ENDOCRINOLOGY UPDATE
From the 10th Annual Mayo Clinic Internal Medicine Update
Michael D. Whitaker, MD, Assistant Professor of Medicine, Mayo Clinic College of Medicine, and Consultant in
Endocrinology, Mayo Clinic, Scottsdale, AZ
| SUBCLINICAL THYROID DISEASE: FACT OR FICTION?
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| Thyroid function: controlled by hypothalamus and pituitary; hypothalamus secretes thyrotropin-releasing hormone,
which causes secretion of thyrotropin (TSH) by thyroid; negative feedback loop; level of thyroxine (T4 ) and triiodothyronine
(T3 ) feedback to hypothalamus and pituitary to shut down TSH production; TSH driver
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| Subclinical hypothyroidism: individual has no symptoms; TSH 5 to 10 mIU/mL (slightly elevated), with normal
T4 and T3 ; potential problems include progression to overt hypothyroidism, and lipid, cardiac, and overall mortality issues;
effect of treatment controversial; normal TSH—National Health and Nutrition Examination Survey (NHANES)
data from 1994 show normal range 0.4 to 4.0 mIU/L; 95% of rigorously screened normal volunteers have range of 0.4
to 2.5 mIU/L; no evidence of adverse outcomes with TSH of 2.5 to 4.0 mIU/L; question whether upper limit of normal
for TSH should be lowered (would result in more patients falling into category of subclinical hypothyroidism); how
common—study in Colorado of 25,000 participants with median age of 56 yr showed 9.5% had TSH >5.0 mIU/L, and
almost 20% of those taking thyroid hormone had TSH >5.0 mIU/L; TSH level tends to be higher in older women
(25% of women in senior citizen centers; Framingham data suggest ≈15% of women >60 yr of age have subclinical
hypothyroidism); prevalence ≈10% in overall population; 20% to 25% of women >60 yr of age probably have condition;
clinical significance of slightly elevated TSH—progressive rise in cholesterol level as TSH rises; compared to
normal individuals, mean low-density lipoprotein ≈4% higher, high-density lipoprotein equal, and triglycerides minimally
elevated; link between subclinical hypothyroidism and cardiovascular disease—meta-analysis showed risk
for coronary disease increased 1.65-fold (statistically significant); concluded that subclinical hypothyroidism associated
with coronary disease; however, unknown whether treatment will remove association; all-cause mortality and
circulatory mortality—meta-analysis showed discrepant results and no clear association; suggested that perhaps better
follow-up after hypothyroidism found explains decreased mortality; no indication about effect of treatment; mood,
cognition, and health status—double-blind crossover study looked at patients on thyroid hormone (euthyroid vs sublinical
hypothyroidism) over 12 wk; mild decrements in overall health status and mood (not significant) and significant
decrements in working memory; expert opinions—2004 “blue ribbon” panel stated that data associating
subclinical disease with adverse outcomes few and inconsistent; benefits of treatment not clearly documented, and
consequences of subclinical disease unknown; recommendation that not necessary to treat, except in pregnant women,
women >60 yr of age, and those at risk for thyroid dysfunction; consensus statement from Endocrine Society, American
Association of Clinical Endocrinologists, and American Thyroid Association—subclinical hypothyroidism
continuum of disease; treat most patients with TSH of 5 to 10 mIU/L, with determinant being clinical judgment of clinician;
treat all patients with TSH >10 mIU/L; should not overtreat; progression to overt hypothyroidism—study of
thyroid antibody-positive patients showed that 1 in 4 of those with TSH <5 mIU/L progressed to overt hypothyroidism
(20 yr later), 50% of those with TSH of 5 to 10 mIU/L; ≈99% of cases of hypothyroidism related to Hashimoto’s thyroiditis
(autoimmune disease); when to treat—in speaker’s practice, in all cases; reasons include increased lipids,
presence of goiter, antibody-positivity, and pregnancy; treatment easy, effective, and inexpensive, with no side effects
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| Subclinical hyperthyroidism: patient asymptomatic, with normal T4 , free T4 (FT4 ), or T3 ; suppressed TSH (if <0.1
mIU/L, diagnostic; 0.1 to 0.3 mIU/L “gray zone); differential diagnosis of low TSH—pituitary disease; patient on
thyroid hormone; drugs (amiodarone, dopamine, and dobutamine); patient recovering from hyperthyroidism; how
common—Colorado Thyroid Disease Prevalence Study (≈26,000 participants) showed 2% had subclinical hyperthyroidism,
and 20% of patients on thyroid hormone overtreated; associated cardiac problems—atrial fibrillation (AF);
