THYROID/VITAMIN D
| PARATHYROID DISEASE —Leonard J. Deftos, MD, Professor of Medicine in Residence, Department of Endocrinology,
University of California, San Diego, School of Medicine, and Head, Endocrine Research Laboratories, San
Diego Veterans Affairs Medical Center
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| Etiologies of hypercalcemia: hyperparathyroidism (most common); malignancies, including skeletal metastases;
high intake of vitamin D, A, or calcium (eg, erosive gastritis may allow increased absorption of calcium); dialysis
(eg, calcium concentration of dialysate too high); medications (eg, lithium, thiazide diuretics, theophylline); renal
disease (hypocalcemia more common, but hypercalcemia may occur transiently during diuretic phase or, rarely, as
tertiary hyperparathyroidism); genetic and endocrine dis--orders—primary hyperparathyroidism occurs as primary
disease or as part of multiple endocrine disorder; familial hypocalciuric hypercalcemia (FHH; autosomal dominant
trait); hyperthyroidism results in mild hypercalcemia in 10% to 15% of patients (resolves with treatment of thyroid
disease); hypoadrenalism (mechanism not fully understood); granulomatous diseases; other—immobilization in
patients with high bone turnover (eg, adolescents with long-bone fracture)
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| Calcium metabolism: gastrointestinal (GI) absorption largely depends on vitamin D; vitamin D and calcitonin stimulate
deposition in bone; bone resorption, influenced by parathyroid hormone (PTH), increases serum levels of calcium;
PTH and vitamin D influence reabsorption of calcium in urinary tract; physiologic pathways to
hypercalcemia—increased bone resorption; decreased renal excretion; increased GI absorption
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| History: useful for determining etiology (eg, distinguishing between primary hyperparathyroidism and malignancy);
primary hyperparathyroidism generally associated with long history of hypercalcemia (often mild); malignancies
associated with short history; more likely to see patient with hypercalcemia due to primary hyperparathyroidism in
office; if patient in hospital, malignancy more likely cause; family history—FHH; multiple endocrine neoplasia
(MEN); medical history—including immobilization, trauma, and medications
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| Laboratory studies: upper limit of normal calcium level may vary with laboratory; speaker uses 10.2 mg/dL, 10 mg/
dL for patients ≥50 yr of age; calcium levels decrease with age, so borderline levels in older patients should increase
index of suspicion; multiple determinations may be required; total serum calcium (corrected for albumin)
best test for hypercalcemia; serum phosphorus useful only during fasting state (prandial excursions obscure diagnostic
value); diagnosis—high serum calcium with low fasting serum phosphorus almost always primary hyperparathyroidism;
other studies—appropriate tests for malignancy and renal function; PTH assay and thyroxine (T4 )
levels to assess thyroid function; urine protein electrophoresis if myeloma suspected; levels of vitamins D and A
(dietary and medical sources); pituitary function if MEN suspected; calcitonin levels if medullary thyroid carcinoma
suspected; pancreatic function and catecholamine levels
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| Parathyroid glands: although most patients have 4 parathyroid glands, multiple ectopic glands may occur; normal
weight, 35 to 40 mg; circulation supplied by inferior thyroid artery; glands may be outside body of thyroid, as far
down as pericardium
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| Signs and symptoms: renal calculi; bone pain; peptic ulcer disease; pancreatitis; fatigue, depression, and confusion;
cardiovascular complications (controversial); many patients asymptomatic; mnemonic—“stones, bones, groans
(abdominal), and moans (psychologic)”; skeletal complica--tions—subperiosteal resorption highest in digits (radial
side), distal clavicle, and distal radius; densitometry of distal radius particularly useful for diagnosis (distinguishes
hyperparathyroidism from osteoporosis) and monitoring; kidney stones—classic symptom resulting from hypercalciuria;
24-hr urinary calcium level warranted when FHH suspected (diagnosis affects management; parathyroidectomy
not indicated)
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| Tertiary hyperparathyroidism: prolonged secondary hyperparathyroidism (associated with renal disease) leads to
