Endocrinology

Alan L. Cowan, MDFrancis B. Quinn, Jr, MDNovember 2003

OutlineGeneral Principles of EndocrinologyCentral Axis

HPAPeripheral Axis

ThyroidParathyroidAdrenalGonadalGastrointestinal

Disorders

Hypophyseal-Pituitary AxisSite of Neural – Hormonal interactionSets temporal release of hormonesResponsible for stress reaction of hormones

HPA BasicsHypophysis

Third VentricleGRH, TRH, CRH, GnRH, Dopamine, Somatostatin

NeurohypophysisDerived from HypophysisADH, Oxytocin

AdenohypophysisDerived from Rathke’s pouchACTH, LH, FSH, TSH, GH, PRL

Pituitary DiseasesPrimary Tumors

AdenomasCraniopharyngioma

MetastasisEmpty Sella

Surgical, post-Sheehand’sHemorrhage

Sheehand’s syndromeHyperfunction

ProlactinInsufficiency

Thyroid

ThyroidLargest Endocrine organ in the bodyInvolved in production, storage, and release of thyroid hormoneFunction influenced by

Central axis (TRH)Pituitary function (TSH)Comorbid diseases (Cirrhosis, Graves, etc.)Environmental factors (iodine intake)

Thyroid (cont)Regulates basal metabolic rateImproves cardiac contractilityIncreases the gain of catecholaminesIncreases bowel motilityIncreases speed of muscle contractionDecreases cholesterol (LDL)Required for proper fetal neural growth

Thyroid PhysiologyUptake of Iodine by thyroidCoupling of Iodine to ThyroglobulinStorage of MIT / DIT in follicular spaceRe-absorption of MIT / DITFormation of T3, T4 from MIT / DITRelease of T3, T4 into serumBreakdown of T3, T4 with release of Iodine

Iodine uptakeNa+/I- symport protein controls serum I- uptakeBased on Na+/K+

antiport potentialStimulated by TSHInhibited by Perchlorate

MIT / DIT formationThyroid Peroxidase (TPO)

Apical membrane proteinCatalyzes Iodine organification to Tyrosine residues of ThyroglobulinAntagonized by methimazole

Iodine coupled to ThyroglobulinMonoiodotyrosine (Tg + one I-)Diiodotyrosine (Tg + two I-)

Pre-hormones secreted into follicular space

Secretion of Thyroid HormoneStimulated by TSHEndocytosis of colloid on apical membraneCoupling of MIT & DIT residues

Catalyzed by TPOMIT + DIT = T3DIT + DIT = T4

Hydrolysis of ThyroglobulinRelease of T3, T4

Release inhibited by Lithium

Thyroid Hormones

Thyroid HormoneMajority of circulating hormone is T4

98.5% T41.5% T3

Total Hormone load is influenced by serum binding proteins (TBP, Albumin, ??)

Thyroid Binding Globulin 70%Albumin 15%Transthyretin 10%

Regulation is based on the free component of thyroid hormone

Hormone Binding FactorsIncreased TBG

High estrogen states (pregnancy, OCP, HRT, Tamoxifen)Liver disease (early)

Decreased TBGAndrogens or anabolic steroidsLiver disease (late)

Binding Site CompetitionNSAID’sFurosemide IVAnticonvulsants (Phenytoin, Carbamazepine)

Hormone DegredationT4 is converted to T3 (active) by 5’ deiodinaseT4 can be converted to rT3 (inactive) by 5 deiodinaseT3 is converted to rT2 (inactive)by 5 deiodinaserT3 is inactive but measured by serum tests

Thyroid Hormone Control

TRHProduced by HypothalamusRelease is pulsatile, circadianDownregulated by T4, T3

Travels through portal venous system to adenohypophysisStimulates TSH formation

TSHProduced by Adenohypophysis ThyrotrophsUpregulated by TRH Downregulated by T4, T3

Travels through portal venous system to cavernous sinus, body.Stimulates several processes