20% of elderly patients with AF have subclinical hyperthyroidism (≈50% convert with therapy; 10% will have embolic
event); associated with increased heart rate, premature atrial contractions, increased mass of left ventricle (LV),
and decreased LV filling; bone problems—as TSH falls, risk for hip fracture increases (at TSH <1.0 mIU/L, risk significantly
increased); similar data for vertebral fractures; no increased risk for fracture if patient on thyroid hormone
and TSH normal; all-cause mortality—study of ≈1200 participants >60 yr of age; 6% had TSH <0.5 mIU/L, and all-
cause mortality ≈2 times greater than expected; cardiovascular and circulatory disease made up bulk of mortality; conclusion
that all-cause mortality and cardiovascular mortality, in particular, greater than normal in patients whose TSH
even slightly suppressed; dementia and Alzheimer’s disease—European study of ≈1800 participants >55 yr of age
over several years; those with suppressed TSH, when other variables adjusted, had 3.5-fold increased risk for dementia
and Alzheimer’s disease; effects of treatment not addresssed; bottom line—no good studies showing that normalization
of TSH improves problems associated with subclinical hyperthyroidism; consensus statement from Endocrine
Society, American Association of Clinical Endocrinologists, and American Thyroid Association (2004)—consider
observation and monitoring when TSH in 0.1 to 0.3 mIU/L range; however, prudent to investigate and treat if patient
symptomatic; if TSH <0.1 mIU/L, investigation and treatment warranted; utility of sensitive TSH assay—best test for
screening thyroid dysfunction and monitoring therapy in patients taking thyroid hormone (only test for patients taking
desiccated thyroid [combination of T3 and T4 ])
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| OSTEOPOROSIS TREATMENT FAILURE—NOW WHAT?
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| Treatment failure: defined in clinical and radiographic terms; clinically, means patients with ongoing atraumatic
fractures despite good therapy; bone density report—should contain patient demographics, model and manufacturer
of densitometer, region of interest (ROI; including side), name of technician, and coefficient of variation (CV) for machine;
technical quality of site and why site not examined (if this) occurred; actual bone mineral density (BMD) in gm/
cm2 and T score for each site examined; previous reports included if available; statement about which previous or
baseline study and ROI being used for comparison; statement about least significant change (LSC) at center (based on
measured precision error using 95% confidence interval) and statistical significance of comparison; report of any statistically
significant change in 2 sites between current study and previous study (in gm/cm2 and percentage of change);
comments on any outside study, including manufacturer and model on which previous studies performed; LSC—
minimal percentage change that indicates real biologic effect; most densitometers have good precision error (CV 1%-
2%); to obtain statistically significant difference between 2 regions, need to have change of at least 3% to 6%; when
following BMD, must have same densitometer, technician, and ROI used; compare actual BMD (not T score); need to
know LSC to determine whether changes statistically significant; if statistically significant, determination of biologic
effect possible; to prove radiographic failure, need to show statistically significant drop in actual BMD from one point
in time to another on same densitometer and same ROI; the more points in time compared, the more valid the conclusions;
all that is thin not necessarily osteoporosis
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| Osteomalacia: etiology drug-induced or nutritional; vitamin D deficiency—common; causes of abnormal vitamin D
metabolism include dietary insufficiency, malabsorption (eg, sprue), hepatic insufficiency, abnormal metabolism, and
drug-induced; when assessing, use total 25-hydroxy vitamin D (ergocalciferol [D2 ] and cholecalciferol [D3 ]); 3% of
human genes affected by vitamin D; most common disorder worldwide; need 1,25-dihydroxyvitamin D to absorb calcium
in gut; if calcium not absorbed properly, stimulation of parathyroid hormone (PTH) secretion; PTH levels increase,
leading to secondary hyperparathyroidism, which leads to phosphorus loss and increased bone turnover (as
shown by elevated bone alkaline phosphatase), leading to osteoporosis; if osteoporosis severe enough over time, impaired
mineralization leads to osteomalacia; how common—study of women with postmenopausal osteoporosis
showed that >50% had vitamin D insufficiency (values <30 ng/mL); 15% to 20% have frank vitamin D deficiency
