Thyroid & Parathyroid Gland

Regulasi Aksis TiroidPENDREDSYNDROME

Iodine +Tyrosil ResiduesIodidePeroxidasePLASMAFOLLICULAR CELLCOLLOIDIodideDietary IodideTraping Iodine + Tyrosil ResiduesMIT + DITT4 + T3 Thyroglobulin Deiodo- TyrosinaseMIT + DITT4 + T3T4 + T3 ThyroglobulinT4 T3MIT DITProtease

Thyroid Disease Can Have Widespread EffectsThyroidIncreased LDL CholesterolElevated TriglyceridesLiverConstipationDecreased GI Activity IntestinesDecreased FertilityMenstrual AbnormalitiesMay Harm Development of Infant

ReproductiveSystemDepressionDecreased ConcentrationGeneral Lack of InterestBrainDecreased Heart RateIncreased/Decreased Blood PressureDecreased Cardiac OutputHeartDecreased FunctionFluid Retention and EdemaKidneysHypohyroidism AffectsMany Body Systems and Overall Health

Prevalence of Elevated Serum TSH by Decade of Age and GenderAt

Prevalence of Abnormal Thyroid FunctionThe Colorado Thyroid Disease Prevalence study Used thyroid stimulating hormone (TSH) levels as a measure of thyroid functionPrevalence of elevated TSH levels (hypothyroidism) was 9.5% and the prevalence of decreased TSH levels (hyperthyroidism) was 2.2%Lipid levels increased as thyroid function declined40% of patients taking thyroid medications had abnormal TSH levelsCanaris GJ, et al. Arch Intern Med. 2000;160:526-534.

McDermot MT and Ridgway EC. J Clin Endocrinol Metab 86:4585-4590

1%10%1%13%NHANES* (2002)NA12%Rotterdam (1993)3%16%4%21%Colorado* (2000)2.3%5.9%Framingham (1987)3%8%Whickham follow-up (1995)MenWomenStudySawin CT, et al. Arch Intern Med. 1985;145:1386-1388.Vanderpump MP et al. Clin Endocrinol (Oxf). 1995;43:55-68. Canaris GJ, et al. Arch Intern Med. 2000; 160:526-534.Hak AE, et al. Ann Intern Med. 2000;132:270-278.Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.Prevalence of Elevated TSH by Gender*Percentage calculated by decade of life.

Thyroid-Stimulating Hormone (TSH) AssaysKey test for diagnosis of hypothyroidism and hyperthyroidismTSH assay sensitivity has improved with subsequent test generationsFirst generation: RIA Sensitivity: 1.0 IU/mLSecond generation: IRMASensitivity: 0.1 IU/mLThird generation: ELISASensitivity: 0.03 IU/mLLadenson PW, et al. Arch Intern Med. 2000;160:1573-1575.Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.Zophel K, et al. Nuklearmedizin. 1999;38:150-155.

Thyroid Disease Spectrum0105TSH, IU/mLMild Thyroid FailureTSH >4.0 IU/mL, Free T4 NormalOvert HypothyroidismTSH >4.0 IU/mL, Free T4 LowEuthyroidTSH 0.4-4.0 IU/mL, Free T4 NormalThyrotoxicosisTSH

Screening for Thyroid Dysfunction Recommendations for Asymptomatic AdultsOrganizationAmerican Thyroid Association

American Association ofClinical Endocrinologists

American College ofPhysiciansScreening RecommendationWomen and men >35 years of age should be screened and every 5 years later

Older patients, especially women, should be screened

Women >50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluatedLadenson PW, et al. Arch Intern Med. 2000;160:1573-1575.Cooper DS. N Engl J Med. 2001;345:260-265.Ann Intern Med. 1998;129:141-143.

Additional Laboratory Tests for Thyroid FunctionTestNormal LevelsWhen to UseSerum total T45-11 g/dLBound and free T4; use with TSH for diagnosis

Free T40.7-1.8 ng/dLUse with TSH to assess degree of hypothyroidism

TPOAb, TgAbNegativeIn combination with TSH, predictor of disease progressionEndocr Pract. 2002;8:457-469.Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Goals for Treating Thyroid DiseaseHypothyroidismRestore thyroid hormones to normal levelsLevothyroxine sodium is the treatment of choice HyperthyroidismRestore a eumetabolic state3 treatments available: antithyroid drugs, radioactive iodine (131I), and thyroid surgerySinger PA, et al. JAMA. 1995;273:808-812.

