THYROID & PARATHYROIDTHYROID & PARATHYROID

COLIN G. THOMAS, JR., MDCOLIN G. THOMAS, JR., MD

The Thyroid GlandThe Thyroid Gland130-201130-201GalenGalen1543 1543 VesaliusVesalius16561656 Wharton “Oblong Shield”Wharton “Oblong Shield”18731873 Gull – “Adult Cretinism”Gull – “Adult Cretinism”18891889 Murray “Liquor Thyroidei”Murray “Liquor Thyroidei”19091909 Kocher – Nobel PrizeKocher – Nobel Prize19151915 Kendall –Isolation of thyroxineKendall –Isolation of thyroxine19511951 Pitt-Rivers-isolation of T3Pitt-Rivers-isolation of T3

Historical Aspects of GoiterHistorical Aspects of Goiter200 BC200 BC

Atharva Veda (Hindu): exorcism of goiterAtharva Veda (Hindu): exorcism of goiter

12711271

Marco Polo: “They are in general afflicted Marco Polo: “They are in general afflicted with tumors in the throat occasioned by with tumors in the throat occasioned by the nature of the water which they drink.”the nature of the water which they drink.”

Incidence of Thyroid Disorders in ConnecticutIncidence of Thyroid Disorders in Connecticut(Annual physical Examination, 1544 Patients – One Year)(Annual physical Examination, 1544 Patients – One Year)

## %%Simple goiterSimple goiter 29291.881.88Graves’ diseaseGraves’ disease 15150.970.97Iatrogenic hyperthyroidismIatrogenic hyperthyroidism 220.100.10Hot noduleHot nodule 990.580.58Multinodular goiterMultinodular goiter 13130.840.84ThyroiditisThyroiditis 880.510.51Single cold noduleSingle cold nodule 880.510.51HypothyroidismHypothyroidism 660.390.39CancerCancer 000.000.00TotalTotal 90905.785.78

Nodular GoiterNodular Goiter• Prevalence Rate: .08%/yrPrevalence Rate: .08%/yr• Clinical incidence- Adults: 4-7%Clinical incidence- Adults: 4-7%

– Females > MalesFemales > Males• Incidence with ionizing radiation: 20-30%Incidence with ionizing radiation: 20-30%• Autopsy incidence: 50%Autopsy incidence: 50%• Occult cancer (Autopsy): 4-28%Occult cancer (Autopsy): 4-28%

Cancer Incidence and DeathsCancer Incidence and DeathsEstimated- U.S. 2005Estimated- U.S. 2005

Organ SystemOrgan System New CasesNew CasesDeathsDeaths LungLung 172,570 172,570 163,510163,510Colon Colon 104,950104,95056,29056,290RectumRectum 42,00042,0007,000 7,000 PancreasPancreas 32,18032,18031,80031,800BreastBreast 212,930212,93040,87040,870StomachStomach 24,00024,00014,00014,000ThyroidThyroid 25,69025,6901,4901,490Prostate 232,090 30,050Prostate 232,090 30,050

Thyroid CancerThyroid Cancer19851985 1994199419981998

New CasesNew Cases 10,00010,00013,90013,90017,20017,200 ( (↑ 72%)↑ 72%)

DeathsDeaths 1,1001,1001,1201,120 1,200 (↑8%) 1,200 (↑8%)

American Cancer Society 1998American Cancer Society 1998

Evaluations ofEvaluations ofNodular Thyroid DiseaseNodular Thyroid Disease

• History- symptoms, duration, familialHistory- symptoms, duration, familial

• Physical findings, i.e. topography, Physical findings, i.e. topography, firmness, surface, lymphadenopathyfirmness, surface, lymphadenopathy

• Thyroid functions tests- TFT (s) - TSHThyroid functions tests- TFT (s) - TSH

Diagnostic Studies- Thyroid CancerDiagnostic Studies- Thyroid Cancer

Fine Needle Aspiration- Establishes Cytologic Fine Needle Aspiration- Establishes Cytologic DiagnosisDiagnosis

Thyroid function tests (TSH- 1Thyroid function tests (TSH- 1stst in in Thyroiditis)Thyroiditis)Technetium Scan- reflects trapping Technetium Scan- reflects trapping function, “hot nodule”function, “hot nodule”Ultrasonography- reflects volume, Ultrasonography- reflects volume, composition, occult nodulescomposition, occult nodules

