Thyriod problems

What about a low t3 in thyroid replacement?

• Replace with Armor

• Replace with cytomel

• Ignor it

Answer• T3 therapy— overwhelming evidence that T3 supplementation

or partial replacement not beneficial

• neurocognitive function and psychologic well-being may not return to normal with levothyroxine

• creates risk for hyperthyroidism and long-term effects

• subgroup of 16% with D-iodinase gene polymorphism may improve with appropriate T3 supplementation

• thyroid desiccated (eg, Armour Thyroid, S- Thyrar, Thyroid Strong) and liotrix (T4 and T3; Thyrolar) contain higher ratio of T3 (associated with increased risk for hyperthyroidism)

• drugs that interfere with levothyroxine—proton-pump inhibitors,

Should you check for Antithyroid Antibodies and anti TPO

antibodies in Hypothyroid Patients?

• A. True• B. False

Answer• B. False

• antithyroglobulin and antithyroid peroxidase (anti-TPO)—testing generally not recommended for diagnosis of hypothyroidism because >90% due to Hashimoto disease

• testing may be useful prognostically; in subclinical thyroid disease, antibodies may be predictive of likelihood of development of overt thyroid disease

if TSH low, you should check ?

Answer

• check free T4 and free T3

Traditional Chinese Medicine for Treatment of H1N1 Influenza

• In a relatively young and healthy population, a combination of 12 herbs was as effective as oseltamivir.

• A traditional Chinese medicine (TCM) containing 12 herbs (including Ephedra, which is banned in the U.S. and Canada) has been proposed as an alternative to oseltamivir for treating patients with H1N1 influenza. Researchers in China randomized 410 people (mean age, 19) with documented H1N1 infections to no treatment, oseltamivir, TCM, or oseltamivir plus TCM. The study was not blinded, and exclusion criteria included presence of a new infiltrate or substantial chronic illness.

• The median time to fever resolution was 26 hours in the control arm; it was significantly shorter in each of the active treatment groups (oseltamivir, –34%; TCM, –37%; combination, –47%). Resolution of cough, sore throat, rhinorrhea, headache, and fatigue did not differ among treatment groups, and no significant differences were noted in complication rates.

• Comment: In this nonblinded trial, a traditional Chinese medicine was as effective as oseltamivir in shortening fever duration among relatively healthy patients with H1N1 influenza. The precise mechanism is unknown but could be related to modulation of T cell subpopulations, as well as inhibitory effects on the influenza virus itself. Although the findings are interesting, people enrolled in this trial were young and relatively healthy; treatment with an antiviral likely was unnecessary. Whether this TCM is effective in people at higher risk is unclear.

Follow-Up Chest X-Rays After Pneumonia?

• Follow-up imaging probably can be limited to older patients.• Older guidelines recommended routine follow-up chest x-rays at about 6 weeks after episodes of

community-acquired pneumonia, presumably to screen for malignancy after an acute infiltrate has cleared. More recent U.S. guidelines don't address this issue (Clin Infect Dis 2007; 44(Suppl 2):S27), and a recent U.K. guideline recommends this practice only for patients with persistent symptoms or those "at higher risk of underlying malignancy (especially smokers and those aged >50 years)" (Thorax 2009; 64(Suppl 3):iii1).

• In this population-based cohort study, Canadian researchers identified all 3398 patients without known cancer who received inpatient or outpatient treatment for pneumonia between 2000 and 2002 in metropolitan Edmonton. The incidence of newly diagnosed lung cancer was 1.1% at 90 days and 1.7% at 1 year. Only 40% of patients had follow-up chest x-rays performed within 90 days. All but 1 of the 57 patients in whom cancer was diagnosed within 1 year were 50 or older; thus, the authors conclude that routine follow-up chest x-rays should be restricted to people in that age group.

• Comment: Because less than half the patients underwent follow-up chest x-rays and, because this study was not a randomized comparison of imaging versus no imaging, the benefit of routine radiography after pneumonia remains unclear. However, the low 1-year incidence of lung cancer provides reassurance that a selective approach — limiting follow-up chest x-rays to middle-aged and older adults — is reasonable. Obviously, patients of any age who remain symptomatic also should undergo follow-up imaging. (Read the case history of a pneumonia patient, and decide if you would order a follow-up x-ray.)

Choose the correct statement about normal thyrotropin (TSH)

levels. A) Genetically predetermined

 B) <2.0 μIU/mL in most young to middle-aged euthyroid

individuals C) Increased in smokers

 D) Lower limit is 0.8 to 1.0 μIU/mL

Answer

• A) Genetically predetermined

Hyperthyroidism is caused by _______ in 80% of cases.

