Endocrine Issues. Leptin (A) Low levels stimulate hunger and cravings (B) Increased levels stimulate...

Endocrine Issues

Leptin• (A) Low levels stimulate hunger and cravings

• (B) Increased levels stimulate hunger and

• cravings

• (C) Elevated levels in response to stress may

• contribute to abdominal fat

• (D) Upregulates nitric oxide (NO) synthetase

Answer

• (A) Low levels stimulate hunger and cravings

Ghrelin• (A) Low levels stimulate hunger and cravings


• cravings




Answer

• (B) Increased levels stimulate hunger and cravings

Cortisol• (A) Low levels stimulate hunger and cravings


• cravings




Answer

• (C) Elevated levels in response to stress may contribute to abdominal fat

Sleep restriction or deprivation is associated with which of the

following?(A) Impaired glucose tolerance

(B) Increased snacking of carbohydrates and sweet foods at

night(C) Increased risk for diabetes

and obesity(D) All the above

Answer

• (D) All the above

When initiating lifestyle modification, asking the patient to keep a journal about

_______ may be helpful in the initiallifestyle assessment.

(A) Foods and emotions that drive food choices

(B) Physical activity (eg, number of minutes of exercise per day)

(C) Sleep cycle(D) All the above

Answer


Studies show patients who follow a healthy diet high in protein and

low in carbohydrates lose significantly more weightthan patients who follow a

healthy diet comprised of 65% carbohydrates.

(A) True (B) False

Answer

• (B) False

Changes in choice of dietary carbohydrates can affect

expression of genes in abdominal fat.

(A) True (B) False

Answer

• (A) True

Compared to patients who perform a single daily exercise session, those who perform multiple short bouts of exercise

throughout the day tend to:(A) Exercise fewer days per week(B) Accumulate fewer minutes of

exercise per week(C) Have increased appetites

(D) Lose more weight with similar cardiovascular benefits

Answer

• (D) Lose more weight with similar cardiovascular benefits

Choose the correct statement about resveratrol.

(A) Found in beer and chocolate(B) Associated with upregulation

of NO synthetase(C) No evidence of benefits for

cardiovascular risk(D) Likely to increase blood

pressure in patients with metabolic syndrome

Answer

• (B) Associated with upregulation of NO synthetase

Which of the following types of chocolate contains the highest

amount of beneficial flavenoids?(A) Milk chocolate

(B) White chocolate (C) Dark chocolate

(D) Alkalinized dark chocolate

Answer

• (C) Dark chocolate

90% of weight loss is?

• A. Calorie reduction

• B. Exercise

Answer


90% of Weigh Maintenance is?


• B. Exercise

Answer

• B. Exercise

Waist circumference is a very important measurement for abdominal fat and it should be under 40 for men and 35 for women. Asians a waist circumference disadvantaged and they should keep the waist circumference under which of the

following/• A. 38 M, 36 W

• B. 36 M, 34 W

• C. 35 M, 32 W

• D. 36 M, 32 W

Answer

• D. 36 M, 32 W

T4 levels increase by about _______ during the first 20

weeks of pregnancy.(A) 25% (B) 35% (C) 50%

(D) 75%

Answer

• (C) 50%

Women show a stepwise increase in the prevalence of

hypothyroidism, beginning at _______.

(A) 30 yr of age (B) 40 yr of age (C) 50 yr of age (D) 70 yr of age

Answer

• (A) 30 yr of age

Pregnant women with untreated hypothyroidism are more likely

to have:(A) Spontaneous abortions

(B) Low birth weight infants(C) Children with low intelligence quotients

(D) All the above

Answer


All the following interfere with the absorption of thyroid

hormone supplements, except:(A) Hypocaloric diets

(B) Sucralfate (C) Calcium

(D) Iron

Answer

• (A) Hypocaloric diets

Which of the following is the most common adverse effect of

taking methimazole or propylthiouracil to treat

hyperthyroidism?(A) Hepatitis

(B) Agranulocytosis (C) Arthralgia

(D) Pruritus

Answer

• (D) Pruritus

All women with a low thyrotropin (TSH) level during early pregnancy

should be treated for hyperthyroidism.

(A) True (B) False

Answer

• (B) False

Which of the following is not one of the 3 Rotterdam criteria for diagnosis of

polycystic ovary syndrome(PCOS)?