Types of HypothyroidismPrimary hypothyroidism: caused by decreased production of T4 and T3 due to thyroid dysfunctionSecondary hypothyroidism: caused by decreased thyroidal stimulation by TSH; may be caused by pituitary (TSH) or hypothalamic (TRH) diseaseBraverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Causes of primary hypothyroidismCommonAutoimmune lymphocytic thyroiditis (Hahimoto)RadioiodineThyroid surgeryDrugs: antithyroid drugs (PTU,Crbimazole),amiodarone, lithium.RareInfiltrationDysgensisThyroid hormone resistanceIodine deficiencyIodine excess (Wolff-Chaikoff effect)Chew and Leslie. Clinical Endocrinology and Daiabetes,2006

Clinical Manifestations of HypothyroidismFatigueWeight gain Dry skin and cold intolerance Yellowing or yellow hue of the skin Coarseness or loss of hair HoarsenessGoiterDelayed relaxation of deeptendon reflexesAtaxia Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.ConstipationMemory and mental impairment Decreased concentration Depression Irregular or heavy menses and infertilityMyalgiasHyperlipidemiaBradycardia and hypothermiaMyxedema

Cholesterol Levels Elevate With Increasing TSH LevelsCanaris GJ, et al. Arch Intern Med. 2000;160:526-534.209216223226229238239270267200210220230240250260270280Mean Total Cholesterol Level, mg/dL5.1-10>10-15>15-20>20-40>40-60>60-80>80TSH, IU/mLAbnormalEuthyroid

Correlation of Serum TSH and Cholesterol in Hypothyroid PatientsPatients (n)TSH Range (IU/mLMean Cholesterol (mg/dL)390 1.1 to 5.0231130 5.1 to 10.0244*13010.1 to 15.0252* 8115.1 to 20.0248*11520.1 to 40.0260* 9940.1 to 80.0310* 73 >80.0347**Statistically significantly (P

Hypothyroidism and DepressionHave Many Common FeaturesDepressionHypothyroidism Sleep decrease Suicidal ideation Weight loss Appetite increase/ decreaseNemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20. Bradycardia Cardiac and lipidabnormalities Cold intolerance Delayed reflexes Goiter Hair and skin changes Constipation Appetite decrease Decreased concentration Decreased libido Delusions Depressed mood Diminished interest Sleep increase Weight increase Fatigue

Hypothyroidism Treatment Goal EuthyroidismThe goal of hypothyroidism therapy is to replace thyroxine to mimic normal, physiologic levels and alleviate signs, symptoms, and biochemical abnormalities

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Treatment of Hypothyroidism Thyroid Hormone ReplacementTreatment of choice: levothyroxine (synthetic levothyroxine, LT4)Chemically stableT4 converted to T3 in peripheryOther therapies (T3 or T3 and T4 mixtures)Thyroid USP, liothyronine, liotrix, thyroglobulinSome disadvantages, no advantages versus levothyroxineSinger PA, et al. JAMA. 1995;273:808-812.Endocr Pract. 2002;8:457-469.Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Recommendations for Treatment of HypothyroidismAACE guidelines:AACE advocates the use of a high-quality brand preparation of levothyroxine. It is preferable to maintain the patient on the same brand of levothyroxine throughout treatment.Importantly, patients should be reevaluated and retitrated after an interval of at least 6 weeks following any change in levothyroxine brand or dose.American Thyroid Association recommendations:For patients who have recently started receiving levothyroxine or who have had their dosage, type, or brand of thyroid preparation changed, the TSH concentration should be measured after 8 to 12 weeks.Endocr Pract. 2002;8:457-469.Singer PA, et al. JAMA. 1995;273:808-812.

Diagnosis Algorithm for Hypothyroidism TSH0.4 to 4.0 IU/mLPatientEuthyroidTSH4.0 IU/mLGo to Next StepSinger PA, et al. JAMA. 1995;273:808-812.Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.SuspectHypothyroid?Test TSH

Primary Hypothyroidism Diagnosis AlgorithmTSH >4.0 IU/mLTest FT4 *Free T4 estimateDemers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320.Ayala AR, et al. The Endocrinologist. 1997;7:44-50.Endocr Pract. 2002;8:457-469.

Hypothyroidism TreatmentLevothyroxine sodium is the treatment of choice for the routine management of hypothyroidismAdults: about 1.7 g/kg of body weight/dChildren up to 4.0 g/kg of body weight/dElderly

Primary Hypothyroidism Treatment AlgorithmTSH >4 IU/mLTSH

Therapy Initiation and TitrationTherapy with levothyroxine sodium products requires individualized patient dosingCareful titration: use a formulation with consistent dosesClinical evaluation: symptoms resolve more slowly than TSH responseLaboratory monitoring: need consistent, sensitive TSH measurements

Individualized patient dosing is influenced byAge and weightCardiovascular healthSeverity and duration of hypothyroidismConcomitant disease states and treatmentEndocr Pract. 2002;8:457-469.Singer PA, et al. JAMA. 1995;273:808-812.

Therapy MonitoringClinical and laboratory monitoring enableEvaluation of the clinical responseAssessment of patient complianceAssessment of drug interactions, if applicableAdjustment of dosage, as neededClinical and laboratory evaluations should be performed At 6- to 8-week intervals while titratingAnnually once a euthyroid state is establishedSinger PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds.Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Special Considerations Elderly PatientsHigher prevalence of hypothyroidism compared with younger personsAppropriate dose selection and monitoring critical for elderly patients with cardiac abnormalitiesPoor patient compliance, adherence, and persistence may be an issueFelicetta JV. Consultant. 2002;1597-1606. Available at: www.consultantlive.com. Accessed July 1, 2003.