 A) Toxic multinodular goiter B) Graves disease

 C) Smoking D) Iatrogenic cause

Answer

• B) Graves disease

Compared to methimazole, propylthiouracil:

 A) Must be dosed less frequently B) Has a faster onset C) Is more effective

 D) May be more likely to lead to failure of radioiodine therapy

Answer

•  D) May be more likely to lead to failure of radioiodine therapy

Antithyroid drugs cause remission of toxic multinodular

goiters in 50% of patients. A) True B) False

Answer

•  B) False

Thyroid surgery is usually indicated for which of the

following? A) Smaller nonobstructive

goiters B) Toxic nodules in patients >65

yr of age C) Pregnant patients or those

with drug intolerance  D) All "hot" nodules

Answer

• C) Pregnant patients or those with drug intolerance 

Hypothyroidism is caused by _______ in >90% of cases.

 A) Hashimoto disease B) Iatrogenic cause C) Iodine deficiency D) Thyroid agenesis

Answer

• A) Hashimoto disease

Choose the correct statement about the treatment of hypothyroidism.

 A) Levothyroxine should be taken with food B) T3 supplementation shown to be highly

beneficial C) Proton-pump inhibitors and H2-blockers

interfere with levothyroxine D) Levothyroxine has no effect on

neurocognitive function or psychologic well-being

Answer

•  C) Proton-pump inhibitors and H2-blockers interfere with levothyroxine

Which of the following patients with postpartum thyroiditis are least likely to

develop chronic thyroid disease? A) Women who develop only hyperthyroid

phase B) Women who develop only hypothyroid

phase C) Women who develop hyperthyroidism

after transient hypothyroidism D) Women with hypothyroidism and

postpartum depression

Answer

• A) Women who develop only hyperthyroid phase

Compared to postpartum thyroiditis, Graves disease: 

 A) Is more common B) Presents with milder

symptoms C) Is associated with larger

goiters D) Is not associated with

ophthalmopathy

Answer

• C) Is associated with larger goiters

In pregnant women, which of the following is more likely to occur

in hyperthyroidism than in hypothyroidism?

 A) Abruption B) Heart failure

 C) Stillbirth D) Low birth weight

Answer

• B) Heart failure

Which of the following is diagnostic for diabetes mellitus (DM)?

 A) Fasting plasma glucose (FPG) of 110 mg/dL

 B) 2-hr postprandial glucose (on oral glucose tolerance test [OGTT]) of l65

mg/dL C) Hemoglobin (Hb)A1c ≥6.5%

 D) Any of the above

Answer

• C) Hemoglobin (Hb)A1c ≥6.5%

The strongest acquired risk factor for developing type 2 DM

(T2DM) is: A) Obesity

 B) High-fat, low-fiber diet C) Physical inactivity D) Excessive alcohol

consumption

Answer

•  A) Obesity

Every person who develops insulin resistance (IR) will

eventually progress to IGT or overt DM. A) True B) False

Answer

•  B) False

In a meta-analysis of several clinical trials involving >100,000 patients randomized to

different therapies, all the following classes of drugs were associated with a lower risk for

developing T2DM, except: A) Calcium channel blockers

 B) Angiotensin-converting enzyme inhibitors (ACEIs) 

 C) Diuretics D) Angiotensin-receptor blockers (ARBs)

Answer

• C) Diuretics

If a patient's HbA1c is not at target goal with a basal insulin dose of _______U/kg per day,

then insulin therapy needs to be intensified and prandial coverage

should be considered. A) 0.1 to 0.2 U/kg B) 0.2 to 0.3 U/kg C) 0.3 to 0.5 U/kg  D) 0.4 to 0.6 U/kg

Answer

•  D) 0.4 to 0.6 U/kg

In the Treating to Target in Type 2 Diabetes study, the 3-yr

cumulative rates for hypoglycemia and weight gain

were lowest in patients with T2DM whose insulin therapy was

initiated with: A) Basal insulin

 B) Prandial insulin C) Premix insulin

Answer

• A) Basal insulin

In the STEP-Wise study, the greatest reduction(s) in

HbA1cwere achieved with addition of the ______ bolus(es)

of prandial insulin. A) First B) Third

 C) First and second D) Second and third

Answer

•  C) First and second

Which of the following is a mechanism of anemia in patients

with chronic kidney disease (CKD)?

