Learning Objectives from the ICM Manual on Endocrinology

1) UNDERSTAND THE CLINICAL SIGNIFICANCE OF ENDO FEEDBACK CONTROL LOOPSThe Hypothalamic-Pituitary Axis is major site of tropic hormone control and there is often a negative feedback between the levels of tropic and target hormone. For example, in the case of T4 and T3 hormones, when there levels are high, they feed back onto the anterior pituitary to suppress the further release of TSH. In this sense, there is always a homeostatic mechanism that is maintained.

2) UNDERSTAND THE DIFFERENCES BETWEEN TARGET AND TROPHIC HORMONESTropic hormones control the levels of target hormones, whereas the target hormone will act upon a particular cell/tissue/organ of interest. Tropic hormones may either stimulate or suppress target hormones. An example of this would be the following: 1) Dopamine (DA) is a tropic hormone released that suppresses the release of prolactin (target hormone). 2) If prolactin is not suppressed, this target hormone will work on the breast tissue in order to stimulate the production of milk

3) UNDERSTAND THE POTENTIAL CAUSES OF VARIABLITY IN HORMONE MEASUREMENTSWhen looking at hormone measurement, one must interpret results in the context of the circumstances under which the test was performed. Big time example of this is the natural variation in cortisol levels. Daily levels are the highest whereas the levels in early sleep are the lowest

The following are ways/causes for potential variability in the hormone measurement Sample Collection Conditions and Assay Sensitivity and Specificity Variant hormone forms and alternate splicing Pulsatile secretion and both Chronotrophic and Biologic Rhythm Primary versus Secondary Alteration Feedback Suppression or Stimulation

4) UNDERSTAND THE CLINICAL AND LAB FEATURES OF MAJOR FUNCTIONAL CLASSES OF ENDOCRINE DISORDERSIn Clinical Endocrinology, Functional Disorders are as follows:

Hormone Deficiencyo Primary Gland Failure or Tropic Hormone Secondary Deficiencyo Characteristic Syndromes Like Type I DM and Hyporeninemic

Hypoaldosteronismo Target hormone can be low or not able to stimulate and tropic hormone can be

either high (Primary Failure) or Low (Secondary Failure)o Etiology: Gland Destruction, Abnormal Development, or Inactive Hormone

Hormone Excesso Target or Tropic Gland autonomy or Ectopic Productiono Characteristic Syndromes like Cushing and Insulinoma where there is an

elevated target hormone, it is not suppressible, and the tropic hormone can be low (primary/ectopic) or high (secondary)

o Etiology: Abnormal Production; Gland Hyperplasia Hormone Resistance

o Receptor or Post-Receptor defect. Endogenous Receptor Blockero Variable Clinical Syndromes like Testicular Feminization and Severe insulin

resistance type B, with features consistent with hormone deficiency, target hormone levels normal or elevated, and diminished/absent response to exogenous administration of hormone

o Etiology: Abnormal Development Target cell Autonomy

o Receptor Activating Mutation, Post Receptor Autonomy and Endogenous hormone agonist.

o Clinical Syndromes like McCune-Albright and Humoral Hypercalcemia of Malignancy, where there is a syndrome consistent with hormone excess and the actual hormone level is low

o Etiology: Neoplasia, Excess Hormone Production

5) UNDERSTAND THE STIMULATION AND SUPPRESSION TESTS IN ENDOStimulation-May be useful in suspected Deficiency; normal versus abnormal instead of basal measurementSuppression- Used to evaluate suspected autonomous hormone production; maneuver that should suppress hormone secretion and measure response

6) UNDERSTAND THE ETIOLOGIES OF ENDOCRINE DYSFUNCTIONSee Question 4 for specifics relating to each type of major functional endocrine dysfunctionThe categories for endocrine dysfunction etiologies are as follows:

Genetic Nutrition Neoplasia Autoimmunity Destructive Processes Drug effects Excess or Abnormal Hormones and Receptor

7) UNDERSTAND THE CLINCAL SIGNIFICANCE OF PITUITARY ANATOMY AND FUNCTIONAL ORGANIZATIONThe anatomy has clinical significance for at least 2 reasons: 1) It sits between the Hypothalamus and the Hypophyseal Vein in order to deliver hormones to the blood stream; and 2) the area in which it sits does not allow for a lot of room in the cases of tumors/ neoplasia. Therefore, there can be compression of the surrounding structures, as well as the over-production of the hormones of interest. The CN compression can give you an inkling of what etiology is present

The Functional Organization has it so that a majority of the endocrine cells in the anterior pituitary are for the reason/purpose of GH production. There is also a considerable amount dedicated to Prolactin and LH/FSH and ACTH. Again, this can direct you towards where a particular tumor and of what origin it is; whether there is an overproduction of GH etc

8) UNDERSTAND THE CLINICAL PRESENTATIONS & CAUSES OF PROLACTINEMIAClinical PresentationsWomen Present with Galactorrhea, Amenorrhea, and InfertilityMen can present with Infertility, Hypogonadism/Panhypopituitarism, and Mass Effects

Causes Physiological Causes

o Pregnancyo Lactation and Sucklingo Acute release

Secondary Causeso Severe Primary Hypothyroidismo Chronic renal Failureo PCOSo Chest Wall Lesionso Drugs that Block DA- Phenothiazines, AD, Opiate, alpha-methyldopa

9) UNDERSTAND THE BIOLOGICAL ACTIONS OF GH

IGF-1 Mediated Actions Direct Effects of GHChrondrocyte Stimulation IGF-1 Production (Made in the liver)Cartilage Sulfation LipolysisRenal PO4 and NA retention IGFBP-3 ProductionAnabolic effects Hypothalamic Somatostatin SecretionLinear Bone growth

10) UNDERSTAND THE CLINICAL FEATURES, DIAGNOSIS, AND TX OF ACROMEGALY

Clinical Features Diagnosis TreatmentAcromegaly Coarsened Facial Features

Changes to the SkinSoft Tissue SwellingVisceromegaly Deepened Voice

IGF-1 LevelIGFBP-3 LevelRandom GH is neither sensitive or specificPost-glucose GH (Suppression Test)Imaging Tests- CT, MRI, Octreotide

Transphenoidal SurgeryRadiation TherapyAdjunctive Suppressive Therapy

11) UNDERSTAND THE CLINICAL FEATURES OF HYPOPITUITARISM

Target Gland Failure as a Result Mass Effects as a ResultAdrenal Insufficiency Headache (HA)Hypothyroidism Visual Field CutsHypogonadism Cranial NeuropathyGrowth Retardation CN PalsiesPostpartum Failure to Lactate Invasion of the Sinuses

12) UNDERSTAND THE PITUITARY STALK SECTION SYNDROMEThis is one of the causes of Hypopituitarism. The Syndrome is due to mass effects on the HPP circulation. There is Hyperprolactinemia due to loss of DA inhibition and there is Hypofunction of other pituitary axes.