(A) Oligo-ovulation or anovulation(B) Clinical or laboratory evidence of

hyperandrogenism(C) Polycystic ovaries

(D) Presence of acanthosis nigricans

Answer

• (D) Presence of acanthosis nigricans

Which of the following statements about treatment of infertility with clomiphene and

metformin is incorrect?(A) A meta-analysis found that a combination

of the 2 drugs was most effective(B) In a randomized trial, the chance of

conception over 6 mo was much higher with clomiphene

(C) Metformin is associated with a lower rate of miscarriage

(D) Metformin may take longer to work than clomiphene

Answer

• (C) Metformin is associated with a lower rate of miscarriage

Which of the following is not a predictor of successful fertility therapy in women with PCOS?

(A) High educational level (B) Younger age

(C) Lower body mass index (D) Lower hirsutism score

Answer

• (A) High educational level

Lean women with PCOS have a lower probability of developing

type 2 diabetes than obese women without

PCOS.(A) True (B) False

Answer

• (A) True

Choose the correct statement about Graves disease.

(A) More common in men than in women

(B) Incidence peaks at age 20 to 40 yr

(C) Ratio of triiodothyronine (T3) to thyroxine (T4) increases

(D) Concordance rate higher in dizyogotic twins than in

monozygotic twins

Answer

• (C) Ratio of triiodothyronine (T3) to thyroxine (T4) increases

Which of the following is the most common clinical

manifestation of Graves disease?(A) Diffuse goiter

(B) Overt ophthalmopathy(C) Infiltrative dermopathy (D) Thyroid achropachy

Answer

• (A) Diffuse goiter

Compared to propylthiouracil, methimazole:(A) Has a more rapid half-time of disappearance from thyroid tissue

(B) Has higher incidence of minor adverse effects

(C) Is more commonly associated with myeloperoxidase antineutrophil cytoplasmic

autoantibody (MPOANCA)vasculitis

(D) More frequently associated with teratogenic complications

Answer

• (D) More frequently associated with teratogenic complications

Which of the following is the strongest predictor of relapse in

patients treated for Graves disease?

(A) Older age (B) Female sex (C) Large goiter

(D) Moderate level of thyrotropin (TSH)

Answer

• (C) Large goiter

Radioiodine treatment is indicated for patients with:

(A) Severe thyrocardiac disease (B) Toxic nodular goiter (C) Adverse reaction to

antithyroid drugs (D) All the above

Answer


Thyroidectomy in pregnant patients should be performed

during the _______ to reduce risk for miscarriage orpreterm delivery.

(A) First month of pregnancy (B) First trimester

(C) Second trimester (D) Third trimester

Answer

• (C) Second trimester

Which of the following are correctly described as multiple

hyperplastic thyroid nodules with low cellularity?

(A) Colloid nodules (B) Follicular adenoma lesions

(C) Hashimoto’s thyroiditis nodules

(D) Subacute thyroiditis nodules

Answer

• (A) Colloid nodules

The most common form of thyroid cancer is _______

carcinoma.(A) Follicular (B) Papillary

(C) Anaplastic (D) Medullary

Answer

• (B) Papillary

Radioiodine imaging and work-up of hyperfunctioning (“hot”)

nodules is useful only in patients with low

levels of TSH.(A) True (B) False

Answer

• (A) True

When evaluating thyroid nodules, which of the following

findings increase(s) suspicion for thyroid cancer?

(A) Enlarged lymph nodes (B) Palpable nodule is hard and

fixed (C) Irregular margins on

ultrasonography (D) All the above

Answer


Introduction

• lifestyle shown to cause >50% of deaths among middle-aged women

• 72% of cardiovascular mortality attributed to lifestyle

• family history and genetics play role in hunger, satiety cues, and metabolic rate

• Environmental exposure and diet patterns cause changes in brain and relationship to food

Crosstalk between gastrointestinal (GI) tract, brain, and

fat stores• throughout GI tract, chemicals give feedback about eating (eg, what is being eaten, last time food eaten)

• to brain through bloodstream and vagus nerve to help brain regulate hunger• fat is endocrine organ that can produce and release chemical messages into bloodstream • Telling brain about level of fat stores• constant crosstalk occurs throughout day• person with sufficient fat stores and no weight loss—after lunch, satiety peptides

released by gut and adipose cells suppress chemicals associated with increased appetite (eg, neuropeptide Y, agouti-related peptide)