 A) Decreased production of erythropoietin

 B) Inflammation C) Hemolysis

 D) All the above

Answer

• D) All the above

Before the introduction of erythropoiesis-stimulating agents (ESAs)

for treating renal anemia, patients on dialysis required an average of 26 U

blood/year. Currently, about ________ of dialysis patients with CKD and

________ of non-dialysis-dependent CKD patients still receive transfusions.

 A) 33%; 15% B) 25%; 10% C) 13%; 8% D) 5%; 2%

Answer

•  B) 25%; 10%

Results of a landmark study on the effects of normal vs low hemoglobin (Hb) values in patients with cardiac disease receiving hemodialysis and

epoetin clearly show that normalization of Hb _______ in dialysis patients with

cardiac disease. A) Is harmful

 B) Is beneficial C) Has no effect on outcomes

Answer

•  A) Is harmful

Thyroid hormones

• levorotatory thyroxine (T4)—produced by thyroid

• half-life 1 wk

• triiodothyronine (T3)—produced by peripheral tissues

• half-life 1 day

• more potent than T4

Thyroid testing• high-sensitivity or third-generation thyrotropin (TSH) testing—initial test

• normal TSH level genetically predetermined

• lower limit of normal of new TSH assays, 0.3 to 0.4 μIU/mL

• upper limits of normal vary between laboratories (controversial); most young to middle-aged euthyroid individuals have TSH <3.5 μIU/mL

• TSH of 5.0 μIU/mL probably not normal for young healthy individuals, but does not necessarily indicate need for treatment

• smoking appears to lower TSH and may be associated with less hypothyroidism

• total T4 and total T3 assays—rarely clinically useful

• should only be ordered in conjunction with estimate of free vs bound hormone

• some studies indicate total T3 as accurate as free T3, but not true for T4 (total T4 should rarely be obtained alone)

• thyroid panels—third-generation TSH, T4, T3 uptake, and free T4 index (FTI)

• FTI—total T4 converted to estimate of free T4

• T3 resin uptake estimates rather than measures free thyroid hormones

• multiplying T3 resin uptake by total T4 results in FTI

• FTI should be used in pregnant women and may be preferred in hospitalized patients

• Direct reference methods—equilibrium dialysis

• labeled antibody tests usually accurate in estimating free thyroid hormone concentrations

• TSH measurement usually reliable, even when it does not agree with free T4 measurement

• Laboratory tests acceptable for most ambulatory patients

Manifestations of hyperthyroidism:

• dysphoria, emotional lability, cognitive dysfunction, and depression occur in hyperthyroidism and hypothyroidism;

• lid lag—sclerae atop irises visible when patient looks down

• present in nearly all hyperthyroid patients

• extreme exophthalmos due to Graves disease with lid retraction not lid lag

Diagnosing hyperthyroidism• free T4 assay—eg, enzymelinked immunosorbent

assay (ELISA) or radioimmunoassay (RIA) likely accurate in confirming biochemical hyperthyroidism

• free T4 may be normal early in course (consider free T3 testing), or results may be free T3-predominant

• if TSH low, check free T4 and free T3• if free T4 and free T3 normal but TSH suppressed,

TSH results more likely accurate (follow and refer if indicated)

Signs and symptoms of hyperthyroidism

• hyperthyroidism

• more prevalent in women and increases with age

• older women more likely to develop toxic multinodular goiter

• Younger women more likely to develop Graves disease

• risk greater in smokers

• THYROIDISM mnemonic—tremor; heart rate (ie, tachycardia); yawning (ie, fatigue); restlessness (ie, anxiety); oligomenorrhea or amenorrhea; intolerance to heat; diarrhea; irritability; sweating; muscle wasting or loss;others—systolic hypertension; increased appetite

Causes of hyperthyroidism• iatrogenic hyperthyroidism;• Graves disease—80% of hyperthyroidism• diffusely enlarged gland produces excess thyroid hormone• toxic multinodular goiter (TMNG)—15% of hyperthyroidism

• Multiple nodules on thyroid independently secrete thyroid hormones (“hot” nodules)

• secondary hyperthyroidism—<0.1% of all hyperthyroidism due to TSH-producing tumor

• TSH, free T3, and free T4 increased• characterized by pituitary symptoms

Radioiodine uptake scanning• high uptake indicates increased hormone

synthesis (low uptake indicates no increase)• Differential diagnosis—if uptake high, consider

Graves disease, TMNG, or toxic or hot nodule, and hashitoxicosis (early phase of Hashimoto disease

• some patients present hyperthyroid)• if uptake low, consider thyroiditis (eg, subacute de