13) UNDERSTAND THE CAUSES OF HYPOPITUITARISMCauses of Hypopituitarism are listed below. Again, it goes back to both the anatomy and functionality of the pituitary gland itself. With tumors there can be a literal/physical compression of the gland itself, whereas in trauma and infarction, there is loss of particular functional tissue

Tumors, Infarction, Trauma, Radiation, Autoimmune Processes, Infiltrative, and Functional Defects are all causes

14) UNDERSTAND THE MASS EFFECTS PRODUCED BY PITUITARY MACROADENOMASLarge Pituitary Adenomas can cause mass effects. Again, the pituitary sits in the sella turcica. There is not a lot of room and there are also very important structures surrounding the pituitary like certain CN and the ICA. Therefore, the mass effects are related to the structural closeness

Visual Field Defects and CN Palsies Hypopituitarism HA and Invasion into the Cavernous Sinus

15) UNDERSTAND THE CLINICAL PRESENTATION OF PITUITARY APOPLEXYClinical Presentation is as follows:Acute syndrome resulting from Hemorrhagic Infarction of the Pituitary

Almost always occurs in the presence of an adenomaAdenomas may be small and if non-functioning, not previously recognized. Its frequency is 1% of adenomas, with common symptoms being HA, Ocular Palsy, Vomitting, and Visual Field Defect

16) UNDERSTAND THE CAUSES/IMPACT OF GH DEFICIENCY IN CHILDREN AND ADULTSHP Causes of Growth Delay in Children

Inherited Disorders Developmental Disorders Perinatal Disorders Craniopharyngioma Neurosecretory Dysfunction Psychosocial Deprivation Dwarfism Cushing Disease Familial is considered an isolated GH deficiency

GH Deficiency In adults and FeaturesGeneralized underproduction of pituitary hormones (panhypopituitarism) - While most patients do not have underproduction of every hormone, some degree of underproduction of more than one hormone is common with pituitary tumors and in patients with infarcts of the pituitary. The first hormone to be under-produced is usually growth hormone, but this causes no specific symptoms in adultsFeatures include the following:

Altered Body Composition: Increased Fat and Decreased Lean Body mass Diminished QAL Increased Atherosclerotic Risk

17) UNDERSTAND THE FEATURES/CAUSES OF HYPOGONADOTROPHIC HYPOGONADISMThis is often associated with anosmia (lack of smell/ Kallman syndrome). GNRH neurons originate with the olfactory cells so that they maintain close association with axons and glia of the olfactory cells. When there is an X-Linked KS mutation to the KAL 1 gene causes loss of function of the adhesive substrate.

Features of it include amenorrhea, infertility, loss of libido, depression, decreased muscle mass for both sexes

18) UNDERSTAND THE CLINICAL FEATURES OF DIABETES INSIPIDUSBecause of the lack of ADH or ADH resistance in the kidney, the clinical features include polyuria, polydipsia, dehydration, hypernatremia, and dilute urine

19) UNDERSTAND SIADHA.K.A. Syndrome of Inappropriate ADHClinical Findings: Hyponatremia, Euvolemia, NormokalemiaDiagnosis: Hyponatremia, Inappropriate Elevated Urine Sodium (Fe NA > 20), and no evidence of volume depletionEtiology: Glucocortocoid Deficiency, Hypothyroidism, Pulmonary Lesions, CNS lesions, DrugsTreatment: Water Deprivation, Glucocorticoid/TH replacement if necessary

20) UNDERSTAND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXISHypothalamus: CRHPituitary: ACTHAdrenal: Cortisol

21) UNDERSTAND THE MAJOR FFECTS OF CORTISOL

Major effects are 2-fold:Supports Increased Energy substrate availability during stress-gluconeogenesis and FFARegulates Immune and Inflammatory responses-Suppression of inflammation

Other Cortisol Actions are as follows:Bone-Inhibition of collagen synthesisSkin-Inhibition of Fibroblast ProliferationCNS-Affects/Modulated Depression and/or EuphoriaCV- Increased Contractility, Increased Vascular Reactivity to Constrictors (ANG II)Kidney- Decreased Calcium Reabsorption and Increased GFR

22) UNDERSTAND THE DDX AND CLINICAL FEATURES OF CUSHING SYNDROMEDDX: Pituitary Adenoma, Adrenal neoplasm, Ectopic ACTH (60 versus 25 versus 15 percent)Clinical Features: Moon Face, HTN, Hyperglycemia, Fat Pads, Striae

23) UNDERSTAND THE USE DEXA SUPPRESSION TESTS AND THE USE OF CRH STIMULATION TEST IN THE EVALUATION OF A SUSPCTED CUSHING SYNDROMECRH Test is used in the ACTH-Dependent Cushing Syndrome-the cortisol increases further with injection of CRH.

The DEXA suppression test is as follows: Used when cortisol excess (Cushing’s syndrome) suspected 3 types of Dexa suppression tests

i. Overnight1. Dexa given in the evening, so morning cortisol levels are expected to

be low (in a healthy person)2. But, people under stress don’t shut off ACTH with a normal dose of

dexa – so they will give false positives3. So, a high cortisol level in the morning indicates either Cushing’s OR

stress ii. Low dose dexa

1. this test is used to rule out false positives (stress, illness) from the overnight suppression test

2. But, 20% of people with Cushing’s may have normal results with this test – because in the early stages of Cushing’s, it is hard to tell whether the patient has cortisol overproduction

iii. High dose dexa1. this test is used to distinguish between the different causes of Cushing’s 2. a really high does of dexa will suppress ACTH production in a person

with a pituitary tumor; other causes of Cushing’s will have no change in cortisol production

Table 1. Dexamethasone Suppression Testing

Test Dose Uses Expected Results

Overnight 1 mg at 11 pm Screen Serum cortisol < 5 g/dL (150 nmol/L)

Low Dose 0.5 mg q 6 h x 2 d Confirmation of Cushing’s Syndrome

Urine cortisol < 20 g/d (5.6 mol/d)

High Dose 2 mg q 6h x 2 d or 8 mg at 11 pm

Differential diagnosis – Cushing’s disease: cortisolNo suppression in Ectopic ACTH Syn.