• energy-controlling pathway stimulated• satiety hormones increase; metabolism increases (ie, more calories burned off as heat)• person with decreasing fat stores and weight loss—leptin levels low• 4 to 5 hr before lunch, ghrelin released from stomach stimulates hunger and cravings• appetite-motivating pathway stimulated; satiety hormones suppressed

Low levels of leptin• active in hypothalamus and limbic system• (ie, reward system)• affect chemicals in brain (eg, dopamine)• magnetic resonance imaging (MRI) studies show increases in

areas of brain (eg, nucleus accumbens, caudate nucleus) that cause greater cravings and higher drive for

• food, even immediately after feeding• when patients genetically deficient in leptin shown picture of

food, cravings stimulated, even when not hungry

Addiction-like behavior• animal studies suggest sugar causes release of endogenous

opiates and dopamine similar to addictive drugs• rats given intravenous (IV) sugar bolus had brain changes

similar to rats who self-administer addictive drugs• when sugar taken away, withdrawal behavior and decrease in

dopamine similar to that seen with addictive addictive drugs• under certain conditions, foods rich in fat and capable of

promoting addiction-like behavior and neuronal changes• in certain individuals, diet pattern of restricting food followed

by overeating (ie, decreases in leptin followed by increases in dopamine) can lead to addiction-like pattern

Adapting to weight loss and starvation

• with weight loss, body receives signal about decrease in fat stores

• Metabolism decreases• enzymes that cause fat storage (eg, lipoprotein lipase)

increase• chemicals in brain that stimulate hunger increase• over time, suppression of thyroid axis continues to

decrease metabolism• stimulation of limbic reward system drives desire to

obtain high-calorie, high-fat foods

Stress and cortisol• stress decreases leptin and increases ghrelin (stimulator of hunger and

craving)

• study of 50 women—salivary cortisol measured at baseline and repeated after 15 min of relaxation

• women told to prepare and present 5-min presentation on controversial topic to group of experts

• in some women, cortisol levels remained unchanged after presentation

• in other women (“high stress reactors”), cortisol increased significantly in response to stress

• women asked to document daily intake of food and daily stresses for 2 wk

• in high stress reactors, snacking strongly associated with daily stresses (suggests high cortisol reactivity to stress promotes food intake)

Stress and cortisol• Abdominal fat—men and women with high waist-to-hip ratio had greater cortisol reactivity to stress and

poorer coping skills, compared to those with low waist-to-hip ratio• Suggested that elevated cortisol in response to stress may contribute to development of abdominal fat• recent research suggests cortisol stimulates preadipocytes to proliferate, differentiate• into fat cells, and fill with fat• rats fed high-fat, highsugar diet and exposed to long-term stress had 50% greater increase in visceral fat,

compared to animals on same diet alone• over 3 mo, rats developed symptoms of metabolic syndrome• bathing preadipocytes cultured from human visceral and subcutaneous fat in cortisol solution found to have

profound effect on gene expression in fat cells (eg, upregulation of genes that cause insulin resistance and stimulate adipogenesis)

• 11-β hydroxysteroid dehydrogenase type 1—enzyme induced by cortisol• amplifies cortisol action by converting inactive cortisone to active cortisol• highly expressed in visceral fat• fat cells may have ability to generate cortisol locally, independent of serum cortisol levels• fat cell recognized as endocrine organ with ability to produce and release chemicals that affect metabolism

(eg, leptin, tumor necrosis factor [TNF]-α, interleukin [IL]-6, angiotensinogen, and cortisol)• increased deposition of visceral fat leads to characteristics of metabolic syndrome

Sleep• sleep restriction (<6.5 hr per night) causes increased hunger

and impaired glucose tolerance (partially mediated by higher levels of cortisol and ghrelin)

• small study found subjects with sleep deprivation had significant increases in snacking of carbohydrates and sweet foods at night (when individual would normally be asleep)

• laboratory studies show sleep deprivation causes rapid drop in insulin sensitivity, thereby causing predisposition to glucose intolerance

• epidemiologic studies show reduced sleep increases risk for diabetes and obesity in adults and children