Caution in Patients With Underlying Cardiac DiseaseUsing LT4 in those with ischemic heart disease increases the risk of MI, aggravation of angina, or cardiac arrhythmiasFor patients

Impact of Maternal Hypothyroidism on Subsequent Neuropsychological Development of OffspringUndiagnosed hypothyroidism in pregnant women may adversely affect fetusesTreating maternal hypothyroidism during pregnancy appears to be beneficial, even when treatment falls short of euthyroid statusScreening for hypothyroidism before or very early in pregnancy may be warrantedHaddow JE, et al. N Engl J Med. 1999;341:549-555.

Special Considerations Levothyroxine Therapy With Other PopulationsPregnant womenThyroid failure may impede the intellectual development of the childIncreased LT4 doses may be necessaryTSH levels should be monitored each trimesterPostpartum thyroiditisCan lead to symptomatic thyrotoxicosis and/or hypothyroidismReported prevalence varies from 2% to 21%Has been associated with postpartum depressionCan lead to chronic hypothyroidismSynthroid [package insert]. Abbott Laboratories; 2003.Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Treating Hypothyroidism Before and During PregnancyEncourage adherence with levothyroxine replacement therapy before conceptionMonitor TSH levels before conception and during first trimesterIncrease the levothyroxine dosage in athyreotic patients by 25%-50% when pregnancy is confirmedMonitor TSH levels every 6 to 8 weeks throughout pregnancyReinstate prepregnancy levothyroxine dosage immediately following deliveryGharib H, et al. Endocr Pract. 1999;5:367-368.Mandel SJ, et al. N Engl J Med. 1990;323:91-96.

Subclinical HypothyroidismTreatments

Subclinical HypothyroidismPrevalenceWorldwide prevalence between 1% and 10%Highest rates are in women older than 60 years of ageOver the age of 74, 16% of men and 21% of women have the disorderCooper DS. N Engl J Med. 2001;345:260-264.

Prevalence and Incidence of Subclinical HypothyroidismPrevalence4% to 10% in large population screening surveysIncreases with increasing ageIs more common in women than in menIncidence2.1% to 3.8% per year in thyroid antibody-positive patients0.3% per year in thyroid antibody-negative patients McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.Biondi B, et al. Ann Intern Med. 2002;137:904-914.

Definition of Subclinical HypothyroidismElevated TSH level (>4.0 IU/mL)Normal total or free serum T4 and T3 levelsFew or no signs or symptoms of hypothyroidismMcDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000;1001.

50403020100Participants, %01234Number of SymptomsEuthyroidMild Thyroid FailureHypothyroid>35%>25%Many Patients With Hypothyroidism Report No Symptoms Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.

Causes of Subclinical HypothyroidismExogenous factorsLevothyroxine underreplacementMedications, such as lithium, cytokines, or iodine-containing agents (eg, amiodarone)Antithyroid medications131I therapy or thyroidectomyEndogenous factorsPrevious subacute or silent thyroiditis Hashimoto thyroiditisBiondi B, et al. Ann Intern Med. 2002;137:904-914.

Subclinical Hypothyroidism and Cardiovascular DiseaseCardiac manifestationsLeft ventricular systolic and diastolic dysfunctionIncreased systolic time intervalMyocardial infarctionCoronary artery diseaseElevated total cholesterol levels, LDL-C levels, and triglyceride levelsAortic atherosclerosisHyperhomocysteinemiaBiondi B, et al. Ann Intern Med. 2002;137:904-914.Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320.Aldin V, et al. Am Fam Physician. 1998;57:776-780.

Subclinical Hypothyroidism and Aortic Atherosclerosis in WomenPresence of Aortic AtherosclerosisHak AE, et al. Ann Intern Med. 2000;132:270-278.Women With Mild Thyroid FailureEuthyroidWomenWomen With Mild Thyroid Failure and Antibodies to Thyroid PeroxidaseEuthyroid Women Without Antibodies to Thyroid Peroxidase

Subclinical Hypothyroidism Affects Cardiac FunctionCardiac function is subtly impaired in patients with mild thyroid failureAbnormalities can include Subtle abnormalities in systolic time intervals and myocardial contractilityDiastolic dysfunction at rest or with exerciseReduction of exercise-related stroke volume, cardiac index, and maximal aortic flow velocityThe clinical significance of the changes is unclearMcDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:1004.

Subclinical Hypothyroidism May Increase Cardiovascular Disease RiskMild thyroid failure has been evaluated as a cardiovascular risk factor associated withIncreased serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levelsReduced high-density lipoprotein cholesterol (HDL-C) levelsIncreased prevalence of aortic atherosclerosisIncreased incidence of myocardial infarction

The Rotterdam Study Design and ObjectivesA population-based cross-sectional cohort study conducted in a district of Rotterdam, the NetherlandsCohort included 3105 men and 4878 women aged 55 and olderThyroid status was determined from a random sample of 1149 elderly women (mean age 69 7.5 years) selected from the studyThe study's objective was to investigate whether mild thyroid failure and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction

Subclinical Hypothyroidism Increases Risk of Myocardial Infarction (MI)Findings from the Rotterdam StudySubclinical Hypothyroidism contributed to 60% of MI cases in patients with diagnosed subclinical hypothyroidism, and 14% of all MI instances in the study populationSubclinical Hypothyroidism appeared to be a strong indicator of risk for aortic atherosclerosis and MI in older womenThyroid autoimmunity by itself was not associated with aortic atherosclerosis or MIHak AE, et al. Ann Intern Med. 2000;132:270-278.