Urine cortisol < 20% of baseline or serum cortisol < 50% of baseline

24) UNDERSTAND THE DIFFERENCE BETWEEN PRIMARY AND SECONDARY ADRENAL INSUFFICIENCY

Adrenal insufficiency Clinical Picture

Several times more common than Cushing’s Symptoms of mineralcorticoid deficiency – dehydration, hyponatremia,

hyperkalemia, hypotension, volume depletion, metabolic acidosis Symptoms of glucocorticoid deficiency – weakness, muscle wasting, weight loss,

vomiting, hypotension, hypoglycemia May be due to pituitary (50%) or adrenal (50%) pathology If due to adrenal pathology, patients also show increased skin pigmentation due to

excess ACTH

Etiology – adrenal insufficiency Primary (Addison’s disease) has lack of both types of hormones; increased ACTH

increases pigmentation Secondary (pituitary disease). Tertiary (hypothalamic disease) have a lack of

glucocorticoids only, harder to recognize

Causes of adrenal insufficiency Must destroy >90% of cortex In US, most commonly due to autoimmune damage – often seen with other

endocrine insufficiency (thyroid) Waterhouse-Frederichsen: adrenal hemorrhagic necrosis, due to gram negative sepsis

(meningococcal) or other infections Granulomas (e.g. TB) less common in US Metastatic tumors Opportunistic infections from HIV

25) UNDERSTAND THE USE OF COSYNTROPIN STIMULATION TEST (CST) IN THE EVALUATION OF SUSPECTED ADRENAL INSUFFICIENCY

Diagnosis – adrenal insufficiency A normal person has cortisol levels of 5-25 ug/dl in the morning – if <3 ug/dl

confirms diagnosis of adrenal insufficiency (inappropriately low) Lack of response in stimulation tests

o If you give cortrysin and there is no response, that indicates adrenal failure ACTH levels are helpful to distinguish primary (high ACTH) from secondary or

tertiary (low ACTH)

26) UNDERSTAND THE RAASStimulation for Renin Release: Decrease in NaCl, Volume, and PressureRenin Converts: Angiotensinogen to Angio IAngio I is converted to Angio II via ACEAngio II stimulates Aldosterone- Increase in Na, Increase in K secretion, and Increase in H secretion.

27) UNDERSTAND THE CLINICAL FEATURES OF HYPERALDOSTERONISM AND MINERALOCORTICOID EXCESSPrimary Hyperaldosteronism-

HTN Hypokalemia Kaliuresis Alkalosis

Secondary Hyperaldosteronism-

With HTN: Renal Artery Stenosis, Malignant HTN, Renin-Secreting Tumor Without HTN- Decrease in Effective Central Vascular Volume

Mineralocorticoid Excess- HTN Hypokalemia Alkalosis Suppressed Renin Aldosterone is low

28) UNDERSTAND THE PATHOPHYSIOLOGY OF CAH This is 21-Hydroxylase Deficiency Diagnosis: Elevated 17 Hydroxyprogesterone Features: Virilization, Glucocorticoid deficiency, salt-wasting Varied Clinical Spectrum

29) UNDERSTAND THE CLINICAL FEATURES OF PHEOHTN HADiaphoresisPalpitationsGlucose IntoleranceChest Pain Orthostatic HypotensionPallorSymptoms May Be Episodic

Pheochromocytoma from Pathology Notes Adult tumor of the adrenal medulla, rare cause of hypertension 10% tumor – 10% bilateral, 10% familial, 10% extra adrenal, 10% malignant May cause episodic HTN (but most commonly constant), sweating, tachycardia,

hyperglycemia, feeling of doom that they are relatively small tumors, tend to be dark brown Pleomorphism and cell division are not reliable features of malignancy in the adrenal

glands – the only reliable feature is the presence of metastases

30) UNDERSTAND THE FUNCTIONAL ORGANIZATION OF THE THRYOID FOLLICLESThe Thyroid Morphology is very interesting in the sense that it stores its product outside the cells (follicle cells surround the colloid)

31) UNDERSTAND THE MAJOR STEPS IN THE BIOSYNTHESIS OF TH AND THEIR PERIPHERAL METABOLISM

Iodide Taken Up by Thyroid Gland and oxidized by Thyroidal peroxidase Iodine Rapidly iodinates tyrosine residues with TG molecule to MIT and DIT 2 molecules of DIT form T4 and One molecule of DIT and MIT form T3 T4 metabolism is peripheral tissues accounts for 80% of T3 (active hormone)

32) UNDERSTAND THE HYPOTHALAMIC-PITUITARY-THRYOID AXIS Hypothalamus- TRH Anterior Pituitary-TSH Thyroid- Production of T4 and T3; negative feedback of TSH and TRH

33) UNDERSTAND THE SIGNIFICANCE OF FREE AND BOUND THOnly the Free levels of the hormone are regulated by TSH and TRH. However, there can be alterations in the TBG that either increase or decrease total TH levels.