Thyroid Cancer- DiagnosisThyroid Cancer- Diagnosis• CytologyCytology• ScansScans

– TechnetiumTechnetium– RadioiodineRadioiodine– SestamibiSestamibi– MR/CT/PETMR/CT/PET

• UltrasoundUltrasound• Frozen SectionsFrozen Sections• Fixed SectionsFixed Sections

Thyroid Cancers*Thyroid Cancers*

PapillaryPapillary 80%80%FollicularFollicular 11%11%HHürthleürthle 3%3%MedullaryMedullary 4%4%AnaplasticAnaplastic 2%2%

*National Cancer Data Base*National Cancer Data Base31,513 patients (1985-1995)31,513 patients (1985-1995)

Biological CharactersticsBiological Characterstics• Thyrotropin Receptor-Thyrotropin Receptor-

– Adenylate Cyclase SystemsAdenylate Cyclase Systems• Iodine Trapping/OrganificationIodine Trapping/Organification• Thyroglobin ProductionThyroglobin Production

Thyroid CancerThyroid CancerA Spectrum of NeoplasmsA Spectrum of Neoplasms

Surgical Treatment: Reflect Biological Surgical Treatment: Reflect Biological CharacteristicsCharacteristics

Papillary CarcinomaPapillary Carcinoma• Ames (Age, Distant Metastases, Extent, Ames (Age, Distant Metastases, Extent,

Size)Size)

• 89%- Low risk; Mortality 1.8% and 89%- Low risk; Mortality 1.8% and • 11% High Risk, Mortality 46%11% High Risk, Mortality 46%

Adjuvant TherapyAdjuvant TherapyThyroxine Thyroxine → TSH Suppression→ TSH Suppression

Radiodiodine (Ablation/Rx)Radiodiodine (Ablation/Rx)

Thyroxine ↓ → TSH ↑Thyroxine ↓ → TSH ↑Recombinant TSHRecombinant TSH

External Radiation (?)External Radiation (?)Chemotherapy (?)Chemotherapy (?)

On a New Gland in Man and On a New Gland in Man and Several MammalsSeveral Mammals

Ivar SandstrIvar SandstrŐŐmm “ “About three years ago (1877) I found on About three years ago (1877) I found on

the thyroid gland of a dog a small organ, the thyroid gland of a dog a small organ, hardly as big as a hemp seed, which was hardly as big as a hemp seed, which was enclosed in the same connective tissue enclosed in the same connective tissue capsule as the thyroid, but could be capsule as the thyroid, but could be distinguished there from by a lighter color. distinguished there from by a lighter color. A superficial examination revealed an A superficial examination revealed an organ of totally different than that of the organ of totally different than that of the thyroid and with a very rich versatility.”thyroid and with a very rich versatility.”

Ivar SandstrIvar SandstrŐŐmm

““So much the greater was my astonishment So much the greater was my astonishment therefore when in the first individual therefore when in the first individual (patient) examined I found on both sides at (patient) examined I found on both sides at the inferior border of the thyroid gland an the inferior border of the thyroid gland an organ of the size of a small pea, which organ of the size of a small pea, which judging from its exterior did not appear to judging from its exterior did not appear to be a lymph gland nor an accessory thyroid be a lymph gland nor an accessory thyroid gland and upon histological examination gland and upon histological examination showed a rather peculiar structure.”showed a rather peculiar structure.”

Herr Bleich, 40, Male, MasonHerr Bleich, 40, Male, Mason• April 1888April 1888 Fall, ? Femoral neck fractureFall, ? Femoral neck fracture

• August 1888August 1888 Fall, Clavicle fractureFall, Clavicle fracture Hospitalized- Fracture of femur in Hospitalized- Fracture of femur in

bed.bed.

• July 1889July 1889 Bending of bones, bone painBending of bones, bone pain

• October 1889October 1889 Marasmus- DeathMarasmus- Death

Herr Bleich: AutopsyHerr Bleich: Autopsy(Pathological Institute of Strassburg)(Pathological Institute of Strassburg)• 1889 Von Recklinghausen1889 Von Recklinghausen

Skeletal Findings: Widespread Skeletal Findings: Widespread fibrosis, fibrosis, cysts, brown (giant cell) tumorscysts, brown (giant cell) tumors

• 1933 Jung1933 Jung “ “Above the left Thyroid gland, a lymph Above the left Thyroid gland, a lymph

gland, red-brown in color is present.”gland, red-brown in color is present.”

