Endocrinology encompasses many of endocrine disorders

Disorders of pituitary, thyroid, adrenal and pancreas

1. Thyroid disorders

2. 9/15/2024 2 PHYSIOLOGY

3. Diagnosis of thyroid disorders TFT Radioiodine uptake and thyroid scanning Thyroid Ultrasound Antibody tests - Anti-TPO [ thyroid peroxidase] - Anti- Tg [ thyroglobulin ] - Anti-TRAB [ TSH receptor antibody ] FNAC

4. LABORATORY TESTS USED TO ASSESS THYROID FUNCTION  TFT is assessed by one or more of the following tests - Serum TSH concentration - Serum total T4 concentration - Serum total T3 concentration - Serum free T4 (or T3) concentration

5. TSH Low High FT4 FT4 & FT3 Low 1 ° Hypothyroid Low Central Hypothyroid TRH Stim . If equivocal MRI High 1 ° Thyrotoxicosis High 2 ° thyrotoxicosis RAIU

6. Thyroid uptake- RAIU A normal RAIU 6 hours: 3 to 16% 24 hours: 8 to 25%

7. Thyroid scan

8. 8

9. Radioisotpe scan Single or multiple nodules Over functioning (hot nodules) or non-functioning (cold nodules) 20% of cold nodules are malignant Hot nodules … .rarely malignant Cold nodule Hot nodule

10. 9/15/2024 10 PATHOLOGY of thyroid gland : - FUNCTIONAL - STRUCTURAL

11. Functional Disorders of the thyroid Gland 9/15/2024 11 Primary - disorders resulting from the pathologies of thyroid gland itself Secondary – thyroid disorders resulting from pituitary gland abnormalities Tertiary - disorder resulting from hypothalamic pathologies

12. Specific thyroid abnormalities Hypothyroidism Hyperthyroidism Thyroiditis Thyroid enlargement Diffuse or multiple nodular Goiter Solitary nodules Cold Warm or Hot Cysts Malignancies Functional / Biochemical Structural / Anatomy 9/15/2024 12

13. 9/15/2024 13 HYPOTHYROIDISM

14. Hypothyroidism 9/15/2024 14 1 . Primary - Goiterous VS Non- goiterous - Prevalence: 4 - 8% general pop - Mean age of Dx : 5 th decade of life - Female to male ratio: 10:1 2. Secondary/tertiary - From insults to the pituitary and hypothalamus

15. Etiology of primary hypothyroidism 1. Autoimmune : the most common cause in developed countries - Chronic lymphocytic thyroiditis = Hashimoto’s - Positive TPO- Ab’s 2. Iatrogenic : - Radio active iodine treatment, total/subtotal thyroidectomy, neck irradiation 3. Iodine deficiency common cause in our set up 4. Congenital : Thyroid agenesis, dysgenesis , biochemical defect 5. Drug induced: Lithium, amiodarone , chemotherapy.. 6. S ubacute thyroiditis 7. Peripheral tissue hormone insensitivity (resistance ) 9/15/2024 15

16. 9/15/2024 16 Clinical presentation of Hypothyroidism - Signs & symptoms relates to hypo-metabolism Weakness & lethargy Sleepiness Fatigue, slow speech & thinking Cold intolerance Puffy appearance Constipation Weight gain despite ↓ appetite Irregular and heavy menses Hoarseness of voice

17. 9/15/2024 17 N on-pitting edema + puffiness Hypothermia Macroglosia Goiter Hypoventilation, pleural effusion ↓ PR, pericardial effusion (↓ CO) Dry coarse skin & hair, hair loss Signs of anemia (NC, NC) “hang-up” reflex (DTR) Psychiatric features (e.g. depression) Cretinism (if severe & in infancy) Myxedema coma .. Clinical presentation

18. Hypothyroidism facial features 9/15/2024 18

19. 9/15/2024 19 CXR-Hypothyroidism-before and after Rx

20. Diagnosis of hypothyroidism Laboratory : TSH - high Free T4 - low - Check both if new diagnosis to make sure PITUITARY-THYROID AXIS intact 9/15/2024 20