autonomous function of parathyroid; diagnosis requires withholding vitamin D supplementation
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| Primary hyperparathyroidism: 100000 new cases each year in United States; higher incidence in women; most patients
have single adenoma (good cure rate); carcinoma rare, but clinically severe (calcium ≈15 mg/dL; PTH >10
times normal) and often recalcitrant to surgery; technetium 99m-sestamibi scan—localizing procedure to find adenoma;
not diagnostic
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| Secondary hyperparathyroidism: renal failure results in enlargement of all endocrine glands; medical manage--
ment—maintain high level of calcium during dialysis; use vitamin D preparations to suppress parathyroid gland;
use calcium-sensing-receptor antagonist (eg, cinacalcet) to inhibit secretion of PTH
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| Multiple endocrine neoplasia: type 1 generally associated with hyperparathyroidism; tumors affect parathyroid, pituitary,
and pancreas; screening family members may lead to early identification and treatment of subclinical disease
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| Treatment of hyperparathyroidism: surgery usually curative; localizing techniques—sestamibi scan (most popular;
radioactive isotope localizes to parathyroid at ≈2 hr); ultrasonography; computed tomography; magnetic resonance
imaging; fusion diagnostic procedures (images from ≥1 modality used to enhance visualization of gland);
tissue transplantation—patients with secondary hyperparathyroidism may have glandular tissue transplanted to
forearm, where it may remain functional; procedure contraindicated in patients with primary hyperparathyroidism,
even with 4-gland hyperplasia, because of neoplastic nature of tissue; intraoperative techniques—radio-guided parathyroidectomy
uses sestamibi probe to localize adenoma; monitoring PTH levels using quick assay (decrease of
≥50% indicates successful removal of tissue); quick PTH assay involves additional cost and may not result in
added benefit; not necessary for experienced surgeon
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| Clinical conundrums: normocalcemic hyperparathyroid--ism—patient has elevated PTH but normal levels of calcium;
scenario likely indicative of early-stage disease, when PTH and calcium levels intermittently elevated; surgery
not recommended, but patients should be monitored; persistently elevated PTH—PTH remains elevated (but
calcium levels within normal range) after successful para-thyroidectomy; levels eventually decrease; PTH assays—
if results do not agree with clinical diagnosis, consider more precise assay (eg, intact PTH, biointact PTH, whole
PTH)
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| Questions and answers: lithium and hypercalcemia—lithium increases serum calcium by inhibiting renal excretion
of calcium and (rarely) by stimulating production of high levels of PTH by parathyroid gland; hypercalcemia resolves
when lithium discontinued; watchful waiting—formerly recommended for all asymptomatic patients; currently
advised only when surgery contraindicated (or diagnosis uncertain) or in accordance with patient
preferences; damage to larynx during surgery—rare, especially when surgery performed by experienced surgeon;
preoperative localization of unilateral disease reduces risk
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| THE ABCS OF VITAMIN D—Ronald Tamler, MD, PhD, Instructor, Department of Medicine, Division of Endocrinology,
Diabetes, and Bone Diseases, Mount Sinai School of Medicine, New York, NY
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| Case study: man admitted with left-sided hip fracture and suspected “brittle bones”; bone mineral density (BMD)
measured 3 mo earlier revealed T-scores of -4.5 for lumbar spine and -3.8 for hip; risk factors for osteoporosis in
men—steroid use; alcohol consumption; low testosterone; others; patient history—HIV-positive; history of intravenous
drug use, smoking, and heavy consumption of alcohol; previous fracture; gastroesophageal reflux disease;
liver work-up for isolated elevated alkaline phosphatase (>1000 U/L); medications—heparin; oxycodone and acetaminophen
(Percocet); morphine; pantoprazole (Protonix); all can cause decreases in BMD; activity—sedentary
lifestyle; physical examination—soft tender shin bones; laboratory results—vitamin D not measurable; PTH 322