Initiating lifestyle modification

• 5% to 10% weight loss improves manifestations of metabolic syndrome• Challenges include working with patient to achieve long-term lifestyle change and

ongoing success• 1) understand starting point• ask patient for 3-day food record that documents foods eaten and emotions and moods that

drive food choices• Ask patient to wear step counter for 3 days to obtain baseline assessment of activity• ask for 7-day record of sleep cycle• ask patient about recreational activities and stress relief• 2) discuss lifestyle assessment with patient; patients often feel overwhelmed and

challenged by daily life• difficult for patients to invest time and energy into intervention• help patient set reasonable goals• therapy should be patientc entered• (guide patient through important decisions)

Diet study• reviewed various healthy diets, all comprised of <8% fat, adequate fiber, and low cholesterol, with carbohydrates

from foods with low glycemic index

• primary outcome, weight loss after 2 yr; excluded patients with diabetes and unstable heart disease

• recommended calorie deficit of 750 calories less than amount needed for weight maintenance

• patients received strong support (eg, group and individual sessions), given 2-wk meal plans, and asked to document foods and exercise for 90 min/wk

• results—at 2 yr, no significant difference in change in weight or waist circumference among diet groups

• most patients lost weight

• most weight loss occurred in first 6 mo

• ≈25% of patients continued to lose weight for 2 yr

• at 2 yr, ≈33% lost 5% of initial body weight, ≈15% had lost 10% of initial body weight

• drop in fasting insulin seen with all diets except diet comprised of 65% carbohydrates (greatest drop seen with high-protein diet)

• similar decrease in triglycerides and benefit in reducing metabolic syndrome seen among diet groups

• participation in group sessions positive predictor of success

• patients who attended 66% of group sessions lost average of 9 kg over 2 yr

• modest calorie reduction and healthy diet regardless of macronutrient composition resulted in weight loss and reduction in cardiovascular risk

• select diet that patient feels will work for him or her

Effect of type of carbohydrate on gene expression

• study—one group given oat bread and 210 g of mashed potatoes each week; other group given rye bread and 210 g of pasta

• diets similar in fiber and no difference in fat or protein• rye and pasta group characterized by low postprandial insulin response, compared to high response

in oat and potatoes group• study looked at effect on gene expression and abdominal fat in patients with metabolic syndrome• results—dietary change in carbohydrate affected expression of genes in abdominal fat• in low glycemic index group, insulin-signaling genes downregulated• Upregulation of 62 genes linked to stress response and cytokine-mediated immunity seen in high

glycemic index group• Significant effect of diet on gene regulation independent of energy intake and body weight• subsequent study—looked at effect of whole grains vs refined grains on cardiovascular risk in

patients with metabolic syndrome• patients asked to reduce calories by 500 per day• after 12 wk, despite no difference in weight loss, greater percentage of abdominal fat lost in whole

grain group, with 38% reduction in C-reactive protein (magnitude of reduction similar to results achieved with statins)

Exercise• cohort study of patients who maintained ≥30-lb

weight loss found physical activity (burning 2800 calories/ wk by walking [≈11,000 steps/day], and performing higher-intensity exercise twice weekly) powerful predictor of success

• over 20 wk, patients who performed multiple short bouts of exercise throughout day (compared to single continuous exercise session) exercised more days, accumulated more minutes of exercise per week, and lost more weight with similar cardiovascular benefits

Supplements• Rho-iso-α acids: found in hops; high activity on glycogen synthetase kinase pathway• regulates insulin signaling and its association with inflammation• study found adding rho-iso-α acids and acai berry extract to healthy Mediterranean-style diet (eg, diet

high in omega-3 fatty acids, low glycemic index carbohydrates, high quality proteins, and fruits and vegetables) for 12 wk reduced cholesterol and triglycerides more than standard group

• resolution of metabolic syndrome in phytochemical group, 43% vs 22% in standard group• Framingham 10- yr risk scores dropped by 5.6% in phytochemical group vs 2.9% in standard group• no difference in weight loss between groups; reduction in low-density lipoprotein (LDL), 17% in

phytochemical group vs 8.4% in standard group• increase in high-density lipoprotein (HDL), 7% in phytochemical group vs 3% in standard group• drop in triglycerides, 35% in phytochemical group vs 14% in standard group• consumption of phytochemicals in whole foods recommended as part of healthy diet rather than in

pill form• diets high in saturated fat have negative effect on protein kinase pathways and may negate beneficial

effects of phytochemicals

Resveratrol• use of products containing polyphenols (eg, grapes, wine) shown to

reduce cardiovascular risk• Benefit of wine greater than that of other alcoholic beverages• resveratrol found in skins of grapes• other active polyphenol found in grape seeds• reduces BP, improves endothelial function, decreases platelet

aggregation, and activates proteins that prevent cell death in bacteria• Incubation of endothelial cells that line vasculature with flavenoid-

rich red wine shown to upregulate nitric oxide (NO) synthetase and protein expression for NO, resulting in 3-fold increase in NO in endothelial cells