Quervain disease); amiodarone can cause hypothyroidism

Graves disease• confirming diagnosis—thyroid-stimulating antibodies or

immunoglobulin (fairly sensitive• >99% specificity• safe in pregnancy); TSH-receptor antibody testing not• recommended because only 1 of 3 types associated with• Graves disease; risk factors—greater female predominance than with

hyperthyroidism in general• positive family history of Graves disease or other autoimmune disorder• stress (may lead to rebound immune phenomenon)• Smoking• occurs in pregnancy and postpartum period• for suspected asymmetric thyroid, perform ultrasonography

Treatment of hyperthyroidism• acute use of Beta-blockers—all equally effective• study showed 5-fold increase in miscarriage in pregnant women treated with

propranolol and antithyroid drug (shared decision making important)• goal of antithyroid drugs (thionamides) to achieve euthyroidism within 8

wk• methimazole—preferred due to fewer side effects, longer duration of action,

once-daily dosing, and less dosing variability; for mild cases, start with 10 mg once daily; for larger goiter and/or more severe cases, start with 20 to 40 mg once daily

• no advantage of starting at high doses, except in more severe patients • propylthiouracil (PTU)— must be dosed more frequently• onset slower, less effective, more toxic, and may be more likely than

methimazole to lead to failure of radioiodine therapy

Drug toxicity and risks• most toxic reactions occur in first 3 mo• Hepatotoxicity• methimazole more likely to cause cholestasis (usually reversible)• PTU causes hepatocellular damage (may be• irreversible), which can lead to liver failure and need for transplantation (reports in children increasing)• agranulocytosis—rare• usually occurs in first 2 mo• 78% detected via biweekly complete blood cell counts (CBCs; shared decision making important)• Advise patients to seek immediate medical care for any sign of infection, fever, or sore throat (stop drug; obtain CBC)• others—skin conditions, arthralgias, arthritis, nausea, vomiting, and abnormal taste• 50% of patients on one antithyroid drug have similar side effects when on another• PTU more likely to cause antineutrophil cytoplasmic antibodies (ANCA)-positive vasculitis (rare)• methimazole—first drug of choice• use PTU if patient in first trimester of pregnancy, has life-threatening thyroid storm, or cannot tolerate methimazole• after first trimester of pregnancy, teratogenic• risks of methimazole appear less than those of maternal PTU hepatotoxicity• informed consent—discuss risk for liver damage and immune suppression• advise reporting signs of infection• offer periodic blood testing

Long-term use of antithyroid drugs

• remission rate 50%

• Monitor TSH and free thyroid hormone

• after TSH normalizes, following TSH alone acceptable

• duration of treatment 1 to 2 yr

• can be used for 10 yr without loss of effect

• Antithyroid drugs do not cause remission of TMNG, but can be used as bridge to more definitive therapy or as long-term therapy

Radioiodine ablation• oral pill

• preferred method in United States

• destruction of thyroid tissue occurs in 6 to 18 wk

• studies suggest avoiding antithyroid drugs 1 wk before, during treatment, and 1 wk after treatment

• Graves disease—high dose curative in 90% of patients, and 80% become permanently hypothyroid

• Can worsen or occasionally cause ophthalmopathy

• TMNG— radioiodine tends to destroy hyperfunctioning areas

• some patients remain euthyroid, but hypothyroidism increases with time

• some patients need second dose

Surgery• indications—large or obstructive goiter

• need for rapid or definitive correction

• may be more cost effective for toxic nodules in patients <60 yr of age

• coexisting “cold” nodule and concern for neoplasia

• Graves ophthalmopathy

• Pregnancy

• Drug intolerance

• complications—hypoparathyroidism (may be permanent)

• permanent vocal cord palsy

• experience of surgeon and center important

Apathetic hyperthyroidism

• more common in elderly

• Most common signs include tachycardia, fatigue, and weight loss

• fewer signs and symptoms of sympathetic overactivity

• Commonly associated with anorexia and atrial fibrillation

Signs and symptoms of hypothyroidism

• Hypothyroidism more prevalent than hyperthyroidism• 90% of cases subclinical or undiagnosed• more common in women (increases with age)• metabolic slowing—fatigue• cold intolerance• weight gain• exertional dyspnea• cognitive dysfunction• constipation;• delayed growth or puberty in children• bradycardia• slowed movement and speech• delayed return of deep tendon reflexes • accumulation of matrix substances—dry skin; edema; hoarse voice; goiter; coarse, cool, and/or pale skin; edema and puffy face; enlargement

of tongue; loss of• eyebrows; other diffuse symptoms and signs—arthralgias• myalgias; depression; menstrual changes; hearing loss; diastolic hypertension due to increased peripheral vascular resistance• pleural and pericardial effusions• myxedema coma• anemia; macrocytosis without anemia; high-output heart failure or angina• carpal tunnel syndrome• celiac disease• Laboratory abnormalities—hyponatremia; increased low-density lipoprotein and triglycerides; transient increase in creatinine