21. Treatment hypothyroidism Levothyroxine (LT4 ) Lifelong treatment in most cases Check TSH no sooner than 6 weeks after initial start of LT4 or any adjustment Annually once a euthyroid state is established Start at low dose in - Elderly patients or any patient  50 years of age or with underlying cardiac disease 9/15/2024 22

22. Myxedema Coma Clinical Characteristics S evere form of hypothyroidism Decreased mental status…coma Hypoventilation Hypothermia Bradycardia Hyponatremia Hypoglycemia Associated Infection Treatment - A medical emergency - Treatment includes Admission (ICU) IV fluid Nutrition support RX precipitating factor thyroid hormone (High dose) Steroids

23. Subclinical hypothyroidism Very difficult to diagnose clinically High index of suspicion needed as it is often asymptomatic 4 -15% of general population 20% of patients over 60 yrs of age (esp. women ) LABS : TSH - minimally high (6 - 10  IU/ mL ) Free T4 – normal TREATMENT : may consider Rx if has symptoms, dyslipidemia or TPO- Ab positive Low dose LT-4 vs follow-up without treatment 24

24. 9/15/2024 25 THYROTOXICOSIS

25. 9/15/2024 26 Etiology of thyrotoxicosis : - Diffuse toxic goiter (Graves’ disease) The most common cause Autoimmune (TSI) F > M, most females b/n age 20 & 50 - Nodular toxic goiter – Solitary or multi nodular Usually older Patients - Sub acute thyroiditis – transient Thyrotoxicosis - Factitious/ iatrogenic - Rare forms : TSH e.g. pituitary (2 or 3 ) , ovarian tumor Excess Iodine ingestions ( Jod Basedow phenomenan )

26. Common Symptoms and Signs of Thyrotoxicosis Symptoms Nervousness / behavioral changes restlessness Fatigue, weight loss Muscle weakness Increased perspiration Heat intolerance Tremor Palpitations Appetite/weight changes, diarrhea Menstrual disturbances ( oligomenorrhea / amenorrhea) Signs Goiter +/- bruit Hyperactivity Tachycardia / arrhythmia Systolic hypertension Warm, moist, or smooth skin Stare and eyelid retraction Tremor Hyperreflexia Pretibial myxoedema Clubbing ( Acropathy ) 9/15/2024 27

27. 9/15/2024 28 Grave’ disease Enlarged Thyroid Normal Thyroid Multinodular goiter

28. Thyroid orbitopathy - orbital decompression 9/15/2024 29 Before After

29. 9/15/2024 30 CLUBBING OF FINGERS (ACROPATHY)

30. 9/15/2024 31 PRETIBIAL MIXEDEMA OF GRAVES' DISEASE ( hyaluronic acid deposition in the dermis)

31. 9/15/2024 32 Thyroid Storm - Is the most severe form of thyrotoxicosis - Is a medical emergency - Attended by high mortality - Diagnosis is clinical - Burch and Wartovisky scoring may help

32. Subclinical Hyperthyroidism 9/15/2024 33 Definition Low TSH Normal thyroxine (T4) Normal triiodothyronine (T3 ) Effects Cardiac effects Cardiac arrythmias Increased ventricular mass Accelerated bone loss Especially in post menopausal women not receiving estrogen replacement therapy Treatment is individualized

33. Thyrotoxicosis - work-up Lab tests TSH - Low or undetectable Free T4 and/or Free T3 – Increased radioiodine uptake/ thyroid scan Uptake is increased Increased radiotracer uptake Homogeneous ( Graves’ disease) multiple areas (Toxic MNG) single area (Hot or warm nodule) 9/15/2024 34

34. Treatment Options for Thyrotoxicosis I 131 RAI thyroid ablation Anti-Thyroid Drugs (ATD’s) Methimazole Propylthiouracil (PTU) Surgery 9/15/2024 35