34) UNDERSTAND THE INTERPRETATION OF FREE T4 AND TSH FOR THE DX OF THRYOID DISORDERS

Table 1 - Thyroid Function Tests in Various States

STATE T4 FT4 T3 FT3 T3RU

TSH

RAIU OTHER

Grave's Disease S Anti-TPO, TSI Nodular Goiter Nl- Nl- Nl Nl Nl- S NlHyperthyroid Stage of Thyroiditis

sl sl sl sl S Anti-TPO

Sub clinical Hyperthyroidism

Nl Nl Nl Nl Nl S Nl-

Hashimoto's Thyroiditis Nl- Nl- Anti-TPO Hypopituitarism Nl- Nl- Nl- Subclinical Hypothyroidism

Nl Nl Nl Nl Nl Nl-

Non-Thyroidal Illness Nl Nl Nl- Nl- NlSevere Non-Thyroid Illness

sl sl Nl- Nl- Nl-

Increased TBG Nl Nl Nl NlT4 - total T4; F T4 - free T4; T3 - total T3; T3 - free T3; T3RU - T3 resin uptake; RAIU - radioactive iodine uptake; TPO - thyroid peroxidase; TSI - thyroid stimulating immunoglobulins; Nl - normal; sl - slightly; S - suppressed (undetectable); - increased; - markedly increased; - decreased

35) UNDERSTAND THE SIGNIFICANCE OF ALTERATIONS IN RADIOACTIVE IODINE UPTAKEIodine is required for the production of TH; increased uptake could suggest and increase in TH production, while a decrease in uptake could suggest a decrease in TH production

36) UNDERSTAND THE CLINICAL FEATURES OF HYPERTHYROIDISMCommon Symptoms of Hyperthyroidism are Weight loss, Tachycardia, Dyspnea, Heat Intolerance, Diaphoresis, Restlessness, Nervousness, Tremor, Amenorrhea, and Frequent Defecation.

This is due to the increase in free TH levels

37) UNDERSTAND THE PRESENTATION OF THYROID STORMThere are specific symptoms related to Thyroid Storm

CNS-Agitation, Delirium, and Coma CVD- Arrhythmias, CHF Thermoregulation-Hyperthermia GI- Frequent Defecation

38) UNDERSTAND THE LAB DX OF HYPERTHYROIDISM

TSH

NotHyperthyroid

Free T4(or FTI)

Free T3Thyroid

Exam, RAIU

Thyroiditis OtherCauses

TSI

SubclinicalHyperthyroid

ToxicNodule

Anti-TPOGraves'

Graves' ToxicGoiter

SUSPECTEDHYPERTHYROIDISM Not Suppressed

High Uptake

Suppressed

NormalHighNormal

High

Low Uptake

Positive

1 Nodule, Hi Uptake

>1 Nodule, Patchy Uptake

>1 NoduleDiffuse High Uptake

NegativePositive Negative

Figure 6. Approach to hyperthyroidism - In patients with suppressed TSH and elevated free T3 or free T4 (or both), thyroid examination and radioactive iodine uptake (RAIU) will correctly classify most patients. Graves' disease causes a diffusely enlarged thyroid gland with high RAIU, toxic adenomas produce solitary nodules with high uptake, toxic nodular goiter produces patchy uptake in a gland with many nodules, and thyroiditis produces low uptake. Patients with high uptake and multiple nodules may have coexisting Graves’s disease and multinodular goiter; measurement of thyroid stimulating immunoglobulins (TSI) will resolve the dilemma. A low uptake due to thyroiditis can be confirmed by measurement of anti-thyroid peroxidase (TPO), which should be positive in all forms of thyroiditis. Patients with thyroiditis usually have only transient hyperthyroidism, and often progress rapidly to hypothyroidism which then resolves. A negative anti-TPO suggests a rare cause of hyperthyroidism, such as ingestion of thyroid hormone, iodine induced hyperthyroidism, or ectopic thyroid tissue as may occur with ovarian teratomas (struma ovarii).

39) UNDERSTAND THE PATHOPHYSIOLOGY AND CLINICAL FEATURES OF GRAVES DISEASE

STATE T4 FT4 T3 FT3 T3RU

TSH

RAIU OTHER

Grave's Disease S Anti-TPO, TSI

Grave’s disease is an autoimmune disease causing hyperthyroidism. TSI attaches to the TSH receptors increasing the production of TH. Clinical Features of Hyperthyroidism include Thyrotoxicosis, Diffuse Goiter, Orbitopathy, Pretibial myxedema, Elevated RAIU, and Detectable TSI.

40) UNDERSTAND THE TX OPTIONS FOR GRAVES DISEASEAblation- Surgery or Radioactive Iodine

Or

Medical TX including Anti-thyroid Drugs (PTU, Methimazole), Beta-adrenergic blocking agents, Iodine, and Glucocorticoids/Ipodate

41) UNDERSTAND THE PATHPHYSIOLOGY OF TOXIC NODULAR GOITER AND THE CLINICAL DISTINCTIONS BETWEEN THIS AND GRAVES DISEASEMultinodular Goiter –

o Chronic mild iodine deficiency causes alternating cycles of hyperplasia and involution of the thyroid gland; over time, this creates nodules of thyroid tissue which often show cystic degeneration and hemorrhage from times of involution.

o Complications include compression of normal structures, such as the trachea or esophagus, causing difficulty breathing or swallowing.

o With widespread availability of iodine in salt (used in many processed foods), patients

with nodular goiter may develop hyperthyroidism later in life. o In contrast to Graves' disease and most other forms of hyperthyroidism, the iodine excess

preserves production of T4, so that T3 is often normal or less elevated than T4. RAIU is typically normal or only slightly increased.

o On physical examination, the thyroid is moderately to markedly enlarged, sometimes reaching weights of several hundred grams (normal thyroid glands weigh < 20 grams).

o Grossly, the thyroid is typically irregular in outline, often not recognizable as a thyroid; on cut section, the nodules vary in size, often associated with hemorrhage and cystic degeneration.

o Microscopically, the nodules often have a "capsule", making it impossible to distinguish a single nodule from an adenoma of the thyroid.