Causes of hypothyroidism

• >90% Hashimoto disease (autoimmune thyroiditis)

• iatrogenic cause

• iodine deficiency

• thyroid agenesis

• thyroiditis

Secondary hypothyroidism

• low TSH and low free T4

• causes—brain lesions; pituitary hemorrhage; surgery or radiotherapy

• infiltrative conditions (rare)

• <1% of all hypothyroidism

• TSH may be normal or high

• TSH level may be inappropriate for low free T4 (free T4 assays not highly reliable)

• thyroid tests must be interpreted in context of entire clinical picture

Hashimoto autoimmune thyroiditis• high female predominance

• may begin with hashitoxicosis; antithyroglobulin and antithyroid peroxidase (anti-TPO)—testing generally not recommended

• for diagnosis of hypothyroidism because >90% due to Hashimoto disease; testing may be useful prognostically

• In subclinical thyroid disease, antibodies may be predictive of likelihood

• of development of overt thyroid disease

Treatment of hypothyroidism• levothyroxine—mean dose, 1.6 μg/kg per day (based on lean body weight)

• can be started if patient young and healthy

• for older patients and/or patients with more cardiovascular problems, start with lower dose (eg, 25-50 μg/day)

• should be taken on empty stomach

• soy formulas known to interfere with absorption in infants (unclear in adults)

• goal of thyroid replacement, TSH level of 0.5 to 2.0 μIU/mL

• measure TSH every 6 wk; dose can be increasedm earlier if needed and if tolerated

• once patient stable, TSH can be checked once per year

• T3 therapy— overwhelming evidence that T3 supplementation or partial replacement not beneficial

• neurocognitive function and psychologic well-being may not return to normal with levothyroxine

• creates risk for hyperthyroidism and long-term effects

• subgroup of 16% with D-iodinase gene polymorphism may improve with appropriate T3 supplementation

• thyroid desiccated (eg, Armour Thyroid, S- Thyrar, Thyroid

• Strong) and liotrix (T4 and T3; Thyrolar) contain higher ratio of T3 (associated with increased risk for hyperthyroidism);

• drugs that interfere with levothyroxine—proton-pump inhibitors, H2-blockers, sucralfate, and antacids; bile acid sequestrants; calcium; carbamazepine (eg, Tegretol, Carbatrol, Epitol); dilantin; estrogen and estrogen derivatives; iron

Postpartum thyroiditis• occurs within 1 yr of delivery

• can occur after miscarriage or elective abortion

• occurs in 10% of pregnancies

• 25% in type 1 diabetes

• anti-TPO predictive in some patients

• common presentations—1) transient hyperthyroidism

• 2) transient hypothyroidism

• 3) transient hyperthyroidism, followed

• by transient hypothyroidism, then full recovery

• Each phase last few weeks to months

• symptoms generally milder than other forms of thyroid disease

• symptoms (eg, weakness, fatigue) overlap among hyperthyroidism, hypothyroidism, and postpartum depression

• screening for postpartum thyroiditis recommended in women with prolonged (>6 mo) postpartum depression

• (no evidence that screening changes outcome)

• prognosis—women who develop only hyperthyroid phase make complete recovery and do not develop chronic thyroid disease

• 25% to 50% of women who develop hypothyroid phase later develop long-term hypothyroidism

• postpartum thyroiditis likely to recur in subsequent pregnancy

Graves disease vs postpartum thyroiditis

• Graves disease —

• symptoms worse

• goiters larger and more likely to occur

• postpartum thyroiditis—no ophthalmopathy

• more common

• transient

Thyroid disease in pregnancy• measuring thyroid function—1) TSH ranges• upper limit in first trimester 2.5 μIU/mL, second trimester 3.0 μIU/mL, third trimester 3.5 μIU/mL• Lower limits, 0.1 to 0.3 μIU/mL• free thyroid assays (eg, ELISA, RIA) not accurate; 2) obtain FTI• 3) obtain total T4 and multiply upper and lower limits of normal by 1.5• risks—stillbirth spontaneous abortion; low birth weight; preterm delivery; preeclampsia• heart failure more likely in overt hyperthyroidism;• abruption more likely in overt hypothyroidism• symptoms of thyroid disease overlap with symptoms of pregnancy• Subclinical hyperthyroidism in pregnancy not associated with adverse pregnancy outcomes• some studies show subclinical hypothyroidism associated with adverse outcomes (including abruption

and low IQ)• thyroid hormone needs increase significantly in pregnancy• 75% of pregnant women need increased daily dose• measure FTI when pregnancy confirmed and when medications change• return to normal prepregnancy dose shortly after delivery