Subclinical Hypothyroidism Elevates Serum Lipid LevelsCanaris GJ, et al. Arch Intern Med. 2000;160:526-534.*Total-C indicates total cholesterol; LDL-C, LDL-Cholesterol; HDL-C, HDL-Cholesterol050100150200250300Lipid Levels, mg/dLTotal-C* LDL-C*HDL-C*Triglycerides

Potential benefits from treatmentPrevent progression to overt hypothyroidismImprove serum lipid profile, which may reduce the risk of death from cardiovascular causesReduce symptoms, including psychiatric and cognitive abnormalitiesCooper DS. N Engl J Med. 2001;345:260-264.Rationale for Treating Mild Thyroid Failure

Mild Thyroid Failure Treated With Levothyroxine Therapy: Effects on Total Cholesterol-40-35-30-25-20-15-10-50Gorman etal, 1979Elder et al,1990Wiseman et al,1993 Change in Total Cholesterol (mg/dL), %Tanis BC, et al. Clin Endocrinol. 1996;44:643-649.

Levothyroxine Therapy Reduces Cholesterol in Subclinical HypothyroidismTSHTotal CholesterolLDL-C02468101214TSH (IU/mL)LT4Placebo230240250PlaceboTC (mg/dL)140145150155LDL-C (mg/dL)Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.Basel Thyroid Study (N=63)PlaceboLT4LT4

The Rate of Progression of Subclinical Hypothyroidism to Overt HypothyroidismSubclinical Hypothyroidism is a common disorder that frequently progresses to overt hypothyroidismProgression has been reported in about 3% to 18% of affected patients per yearProgression may take years or may rapidly occurThe rate is greater if TSH is higher or if there are positive antithyroid antibodiesThe rate may also be greater in patients who were previously treated with radioiodine or surgery

Treatment of subclinical hypothyroidism Whether to treat subclinical hypothyroidism remains a dilemma.Most clinicians treat subclinical hypothyroidism who have a serum TSH > 10 mIU/L. Whereas opinions differ about the management of mild disease in which TSH ranges between 4.5 10 mIU/L especially in elderly asymptomatic patients

Biondi and Cooper Endocrine Reviews. 2008 ; 29:76-131

Factors That May Reduce Levothyroxine EffectivenessMalabsorption SyndromesPostjejunoileal bypass surgeryShort bowel syndromeCeliac diseaseReduced AbsorptionColestipol hydrochloride SucralfateFerrous sulfateFood (eg, soybean formula)Aluminum hydroxideCholestyramineSodium polystyrene sulfonateDrugs That Increase ClearanceRifampinCarbamazepinePhenytoinFactors That Reduced T4 to T3 ClearanceAmiodaroneSelenium deficiencyOther MechanismsLovastatinSertraline Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. 2000.Synthroid [package insert]. Abbott Laboratories; 2003.

Thyroid Status of Treated PatientsCanaris GJ, et al. Arch Intern Med. 2000;160:526-534.020406080100Participants, %HyperthyroidSubclinicalHyperthyroid 0.9 20.7>20%SubclinicalHypothyroidHypothyroid 17.6 0.7Undertreated>18%Colorado Thyroid Disease Prevalence Study

Under-Replacement RisksSwitching between different levothyroxine formulations can lead to under-replacementUnder-replacement risk (TSH >5.0 IU/mL)Continued hypothyroid stateHyperlipidemiaDecreased heart rate and ventricular contractilityIncreased peripheral vascular resistance and diastolic pressureMemory loss, fatigue, and weight gainDepression

Over-Replacement RisksSwitching a narrow therapeutic index drug, such as LT4, without retesting and retitrating can cause inconsistent TSH control, resulting in over-replacement Over-replacement risks (TSH

SummaryHypothyroidism increases in prevalence and incidence among the elderly.Autoimmune thyroiditis is the most common cause of hypothyroidism Levothyroxine sodium is the treatment of choice for the routine management of hypothyroidismTreatment and management of subclinical hypothyroidism and population screening are still controversialSpecial considerations may apply in planning treatment due to changes in the metabolic clearance of thyroid hormone, drug interactions and potential adverse reaction

Parathyroid Hormone (PTH)Is an 84 aminoacid chain, but its biologically activity resides in the first 34 residues.In the parathyroid gland, a Pre-Pro-PTH are synthesizedPre-Pro-PTH is converted to Pro-PTH and Pro-PTH converted to PTH.When serum Calcium level falls, signal is transduced through calcium sensing receptors, and secretion of PTH increased.