35. 9/15/2024 36 THYROIDITIS

36. 9/15/2024 37 - Is an inflamation of the thyroid gland Types: 1. Subacute ( granulomatous or de Quervian’s ) - Viral (Coxsackie, mumps etc) - C/F - Malaise, symptoms of URTI, fever for 1-2 wks ⇩ - Pain in the anterior neck and the arms - Firm and tender goiter ⇓ Hormone leak  thyrotoxicosis (subsides in Weeks to Months) -  Increased T3 & T4 - ↓ RAIU - Increased ESR   THYROIDITIS

37. 9/15/2024 38 Is a common thyroid abnormality - Auto immune disease with anti thyroid ab s -  Predominantly in females - Lymphocytes infiltration of the thyroid  fibrosis - Often firm & painless goiter - Hypothyroidism seen in up to 20% at diagnosis, in others later Diagnosis: - Firm, non-toxic goiter - High anti Tg and anti microsomal antibody titer or both - TFT is often normal (unless hypothyroid) Rx:- L- thyroxin (even when euthyroid ) 2. Chronic thyroiditis (Hashimoto’s ):

38. Adrenal GlanD

39. Adrenal anatomy Adrenal glands are located above the kidneys, The normal gland weigh 6-11 gms each Adrenal sterioiodogenesis occur in zone specific fashion Mineralocorticoid synthesis occuring in the outer zona glomerulosa Glucocorticoides synthesis occuring in intermidate , zona Fasciculata Dehydroepianderosterone (DHEA) synthesis (Androgen precurssor ) occuring in the inner zone zona Reticularis

40. Hormone products of the Adrenal Gland The adrenal cortex produces three major classes of steroids: 1. Glucocorticoids: e.g cortisol 2. Mineralocorticoids: e. g aldosterone 3. Adrenal androgens: e.g dehydroepiandrosterone , DHEA Adrenal Medulla: Epinephrine, Nor epinephrine

41. Regulation of cortisol Plasma ACTH varies during the day as a result of its pulsatile secretion and follows a circadian pattern, with a peak just prior to waking and a nadir before sleeping.

42. Regulation of Aldosterone Aldosterone – Initial production relies on ACTH Controlled by renin –angiotensin

43. Pathophysiology Adrenocortical disorders include: hyperfunction -Cushing's syndrome hypofunction -adrenal insufficiency (Addison’s disease) A variety of genetic abnormalities of steroidogenesis .

44. Pathophysiology

45. Cushing’s Syndrome (CS) Definition: Is a constellation of clinical features that results from chronic exposure to glucocorticoid of any etiology

46. Causes of CS ACTH Dependent Cushing’s Cushing’s disease (= ACTH producing pituitary adenoma) Ectopic ACTH Syndrome (due to ACTH secretion by bronchial or pancreatic carcinoid, small cell lung cancer, medullary thyroid carcinoma, pheochromocytoma ) ACTH Independent Cushing’s Adrenocortical adenoma Adrenocortical Carcinoma Primary pigmented nodular adrenal disease Macune Albright Syndrome Iatrogenic – Steroid administration

47. Causes of Cushing's syndrome Cushing’s Disease accounts 70-80 % 90% caused by pitutary microadenoma (< 10 mm in size) Occur sporadically or as part of MEN 1 Ectopic ACTH- 5-10% Occult carcinoid tumour , small cell lung Ca , Medullary carcinoma of thyroid,pheochromocytoma Primary Adrenal : 20-25% Carcinoma Adenoma Micronodular hyperplasia

48. Clinical manifestation of Cushing's syndrome

49. Cushing’s syndrome

50. Moon face, fullness of supraclavicular pad, Buffalo hump, purplish striae

51. Diagnosis 24 hrs. Urine free cortisol ( > 100 µg/dl per 24 hrs ) Overnight 1 mg Dexamethasone suppression test (> 1.8 µg/dl) Midnight Salivary cortisol (>130 nmol/l ) - Loss of Diurnal variation Low dose dexamethasone suppression test The diagnosis of CS => depends on the demonstration of increased cortisol production => failure to suppress cortisol secretion normally when dexamethasone is administered