Subclinical thyroid disease in nonpregnancy

• data conflict

• subclinical hyperthyroidism probably more dangerous than subclinical hypothyroidism

• studies show decreased quality of life in subclinical hyperthyroid patients

Questions and answers:• elderly patient with hyperthyroidism dementia—can develop increased agitated behavior

anxiety changes, and depression

• consider treatment

• Pregnancy after radioablation therapy—waiting 6 mo generally recommended• patients on polypharmacy—check for

• interactions and advise patients when medications should be taken (eg, 2-4 hr after thyroid medication)

• patient with normal TSH and low free T4—generally, patient should not be treated

• if patient has signs or symptoms, perform further testing look for secondary hypothyroidism• greatest risks include atrial tachydysrhythmia (more common in elderly and in patients with

existing cardiovascular disease• May present in younger patients) and bone loss (risk for osteoporosis increased in uncontrolled

hyperthyroidism)

• Iodine deficiency—effects of specialty or noniodinized salts unclear;• patient with abnormal TSH (eg, 0.01 μIU/mL) and normal free T4—recheck in 3 to 6 mo;

consider shared decision making about magnetic resonance imaging

A 65-year-old woman is evaluated for a 3-week history of fatigue, nausea, and poor appetite. In the week before symptom onset, she had acute bronchitis with productive cough and fever. The patient has a 2-year

history of osteoarthritis of the knees that requires intra-articular corticosteroid injections every 3 to 4 months; her last injection was 3 months ago. Her only other medication is acetaminophen.

On physical examination, the patient looks tired. Temperature is 37.5 °C (99.5 °F), blood pressure is 112/58 mm Hg, pulse rate is 92/min, respiration rate is 17/min, and BMI is 32. The patient has cushingoid features and central obesity. There are multiple ecchymoses on the upper and lower

extremities. Decreased axillary and pubic hair is noted. There is bony hypertrophy and small effusions of the knees bilaterally but no evidence of warmth or erythema.

Laboratory studies: Adrenocorticotropic hormone (AM) 9 pg/mL (1.98 pmol/L)

Cortisol (8 AM) Initial measurement

1.4 µg/dL (38.6 nmol/L) (normal range, 5-25 µg/dL [138-690 nmol/L])After cosyntropin stimulation

9.0 µg/dL (248.4 nmol/L)Follicle-stimulating hormone

40 mU/mL (40 U/L)Luteinizing hormone35 mU/mL (35 U/L)

Prolactin14 ng/mL (14 µg/L)

Thyroid-stimulating hormone3.1 µU/mL (3.1 mU/L)Thyroxine (T4), free

1.2 ng/dL (15.5 pmol/L)Which of the following is the most likely cause of this patient’s current symptoms?

AAdrenal adenomaBExogenous corticosteroidsCPituitary microadenoma

DPrimary adrenal insufficiency

B Exogenous corticosteroids• This patient has central adrenal insufficiency. Use of systemic corticosteroids is the most common cause of

central adrenal insufficiency, with supraphysiologic dosages of exogenous corticosteroids causing disruption of hypothalamic/pituitary adrenocorticotropic hormone (ACTH) production. Consequently, the adrenal cortex atrophies. When subsequently challenged by stress, the hypothalamus and pituitary gland are unable to stimulate adequate adrenal production of cortisol. This central effect of exogenous corticosteroids can occur after only 3 weeks of suppressive therapy. The patient appears to have developed Cushing syndrome as a result of chronic systemic exposure to the intra-articular injections of corticosteroids. Despite her cushingoid features, however, she has clinical and biochemical evidence of adrenal insufficiency. Her low-normal serum ACTH level and her partial response to cosyntropin stimulation indicate that she has central (secondary) adrenal insufficiency. Patients with adrenal insufficiency often decompensate during concurrent illnesses. Because the rest of her pituitary function is normal, another cause of her loss of ACTH secretion is unlikely.

• An adrenal adenoma could cause a suppressed ACTH level, cushingoid features, and central obesity, but her symptoms suggest glucocorticoid deficiency. Furthermore, an adrenal adenoma would cause an elevated, not suppressed, cortisol level.

• A nonfunctioning pituitary adenoma is extremely unlikely in light of the isolated ACTH deficiency and the timing of symptom onset—3 months after exogenous corticosteroid administration. A functioning pituitary adenoma might produce excessive ACTH, but in that case both the ACTH and cortisol levels would be elevated, not suppressed as they are in this patient.