Iodine uptakeColloid endocytosisGrowth of thyroid gland

TSH Response

Thyroid Lab EvaluationTRHTSHTT3, TT4

FT3, FT4

RAIUThyroglobulin, Thyroglobulin AbPerchlorate TestStimulation Tests

RAIUScintillation counter measures radioactivity 6 & 24 hours after I123 administration.Uptake varies greatly by iodine status

Indigenous diet (normal uptake 10% vs. 90%)Amiodarone, Contrast study, Topical betadine

Symptomatic elevated RAIUGraves’Toxic goiter

Symptomatic low RAIUThyroiditis (Subacute, Active Hashimoto’s)Hormone ingestion (Thyrotoxicosis factitia, Hamburger Thyrotoxicosis)Excess I- intake in Graves’ (Jod-Basedow effect)Ectopic thyroid carcinoma (Struma ovarii)

Iodine statesNormal Thyroid

Inactive Thyroid

Hyperactive Thyroid

Wolff-ChaikoffIncreasing doses of I- increase hormone synthesis initiallyHigher doses cause cessation of hormone formation.This effect is countered by the Iodide leak from normal thyroid tissue.Patients with autoimmune thyroiditis may fail to adapt and become hypothyroid.

Jod-BasedowAberration of the Wolff-Chaikoff effectExcessive iodine loads induce hyperthyroidismObserved in several disease processes

Graves’ diseaseMultinodular goiter

PerchlorateClO4

- ion inhibits the Na+ / I-

transport protein.Normal individuals show no leak of I123 after ClO4

- due to organification of I- to MIT / DITPatients with organificationdefects show loss of RAIU.Used in diagnosis of Pendredsyndrome

HypothyroidSymptoms – fatigability, coldness, weight gain, constipation, low voiceSigns – Cool skin, dry skin, swelling of face/hands/legs, slow reflexes, myxedemaNewborn – Retardation, short stature, swelling of face/hands, possible deafnessTypes of Hypothyroidism

Primary – Thyroid gland failureSecondary – Pituitary failureTertiary – Hypothalamic failurePeripheral resistance

HypothyroidCause is determined by geographyDiagnosis

Low FT4, High TSH (Primary, check for antibodies)Low FT4, Low TSH (Secondary or Tertiary, TRH stimulation test, MRI)

TreatmentLevothyroxine (T4) due to longer half lifeTreatment prevents bone loss, cardiomyopathy, myxedema

Hashimoto’s(Chronic, Lymphocytic)

Most common cause of hypothyroidismResult of antibodies to TPO, TBGCommonly presents in females 30-50 yrs.Usually non-tender and asymptomaticLab values

High TSHLow T4Anti-TPO AbAnti-TBG Ab

Treat with Levothyroxine

GoiterEndemic goiter

Caused by dietary deficiency of IodideIncreased TSH stimulates gland growthAlso results in cretinism

Goiter in developed countriesHashimoto’s thryoiditisSubacute thyroiditis

Other causesExcess Iodide (Amiodarone, Kelp, Lithium)Adenoma, MalignancyGenetic / Familial hormone synthesis defects

HyperthyroidSymptoms – Palpitations, nervousness, fatigue, diarrhea, sweating, heat intoleranceSigns – Thyroid enlargement (?), tremorLab workup

TSHFT4RAIU

Other LabsAnti-TSH-R Ab, Anti-TPO Ab, Anti-TBG AbFT3FNAMRI, US

HyperthyroidCommon Causes

*GravesAdenoma Multinodular Goiter*Subacute Thyroiditis*Hashimoto’s Thyroiditis

Rare CausesThyrotoxicosis factitia, struma ovarii, thyroid metastasis, TSH-secreting tumor, hamburger

GravesMost common cause of hyperthyroidismResult of anti-TSH receptor antibodiesDiagnosis

Symptoms of hyperthyroidismClinical exopthalmos and goiterLow TSH, normal/high FT4, anti-TSH Ab (Optional)

If no clinical findings I123 may demonstrate increased uptake.Treatments

Medical – Propothyouracil, Methimazole, PropranololSurgical – Subtotal ThyroidectomyRadiation – RAI ablation [I131(µCi/g) x weight / %RAIU]

Subacute Thyroiditis(DeQuervain’s, Granulomatous)

Acute viral infection of thyroid glandPresents with viral prodrome, thyroid tenderness, and hyperthyroid symptomsLab values

Variable TSH, T4High ESRNo antibodies

Treatment APAP, NSAIDPrednisone (?)Levothyroxine (?)