Principles of Human Anatomy and Physiology, 11e*PARATHYROID GLANDSThe parathyroid glands are embedded on the posterior surfaces of the lateral lobes of the thyroid principal cells produce parathyroid hormoneoxyphil cells function is unknown Parathyroid hormone (PTH) regulates the homeostasis of calcium and phosphate increase blood calcium leveldecrease blood phosphate levelincreases the number and activity of osteoclastsincreases the rate of Ca+2 and Mg+2 from reabsorption from urine and inhibits the reabsorption of HPO4-2 so more is secreted in the urinepromotes formation of calcitriol, which increases the absorption of Ca+2, Mg+2,and HPO4-2 from the GI tract

Principles of Human Anatomy and Physiology, 11e*Histology of Parathyroid GlandPrincipal cells produce parathyroid hormone (PTH)Oxyphil cell function is unknown

Biologic Effects of PTH The central function of PTH is to regulate ionized ( Ca2+) levels by concerted effects on three principal target organ :BoneIntestinal mucosa KidneyThe effect of PTH on intestinal calcium absorpsion is indirect, resulting from increased renal production of the intestinally active vitamin D metabolite 1,25(OH)2D. By its integrated effects on kidney, gut and bone PTH acts to increased the flow of calcium into the extracellular fluid and thus defend against hypocalcemia. Removal of the parathyroid glands results in profound hypocalcemia and ultimately in tetani and death

Principles of Human Anatomy and Physiology, 11e*

Figure 1813

Principles of Human Anatomy and Physiology, 11e*Regulation of Calcium Blood LevelsHigh or low blood levels of Ca+2 stimulate the release of different hormones --- PTH or Calcitonin

Biosynthesis, Storage & Secretion of PTH PTH is synthesized as the preprohormone (Preproparathyroid Hormone) by parathyroid gland chief cells The active form of PTH is cleaved from the preprohormone before release from the gland PTH is synthesized continously (it is either released from the gland or degraded)PTH is released by exocytosis in response to reduced plasma calciumVitamin D feeds back to reduce PTH secretion as a secondary mechanism

Biological Activity of PTHBONE PTH stimulates bone osteoblasts to increase growth & metabolic activityPTH stimulated bone resorption releases calcium & phosphate into bloodKIDNEYPTH increases reabsorption of calcium & reduces reabsorption of phosphateNet effect of its action is increased calcium & reduced phosphate in plasmaINTESTINEIncreases calcium reabsorption via vitamin D

CalcitoninCalcitonin is a peptide hormone secreted by the parafollicular or C cells of the thyroid glandIt is synthesized as the preprohormone & released in response to high plasma calciumCalcitonin acts on bone osteoclasts to reduce bone resorption. Net result of its action is a decline in plasma calcium & phosphate

Synthesis, Release & Activity of Active Vitamin DVitamin D3 is may be obtained from the diet or made in the skinIt is converted to the active form (1,25-OH-D3 by sequential enzymatic reactions in the liver and kidney (stimulated by PTH)Vitamin D3 stimulates intestinal calcium uptake, increased bone calcium resorption & increased kidney phosphate uptake

Calcium Metabolism:Figure 23-20: Calcium balance in the body

Hormonal Regulation of Calcium and Phosphate Balance Decreased Plasma Calcium Causes:Increased PTH Resulting in mobilization of bone Ca & phosphate, increased renal phosphate excretion & Ca retention and increased Vitamin D3 synthesisThe outcome is a rise in plasma Ca levels & maintenance of normal phosphate levels

*Alterations of Parathyroid FunctionHyperparathyroidismPrimary hyperparathyroidismExcess secretion of PTH from one or more parathyroid glandsSecondary hyperparathyroidismIncrease in PTH secondary to a chronic diseaseHypoparathyroidismAbnormally low PTH levelsUsually caused by parathyroid damage in thyroid surgery

Hyperparathyroidism The incidence of the disease increases dramatically after the age of 50 and it is 2-4 folds more common in women.A single adenoma occurs in about 80% of patients with primary hyperparathyroidism. Four glands hyprplasia account for 15-20% of cases. A parathyroid carcinoma could be the etiology in a rare incidence of less then 1%.

Clinical Feature of HyperparathyroidismIn skeleton a condition called osteitis fibrosa cystica could occur with subperiosteal resorption of the distal phalanges, distal tappering of the clavicles, a salt and pepper appearance of the skull as well as bone cysts and brown tumors of the long bones. Such overt bone disease even though typical of primary hyperparathyroidism is very rarely encountered.

Clinical Feature of HyperparathyroidismThe two major sites of potential complications are the bones and the kidneys.The kidneys may have renal stones (nephrolithiasis) or diffuse deposition of calcium-phosphate complexes in the parachyma (nephrocalcinosis). Now a days such complications are seen less commonly and around 20% of patients or less show such complications.Clinical Features:

HypoparathyroidismIn the absence of renal failure the presence of hypocalcaemia with hyperphosphataemia is virtually diagnostic of hypoparathyroidism. Undetectable serum iPTH confirms the diagnosis or it can be detectable if the assay is very sensitive. Diagnosis:

HypoparathyroidismNeuromuscularParathesiaTetanyHyperventilationAdrenergic symptomsConvulsion (More common in young people and it can take the form of either generalized tetany followed by prolonged tonic spasms or the typical epileptiform seizures.Signs of latent tetany Chvostek sign,Trousseau sign and extrapyramidal signs (due to basal ganglia calcification)Clinical Features:

HypoparathyroidismOther clinical manifestationPosterio lenticular cataractCardiac manifestation:Prolonged QT interval in the ECGResistance to digitalisHypotensionRefractory heart failure with cardiomegally can occur.