• Primary adrenal insufficiency (Addison disease) is typically associated with low cortisol production and elevated ACTH levels.

A 49-year-old woman is evaluated for recurrent urinary tract infections. Over the past 6 months, she has had four urinary tract infections. She has a 35-year history of poorly controlled type 1 diabetes mellitus. Home blood glucose readings range between 150 and 300 mg/dL (8.3 and 16.7 mmol/L), and hemoglobin A1c values

are typically greater than 8.7%. A review of systems is notable for orthostatic dizziness and intermittent episodes of constipation and diarrhea. She describes frequent urination of small volumes, difficulty initiating urination, and nearly

constant urinary dribbling. Current medications include nighttime insulin glargine and multiple daily injections of insulin lispro.

On physical examination, blood pressure is 140/86 mm Hg supine and 120/78 mm Hg standing, and pulse rate is 104/min both supine and standing. Results of the

general physical examination are otherwise noncontributory. On neurologic examination, she cannot feel a 10-g Semmes-Weinstein monofilament and has no

vibratory sensation below the knees. Her serum creatinine level has recently increased from 1.5 mg/dL (132.6 µmol/L)

to 2.3 mg/dL (203.3 µmol/L).Which of the following is the best next step in management?

ABegin chronic suppressive ciprofloxacin therapyBBegin oxybutynin

CMeasure postvoid urinary residual volumesDOrder pelvic CT

C Measure postvoid urinary residual volumes

• The most appropriate next step in management for this patient is to measure her postvoid urinary residual volumes. Diabetic neuropathy, a disorder that typically occurs in patients with a long history of diabetes mellitus, has various manifestations and may affect both the somatosensory and autonomic nervous systems. Symptoms of autonomic dysfunction include gastroparesis, constipation and/or diarrhea, orthostatic hypotension, and an atonic bladder. This patient with long-standing diabetes and established peripheral neuropathy is at risk for a neurogenic bladder, which can manifest as recurrent urinary tract infections and overflow incontinence. Measuring postvoid urinary residual volumes or obtaining a bladder ultrasonogram will determine whether high urinary residual volumes are present. If they are, prokinetic drugs (such as bethanechol chloride) can be given, or an intermittent urinary self-catheterization regimen can be initiated. Regular and complete bladder emptying will help reduce the incidence of urinary tract infection and possibly reverse or improve the patient’s renal insufficiency.

• Chronic suppressive antibiotic therapy with ciprofloxacin may create resistant bacterial strains. More importantly, such therapy will not address the urinary stasis that may be present because of her bladder dysfunction.

• Anticholinergic agents, such as oxybutynin, inhibit contraction of both the normal and unstable bladder. Oxybutynin is highly effective in the treatment of detrusor instability (overactive bladder). However, oxybutynin is contraindicated in patients with an atonic bladder and would likely exacerbate this patient’s problems.

• This patient’s history and examination findings do not suggest the presence of malignancy, so pelvic CT is not the appropriate next step in management. A CT scan would likely reveal nothing but an enlarged bladder and, possibly, hydronephrosis if contrast is used, and the contrast material could worsen renal function.

A 34-year-old woman comes for a follow-up evaluation. At an initial visit 4 weeks ago, she had fatigue, weight gain, and increased menstrual flow. At that time, results of laboratory studies included a thyroid-stimulating

hormone (TSH) level of 50 µU/mL (50 mU/L), a free thyroxine (T4) level of 0.5 ng/dL (6.5 pmol/L), and the presence of anti–thyroperoxidase and anti–thyroglobulin antibodies, and she was started on levothyroxine, 75

µg/d. Her history is notable for pernicious anemia treated with oral vitamin B12, 1000 µg daily.

Physical examination reveals a young woman with fully gray hair. Blood pressure is 94/58 mm Hg, pulse rate is 75/min, respiration rate is 12/min, and BMI is 25.7. There is a slight increase in the pigment of the mucous

membranes, and the thyroid gland is slightly enlarged and smooth. Cardiopulmonary examination findings are normal.

Results of repeat laboratory studies now show a TSH level of 7.1 µU/mL (7.1 mU/L) and free T4 level of 1.5 ng/dL (19.4 pmol/L).