42) UNDERSTAND THE DISTINCTIONS BETWEEN HYPERTHYROIDISM WITH ELEVATED RADIOACTIVE IODINE UPTAKE VERSUS SUPPRESSED UPTAKEElevated Uptake-

Increased TH Production Thyroid Stimulator may be present Thyroid cells may be autonomous Responds to anti-thyroid drugs

Suppressed Uptake- Thyroiditis, Exogenous Excess TH, and Iodine InducedThyroid is not synthesizing new TH; decreased Iodine uptake and hormone synthesisThyroid stimulators not presentThyrotoxicosis due to release of TH from damaged cellsNot responsive to anti-thyroid drugs

43) UNDERSTAND THE FEATURES OF SUBACUTE THYROIDITIS AND LYMPHOCYTIC (SILENT) THYROIDITIS

Sub-acute Thyroiditis Lymphocytic (silent) ThyroiditisAntecedent viral infection common May be a variant of chronic thyroiditisSpring and Fall Post-Partum women noted; may recurHard, tender with constitutional symptoms and ESR elevation

Painless, non-tender thyroid

Self-Limited; recurrence is rare High risk of permanent hypothyroidismBeta Adrenergic blockers used Anti-thyroid peroxidase AB often detectableAnti-inflammatory drugs Beta Adrenergic blockers used as TreatmentMay require temporary Replacement

44) UNDERSTAND THE CLINICAL FEATURES, DX, AND TX OF HYPOTHYROIDISM

R/O SecondaryHypothyroid

TSH

Thyroid Exam,History

OtherThyroiditis

Hashimoto'sThyroiditis

ThyroidAtrophy

SubclinicalHypothyroid

Post-Ablative

Anti-TPOAnti-TPO

Low Risk High Risk

SUSPECTEDHYPOTHYROIDISMIN ADULTS

Free T4(or FTI)

HypothyroidSymptoms?

NotHypothyroid

No

High Normal

Prior Surgery

Low YesNormal

Absent

Normal or LargeSmall Gland

Low TiterHigh Titer High Titer

Figure 8. Approach to hypothyroidism in adults - The vast majority of cases of hypothyroidism in adults are primary in the thyroid gland, detected by increased TSH. If TSH is elevated and free T4 is normal, the patient has sub

clinical hypothyroidism; a TSH > 20 mU/L or positive anti-thyroid peroxidase (anti-TPO) indicates high risk of subsequent clinical hypothyroidism. Such patients should be closely followed or be started on replacement hormone. If free T4 is decreased, thyroid exam and clinical history will categorize most patients accurately. A previous history of thyroid surgery or presence of an atrophic thyroid strongly suggests post-ablative and atrophic hypothyroidism, respectively. A normal or enlarged thyroid in a hypothyroid patient is usually due to thyroiditis. Anti-TPO titers will help to separate the different forms, which is important for prognosis. Patients with Hashimoto's thyroiditis have high titers of anti-TPO, and typically have persistent hypothyroidism. Patients with sub acute, lymphocytic and postpartum thyroiditis usually have low to moderate titers of anti-TPO; in the majority of cases, hypothyroidism is transient. If a low titer anti-TPO is found, repeat testing may be done 3-6 months later. If antibody is no longer detected, a trial of discontinuation of thyroid hormone will indicate whether thyroid function has returned to normal.

Clinical Features-Fatigue, Lethargy, Somnolence, Depression, Memory Loss, Weight gain, cold IntoleranceSigns: Bradycardia, Brittle Hair, Delayed DTR, “Doughy skin”, and Pleural/Pericardial effusion

Treatment-Replacement of TH (T4; Synthroid)

45) UNDERSTAND THE PRESENTATION OF MYXEDEMA COMAPathophysiology of Coma is as follows:Compensated Severe Hypothyroidism-----Stress------Coma

Stress can be in the form of the following:o Infectiono Anesthesia and surgeryo Drugs: Sedatives and Hypnoticso Acute Illness: MI, CVA, etc

Presentation is as follows: Stupor or Coma Hypothermia Respiratory Failure Bradycardia and Hypotension

46) UNDERSTAND THE FEATURES OF CHRONIC (HASHIMOTO) THYROIDITISEpi: 4-6th decade with female to male (9:1) Associated with high iodine intake

Autoimmune Etiology- HLA association with DR3, 4, and 5. Antibodies include anti-thyroid peroxidase, anti-TG and TSH-binding inhibitor. Associated with other organ-specific autoimmune diseases

Clinical Features: Irregular Goiter Wide Spectrum of Thyroid Dysfunction May be clinically exacerbated by an iodine load and may remit during pregnancy Atrophic version may be due to TSH receptor blocking antibodies

47) UNDERSTAND THE IMPACT OF ENDEMIC IODINE DEFICIENCYThis is a huge public health problem (Infant Mortality, Growth Retardation, and Diminished IQ). Iodine deficiency can lead to the following:

Goiter Child and Adult Hypothyroidism Neonatal Hypothyroidism Cretinism with both neurological and MSK problems

48) UNDERSTAND THE CLINICAL FEATURES OF MULTINODULAR GOITERClinical Presentations of Multinodular Goiter

Asymptomatic Obstructive Symptoms

o Neck discomforto Dysphagiao Stridor and Voice Change

Thyrotoxicosiso Symptomatic, Sub acute, or Iodine-Induced

49) UNDERSTAND THE EVALUATION OF SOLITARY THYROID NODULEMost commonly, according to Pathology notes, solitary thyroid nodules are neoplastic in nature and can be either benign adenomas or carcinomas. The next two steps would include an ultrasound (Thyroid scan to see whether it is a cold/warm or hot nodule) and then finally a fine needle aspirate of the nodule.

According to the Path notes, the two most common methods for evaluation of solitary nodules are thyroid radioactive isotope scan and fine needle aspiration biopsy. Scans can be done with either radioactive iodine (useful if RAIU is also needed) or technetium; the latter is preferred because of more rapid scanning. Nodules are typically described as "cold" (do not take up the isotope) or "hot" (concentrate the isotope); the majority of nodules are cold. Scans can also detect the presence of multiple nodules not apparent by physical examination. Fine needle aspiration is often helpful for diagnosis of papillary, medullary, and anaplastic thyroid cancers. Because most follicular carcinomas are well differentiated, it is usually not possible to distinguish multinodular goiter, follicular adenoma, and follicular carcinoma by cytology using a fine needle aspirate.

50) UNDERSTAND THE USE OF RADIOACTIVE IODINE IN THE EVALUATION AND TREATMENT OF THYROID CANCERRadioactive Iodine can help ascertain if there is a neoplastic etiology (cold or warm nodule)Radioactive Iodine can be used to treat thyroid cancer in the sense that it used to destroy the thyroid tissue

51) UNDERSTAND THE MEASUREMENT OF TG IN THE FOLLOW-UP OF THYROID CANCERTG is produced by normal thyroid tissue and most papillary (and also follicular) thyroid cancers. Therefore, measurement of TG, especially after administration of r-TSH to stimulate production, us an excellent way to detect residual or recurrent thyroid cancer.