Natural Antioxidants• Cocoa: beneficial effect on BP, insulin resistance, and platelet function

• proposed mechanisms include activation of NO and antioxidant and anti-inflammatory effects

• consumption of 75 g of dark chocolate for 3 wk shown to improve HDL cholesterol by ≈14% and decrease LDL oxidation in healthy subjects

• in hypertensive patients, 100 g over 2 wk showed beneficial effects on some markers

• meta-analysis of randomized controlled trials of 173 subjects showed dark chocolate reduced systolic and diastolic BP after 2 wk

• effects on BP appear to require less intake than other changes

• Beneficial effects most likely due to increased bioavailabity of NO

• polyphenols stimulate NO synthetase, increase vascular arginase (helps to prevent breakdown of NO), and decrease white blood cell adhesion and migration (early signs of atherosclerosis inhibited by polyphenols)

• Milk chocolate and white chocolate do not have same beneficial effects

• alkalinization of dark chocolate reduces flavenoids

• in nondiabetic patients, chocolate consumption associated with dose-dependent decrease in cardiac mortality after first myocardial infarction

Stress reduction• exercise—can reduce stress, anxiety, and depression• raises dopamine and may reduce cravings for foods high in fat

and sugar• in animals, shown protective, against stress-induced anxiety

and depression• Attenuates stress-induced changes in serotonin and

noradrenaline• breathing technique—take deep breath and hold for 4 sec, then

exhale• breathe from abdomen; within 1 min, parasympathetic tone

increases; heart rate, BP, and salivary cortisol decrease

Implementing plan• select specific behavior to change• Set reasonable goals (eg, walk for 10 min/day) and increase

gradually• plan should be clear and specific; performing physical activity

with friend or partner increases likelihood of success• online community support helpful• Rewarding successful lifestyle changes helpful• track changes often enough to make benefits clear to patient• but not so often patients feel discouraged

Questions and answers• caffeine—shown to reduce insulin resistance• amounts variable• both green tea and coffee beneficial• coding for weight-related comorbidities—code for high BP, type 2 diabetes,

hyperlipidemia, or metabolic syndrome• vitamin D—affects immune system• data suggest it may affect glycolysis• according to guidelines, serum level >30 ng/mL sufficient• treat deficiencymaggressively (eg, 50,000 IU/wk of ergocalciferol• if parathyroid hormone elevated, consider twice weekly dosing)• 1000 to 2000 IU/day of vitamin D3 (inexpensive, over-thecounter form) more

effective at raising serum levels than vitamin D2 (ergocalciferol)• start patients on vitamin D3 when starting high-dose prescription supplementation

Causes of hyperthyroidism

• excess exogenous thyroid hormone

• About 20% of patients receiving levothyroxine for hypothyroidism have suppressed thyrotropin (TSH) levels

• Excess iodine; gestational transient thyrotoxicosis (occurs in 20% of pregnancies)

• ratio of triiodothyronine (T3) to thyroxine (T4) increases in patients with endogenous hyperthyroidism due to Graves disease or toxic multinodular goiter (ratio not increased in patients with thyroiditis or excess levothyroxine)

Graves disease• most common cause of hyperthyroidism

• more common in women than in men

• incidence peaks at 40 to 60 yr of age

• concordance rate in monozygotic twins, 35% (lower in dizygotic twins, and significantly lower in

• human leukocyte antigen [HLA]-identical twins [indicates gene loci other than HLA play important role])

• Predisposition to Graves disease 80% genetic

• female siblings and daughters have 5% to 8% risk for Graves disease

Susceptibility genes• HLA-DRB1 gene variant—excess in patients with Graves

disease results in altered peptide presentation to T cells• present in many patients negative for HLA-DR3 antigen• cytotoxic T lymphocyte-associated molecule-4—normally

suppresses T cell activation; single nucleotide polymorphism leads to T cell activation