Albert Albert ____ 38, Male, Street Car Conductor____ 38, Male, Street Car Conductor

Chicken pox [5], Measles [6], Syphilis [19], Chicken pox [5], Measles [6], Syphilis [19], TuberculosisTuberculosis

1921- Pain legs, hips, tiredness-pensioned1921- Pain legs, hips, tiredness-pensioned1923- X-Rays Bone cysts1923- X-Rays Bone cysts1924- Diagnosis: Von Recklinghausen’s 1924- Diagnosis: Von Recklinghausen’s

DiseaseDisease

Albert JAlbert JäähnehneRX: Von Recklinghausen’s DiseaseRX: Von Recklinghausen’s Disease

19241924 Parathyroid Extract from animals,Parathyroid Extract from animals,Parathyroid Transplantation Parathyroid Transplantation

(MANDL)(MANDL)

19251925 Jellyfish stage: Parathyroid tumor Jellyfish stage: Parathyroid tumor removed 92.5 X 1.5 X 1.2 cm.) July 20removed 92.5 X 1.5 X 1.2 cm.) July 20

19321932 Recurrence: Two normal glands Recurrence: Two normal glands removedremoved

19361936 Death: No tumor at autopsyDeath: No tumor at autopsy

Elva DawkinsElva Dawkins

February 1928February 1928Fractured left humerus, tumor of Fractured left humerus, tumor of maxilla, maxilla, benign giant cell sarcoma- left ulnabenign giant cell sarcoma- left ulnaDixon (student) studying nerve- muscle Dixon (student) studying nerve- muscle preparationpreparationCalcium 16 mgs. %, phosphorus- 1.4 Calcium 16 mgs. %, phosphorus- 1.4 mgs. %mgs. %Walnut sized mass – left lobe of thyroidWalnut sized mass – left lobe of thyroidJuly 1929, Paraparesis, UTI, renal function July 1929, Paraparesis, UTI, renal function ↓↓

HyperparathyroidismHyperparathyroidism• Rarefaction of boneRarefaction of bone• Multiple cystic bone tumors, giant cell Multiple cystic bone tumors, giant cell

sarcomasarcoma• Muscular weakness and hypotoniaMuscular weakness and hypotonia• Abnormal excretion of calcium and Abnormal excretion of calcium and

formation of calcium stonesformation of calcium stones• Abnormally high serum calciumAbnormally high serum calcium

Captain Charles Martell (1889-1932)Captain Charles Martell (1889-1932)19261926 “Hyperparathyroidism” suggested by Dr. “Hyperparathyroidism” suggested by Dr.

Dubois, Bellvue HospitalDubois, Bellvue Hospital19261926 May and June- Two normally parathyroid May and June- Two normally parathyroid

glands removed by Dr. E.P. glands removed by Dr. E.P. Richardson, MGHRichardson, MGH19321932 (March) Neck exploration- Dr. Russell (March) Neck exploration- Dr. Russell

Patterson, New YorkPatterson, New York19321932 Three neck explorations- Drs. Oliver Cope Three neck explorations- Drs. Oliver Cope

and and E. D. Churchill, MGHE. D. Churchill, MGH19321932 (November) Mediastinal parathyroid (November) Mediastinal parathyroid

adenoma adenoma partially excised- Dr. E. D. Churchill, MGHpartially excised- Dr. E. D. Churchill, MGH19321932 Death from tetanyDeath from tetany

1932 1932 _____ ______ (J. Morelle) Louvain_____ ______ (J. Morelle) Louvain

Diagnosis by SerendipityDiagnosis by Serendipity

Primary HyperparathyroidismPrimary Hyperparathyroidism

Abnormal relationship between calcium andAbnormal relationship between calcium andPTH levels with changes in parathyroidPTH levels with changes in parathyroidmass and calcium setpoints.mass and calcium setpoints.

HyperparathyroidismHyperparathyroidism• Incidence 1:700 (0.14%)Incidence 1:700 (0.14%)• Most common cause of Hypercalcemia in Most common cause of Hypercalcemia in

non-hospitalized patientsnon-hospitalized patients• Female greater than maleFemale greater than male• Most common in peri/post menapausal Most common in peri/post menapausal

femalefemale• Rare in childrenRare in children

HyperparathyroidismHyperparathyroidism(Classification)(Classification)

I.I. 11° HPT-° HPT- Idiopathic inappropriate Idiopathic inappropriate secretion of PTHsecretion of PTH

II.II. 22° HPT-° HPT- Hypersecretion of PTH 2° to ↓ Hypersecretion of PTH 2° to ↓ Ca++Ca++