52) UNDERSTAND THE OVERALL IMPACT OF DM ON AN INDIVIDUAL’S HEALTHThe overall impact of DM in the United States is as follows:

6th leading cause of death Life expectancy is reduced 5 to 10 years CVD increased 2x to 4x Nerve damage in 60-70% of patients Amputation- Number 1 cause of non-traumatic amputations Blindness- Number 1 cause of new cases of blindness Renal Failure- Number 1 cause of Renal Failure (Stage 5)

53) UNDERSTAND THE MAJOR DISTINCTIONS BETWEEN TYPE I AND TYPE IICharacteristic Type I Type II

Prevalence .2-.5% 4-5%Age of Onset Usually <30 Usually > 40

Clinical Presentation Acute Acute, progressive, asymptomaticBody Weight Non-obese Usually obeseKetosis Common RareConcordance <50% >90%HLA-association Yes NoAuto-antibodies Detectable Rarely PresentInsulin secretion Severely Impaired Variable ImpairmentInsulin resistance Occasional Common

54) UNDERSTAND THE PATHOPHYSIOLOGY OF TYPE I DMType I (previously known as IDDM or Juvenile Onset) is due to the complete, or nearly complete, deficiency in insulinThere is an autoimmune destruction of insulin producing Beta-cells of the pancreas. Therefore, there are lymphocytes present in the IsletsThe Development of this type of DM is as a result of the following factor (s):

Genetic Predisposition i. HLA-association

Triggering Eventi. Viral: Rubella, Coxsackie B4 or B5, CMV, or Echovirus

ii. Dietary: Infant Bovine Milk Consumption Active auto-immunity

i. GADii. IA-2

iii. IAA Progressive loss of glucose-stimulated insulin secretion Overt DM

55) UNDERSTAND THE EPI OF TYPE II AND IMPACT OF SOCIAL CHANGE ON THE DEVELOPMENT OF DM IN VULNERABLE POPULATIONSPrevalence: 18 million have DMIncreased by 50% since 1991Women have a greater risk, especially those of Hispanic/Latino and Black ethnicitiesSocial Changes are best evidenced by the PIMA Indians (Difference between rates in Mexico and Arizona)

Adoption of a high-calorie, low exercise lifestyle as a result of emigration or economic/cultural changes

Recent episodes of widespread starvation leading to the selection of “thrifty genotypes”o The Thrifty Gene Hypothesis states that fuel efficiency was evolutionary

pressure select hunter-gatherers to be efficient fuel storage machines in times of famine. Now that food is more plentiful and exercise is less employed, this has now become a liability.

o It has led to obesity, insulin resistance, and Type II DM

56) UNDERSTAND THE IMPACT/ASSOCIATIONS BETWEEN OBESITY, INSULIN RESISTANCE, AND TYPE II DMPrevalence of DM increases proportionately with increases in body weightBMI and DM risk also shows an increase:

There is a substantial risk increase starting at BMI’s of x> 27Impaired Glucose Tolerance (Pre-DM) is usually the result of insulin resistance and declining insulin levels. Further decline in Insulin can lead to Type II DMHormonal Products that block insulin action and increase with obesity are as follows

Leptin TNF-alpha IL-6 Resistin

Hormonal Factors that decrease with obesity, enhances insulin action (adiponectin)

57) UNDERSTAND THE DIAGNOSTIC CRITERIA FOR DM AND PRE-DMDiagnostic Criteria for “Pre-Diabetes”

Impaired Fasting Glucoseo Fasting Glucose of between 100-125

Impaired Glucose Toleranceo OGTT of 140-199 mg/dl after ingestion of 75 grams of GLUCO-COLA

Predicts increased risk of progression to DM and increased risk of atherosclerosis

Diagnostic Criteria for DM in Non-Pregnant Adults Fasting Glucose of greater than or equal to 126 mg/dl Random Glucose of greater than or equal to 200 mg/dl with associated symptoms of

hyperglycemia 2 hour plasma glucose of greater than or equal to 200 during 75 grams OGTT

58) UNDERSTAND THE PATHOPHYSIOLOGY AND CLINICAL PRESENTATION OF SEVERE HYPERGLYCEMIA AND DIABETIC KETOACIDOSISPathophysiology and Clinical Presentation of DKAI am biased in the sense that I always associate DKA with Type I DM. Again, there is no such thing as “always”.Pathophysiology of DKA includes the following:

Hormonal- o Absolute insulin deficiency and Increased Glucagon

Adipose Tissue-o Increased Lipolysis with Increased FFA to the Liver

Liver-o Increased Beta-Oxidation of FFA to ACETYL-COAo Increased Ketone and GLUCONEOGENESIS

Metabolic Features-o Hyperglycemia, Dehydration, Increased plasma FFA and Ketones, o Increased urine ketones, anion gap metabolic acidosis, and HYPOKALEMIA

Typical Lab Features-Blood Glucose Greater than 300 mg/dlPlasma and Urine Ketones PositiveBlood pH Less than 7.3Plasma HCO3 Less than 10 mEQ/LiterpCO2 Less than 25 mmHgAnion gap Greater than 16 mEQ/Liter

Presenting Signs and Symptoms are as follows: History suggestive of Hyperglycemia Signs of dehydration Kussmaul breathing Fruity Breath Odor Impaired Consciousness Abdominal Pain, Nausea and Vomiting

Pathophysiology and Clinical Presentation of Severe HyperglycemiaSevere Hyperglycemia can be seen in patients with Type II DM as a result of insulin resistance And lack of insulin production.Clinical Symptoms are as follows

Polyuria, Polydipsia, Dehydration, Weight Loss, Fatigue, Blurred Vision, and Infections Skin, Urinary tract, and Yeast Infections specifically

Severe Hyperglycemia can lead to the following: Hyperglycemic Hyperosmolar Non-Ketotic Coma Occurs in Type II patients, without ketones, but with higher plasma glucose and

increased serum osmolarity Water loss is greater here than in DKA Serum Osmolarity is associated with mortality; increased levels are more highly

associated Major risk factor for the development of this is the inability to maintain adequate as

evidenced by cases of this in the elderly

59) UNDERSTAND THE CONCEPT OF BASAL-BOLUS INSULIN THERAPY AND USE OF INSULIN IN THE TREATMENT OF TYPE I DMUnlike Type II DM, where there is still some production of insulin, there is no or slight production of insulin. Therefore, Type I DM patients must inject themselves with insulin on order to utilize glucose. Otherwise, as evidenced by patients prior to the introduction of insulin therapy, they would “starve” to death, even in the presence of eating.

