Transcript 1 - RCRMC Family Medicine Residency

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
• (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
• (B) Increased levels stimulate hunger and
cravings
Cortisol
• (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
• (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 initial
lifestyle 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
• (D) All the above
Studies show patients who follow
a healthy diet high in protein and
low in carbohydrates lose
significantly more weight
than 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
• A. Calorie reduction
90% of Weigh Maintenance is?
• A. Calorie reduction
• 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/
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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
• (D) All the above
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
• (D) All the above
Thyroidectomy in pregnant
patients should be performed
during the _______ to reduce risk
for miscarriage or
preterm 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 workup 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
• (D) All the above
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
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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
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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
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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
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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)
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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
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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
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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
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Cocoa: beneficial effect on BP, insulin resistance, and platelet function
proposed mechanisms include activation of NO and antioxidant and antiinflammatory 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 dosedependent 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 stressinduced 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
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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
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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
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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 antigenprocessing cells
various polymorphisms may result in enhanced B
cell activation
single nucleotide polymorphisms—may lead to
alterations in TSH receptor domain
Clinical manifestations
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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
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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
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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
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younger age
male sex
tobacco smoking
large goiter
severe ophthalmopathy
undetectable TSH
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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 lowdensity 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)
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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
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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)
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
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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