonpalpable nodules or cysts in the thyroid gland

60

Diagnosis

Tests of Autoimmunity

Thyroperoxidase & Antithyroglobulin Antibodies

• Thyroperoxidase (TPO) & antithyroglobulin (ATgA) antibodies to the thyroid gland indicate an autoimmune process

• About 60-70% of patients with Graves' disease & 95% of patients with Hashimoto's thyroiditis have +ve antibodies to both thyroid antigens

61

Diagnosis


Thyroperoxidase & Antithyroglobulin Antibodies

• Positive antibodies alone do not indicate thyroid disease because 5-10% of asymptomatic patients, as well as patients with other nonthyroidal autoimmune disorders, have positive antibodies

• Clinically, the TPO is more specific than ATgA in assessing disease activity

62

Diagnosis


Thyroid Receptor Antibodies

• TRAbs are IgG immunoglobulins that are present in virtually all patients with Graves' disease

• Like TSH, these immunoglobulins can stimulate the thyroid gland to produce thyroid hormones

63

Diagnosis


Thyroid Receptor Antibodies

• High titers of TRAb are useful in:

Diagnosing otherwise asymptomatic Graves' disease (i.e., ophthalmopathy)

Predicting the risk of relapse of Graves' disease after discontinuing medication

Predicting the risk of neonatal hyperthyroidism in utero through transplacental passage of TRAb from the pregnant mother

• Otherwise, TRAb measurement is expensive & offers no additional information in patient with Graves' disease

64

Diagnosis

Summary of commonly used tests in thyroid disorders

65

Common Thyroid Function Test

Tests Measures Assay Interference Comments

Measurement of Circulating Hormone Levels

FT4

Direct measurement of free thyroxine

No interference by alterations in TBG

Most accurate determination of FT4

levels; might be higher than normal

in patients on thyroxine

replacement

66

Diagnosis




FT4ICalculated free thyroxine index

Euthyroid sick syndrome

Estimates direct FT4

measurement; compensates for

alterations in TBG

67

Diagnosis




TT4

Total free & bound T4

Alterations in TBG

Specific & sensitive test if no

alterations in TBG

68

Diagnosis




TT3

Total free & bound T3

Alterations in TBG levels; T4 to T3

Euthyroid sick syndrome

Useful in detecting early, relapsing, &

T3 toxicosis

Not useful in evaluation of

hypothyroidism

69

Diagnosis




FT3

Direct measurement of free T3

No interferenceby alterations in TBG

Most accurate determination of FT4

levels; might be lower than normal in patients on thyroxine

replacement

70

Diagnosis




FT3ICalculated free T3

indexEuthyroid sick

syndrome

Estimates direct FT3

measurement; compensates for

alterations in TBG

71

Diagnosis



Tests of Thyroid Gland Function

RAIUGland's use of iodine

after trace dose of either 123I or 131I

False decrease with excess iodide

intake

False elevation with iodide deficiency

Useful in hyperthyroidism to determine RAI dose in Graves'; does not provide information regarding hormone

synthesis

72

Diagnosis



Tests of Thyroid Gland Function

ScanGland size, shape, & tissue activity after

123I

154I scan blocked by antithyroid/ thyroid

medications

Useful in nodular disease to detect

“cold” or “hot” areas

73

Diagnosis



Test of Hypothalamic-Pituitary-Thyroid Axis

TSH Pituitary TSH level

Dopamine, glucocorticoids,

metoclopramide, thyroid hormone,

amiodarone, metformin

Most sensitive index for hyperthyroidism, hypothyroidism, &

replacement therapy

74

Diagnosis




ATgAAntibodies to thyroglobulin

Nonthyroidalautoimmune

disorders

Present in autoimmune thyroid

disease; undetectable during

remission

75

Diagnosis




TPOThyroperoxidase

antibodies

Nonthyroidalautoimmune

disorders

More sensitive of the two antibodies; titers detectable even after

remission

76

Diagnosis




TRAbThyroid receptor

stimulating antibody—

Confirms Graves' disease; detects risk of neonatal Graves'

77

Diagnosis

How to diagnose hypothyroidism &

hyperthyroidism?

78

How to Diagnose?

• First look at signs & symptoms

• Major differences between hypothyroidism & hyperthyroidism?

• Diagnostic test

79

Diagnosis

Diagnostic Tests

Hypothyroidism Hyperthyroidism

↑ TSH ↓ TSH

↓ TT4 ↑ TT4

↓ TT3 ↑ TT3

↓ FT4 ↑ FT4

↓ FT4I ↑ FT4I

↓ FT3I ↑ FT3I

80

Diagnosis

Diagnostic Tests

Hypothyroidism Hyperthyroidism

Positive antibodies (in Hashimoto's) ↑ Alkaline phosphatase

↑ Cholesterol ↓ Cholesterol

↑ AST ↑ AST

Decrease radioiodine uptake by thyroid gland

Increased radioiodine uptake by thyroid gland

↓ Na, Hyponatremia (from excess secretion of antidiuretic hormone)

↑ Calcium

↑ CPK

↓ Hct/Hgb

81

Diagnosis

References

• Pharmacotherapy: A Pathophysiologic Approach, 7e

• Pathophysiology of Disease: An Introduction to Clinical Medicine, 6e

• Applied Therapeutics: The Clinical Use of Drugs, 9e

82

Thank You

83

Documents

Pathophysiology of Diabetes€¦ · Common Thyroid Disorders • Hypothyroidism: clinical syndrome that results from a deficiency of thyroid hormone • Hyperthyroidism: or thyrotoxicosis