Subacute Thyroiditis(DeQuervain’s, Granulomatous)

Euthyroid SickResults from inactivation of 5’-Deiodinase, resulting in conversion of FT4 to rT3.Generally occurs in critically ill patients, but may occur with DM, malnutrition, iodine loads, or medications (Amiodarone, PTU, glucocorticoids)Treatment

Avoid above medicationsTreat primary illnessT3, T4 not helpful

Thyroid StormCauses

SurgeryRadioactive Iodine TherapySevere Illness

DiagnosisClinical – tachycardia, hyperpyrexia, thyrotoxicosis symptomsLabs (Low TSH, High T4, FT4)

TreatmentPropranolol IV vs. Verapamil IVPropylthiouracil, MethimazoleSodium IodideAcetamenophen, cooling blanketsPlasmapheresis (rare)Surgical (rare)

Calcium RegulationParathyroid

CalciumRequired for muscle contraction, intracellular messenger systems, cardiac repolarization.Exists in free and bound states

Albumin (40% total calcium)Phosphate and Citrate (10% total calcium)

Concentration of iCa++ mediated byParathyroid glandParafollicular C cellsKidney Bone

Parathyroid HormoneProduced by Parathyroid Chief cellsSecreted in response to low iCa++

Stimulates renal conversion of 25-(OH)D3 to 1,25-(OH)2D which increases intestinal Ca++ absorptionDirectly stimulates renal Ca++ absorption and PO4

3-

excretionStimulates osteoclastic resorption of bone

CalcitoninProduced by Parafollicular C cells of Thyroid in response to increased iCa++

ActionsInhibit osteoclastic resorption of boneIncrease renal Ca++ and PO4

3- excretionNon-essential hormone. Patients with total thyroidectomy maintain normal Ca++ concentrationsUseful in monitoring treatment of MedullaryThyroid cancerUsed in treatment of Pagets’, Osteoporosis

Vitamin DSources

Food – Vitamin D2

UV light mediated cholesterol metabolism – D3

MetabolismD2 and D3 are converted to 25(OH)-D by the liver25(OH)-D is converted to 1,25(OH)2-D by the Kidney

FunctionStimulation of OsteoblastsIncreases GI absorption of dietary Ca++

HypocalcemiaDecreased PTH

SurgeryHypomagnesemiaIdiopathic

Resistance to PTHGenetic disordersBisphosphonates

Vitamin D abnormalitiesVitamin D deficiencyRickets (VDR or Renal hyroxylase abnormalities)

Binding of CalciumHyperphosphate states (Crush injury, Tumor lysis, etc.)Blood Transfusion (Citrate)

HypercalcemiaHyperparathyroidism

Primary, Secondary, TertiaryMEN Syndromes

MalignancyHumoral HypercalcemiaPTHrP (Lung Cancer)Osteoclastic activity (Myeloma, Lymphoma)

Granulomatous DiseasesOverproduction of 1,25 (OH)2D

Drug-InducedThiazidesLithiumMilk-AlkaliVitamin A, D

Renal failure

HypercalcemiaSigns & Symptoms

Bones (Osteitis fibrosa cystica, osteoporosis, rickets)Stones (Renal stones)Groans (Constipation, peptic ulcer)Moans (Lethargy, depression, confusion)

Medical TreatmentSERM’s (Evista)Bisphosphonates (Pamidronate)Calcitonin (for severe cases)Saline diuresisGlucocorticoids (for malignant/granulomatous diseases)Avoid thiazide diuretics

Surgical TreatmentSingle vs. Double adenoma – simple excisionMultiple Gland hyperplasia – total parathyroid with autotransplant vs.