pg/mL; elevated alkaline phosphatase; elevated international normalized ratio (INR)
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| Vitamin D: family of secosteroid molecules (4 rings with 1 ring half-open, allowing conformational changes); fat-
soluble; 1,25-dihydroxyvitamin D—active form; sites of action include cell membranes and nuclear receptors; steroid
hormone, not vitamin (vitamin defined as required substance not endogenously produced); metabolism—
cholesterol precursor; sunlight converts endogenous 7-dehydrocholecalciferol into previtamin D (also available
from dietary sources); hydroxylation in liver to 25-hydroxy-vitamin D (measured when screening for vitamin D deficiencies;
less variable than other forms because of longer half-life [2 wk]); second hydroxylation (in kidneys)
converts to active form, 1,25-dihyroxyvitamin D, which feeds back negatively to inhibit hydroxylation; PTH increases
hydroxylation to active form; dietary sources—cod liver oil; oily fish; fortified milk; egg yolks; caveat—
limit time in bright sunlight to few minutes because mechanism that protects from vitamin D toxicity levels off
after set amount made
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| Vitamin D deficiency: storage in fat tissue greatly decreases bioavailability; lower limit of normal ≈30 ng/mL; individuals
who spend significant time in sun (eg, lifeguards) may have levels \>100 ng/mL; very low or very high
levels result in overt symptoms (eg, bone pain); causes—high latitudes or low exposure to sunshine; complete
coverage with sunscreen (decreases production to <1%); high concentration of melanin (dark-skinned people
need more exposure to sunlight to produce same amount of vitamin D); aging (reduced levels of previtamin D);
institutionalization (less access to outdoors); fat malabsorption; total parenteral nutrition; renal insufficiency
(low levels of active form of vitamin D [half-life 4 hr]); drugs (eg, antiseizure medications); prevalence—
common, especially at end of winter (one study found prevalence ≈30%); sequelae—rickets; osteomalacia
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 | Osteomalacia: low levels of vitamin D result in decreased absorption of calcium from gut (10%, compared to 30%
when vitamin D levels normal); resultant hypocalcemia stimulates production of PTH, which stimulates differentiation
of osteoclasts (responsible for bone resorption); increased resorption results in osteoporosis; severe osteomalacia
results in hydration and expansion of bone and bending of periosteum, causing diffuse pain, especially in
long bones
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| Stages of vitamin D deficiency: stage I—decreased GI absorption of calcium and decreased calcium reserve; osteoporosis,
but no osteomalacia on biopsy; stage II — biopsy shows osteomalacia, but no laboratory findings
other than low level of vitamin D; stage III — severe deficiency; clinical and chemical evidence of osteomalacia
(eg, elevated alkaline phosphatase)
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| Other consequences of deficiency: muscle weakness; para-thyroid hyperplasia; increase in falls in elderly, even
without osteoporosis
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| New recommendations: ≥800 IU of vitamin D daily for el-derly plus ≥1200 mg/day of elemental calcium (from diet
or supplements); lactating women may need even more vitamin D
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| Vitamin D2 and vitamin D3 : ergocalciferol (vitamin D2 )—plant-derived; originally used to supplement milk; available
as oral formulation of 50000 IU; cholecalciferol (vitamin D3 )—animal-derived; used in most multivitamins;
available up to 5000 IU; study—given initial doses of 50000 IU of vitamin D1 , vitamin D2 , and vitamin D3 , serum
level of vitamin D2 goes down rapidly after 10 days, while vitamin D3 reaches higher level and remains elevated
much longer
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| Repleting vitamin D: 40 IU raises serum level by 1 ng/mL; high doses often required; high doses of standard formulations
safe for patients with normal GI and renal function; 100000 IU vitamin D3 every 4 mo (equivalent to 800
IU/day) acceptable option if patients noncompliant with daily administration; study showed safety of daily administration
of ≤10000 IU for 5 mo; other options—50000 IU vitamin D2 , twice weekly, for 4 wk for patients