Clinical Features:

HypoparathyroidismOther clinical manifestationDental ManifestationAbnormal enamel formation with delayed or absent dental eruption and defective dental root formation.Malabsorption syndromePresumably secondary to decreased calcium level and may lead to steatorrhoea with long standing untreated disease.Clinical Features:

Treating HypoparathyroidismIt seems logical that PTH would be beneficial in treating hypoparathyroidism. However few studies are available that have looked at this traetment possibility. Study among patients with hypoparathyroidism to PTH twice a day or calcium and calcitriol to attain normal calcium concentration. Calcium, phosphorus and magnesium levels did not differ between the group. No significant BMD between the group. PTH however does not have the FDA indication for hypoparathyroidism (Painter and Camacho,2007)*

HypoparathyroidismThe mainstay of treatment is a combination of oral calcium with pharmacological doses of vitamin D or its potent analogues. Phosphate restriction in diet may also be useful with or without aluminum hydroxide gel to lower serum phosphate level.Treatment:

Emergency Treatment for HypocalcaemicCalcium should be given parenterally till adequate serum calcium level is obtained and then vitamin D supplementation with oral calcium should be initiated.Tetany:

Osteoporosis: Disease of Bone Growth & Calcium MetabolismFigure 23-21: Osteoclasts are responsible for bone resorptionBone reabsorption exceeds depositionOsteoclasts mobilize Ca++ to plasmaFactors: inadequate Ca++ intake, genes, hormones, smoking

*

a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Definition of osteoporosisWorld Health Organization (WHO), 1994

World Health Organization (WHO)guidelines for osteoporosis

OsteoporosisOsteopeniaNormalPeak Bone MassT-Score

Mosby items and derived items 2006 by Mosby, Inc.

**Prevalence of Elevated Serum TSH by Decade of Age and Gender. The National Health and Nutrition Examination Survey III (NHANES III) was a large, prospective study to ascertain the prevalence of thyroid disease in the United States.1 Hollowell et al measured serum TSH, total serum T4, antithyroperoxidase (TPOAb), and antithyroglobulin (TgAb) antibodies from a sample of 17 353 people, 12 years of age or older. The investigators found serum TSH concentrations to be greater in females than males and to increase with age, with the greatest increases starting at age 35.In addition, the NHANES III study showed a higher prevalence of antithyroid hormones in women than in men, a phenomenon that increased with age.

Reference1. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

*Prevalence of Abnormal Thyroid Function.The Colorado Thyroid Disease Prevalence study examined the prevalence of abnormal thyroid function in the United States.1 The investigators studied 25 862 participants in a statewide health fair in Colorado in 1995. The main outcome measures were serum thyrotropin (thyroid-stimulating hormone [TSH]) and total thyroxine (T4) concentrations. They also measured serum lipid levels and responses to a hypothyroid symptoms questionnaire. The researchers defined normal TSH levels as between 0.3 and 5.1 IU/mL.They found that the prevalence of elevated TSH in their study population was 9.5%. Lipid levels were reported to increase as thyroid function declined. They also reported that the mean total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels of subjects with TSH values between 5.1 and 10 IU/mL were significantly higher than the mean lipid levels in subjects who were euthyroid.The prevalence of decreased TSH levels was 2.2%. Another finding was that 40% of patients taking thyroid medications had abnormal TSH levels.

Reference1. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.*Prevalence of Elevated TSH by Gender.Five large prevalence studies of thyroid disease placed hypothyroidism among the conditions for which population screening is justified. In each of the studies, there were clear differentials between women and men, with higher rates consistently found in women.1-5The highest prevalence rates were among older individuals, which was true for both women and men.

References1. Sawin CT, et al. Arch Intern Med. 1985;145:1386-1388.2. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68. 3. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.4. Hak AE, et al. Ann Intern Med. 2000;132:270-278.5. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.*Thyroid-Stimulating Hormone (TSH) Assays.TSH measurement is the most reliable test to diagnose common forms of hypothyroidism and hyperthyroidism.1 In both overt and mild hypothyroidism, serum TSH is elevated and its measurement can identify a patient with primary hypothyroidism.1 In secondary hypothyroidism, TSH concentrations may be low, normal, or mildly elevated. Therefore, TSH measurement cannot reliably identify patients with central (secondary) hypothyroidism.1 Typically, hyperthyroidism is accompanied by suppressed TSH concentrations >0.1 IU/mL.1 In order to diagnose hyperthyroidism, the lowest reliably measured TSH concentration (assay sensitivity) must be 0.02 IU/mL or less.1The first generation assay used for measuring TSH was the radioimmunoassay (RIA).2 It has a functional sensitivity of 1.0 IU/mL.2 The sensitivity of tests has improved with subsequent generations. The second generation immunoradiometric assay (IRMA) has a sensitivity of 0.1 IU/mL, and the third generation enzyme-linked immunosorbent assay (ELISA) has a sensitivity of 0.03 IU/mL.2,3

References Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Zophel K, et al. Nuklearmedizin. 1999;38:150-155.*Thyroid Disease Spectrum.Hyperthyroidism is characterized by sustained increases in thyroid hormone biosynthesis and secretion.1 Hypothyroidism is associated with decreases in thyroid hormone production.1Overt hypothyroidism is defined as the triad of classical signs and symptoms of hypothyroidism, elevated serum TSH, and abnormally low free T4.1Mild thyroid failure is less often associated with the classical signs and symptoms of hypothyroidism.1 Serum TSH levels are elevated, but to a lesser extent than in overt hypothyroidism.1 Unlike overt disease, the serum free T4 concentration is typically in the normal range. Mild thyroid failure is associated with health consequences (eg, unhealthy changes in lipid profiles).2 If untreated, it has been estimated that 3% to 18% of patients with mild thyroid failure will progress to overt hypothyroidism.3

References1. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.2. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.3. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.*Screening for Thyroid Dysfunction. Recommendations for Asymptomatic Adults.The following recommendations are from 3 organizations that endorsed the use of screening to detect thyroid dysfunction in asymptomatic adults.1-3American Thyroid Association (ATA): women and men >35 years of age should be screened every 5 years.American Association of Clinical Endocrinologists (AACE): older patients, especially women, should be screened.American College of Physicians: women >50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated.3

References1. Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.2. Cooper DS. N Engl J Med. 2001;345:260-265.3. Ann Intern Med. 1998;129:141-143.*Additional Laboratory Tests for Thyroid Function.Sensitive immunometric assays have become the mainstay of thyroid testing.1 Thyroid disease is a graded phenomenon and changes in serum T4 and especially TSH concentrations can be detected before any clinical evidence of hypothyroidism appears.1,2 These laboratory findings are particularly valuable in diagnosing the spectrum of thyroid dysfunction as well as for monitoring thyroid hormone replacement therapy.2 However, patients with subclinical and milder forms of the disorder have shifts in other measures of thyroid disease. For this reason, TSH assays combined with other measurements, such as free and bound T3 and T4, are useful indicators of disease state.2 Serum total T3 or T4 tests measure the total serum concentration of T3 or T4 using RIA techniques.1,3 Free T4 and T3 measures the quantity of free or unbound serum T4 and T3.3 Free hormones are measured by immunometric assay or by equilibrium dialysis.3 TPOAb and TgAb detection measures antimicrosomal antibodies that are predictors of disease progression. Normal ranges for these tests may vary from laboratory to laboratory, depending on test methodologies and laboratory differences.2 References1. Endocr Pract. 2002;8:457-469.2. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.3. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.*Goals for Treating Thyroid Disease.The goal for managing patients with thyroid disease is to restore the patient to a normal state.For hypothyroidism, the goal is to restore thyroid hormones to normal levels. Levothyroxine sodium is the treatment of choice for managing patients with hypothyroidism.1 For hyperthyroidism, treatment is directed toward lowering the serum concentrations of thyroid hormones in patients to restore a eumetabolic state. The 3 treatments available for achieving this goal are antithyroid drugs, radioactive iodine (131I), and thyroid surgery.1

Reference1. Singer PA, et al. JAMA. 1995;273:808-812.

*Types of Hypothyroidism.Hypothyroidism is the most common type of thyroid function disorder.1 There are 2 types: primary and secondary (or central) hypothyroidism.Primary hypothyroidism is caused by a condition affecting the thyroid gland that leads to decreased production of T4 and T3. Primary hypothyroidism is usually accompanied by increased secretion of TSH. Secondary hypothyroidism is caused by decreased thyroidal stimulation by TSH. Secondary hypothyroidism may be caused by pituitary or hypothalamic disease, the latter associated with decreased thyrotropin-releasing hormone (TRH).

Reference1. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

*Clinical Manifestations of Hypothyroidism.The symptoms of hypothyroidism are usually related to the age of the patient, the rapidity of onset, and the presence of other disorders.1 The number of potential signs and symptoms is large, but most patients will experience some of the following: fatigue, weight gain, dry skin, cold intolerance, yellow skin, coarseness or loss of hair, hoarseness, goiter, delayed relaxation of deep tendon reflexes, ataxia, constipation, memory and mental impairment, decreased concentration, depression, irregular or heavy menses and infertility, myalgias, hyperlipidemia, bradycardia, hypothermia, and myxedema.1Because the symptoms are varied and not unusual, they can be misdiagnosed.2Although hypothyroidism is usually associated with a normal-sized gland, goiter may occur.1 Physical examination of the thyroid gland is best accomplished by an experienced clinical endocrinologist.3