• CD40 gene—expressed by B cells and antigen-processing cells• various polymorphisms may result in enhanced B cell

activation• single nucleotide polymorphisms—may lead to alterations in

TSH receptor domain

Clinical manifestations• diffuse goiter in >90%• overt ophthalmopathym in 50% (>90% of patients have orbital signs on magnetic resonance imaging [MRI], computed

tomography[CT], or ultrasonography [US])• TSH receptor antibodies in 80% (false-negative rate high)• thyroid peroxidase antibodies in 75%; overlap with other autoimmune diseases• disproportionate increase in T3 secretion• Ocular disease—proptosis• periocular swelling• swelling of medial recti muscles classic finding on orbital imaging• Stages 2 to 6 represent infiltrative ophthalmopathy of Graves disease;• many patients with excess thyroid hormone due to conditions other than Graves disease have nonspecific finding of lid

retraction or lid lag• thiazolidinediones (eg, rosiglitazone) reported to cause aggravation of thyroid eye disease due to peroxisome proliferator-

activated receptor gamma (PPAR-) agonism• thyroid achropachy—clubbing of fingers• infiltrative dermopathy—can involve face or hands• occurs in <5% of patients• caused by expression of TSH receptors on extrathyroidal connective tissues• Cytokines released with binding of TSH receptor antibodies• Results in production of mucoglycosaminoglycans, which cause edema and fibrosis

Cardiac disease in hyperthyroidism

• 33% of patients with hyperthyroidism have cardiac involvement (50% with no preexisting cardiac disease)

• atrial fibrillation (AF) occurs in 12% to 15% of patients

• arterial thromboembolism in thyrotoxic

• AF—incidence nearly as high as that in pneumatic heart disease, significantly higher than in nonvalvular AF, and comparable to that in mitral stenosis

• patients should be anticoagulated with warfarin

• warfarin requirements decrease in patients with hyperthyroidism and increase as patients approach euthyroid state (and further increase as patients become hypothyroid

• in thyrotoxicosis, metabolic clearance rate of vitamin K-dependent clotting factors II, VII, IX, and X accelerated [less warfarin required to maintain anticoagulation])

• cardioversion—avoid until patient euthyroid for 3 mo

• Men less likely to spontaneously revert to sinus rhythm

• Patients with longer duration of symptoms, AF, and associated preexisting heart disease less likely to revert

Treatment• in most countries, antithyroid drugs most

common approach to treatment (in United States, radioiodine more commonly used than methimazole)

• carbimazole converted in vivo to methimazole

• Beta-blockers (eg, propranolol)

• iodine

Methimazole or carbimazole vs propylthiouracil (PTU)

• 15 mg of methimazole given once daily as effective as PTU 100 mg tid• half-time of disappearance from thyroid tissue of methimazole,About

36 hr (more rapid with PTU)• incidence of minor adverse effects of methimazole lower than that of

PTU• (14% vs 52%)• methimazole used in mild to moderate cases• in patients with severe hyperthyroidism, 15 mg of methimazole bid

more effective than once daily, but associated with higher incidence of adverse effects (30% vs 14%); serious adverse effects rare with methimazole and PTU

• but tend to occur within first 3 mo

Methimazole or carbimazole vs propylthiouracil (PTU)• when initiating therapy, perform baseline white blood cell count and liver function testing

• Instruct patient to notify physician immediately with development of fever and sore throat (order complete blood cell [CBC] count) or of pruritus or worsening pruritus (perform alanine aminotransferase [ALT] and alkaline phosphatase testing)

• adverse effects—hepatitis associated with methimazole or carbimazole usually cholestatic and reversible when agent withdrawn

• PTU produces necroinflammatory (hepatocellular) hepatitis (often does not reverse and may require liver transplantation, or may lead to death)

• Myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA) vasculitis (lupus-like syndrome) more common with PTU than methimazole

• pregnancy—teratogenic complications and congenital malformations rarely reported with methimazole, but never reported with PTU

• when available, PTU agent of choice in women planning conception; methimazole and carbimazole can reduce efficacy of radioiodine (131I) treatment

• duration of treatment—French study saw higher relapse rates with 6 mo of treatment with carbimazole, compared to 18 mo (not confirmed by subsequent studies)