(values <15 ng/mL); as common in south and southwest United States as in north and northwest; worldwide problem;
multiple myeloma—another condition leading to thin bones and fractures; rate of fracture higher than expected with
osteoporosis; consider if patient failing treatment for osteoporosis; bottom line—osteomalacia not osteoporosis (both
have low BMD and both lead to fractures, but treatments entirely different)
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| Treatment: adherence—studies found patients poorly adherent to bisphosphonate therapy; probably 50% of women
prescribed bisphosphonates not taking them or not taking them properly; improving compliance—study showed
that after 6 mo, compliance lower for those taking weekly dose of bisphosphonate than those on once-monthly ibandronate
(Boniva); another study showed that if pointed out to women ahead of time that fracture data for weekly
dose slightly better than with monthly dose, they tend to adhere to weekly dose better
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 | Effectiveness of bisphosphonates: poorly absorbed orally (<0.5% of tablet); if antiresorptive therapy started (particularly
bisphosphonates), bone resorption markers (eg, urinary N-telopeptide [NTx]) fall by 20% to 80% within 4 to 6
wk and remain low as long as treatment ongoing; failure to show fall in markers means improper absorption or patient
compliance issue
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| Combination therapy: 2 categories of treatment those that decrease bone resorption and those that increase bone formation
(PTH [eg, Forteo]); if need to change treatment, can combine agents (different antiresorptives together or
antiresorptive plus “bone former”) or switch to different class of agents; study data—estrogen and bisphosphonates,
raloxifene and bisphosphonates, estrogen and PTH, and raloxifene and PTH synergistic; bisphosphonates and
PTH not synergistic; no studies about effect on fracture rates; as rule, combination therapy not recommended;
switching to different class of drug (usually from bisphosphonate to PTH) preferred; good data to show that PTH effective
in reducing fractures
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| Summary: if patient truly failing (clinically or radiographically), diagnosis correct, and patient adherent, switch to anabolic
agent or combined therapy (last resort)
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| Questions and answers: frequency of BMD testing—when patient started on therapy, speaker favors monitoring
patient yearly for 1 to 2 yr or up to 3 yr afterward to establish that BMD stable; when stable, reduce to 2-yr intervals;
treatment of vitamin D deficiency—first determine etiology; if total 25-hydroxy vitamin D <15 ng/mL, place patient
on vitamin D 50,000 U once weekly for 6 to 8 wk and recheck 25-hydroxy vitamin D several weeks later; if deficiency
mild, place patient on vitamin D 1000 U daily (over-the-counter); if patient on pharmacologic dose, keep close eye on
serum calcium and 25-hydroxy vitamin D (be aware of vitamin D intoxication); when to perform dual energy x-ray
absorptiometry (DEXA) on men—unknown; goal to assess individual’s risk for fracture; criteria well defined for
women (but not for men); speaker would recommend in man with other historical risk factors that suggest possibility
of developing fracture (eg, on steroids, previous fracture, strong family history, weight loss, chronic diarrhea); when
to screen for thyroid disease—current recommendations include all women >50 yr of age should have screening
TSH; frequency of TSH testing if patient on thyroid hormone—if patient on thyroid hormone for some time, stable,
and weight not changing, TSH checked once yearly; whether woman, 68 yr of age, with osteoporosis, but normal vitamin
D level, not on hormones, on calcium, walks daily, and unable to take oral bisphosphonates should be on intravenous
(IV) ibandronate or zoledronic acid (eg, Reclast)—try another antiresorptive; raloxifene also effective if
no contraindications; IV bisphosphonates effective, eg, ibandronate; new once-yearly formulation of zoledronic acid
(Zometa); also consider anabolic agent (eg, PTH; advantage of using first in this case that antiresorptive agent can be
added later if necessary); takes ≈1 yr to see effect of PTH on bone; length of sunlight exposure to produce 800 IU of
vitamin D per day—unclear; as little as possibly 15 to 20 min while wearing short sleeves and shorts will give adequate
levels of vitamin D; more studies needed; if elevated PTH ever associated with primary hyperthyroidism—
patients with hyperthyroidism can become hypercalcemic (non–PTH-dependent phenomenon); increased bone turnover