References1. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.2. Canaris GJ, et al. Arch Intern Med. 2000; 160(4):526-534.3. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics. 9th ed. 1996.*Cholesterol Levels Elevate With Increasing TSH Levels.In the Colorado Thyroid Disease Prevalence study, Canaris et al studied 25 862 participants at a statewide health fair in Colorado.1 As part of the study, the total study population was divided by investigators according to TSH levels to determine the relationship between declining thyroid function and serum lipid concentrations. The investigators found that total cholesterol and LDL-C concentrations progressively and statistically significantly (P4.0 IU/mL, measuring free thyroxine (FT4) is the second step.1,2 A normal free T4 value in the face of an elevated TSH defines mild thyroid failure.1,3 A low FT4 in the face of an elevated TSH defines overt hypothyroidism.4

References1. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.2. Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320.3. Ayala AR, et al. The Endocrinologist. 1997;7:44-50.4. Endocr Pract. 2002;8:457-469.*Hypothyroidism Treatment.According to the American Thyroid Association1 and the American College of Endocrinology,2 levothyroxine is the treatment of choice for the routine management of hypothyroidism. Levothyroxine preparations are manufactured in many different dosages and allow for the precise titration of an individual patients requirements.1Adults with hypothyroidism require approximately 1.7 g/kg of body weight/d for full replacement.1 Children may require up to 4 g/kg of body weight/d. Older patients may need less than 1 g/kg of body weight/d because of a decrease in their rate of clearance of thyroxine.1 For patients who are older than 50 years of age, or in younger patients with a history of cardiac disease, a lower initial dosage is recommended, starting with .025 mg to .05 mg of levothyroxine daily.1The Standards of Care Committee of the American Thyroid Association also recommends that patients be evaluated at 6- to 8-week intervals until the serum TSH concentration is normalized.1 It is important to remember that patients with exceptionally high levels of TSH may progress to equilibrium slower than those with lower TSH values.2 Given the narrow and precise treatment range for levothyroxine therapy, the AACE recommends that patients should be maintained on the same brand of levothyroxine through the course of treatment.2References1. Singer PA, et al. JAMA. 1995;273:808-812. 2. Endocr Pract. 2002;8:457-469.

*Primary Hypothyroidism Treatment Algorithm.This slide shows a treatment algorithm for primary hypothyroidism. After an initial dose, the patient should receive a repeat TSH measurement after 6 to 8 weeks.1 If the TSH level is low (4 IU/mL), then the dose of levothyroxine should be increased by 12.5 to 25 g/d.2 If the TSH level is in the normal range of 0.5 to 2.0 IU/mL and symptoms are resolved, then the levothyroxine dose should be continued and the patients TSH level should be measured after 6 months, then annually, unless he or she develops symptoms suggestive of thyroid disease.1,2

References1. Singer PA, et al. JAMA. 1995;273:808-812. 2. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.*Therapy Initiation and Titration.Therapy with levothyroxine sodium products requires individualized patient dosing using careful titration, clinical evaluation, and laboratory monitoring.1 Individualized titration should be based on both clinical evaluation and laboratory monitoring in order to optimize serum thyroxine levels, alleviate signs and symptoms of the disorder, and avoid adverse events.2For each patient, the starting dose, the frequency of dose titration, and the optimal full replacement dose must be carefully determined.1 These parameters will be influenced by patient age, weight, cardiovascular status, general health, and the severity and duration of hypothyroidism.1

References1. Endocr Pract. 2002;8:457-469.2. Singer PA, et al. JAMA. 1995;273:808-812.*Therapy Monitoring.Periodic monitoring of patients receiving levothyroxine therapy is essential for effective management.1 Clinical evaluations and laboratory monitoring of serum TSH levels permit evaluation of the clinical response to the medication, assessment of patient compliance, assessment of drug interactions (if applicable), and adjustment of dosage as required in response to changes in patient lifestyle or circumstances.1It is recommended that clinical and laboratory evaluations be performed at 6- to 8-week intervals (2 to 3 weeks in severely hypothyroid patients).2 The levothyroxine dosage should be adjusted by 12.5 to 25 g increments until serum TSH concentration is normalized and signs and symptoms resolve.2 Annual testing is recommended after a euthyroid state is established.2

References1. Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds.2. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.*Special Considerations. Elderly Patients.The prevalence of hypothyroidism is higher in the elderly compared with younger persons.1 The symptoms of hypothyroidism in the elderly may be subtle and include hoarseness, deafness, confusion, dementia, ataxia, depression, dry skin, and hair loss.Appropriate dose selection is critical in the elderly as this patient population is at greater risk for cardiac disorders, and over-replacement with levothyroxine therapy can exacerbate cardiac abnormalities. Poor adherence can be an issue with elderly patients, particularly if they do not have a family or other support system. Furthermore, elderly patients are often taking multiple medications. Therefore, careful monitoring of serum TSH levels and adequate patient education is required to ensure that the patient is given the appropriate dosage and is complying with the dosing regimen.

Reference1. Felicetta JV. Consultant. 2002;1597-1606. Available at: www.consultantlive.com. Accessed July 1, 2003.*Caution in Patients With Underlying Cardiac Disease.Caution should be used when administering levothyroxine to patients who have ischemic heart disease in order to prevent possible MI, aggravation of angina, or cardiac arrhythmias.1,2When administering levothyroxine to patients