52. Diagnosis: Confirm Etiology Once the diagnosis is established, further testing is designed to determine the etiology Plasma ACTH ( > 15 pg /ml, < 5 pg /ml ) High dose dexamethasone suppression test (2 mg 6 hrly for 48 hrs.) Overnight High dose DST, 8 mg stat at mid night CT/MRI scan of the abdomen, pituitary gland Inferior petrosal venous sampling

53. Treatment of Cushing’s syndrome Surgery: Cushing’s disease: Transssphenoidal pitutary adenomectomy Radiation Bilateral adrenalectomy Adrenal Tumors: unilateral or bilateral adrenalectomy Surgical bilateral adrenalectomy is uniformly effective in nodular hyperplasia Bilateral adrenalectomy is also indicated in most patients with macronodular adrenal hyperplasia

54. Treatment of Cushing’s syndrome Inhibitors of steroid synthesis e.g Ketoconazol , metyrapone , Adrenolytic drugs e.g. mitotan

55. Adrenal insufficiency Primary : adrenal destruction => Addison’s Disease Secondary : hypothalamic pituitary dysfunction

56. Adrenal insufficiency Primary Adrenal insufficiency mainly caused- autoimmunity-70% TB/HIV > 30% In developing countries other causes account: 15%

57. Adrenocortical Deficiency causes Adrenoleukodystrophy Surgical removal   Hemorrhage infarction Invasion, metastasis Metabolic failure in hormone production Fungal Infiltrative e.g sarcoidosis , amyloid

58. Cause cont. AIDS related infections Direct infection of adrenal with HIV CMV,TB, MAI, Toxo , Crypto,Kaposi’s , lymphoma of adrenal 12% of patients who die from multiple organ failure have adrenal involvement at autopsy

59. Causes of Secondary adrenal insufficiency Tumors of the pituitary gland, hypothalamus Pituitary Irradiation Pituitary hypophysitis Pituitary hypoplexy or hemorrhage Drugs Congenital diseases of Hypothalamic and pituitary gland

60. Clinical manifestations Patients with chronic primary adrenal insufficiency may have symptoms and signs of glucocorticoid, mineralocorticoid, and in women, androgen deficiency. In contrast, patients with secondary or tertiary adrenal insufficiency usually have normal mineralocorticoid function

61. Frequency of Symptoms and Signs in Adrenal Insufficiency Sign or Symptom Percent of Patients Weakness 99 Pigmentation of skin 98 Weight loss 97 Anorexia, nausea, and vomiting 90 Hypotension (<100/60) 87 Pigmentation of mucous membranes 82 Abdominal pain 34 Salt craving 22 Diarrhea 20 Constipation 19 Syncope 16 Vitiligo 9

62. Hyperpigmentation, Vitiligo

63. Evaluating patients with adrenal insufficiency Serum cortisol values < 5.3 µg/dl ACTH level Short Cosynotrophin stimulation test, cut off value for Dx . serum cortisol value after 60 min. ≤ 18-20 µg/dl Electrolyte : hyperkalemia, hyponatremia , hypercalcaemia CRF Test CT Scan/MRI

64. Treatment All patients with adrenal insufficiency should receive specific hormone replacement. patients require careful education about the disease. Replacement therapy should correct both glucocorticoid and mineralocorticoid deficiencies . Hydrocortisone (cortisol) is the mainstay of treatment. The dose for most adults is Hydrocortisone 20–30 mg/d. 2/3 :am , 1/3 pm Predinsolone 5mg am + 2.5mg pm /day

65. Mineralocorticoid replacement: Fludrocortisone 0.05–0.1 mg per day PO Patients should also be instructed to maintain an ample intake of sodium (3–4 g/d).