Which of the following is the most appropriate next step in management?AIncrease the levothyroxine dosage

BMeasure the glutamic acid decarboxylase antibody levelCMeasure the thyroid-stimulating immunoglobulin titer

DPerform a cosyntropin stimulation test

D Perform a cosyntropin stimulation test• Performing a cosyntropin stimulation test is the most appropriate next step in management. This patient has

hypotension, increased pigmentation, and evidence of two other autoimmune disorders (pernicious anemia and Hashimoto disease). Therefore, adrenal insufficiency is very probable and can be confirmed by such a test. The combination of autoimmune adrenal insufficiency and other autoimmune endocrine disorders is referred to as the polyglandular autoimmune (PGA) syndrome, of which type 2 is the most common form. Nearly 50% of patients with type 2 PGA syndrome have autoimmune adrenal insufficiency on presentation, and another 20% have autoimmune adrenalitis with autoimmune thyroid disease or type 1 diabetes mellitus. Other common associations include pernicious anemia and autoimmune ovarian failure.

• The patient’s thyroid hormone replacement should be withheld until her adrenal function has been checked because treatment of her hypothyroidism alone may increase the clearance of cortisol, which could increase the severity of the cortisol deficiency and provoke an adrenal crisis. Increasing the thyroid hormone dose is likely to exacerbate cortisol deficiency and thus is contraindicated. Once adrenal insufficiency is confirmed, glucocorticoid replacement should be initiated before restarting or adjusting the levothyroxine therapy.

• The glutamic acid decarboxylase antibody level is frequently elevated in the preclinical period of type 1 diabetes mellitus. A positive test may help estimate her risk of developing type 1 diabetes but should have no effect on immediate management in this patient with probable adrenal insufficiency.

• Patients with Graves disease have an unregulated production of thyroxine (T4) and triiodothyronine (T3) because of the presence of autoantibodies against the thyroid-stimulating hormone receptor, which results in hypertrophy of the gland and autonomous production of thyroid hormone. Because this patient does not have Graves disease, checking her thyroid-stimulating immunoglobulin titer is unlikely to be useful.

A 67-year-old woman is seen for a follow-up visit. Three weeks ago, she had a predawn episode of hypoglycemia on the way to the bathroom that caused her to fall, fracturing her hip. The patient has had type 2 diabetes

mellitus for more than 20 years and has repeatedly had mild hypoglycemic episodes since the diagnosis. Although well tolerated to

this point, these episodes have become increasingly frequent over the past 6 months. Her current medications are neutral protamine Hagedorn

(NPH) insulin, 20 units, and regular insulin, 5 units, both injected before breakfast and supper. A review of her glucose log shows blood glucose

readings ranging between 70 and 150 mg/dL (3.9 and 8.3 mmol/L) when fasting and 50 and 250 mg/dL (2.8 and 13.9 mmol/L) during the day. Her

last measured hemoglobin A1c value was 7.8%. Which of the following changes should be made to her diabetes regimen?

AChange her medications to oral metformin and sitagliptinBChange her medications to insulin glargine and insulin lispro

CDecrease the dosages of NPH and regular insulin by 10%DIncrease her caloric intake

B Change her medications to insulin glargine and insulin lispro• Basal and rapid-acting insulin analogues, when dosed properly, reduce the risk of hypoglycemia. Current choices of

long- or intermediate-acting basal insulins include insulin glargine, insulin detemir, and neutral protamine Hagedorn (NPH) insulin. The optimal basal insulin should be peakless and have a 24-hour duration of action. Both insulin glargine and, to a lesser extent, insulin detemir meet these requirements. NPH insulin, on the other hand, does not and is usually administered twice daily because its duration of action typically extends only 12 to 18 hours with a peak of activity at 4 to 8 hours after administration, which can precipitate hypoglycemic episodes at other times. In one study, the risk of hypoglycemia was significantly higher during the overnight hours in patients taking NPH insulin versus insulin glargine at bedtime. An ideal prandial insulin has a brisk peak and a short overall duration of action to properly cover postprandial glucose excursions. Such pharmacokinetics are found with the rapid-acting insulin analogues lispro, aspart, and glulisine. In contrast, regular insulin has a duration of action of 6 to 8 hours and so is not an optimal prandial product.

• She should be encouraged to switch to a regimen of four injections of insulin per day, with a once daily injection of a basal insulin, such as insulin glargine, and mealtime injections of a rapid-acting analogue, such as insulin lispro.

• Patients with advanced type 2 diabetes mellitus who are on insulin should not be transferred to oral agents because the need for insulin suggests an already significant insulin deficiency that oral agents are unlikely to overcome. Glycemic control would inevitably deteriorate.

• Decreasing the dosage of NPH and regular insulin may diminish her overnight hypoglycemic episodes but would also result in higher blood glucose levels. Therefore, this change in the patient’s diabetes regimen is not appropriate.

• Increasing caloric intake to combat hypoglycemia is rarely indicated. Ideally, the insulin regimen should be adjusted on the basis of the patient’s nutritional intake, not vice-versa.