III.III. 33° HPT-° HPT- Autonomous hypersecretion of Autonomous hypersecretion of PTH/2° HPTPTH/2° HPT

HyperparathyroidismHyperparathyroidism(Classification)(Classification)

• IV. Ectopic HyperparathyroidismIV. Ectopic Hyperparathyroidism(Humoral Hypercalcemia of Cancer)(Humoral Hypercalcemia of Cancer)

• Pseudo HyperparathyroidismPseudo Hyperparathyroidism(Bone Resorption via Local Mechanism)(Bone Resorption via Local Mechanism)

• Prostaglandinis EProstaglandinis E• Cytokines (Osteoclast Activating Factor)Cytokines (Osteoclast Activating Factor)

– Interleukin-1Interleukin-1– Cachectin (Tumor Necrosis Factor Cachectin (Tumor Necrosis Factor αα))– Lymphotoxin (Tumor Necrosis Factor Lymphotoxin (Tumor Necrosis Factor ββ))

Table 1. Symptoms and Signs of Table 1. Symptoms and Signs of Hypercalcemia*Hypercalcemia*

PercentPercentSymptomsSymptoms

FatigueFatigue 2828Mental status changeMental status change 2424DepressionDepression 1212GastrointestinalGastrointestinal 2424

SignsSignsCardiovascularCardiovascular 1414NephrolithiasisNephrolithiasis 2828Bone diseaseBone disease 4747PancreatitisPancreatitis 2 2

AsymptomaticAsymptomatic 1111

*Many patients had more then one symptom or sign.*Many patients had more then one symptom or sign.

Udelsman –Udelsman –Ann. SurgAnn. Surg 2001; 113: 59-66 2001; 113: 59-66

Clinical Manifestations of Clinical Manifestations of HyperparathyroidismHyperparathyroidism

• RenalRenal– Hypercalciuria, negative calcium balanceHypercalciuria, negative calcium balance– Renal parenchymal calcification: nephrocalcinosisRenal parenchymal calcification: nephrocalcinosis– Obstructive uropathy: nephrolithiasisObstructive uropathy: nephrolithiasis

• SkeletalSkeletal– Increased bone resoption (also increased formation)Increased bone resoption (also increased formation)– Greater loss of cortical than trabecular boneGreater loss of cortical than trabecular bone– Brown tumors presenting as lytic lesions (uncommon)Brown tumors presenting as lytic lesions (uncommon)

• GastrointestinalGastrointestinal– Anorexia, nausea, vomiting, weight loss, constipationAnorexia, nausea, vomiting, weight loss, constipation– PancreatitisPancreatitis

• NeuromuscularNeuromuscular– CNS depression: lethargy, comaCNS depression: lethargy, coma– Muscle weakness, hyporeflexiaMuscle weakness, hyporeflexia– Peripheral neuropathy: axonopathyPeripheral neuropathy: axonopathy

Hyperparathyroidism in the Hyperparathyroidism in the Elderly (Elderly (≥ 65)≥ 65)

• Incidence – 1.5%Incidence – 1.5%• 40% - Hypercalcemia A Serendipitous Finding40% - Hypercalcemia A Serendipitous Finding• Neuromuscular SymptomsNeuromuscular Symptoms• Easy FatigabilityEasy Fatigability• Emotional InstabilityEmotional Instability• AnorexiaAnorexia• Sudden Accentuated AgingSudden Accentuated Aging• ↓ ↓ Intellectual CapacityIntellectual Capacity• Lack of InitiativeLack of Initiative

(From Tibblin, et. al.: Ann. Of Surg., 197:135, 1983.)(From Tibblin, et. al.: Ann. Of Surg., 197:135, 1983.)

Evaluation of 1Evaluation of 1° ° HyperparathyroidismHyperparathyroidism

• SERUM ELECTROLYTESSERUM ELECTROLYTES• BUN, CREATININEBUN, CREATININE• iPTHiPTH

• Alkaline PhosphataseAlkaline Phosphatase• Bone Density StudiesBone Density Studies• Urinary CalciumUrinary Calcium• Localization ProceduresLocalization Procedures

Asymptomatic HyperthyroidismAsymptomatic Hyperthyroidism

• Natural History – UnknownNatural History – Unknown

• Rapid Progression to Severe Disease – RareRapid Progression to Severe Disease – Rare

• 20% Develop Complications in Ten Years20% Develop Complications in Ten Years

• Accelerated Bone Loss – Mental Function/Well Accelerated Bone Loss – Mental Function/Well Being Compromised?Being Compromised?