66. Stress treatment Minor surgery,minor stress the dose of hydrocortisone should be doubled Major surgery, trauma or addisonian crisis Saline volume extension Hydrocortisone 100 mg q6h iv

67. Adrenal crisis Adrenal crisis : a rapid and overwhelming intensification of chronic adrenal insufficiency, due to corticoid and mineralocorticoid deficiency usually precipitated by sepsis surgical stress anticoagulant therapy acute hemorrhagic in previously well individuals. the rapid withdrawal of steroids from patients with adrenal atrophy

68. Adrenal crisis cont. Clinical presentations Nausea Vomiting Abdominal pain Fever may be severe or absent Lethargy deepens into somnolence Hypovolemic vascular collapse Progressing to stupor and coma

69. Treatment of Adrenal crisis Repletion of circulating glucocorticoids and replacement of the sodium and water deficits An IV infusion of 5% glucose in normal saline solution should be started IV hydrocortisone

70. Pheochromocytoma are catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system Tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type II Prevalence is about 2–8/ 1 million persons per year Accounts < 0.2% of causes of hypertensive patients

71. Pheochromocytoma cont. Mean age at diagnosis is about 40 years The tumors can occur from early childhood until late in life About 10% are bilateral, 10% are extraadrenal , and 10% are malignant May be associated with MEN2, neurofibromatosis, hereditary diseases

72. Clinical presentations Episodes of headache, Palpitation and Sweating Hypertension, sustained or paroxysmal Anxiety and panic attacks Orthostatic hypotension Pallor Nausea Abdominal pain Weakness

73. Diagnosis and Treatment Elevated plasma and urinary levels of catecholamines , CT/MRI Surgical resection after adequate medical preparation is mandatory Control of BP with alfa adrenergic blocking agents ( phenoxybenzamine ) volume expansion

74. Pituitary Disorders

75. Pituitary gland Weighs 500-900mg and is located within the sella turcica ventral to the diaphragma sella It consists of embryological, anatomically and functionally distinct anterior and posterior lobes Produces six major hormones

76. Anterior pituitary cells 50%- Somatotrope 10-30%- Lactotrope 20%- Corticotrope 20%- Gonadotrope 5%- Thyrotrope

77. Pituitary disorders Mass effect (pituitary tumors) Hypopituitarism (anterior or posterior) Pituitary hypersecretory syndromes Prolactinoma Cushing’s disease Acromegaly

78. Pituitary tumors commonest space-occupying lesions in the pituitary fossa are benign adenomas commonest pituitary adenoma does not secrete known active hormones and is termed a ‘nonfunctioning’ adenoma Microadenoma [ 10mm] macro adenoma[ >10mm] –based on size Adenomas result in mass effect, hypopituitarism or hypersecretory syndromes

79. Hypopituitarism Refers to decreased secretion of pituitary hormones Can be due to pituitary or hypothalamic diseases Symptoms appear when 75% of the pituitary is destroyed Panhypopituitarism refers to involvement of all the pituitary hormones

80. Causes Pituitary tumor or treatment of tumor—76% Extra-pituitary tumor----------13% Unknown cause--------8% Sarcoidosis ----1% Sheehan’s syndrome----0.5%

81. Clinical manifestations Depends on the Rapidity of onset Severity of hormonal deficiency Type of cells affected Presence of mass effect

82. ACTH----Cortisol insufficiency TSH------Hypothyroidism FSH and LH--- Hypogonadism ADH----Diabetes insipidus GH---Failure to thrive in children; most adults are asymptomatic, but some may experience fatigue and weakness and decreased quality of life

83. Approach and investigations Diagnosis is based on symptoms, hormone levels and imaging (MRI) Basal hormone levels TSH and free thyroxine FSH and LH, Estradiol or testesterone Cortisol Stimulation tests ACTH stimulation test Water deprivation test for DI