• treatment with methimazole for 12 to 18 mo recommended (remission rate, About 50%)• block-replace regimen—patients given high doses of methimazole followed by levothyroxine to avoid hypothyroidism• slightly higher remission rates reported with combined regimen vs methimazole (in titrated doses) alone not supported

by meta-analysis of 12 randomized trials

Predictors of relapse• younger age

• male sex

• tobacco smoking

• large goiter

• severe ophthalmopathy

• undetectable TSH

Radioiodine treatment• indications—severe thyrocardiac disease• toxic nodular goiter (does not go into remission• [ie, patients permanently hyperthyroid]• patients must be on lifelong methimazole therapy)• adverse reaction to antithyroid drugs• relapse after 12 to 18 mo of antithyroid drug treatment• efficacy—study showed 86% of patients treated with 173 μCi/g at 24 hr became

hypothyroid or euthyroid at 1 yr (80% on PTU or methimazole before treatment)• All nonresponders also on PTU or methimazole before treatment (suggests agents can

reduce single-dose response rate)• inverse asymptotic relationship between radioiodine at 24 hr and persistent hyperthyroidism

(90% responded to dose >138 μCi/g, but no improvement in response rate with 400 μCi/g)• dose calculation—target dose, 150 μCi/g;• multiply 0.15 mCi by estimated gland weight in grams, and divide by fractional uptake of

131I at 24 hr

Adverse effects of radioiodine therapy

• hypothyroidism— occurs at rate of 2% per year after first year; provocation or aggravation of eye disease—study showed patients without new or worsening ophthalmopathy experienced worsening after radioiodine therapy with methimazole or prednisone (progression occurred in 23% of tobacco smokers and 6% of nonsmokers)

• options for patients with active Graves ophthalmopathy who smoke include glucocorticoid therapy (40 mg tapered over 2 mo), or surgery

• outcomes of 10-yr methimazole vs 131I treatment—100% of methimazole group became euthyroid (50% had goiter)

• 61% of 131I group became hypothyroid (25% had goiter)

• quality of life, dual energy x-ray absorptiometry (DEXA), and echocardiographic findings similar, but total cholesterol and low-density lipoprotein (LDL) cholesterol higher in 131I group

• no significant adverse effects

Indications for thyroidectomy

• large goiter with compressive manifestations

• pregnancy with adverse reaction to antithyroid antithyroid drug (surgery should be undertaken during second trimester

• to reduce risk for miscarriage or preterm delivery)

• severe infiltrative eye disease (studies show surgery with radioiodine therapy more beneficial than surgery alone)

Pharmacologic utility of radioiodine• saturated solution of potassium iodide (SSKI) has 6 times

more iodine per drop• than Lugol’s solution• roles—abrupt decrease in thyroid hormone secretion due to

transient (about 10 days) inhibition of thyroglobulin proteolysis (useful for thyroid storm)

• Transient reduction of thyroid vascularity in Graves disease (indicated for 10 days before thyroidectomy)

• occasionally used afterm treatment with 131I while patient approaches euthyroid state (eg, after adverse reaction to methimazole or PTU)

Management of Graves ophthalmopathy

• acute active phase—dark lenses• elevate head of bed by 15º• Artificial tears• diuretics (eg, chlorthalidone)• Prisms• glucocorticoids or orbital radiotherapy for severe disease (studies

suggest intravenous [IV] methylprednisolone more effectivethan oral prednisone and less likely to cause adverse effects)

• large doses associated with hepatotoxicity (4.5- 6.0 g of IV methylprednisolone acceptable)

• chronic inactive phase—eye muscle and eyelid surgery

Questions and answers• thyroid-stimulating immunoglobulin (TSI) levels and severity of ophthalmopathy—roughly

correlated• most patients with active or severe ophthalmopathy have elevated TSI• monitor patients• Postsurgical hypoparathyroidism—patients who recover generally do so within first 6 mo

after surgery• calcium and vitamin D supplementatio required• young woman planning conception—PTU or radioiodine acceptable• must wait about 6 mo after radioiodine therapy to conceive• course of hyperthyroidism associated with Graves disease attenuates during pregnancy (after

parturition, Graves disease worsens or appears for first time due to immune resurgence)• Graves ophthalmopathy in euthyroid patient—patients have high TSI levels• treat eye disease rather than addressing thyroid disease• Avoid hypothyroidism after radioiodine therapy (TSH stimulates TSH receptors expressed

on extrathyroidal tissue)