Table 1. Comparison of Old and New Criteria Table 1. Comparison of Old and New Criteria for Parathyroid Surgery in Patients with for Parathyroid Surgery in Patients with

Asymptomatic Primary Hyperparathyroidism.*Asymptomatic Primary Hyperparathyroidism.*VariableVariable 1990 Guidelines1990 Guidelines 2002 Guidelines2002 Guidelines

Serum calciumSerum calcium 1.0-1.6 mg/dl above1.0-1.6 mg/dl above 1.0 mg/ dl of upper1.0 mg/ dl of upperConcentrationConcentration upper limit ofupper limit of limit of normallimit of normal

normalnormal

24- Hr urinary 24- Hr urinary >400 mg>400 mg >400 mg>400 mgCalcium excretionCalcium excretion

Reduction in Reduction in 30%30% 30%30%Creatinine clearanceCreatinine clearance

Bone mineral Bone mineral Z score below -2.0 in the Z score below -2.0 in the T score below -2.5 at T score below -2.5 at anyany

DensityDensity forearmforearm sitesite

Age Age <50 yr<50 yr <50 yr<50 yr

Parathyroidectomy IndicationsParathyroidectomy Indications

• Symptomatic PatientsSymptomatic Patients

• Asymptomatic PatientsAsymptomatic Patients• Calcium Calcium ≥ 11 mgms. % ( 1 mg > Normal )≥ 11 mgms. % ( 1 mg > Normal )• Not Amenable to SurveillanceNot Amenable to Surveillance• Decreasing Bone Density, Osteopenia Decreasing Bone Density, Osteopenia

Hypertension, Hypercalciuria Decreasing Renal Hypertension, Hypercalciuria Decreasing Renal FunctionFunction

Effects of Successful Surgery on Effects of Successful Surgery on Problems Associated with Problems Associated with

HyperparathyroidismHyperparathyroidismOsteopenia: Increased bone mineral density in spin and hip Osteopenia: Increased bone mineral density in spin and hip

(+ 10-15% within 1-2 yrs)(+ 10-15% within 1-2 yrs)Hypercalciuria and nephrolithiasis are significantly reducedHypercalciuria and nephrolithiasis are significantly reducedNeuromuscular symptoms frequently improveNeuromuscular symptoms frequently improve

- Objective improvements documented in motor strength - Objective improvements documented in motor strength and fine motor control but not sensory functionand fine motor control but not sensory function

Some aspects of psychiatric morbidity are subjectively Some aspects of psychiatric morbidity are subjectively improvedimproved- Improved subjective scores of fatigue, depression, - Improved subjective scores of fatigue, depression, irritability, sleep disturbance and lack of concentrationirritability, sleep disturbance and lack of concentration- No changes in cognitive function or anxiety scores- No changes in cognitive function or anxiety scores

Pre-existing hypertension is generally not improved but Pre-existing hypertension is generally not improved but LVH may regressLVH may regress

Parathyroid Imaging- Parathyroid Imaging- LocalizationLocalization

• Experienced SurgeonExperienced Surgeon• UltrasoundUltrasound• Scintigraphy (sestamibi:technetiumScintigraphy (sestamibi:technetium99m99m) ) • Venous sampling (qPTH – pre-intraoperative)Venous sampling (qPTH – pre-intraoperative)• Computerized tomographyComputerized tomography• Magnetic resonance imagingMagnetic resonance imaging• Angiography (selective digital subtraction Angiography (selective digital subtraction

angiography)angiography)• Fine needle aspiration: cytology/iPTHFine needle aspiration: cytology/iPTH

End Stage Renal DiseaseEnd Stage Renal Disease• Eu- hypercalcemiaEu- hypercalcemia

• HyperphosphatemiaHyperphosphatemia

• ↑ ↑ alkaline phosphatasealkaline phosphatase

• ↑ ↑ iPTHiPTH

• OsteodystrophyOsteodystrophy

Renal OsteodystrophyRenal OsteodystrophyIndications for ParathyroidectomyIndications for Parathyroidectomy

• Bone painBone pain

• Proximal myopathyProximal myopathy

• Persistent hypercalcemiaPersistent hypercalcemia

• Calcinosis – unresponsive to RxCalcinosis – unresponsive to Rx

• CalciphylaxisCalciphylaxis