Basal Suppresses glucose production between meals and overnight Nearly constant levels and 50% of Daily needs

Bolus This is done at mealtime or prandial Limits Hyperglycemia after meals Intermediate rise and sharp peak at 1 hour 10-20% if daily requirement at each meal

60) UNDERSTAND THE ELEMENTS OF A COMPREHENSIVE DM TREATMENT PLANIntensive Treatment plans, especially in the areas of Type II DM treatment, have shown measurable risk reduction (see Nurses Health study)Comprehensive DM treatment plans include the following:

Lifestyle Interventiono DM educationo Weight Loss, Nutrition, Exerciseo Stop Smoking

Progressive Therapy to Correct abnormalities and optimize glycemic controlo Goal: Improve resistance and remove beta cell dysfunctiono Specific goals for glucose, BP, and Lipids

Treat Reversible CVD risk factorso Make sure to treat HTN, Hyperlipidemia, Smoking cessation

61) UNDERSTAND THE IMPACT OF DM ON CVD RISKDM is considered a CHD Risk equivalent10 year risk for CHD is approximately 20%There is also high mortality with established CHD (during acute MI and post MI)The Pathogenesis of accelerated atherosclerosis in DM is as follows

Hyperglycemia Lipid abnormalities HTN Insulin resistance and hyperinsulinism Nephropathy Lifestyle

62) UNDERSTAND THE IMPORTANCE OF GLYCEMIC CONTROL IN REDUCING THE RISK OF MACROVASCULAR AND MICROVASCULAR DIABETIC COMPLICATIONSThe tighter the control on the HBA1C levels, the less the incidence of complicationsFor example, there is a 14% decreased in MI per 1% reduction in levelsFor example, there is a 37% decrease in microvascular end points per 1% reduction in levels

63) UNDERSTAND THE CLASSIFICATION AND CLINICAL FEATURES OF DIABETIC RETINOPATHYHyperglycemia can cause microvascular complications in the eye including retinopathy, cataracts, and glaucoma; these all can lead to blindness, disability, and death

Classification and Clinical Features of Diabetic Retinopathy Nonproliferative/Background

o Asymptomatic usually. Mild cases show microaneurysms only. Moderate-to-severe cases show the above + blot hemorrhages, hard exudates and soft exudates (cotton wool spots)

Proliferativeo Symptoms (if some) can include reduced vision, floaters, or sudden loss of

vision. Findings include neovascularization and intravitreous hemorrhage Macular Edema

o Symptoms can be absent or have blurred vision. Findings in severe cases include hard exudates near the macula

64) UNDERSTAND THE IMPORTANCE OF HTN IN THE DEVELOPMENT OF RETINOPATHY AND NEPHROPATHYStudies have shown that tight control of BP/HTN has had beneficial effects; later incidence of both retinopathy and nephropathy. There is reduced microvascular damage and thus fewer complications.

65) UNDERSTAND THE MAJOR TYPES OF NEUROPATHY ASSOCIATED WITH DMNeuropathic Complications of DM include the following:

Distal Polyneuropathyo Sensory with both Acute changes (KA) and Chronic (Pins and needles) and Loss

of Protective sensationo Sympathetic changes (C fibers) with dry-brittle skin and A-V shuntingo Motor Changes (Aa fibers) with muscle wasting and resulting deformities

Mononeuropathy Autonomic Neuropathy

o GI (Paresis, Diarrhea/Incontinence), CVD (Tachycardia, Ortho HYPOTN), GU (Neurogenic Bladder and Retrograde Ejaculation), abnormal pupillary reflexes, gustatory sweating, and anhydrosis.

66) UNDERSTAND THE FACTORS CONTRIBUTING TO THE DEVELOPMENT OF ULCERATION AND INFECTION OF THE DM FOOTPathophysiology of DM Foot Ulceration

Neuropathy-Increased risk for traumatic damage and foot deformities PVD-Poor tissue oxygenation Hyperglycemia- Leads to poor wound healing and immune dysfunction

Risk Factors for Ulceration Peripheral Sensory Neuropathy Structural Foot Deformation, Trauma, Callus, Prior Ulcerations, Excess Weightbearing Limited Joint Mobility Uncontrolled Hyperglycemia, Age and Duration of DM, Blindness or partial sight and

Chronic renal disease

67) UNDERSTAND THE METABOLIC SYNDROMEA.K.A. Syndrome X, Insulin Resistance Syndrome, etcDiagnosis is established when 3+ risk factors exceed their defining level

Risk Factor Defining LevelAbdominal Obesity Men Women

40 in or 102 cm35 in or 88 cm

TG >/ 150HDL-C Men Women

< 40< 50

BP >/ 130/ 85 mmHgFasting Glucose > 110 or > 6.0

68) WHAT ARE THE CURRENT APPROACHES TO PREVENTION OF TYPE I AND II DMDoes Medicine really do Prevention? =-)Type I= Anti-CD3 antibody since Type I is associated with an autoimmune responseType II- Diet, Exercise and maybe add Metformin if there is a family HX. However, it was shown that the Diet/Intensive Lifestyle Arm of the Diabetes Prevention Program did better than the Metformin arm

69) UNDERSTAND THE HORMONE RESPONSE TO HYPOGLYCEMIA It all comes back to serum glucose (E for the Brain) and the Insulin/Glucagon ratio. If there is a decrease in glucose, then the insulin/glucagons ratio will decrease because there is going to be a release of glucagon from the alpha cells of the pancreas. This will, in turn, promote gluconeogenesis, glycogenolysis, and lipolysis.