related to thyroid itself; case reports of patients with combined hyperthyroidism and hyperparathyroidism; classic
response low PTH in patients with hyperthyroidism if calcium elevated; if PTH normal or elevated, possibly dealing
with 2 disease processes; nasal calcitonin—least effective antiresorptive; used only if patient allergic to bisphosphonates
or has contraindication to estrogen or raloxifene; whether young healthy woman with osteopenia should be
treated—goal to identify individuals at risk for fracture in future; if individual has significant fracture risk, treat; do
not “treat bone density”; no single parameter that determines whether patient should be treated; whether all patients
with osteoporosis should receive vitamin D—yes, as long as calcium dynamics normal; should receive 800 to 1000
IU of vitamin D daily; studies show that 400 IU daily of vitamin D does not prevent fracture; bisphosphonates in setting
of reduced creatinine clearance—studies looked at alendronate and risedronate; neither one lost efficacy in setting of
chronic kidney disease or caused kidney disease to worsen; speaker uses bisphosphonates in up to stage 2 or 3 of
chronic kidney disease; not enough data on IV bisphosphonates
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Suggested Reading
Canalis E et al: Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 357:905, 2007; Cappola AR et
al: Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 295:1033, 2006; Cooper DS: Approach to
the patient with subclinical hyperthyroidism. J Clin Endocrinol Metab 92:3, 2007; Farooki A et al: Anabolic therapies
for osteoporosis. N Engl J Med 357:2410, 2007; Freyschuss B et al: Calcium and vitamin D for prevention of
osteoporotic fractures. Lancet 370:2098, 2007; Gharib H et al: Subclinical thyroid dysfunction: a joint statement on
management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the
Endocrine Society. J Clin Endocrinol Metab 90:581, 2005; Helfand M, U.S. Preventive Services Task Force:
Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive
Services Task Force. Ann Intern Med 140:128, 2004; Holick MF: Vitamin D deficiency. N Engl J Med 357:266,
2007; Ibay AD et al: Management of subclinical hypothyroidism. Am Fam Physician 71:1763, 2005; Khosla S et
al: Clinical practice. Osteopenia. N Engl J Med 356:2293, 2007; Levine JP: Effective strategies to identify postmenopausal
women at risk for osteoporosis. Geriatrics 62:22, 2007; Meltzer M: Vitamin D deficiency: cultural influence
and physician responsibility. Arthritis Rheum 57:1107, 2007; Pinkerton JV et al: Combination therapy for treatment
of osteoporosis: A review. Am J Obstet Gynecol 197:559, 2007; Russell RG: Bisphosphonates: mode of action and
pharmacology. Pediatrics 119 Suppl 2:S150, 2007; Silverman SL et al: Reduced fracture rates observed only in patients
with proper persistence and compliance with bisphosphonate therapies. South Med J 100:1214, 2007; Spong
CY: Subclinical hypothyroidism: should all pregnant women be screened? Obstet Gynecol 105:235, 2005; Surks MI
et al: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228,
2004; Walsh JP et al: Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med
165:2467, 2005; Wilson GR et al: Subclinical thyroid disease. Am Fam Physician 72:1517, 2005.
Educational Objectives
| The goal of this program is to improve the management of subclinical thyroid disease and osteoporosis. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Recognize subclinical hypo- and hyperthyroidism.
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| 2. Determine when to treat subclinical hypo- and hyperthyroidism.
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| 3. Review the problems associated with subclinical thyroid disease.
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| 4. Describe the necessary information in a bone mineral density (BMD) report.
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| 5. Utilize the appropriate treatment strategy for osteoporosis.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee to disclose relevant financial relationships within the past 12 months that might create any personal
conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the faculty and the
planning committee reported nothing to disclose.
Acknowledgements
Dr. Whitaker was recorded at the 10th Annual Mayo Clinic Internal Medicine Update, held October 4-7, 2007, in Sedona,
AZ, and sponsored by the Mayo Clinic College of Medicine. The Audio-Digest Foundation thanks Dr. Whitaker
and the Mayo Clinic College of Medicine for their cooperation in the production of this program.
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