3½ gland excision

Primary HyperparathyroidismDiagnosis

Signs & SymptomsElevated serum calciumElevated PTH

EtiologySolitary Adenoma (80-85%)Double Adenomas (2-4%)Muliple Gland Hyperplasia (10-30%)Parathyroid Carcinoma (0.5%)MEN syndromes (10% of MGH have MEN 1)

Multiple Endocrine NeoplasiaMEN 1

Pituitary adenomaPancreatic endocrine tumorParathyroid neoplasia (90%)

MEN 2aMedullary thyroid cancer (100%)Pheochromocytoma (50%)Parathyroid neoplasia (10-40%)

MEN 2bMedullary thyroid cancer (100%)Pheochromocytoma (50%)Neuromas (100%)

Parathyroidectomy1990 NIH Guidelines

Serum Ca++ > 12 mg/dlHypercalciuria > 400 mg/dayClassic symptoms

NephrolithiasisOsteitis fibrosa cysticaNeuromuscular disease

Cortical bone loss with DEXA Z score < -2Reduced creatinine clearanceAge < 50

Other considerationsVertebral osteopeniaVitamin D deficencyPerimenopause

Preoperative LocalizationThallium / Pertechnetate

Based on subtraction of Tc 99 which concentrates only in thyroid from background Thallium which is absorbed by thyroid and parathyroidModerate sensitivity and specificityThyroid pathology reduces effectiveness

Technetium 99m SestamibiAbsorbed by thyroid and abnormal parathyroidEarly washout from thyroid leaves residual parathyroid signals in later imagesHigher sensitivity and specificity

Single Photon Emission Computed TomographyCreates a three dimensional representation to allow for ectopiclocalizationNot commonly used

Intraoperative Hormone AssaysGarner, S., Leight, G. Surgery 1999; 126: 1132-8.

Intraoperative PTH assays found highly sensitive for remaining disease (98.4%)All cases of false positives were in multiple gland diseaseThe incidence of MGH was low in this study

Weber, C., Ritchie, J. Surgery 1999; 126: 1139-44.Intraoperative PTH assays work well in solitary adenomasMultiple gland disease often gives false results due to “adenomaeffect” of the dominant glandRecomends bilateral exploration with any evidence of multiple gland disease

BibliographyBailey, Byron J. Head and Neck Surgery – Otolaryngology. Lippincott Williams & Wilkins. Baltimore, MD. 2001.Greenspan, Francis S.; Strewler, Gordon J. Basic & Clinical Endocrinology. Appleton & Lange. Stamford, Connecticut. 1997.Koos, W.T.; Spetzler, R.F. Color Atlas of Microneurosurgery. Thieme. New York, New York. 2000.Netter, Frank H. The CIBA Collection of Medical Illustrations – Volume 4, Endocrine System and Selected Metabolic Diseases. Ciba Pharmaceutical Company. New York, New York. 1970.Randolph, Gregory W. Surgery of the Thyroid and Parathyroid Glands. Saunders. Philadelphia, PA. 2003.

BibliographyGoretzki, P. E. et. al. “Management of Primary Hyperparathyroidism Caused by Multiple Gland Disease”. World Journal of Surgery. 1991; 15: 693-7.Pattou, Francois. et. al. “Correlation of parathyroid scanning and anatomy in 261 unselected patients with sporadic primary hyperparathyroidism”. Surgery 1999; 126: 1123-31.Jones, J. Mark. et. al. “Pre-operative Sestamibi-Technetium Subtraction Scintigraphy in Primary Hyperparathyroidism: Experience with 156 Consecutive Patients”. Clinical Radiology. 2001; 56: 556-9.Berger, A. et. al. “Heterogeneous Gland Size in Sporadic Multiple Gland Parathyroid Hyperplasia.” Journal of the American College of Surgery. 1999; 188: 382-9.

BibliographyGarner, Sanford; Leight, George. “Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism”. Surgery 1999;126:1132-8.Weber, Collin; Ritchie, James. “Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration”. Surgery1999; 126: 1139-44.Libutti, Steven. et. al. “Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism.” Surgery 1999; 126: 1145-51.