Thyroid Nodule• 4% to 7% of adults in United States have palpable thyroid nodules• more common in women than in men (4:1 ratio)• malignancy rare (<5%)• most thyroid cancers indolent (mortality rate <10%)• nonpalpable (eg, <1 cm) nodules more common than palpable nodules• Palpable nodules appear at age 20 yr, and prevalence increases with age• >50% of population 60 yr of age has thyroid nodules (statistically

normal)• thyroid cancer—37,000 new cases per year (incidence rising• not known whether due to better detection or actual increase)• 1400 deaths per year

Benign thyroid nodules• colloid nodules—also referred to as nodular goiter or hyperplastic nodules

• >50% of thyroid nodules

• often multiple

• imaging studies show areas of eosinophilic pink stain due to colloid (secretory product of thyroid)

• cellularity low; thyroid cells bland and uniform

• follicular adenoma—neoplastic nodule often solitary

• Diagnosed by presence of capsule lesions appear cellular, with less colloid

• others—Hashimoto’s thyroiditis

• Subacute thyroiditis (less common

• associated with epidemic viral upper respiratory infection

• painful swelling of thyroid occurs during winter)

Thyroid cancers• 85% papillary carcinoma (usually indolent)• 8% follicular carcinoma• anaplastic carcinoma rare (1%-2%) and aggressive (mean

survival, 6 mo)• Medullary carcinoma (10-yr mortality rate, 50%)• thyroid lymphoma (rare; typically occurs in patients with

lymphocytic Hashimoto’s• thyroiditis)• metastasis to thyroid extremely rare (renal cell carcinoma

in 50% of reported cases)

Hyperfunctioning (“hot”) nodule• radioiodine imaging—intense uptake of radioiodine over nodule

• faint or no iodine uptake in contralateral lobe

• 5% of nodules hot

• Likelihood of malignancy <1% (100% predictive value for benign nodule)

• 95% of nodules “cold” (ie, radioiodine uptake decreased compared to surrounding tissue) or “warm” (ie, radioiodine uptake similar or slightly increased, but not suppressed, on other side)

• cold or warm findings have little predictive value for malignancy

• radioiodine imaging and work-up of hot nodules useful only in patients with low levels of TSH

Neck irradiation and thyroid cancer• during 1930s to 1970s, 1 million children in United

States treated with low doses of radiation therapy for benign disease (eg, enlarged thymus glands or tonsils, acne, tinea capitis)

• Study of >4000 patients found 39% developed thyroid nodules

• 11% developed thyroid cancer• cancers typically occurred decades after irradiation;

patients often present with hyperparathyroidism and parotid tumors

Other risk factors for thyroid cancers

• exposure to radioactive iodine in Chernobyl fallout

• Graves disease

• Positive family history of thyroid cancer

Evaluation of thyroid nodules• patient history—33% of nodules in children malignant

• risk for malignancy higher in old age than in midlife

• risk for malignancy higher in men than in women

• hypothyroidism suggests nodule due to Hashimoto’s thyroiditis

• hyperthyroidism suggests hot nodule or Graves disease

• positive family history of Hashimoto’s

• disease, multinodular goiter, medullary carcinoma (mostly sporadic, but approximately one-third familial), or familial colonic polyposis (associated with papillary carcinoma)

• evaluation—red flags include hard, fixed nodules or enlarged lymph nodes

• routine serum TSH

• consider antithyroid antibody testing in suspected Hashimoto’s disease;

• check calcitonin if medullary cancer suspected

• thyroglobulin (marker for recurrence of thyroid cancer) not helpful in patients with intact thyroid

• US—best imaging method

• less costly and better than CT and MRI; advantages include echogenicity of thyroid tissue, high resolution for superficial structures, convenience, low cost and

• in-office availablility

• detects nonpalpable nodules

• Characterizes nodules (cystic vs solid)

• detects cervical node metastases

• accurately measures size of nodule

• can be used to guide fine needle aspiration

• sonographic features of thyroid cancer—hypoechoicity; irregular margins; punctate calcifications; anterior-posterior diameter greater than transverse diameter (“tall greater than wide”)

• Extrathyroidal extension

• presence of 3 features has high predictive Value

• fine needle aspiration—best test and helps determine need for surgery

Endocrine Issues. Leptin (A) Low levels stimulate hunger and cravings (B) Increased levels stimulate...

Documents

Transcript of Endocrine Issues. Leptin (A) Low levels stimulate hunger and cravings (B) Increased levels stimulate...