84. Management Surgery- transsphenoidal surgery Hormone replacement therapy Glucocorticoids, thyroid hormone, sex steroids, growth hormone, and vasopressin Treatment regimens should try to mimic physiologic hormone production Glucocorticoid replacement requires careful dose adjustments during stressful events

85. Pituitary hypersecretory syndromes Result from excess hormone secretion from pituitary adenoma Prolactinoma ---60% GH-secreting pituitary adenoma—20% ACTH-secreting pituitary adenoma---10%

86. Hyperprolactinoma Prolactin is secreted solely by the lactotroph cells of the pituitary gland Is the most common pituitary hypersecretion syndrome Hyperprolactinoma can be physiologic or pathologic

87. Hyperprolactinemia Etiology - Physiological Lactation Pregnancy Exercise Stress Sex

88. Hyperprolactinemia Etiology - Pathological Rathke’s Cyst Granulomas Infiltration Irradiation Trauma Tumors Hypothalamus Pituitary Stalk Prolactinoma Acromegaly GH/PRL/TSHoma Macroadenoma Lymphocytic Hypophysitis Surgery Trauma Pituitary Chest Wall Shingles Surgery Trauma Hypothyroid Cirrhosis Seizures CKD PCO Systemic

89. Hyperprolactinemia Etiology - Pharmacological Anesthetics Anticonvulsants Antidepressants Antihistamines Antihypertensives Antipsychotics Cholinergic Agonists Dopamine Blocker Dopamine Inhibitor Estrogens Opiates

90. Effects of excess Prolactin Females Infertility—90% Galactorrhea ---80% Menustrual irregularity Loss of libido Males Hypogonadism Galactorrhea -<30% Mass effect symptoms

91. Prolactinoma Account for 60% of pituitary adenomas Annual incidence: 3/100, 000 Microadenoma (<1cm)….F:M= 20:1 → 5% macro Macroadenoma (>1 cm)… F:M= 1:1 Serum prolactin ≈ with adenoma size Spontaneous resolution of HPRL… ≈30% micro

92. Diagnostic evaluation- history and physical exam Indications for serum prolactin level measurement Galactorrhea Enlarged sella Suspected pituitary tumor Hypogonadotrophic hypogonadism

93. Management Suppression of prolactin secretion Reducing size of prolactinoma Prevention of progression or recurrence Preferred treatment -Dopamine agonists

94. Acromegaly A clinical syndrome that results from excessive secretion of GH in an adult Annual incidence: 3-4/million people Mean age at Dx : 40 - 45 years Mean duration of Sx (onset – Dx ): 5- 10 years Most common cause… somatotroph adenoma of the anterior pituitary At time of diagnosis, 75% of tumors are macroadenomas

95. GH physiology Secreted by somatotroph cells of the anterior pituitary Principal action is to promote postnatal longitudinal growth Also affects intermediary metabolism of lipids, carbohydrates, nitrogen, and minerals Levels fluctuate throughout the day Follows a pulsatile , circadian pattern including peaks, which occur most often at night –Levels decline with age

96. Insulin like growth factor (IGF-I) Circulating IGF-I is principally derived from the liver – Secretion is regulated by GH and measures of IGF-I serve as an accurate marker of GH production – Levels affected by age and sex

97. Diagnosis of Acromegaly Single measurement of GH is not an accurate indicator of elevation since secretion is pulsatile Diagnosis can be confirmed by demonstrating failure to suppress GH <1 ng /mL after glucose administration Measurement of IGF-I levels is a reliable marker for the diagnosis of acromegaly

98. Additional tests Assess anterior pituitary function Measure prolactin Image pituitary with MRI

99. Prognosis Associated with a 2- to 3-fold increase in mortality Greatest contributors to mortality are cardiac, vascular, and respiratory disease – Patients with the presence of diabetes or cardiac disease at diagnosis have a significantly poorer prognosis If IGF-I or GH levels are normalized, the mortality rate is reduced to that of the general population

100. Thank You