with serum levels of vitamin D <10 ng/mL (patients with malabsorption may require daily administra--tion); calcidiol
for patients with liver failure; calcitriol for patients with kidney failure, but lack of negative feedback loop
increases risk for toxicity (eg, hypercalcemia, kidney stones; close monitoring required)
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| Special cases requiring caution: granulomatous disease— granulomata activate vitamin D to 1,25 vitamin D, increasing
levels without negative feedback and possibly causing toxicity; hypercalcemia—supplementing vitamin
D counterproductive; kidney stones—may be exacerbated by increasing levels of vitamin D and calcium
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| Resolution of case: patient had high INR and low vitamin D and other fat-soluble vitamins, suggesting malabsorption;
treatment—50000 IU vitamin D2 weekly until level reached 30 ng/mL; PTH decreased to 122 pg/mL within
5 days, then to <50 pg/mL; alendronate (Fosamax) begun after vitamin D repleted; follow-up—BMD T-score increased
from -4.5 to -1.5
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Suggested Reading
Al-Aly Z et al: Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol
in patients with CKD. Am J Kidney Dis 50:59, 2007; Ambrogini E et al: Surgery or surveillance for mild
asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab
92:3114, 2007; Barone A et al: Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density
response to alendronate in elderly women with osteoporosis: a randomized controlled trial. J Am Geriatr Soc
55:752, 2007; Joy MS et al: Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct
costs of treatment. J Manag Care Pharm 13:397, 2007; Locatelli F et al: New perspectives in the management of secondary
hyperparathyroidism. Mini Rev Med Chem 7:591, 2007; Lowe H et al: Normocalcemic primary hyperparathyroidism:
further characterization of a new clinical phenotype. J Clin Endocrinol Metab 92:3001, 2007; Lumachi F et
al: Bone mineral density improvement after successful parathyroidectomy in pre- and postmenopausal women with
primary hyperparathyroidism: a prospective study. Ann N Y Acad Sci Jul 23, 2007 [Epub ahead of print]; Mazzeo S et
al: Multidetector CT in diagnostic work-up of patients with primary hyperparathyroidism. Radiol Med (Torino)
112:763, 2007; Mittendorf EA et al: Improvement of sleep disturbance and neurocognitive function after parathyroidectomy
in patients with primary hyperparathyroidism. Endocr Pract 13:338, 2007; Nakamura K et al: Age-related
decrease in serum 25-hydroxyvitamin D concentrations in the frail elderly: a longitudinal study. J Bone Miner
Metab 25:232, 2007; Narayan R et al: Parathyroidectomy versus cinacalcet hydrochloride-based medical therapy in
the management of hyperparathyroidism in ESRD: a cost utitility analysis. Am J Kidney Dis 49:801, 2007; Sakuma
M et al: Serum 25-OHD insufficiency as a risk factor for hip fracture. J Bone Miner Metab 25:147, 2007.
Educational Objectives
| The goal of this program is to improve the diagnosis and management of parathyroid disease and vitamin D deficiency.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Recognize hypercalcemia and determine its cause.
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| 2. List medications that affect serum calcium levels or bone mineral density.
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| 3. Differentiate among primary, secondary, and tertiary hyperparathyroidism.
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| 4. Diagnose vitamin D deficiency and assess stage of associated osteopathy.
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| 5. Implement vitamin D supplementation regimens appropriate to patient’s medical condition.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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 following has been disclosed: Dr. Tamler is on the speakers’ bureau
for Pfizer.
Acknowledgments
Dr. Deftos was recorded at Topics and Advances in Internal Medicine, sponsored by University of California, San Diego,
School of Medicine and held February 22-28, 2007, in San Diego; Dr. Tamler was recorded at Challenges in Internal
Medicine, sponsored by Mount Sinai School of Medicine, and held June 20-22, 2007, in New York, NY. The
Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
Information about upcoming meetings by these sponsors is available at http://cme.ucsd.edu and http://fusion.mssm.edu/cme.
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