Hormone Response Time Course Metabolic ResponseInsulin Decrease Minutes Increase

Gluconeogenesis and Decrease Peripheral Uptake

Glucagon Increase Minutes Increase Gluconeogenesis, GlycogenolysisAntagonize Peripheral Affects of Insulin

Catecholamines Increase Minutes Increase Gluconeogenesis, GlycogenolysisAntagonize Peripheral Affects of Insulin

GH Increase Minutes Antagonize Insulin actions

Corticosteroids Increase Slower Antagonize insulin actions

70) UNDERSTAND THE AUTONOMIC SIGNS OF MODERATE HYPOGLYCEMIA AND THE CNS RESPONSE TO MODERATE AND SEVERSE HYPOGLYCEMIA

Adrenergic Response Cholinergic responseTremors Diaphoresis

Palpitations HungerAnxiety Paresthesias

The Problem with the CNS system is that there is “Hypoglycemic Unawareness”. This is the downward shift in the counter-regulatory hormone response to hypoglycemia resulting in the loss of autonomic warning symptoms prior to the onset of dysfunction

Some of the Symptoms of Hypoglycemia (Neuroglycopenic) are as follows: Sensation of warmth, weakness, and fatigue Difficulty in thinking, confusion, changes in affect/behavior Difficulty in speaking and blurred vision. Amnesia Seizures Coma and Death.

71) WHAT ARE THE MAJOR RISK FACTORS FOR HYPOGLYCEMIA IN A DM PATIENT Intensive control, lower HBA1C Previous Severe Hypoglycemia Absent Insulin Secretion Hypoglycemic Unawareness

72) UNDERSTAND THE WHIPPLE TRIAD FOR THE DX OF HYPOGLYCEMIA Symptoms Consistent with Hypoglycemia Low Plasma Glucose Symptoms relieved when glucose is returned to normal; prompt response

73) UNDERSTAND THE DDX OF HYPOGLYCEMIA Insulin or Insulin-Agonist Stimulated

o Insulinoma/IGF-2 Tumoro Exogenous Insulin

Defective Counter regulationo No Production of Glucose because there is loss of glycogen storage

Drug-Induced Hypoglycemiao Alcohol-Remember the case from Biochemistryo Non-selective Beta-Adrenergic Blockerso Quinidineo Sulfynoureas

In-born Errors of Metabolism Post-Prandial or Reactive Hypoglycemia

o Do not meet the criteria for Whipple’s triado There is autonomic symptoms following a mealo Might be a preclude to Diabetes Mellitus

74) UNDERSTAND THE CLINICAL CHARACTERISTICS OF NEUROENDOCRINE TUMORSClinical Features are as follows:

Originate form neuroendocrine cells May secrete one or more peptide hormone and/or biogenic amines May occur sporadically or as part of the MEN syndrome Variable Biological Behavior with regard to malignancy and aggressiveness Slow Growing and Well-Differentiated-metastasis is one of the only valid criteria for

malignancy Morbidity may be more closely related to hormone effects than to tumor mass and may

contain receptors that could potentially aid in the treatment Require long-term follow-up

75) UNDERSTAND THE FEATURES OF MEDULLARY THYROID CANCER, PANCREATIC ISLET NEOPLASMS AND CARCINOID SYNDROME

Medullary Thyroid Cancer (Path notes) - Malignant tumors derived from the parafollicular C-cells are termed medullary carcinomas. These tumors can occur at any age, and 90% of cases have no known risk factors. About 10% of cases are inherited, either due to isolated mutations in the ret oncogene or as part of the Type II Multiple Endocrine Neoplasia (MEN) Syndrome (also associated with mutations in the ret oncogene). Since C-cells are part of the "neuroendocrine" system, medullary carcinomas may produce not only calcitonin (a normal hormonal product) but also ACTH and, rarely, other hormones. Grossly, medullary thyroid cancers are typically firm solitary nodules. Histologically, tumor cells are arranged in sheets or islands, often surrounded by amorphous pink material which stains as amyloid. The tumor metastasizes by lymphatics early but may spread to other organs such as lung and bone later, and overall survival varies with types. With most forms, prognosis is slightly worse than with papillary carcinoma (about 80% survival), but when part of the MEN IIb syndrome, prognosis is generally poor.

4-10% of Malignancies Derived from Parafollicular C-cells Calcitonin is a sensitive tumor marker Presentations are either Sporadic or Familial (MEN 2a, 2b, or isolated)

o Thyroid Nodule, Watery Diarrhea, Flushing/Pruitus, Elements of MEN syndrome

o Unifocal, Moderate Virulence, Diarrhea, Cushing Syndrome, Elevated Calcitonin with normal calcium levels. METS to the cervical nodes, lung, liver, bone and adrenal gland. The treatment is surgery

PANCREATIC ISLET NEOPLASMS: Clinical Syndromes associated with Hormone ProductionHormone SyndromeGastrin Peptic Ulcer and Secretory DiarrheaInsulin HypoglycemiaSomatostatin DM, Gallstones, Diarrhea, SteatorrheaVIPoma Watery Diarrhea, Hypokalemia, Metabolic Acidosis

CARCINOID SYNDROMEArise from The EC cells scattered throughout the body and common locations are the SI and BowelCarcinoid Syndrome is present in 2-18% of patients with metastatic ileal tumorsTypes are as follows:

Illeal Carcinoid- Classic, Symptoms usually do not occur until hepatic metastases Gastric Carcinoid- Bright red flush at the bottom of the neck; blocked by H1 and H2 RB Bronchial Carcinoid- Flush may last for hours and association with lacrimation and

edema. May secrete ACTH

76) UNDERSTAND THE GENETIC BASIS OF THE FAMILIAL MEN SYNDROMES (MULTIPLE ENDOCRINE NEOPLASIA)MEN 1 Gene: Premature termination of Menin (tumor suppressor qualities)-

Somatic Mutations result in Sporadic Endocrine Tumors Chromosome 11 Usually Represses JunD-Activated Transcription

RET Proto-oncogene- Constitutive activation of tyrosine kinase Chromosome 10 Somatic mutations-associated papillary thyroid cancers MEN 2A : RET proto-oncogene rearrangement (MTC, PHEO, and Hyperparathyroidism)

o Extracellular Domain

MEN 2B : RET proto-oncogene rearrangement (MTC, PHEP, Mucosal Neuromas, and Intestinal Ganglioneuromas)

o Intracellular Domain