thyroid and adrenal cortex handout

7/28/2019 Thyroid and Adrenal Cortex Handout

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Thyroid and adrenal cortex

Milagros B. Rabe, M.D., M.S., Ph.D.



Thyroid hormone synthesis



Effects of thyroid hormone• Increased BMR• Increased temperature• Increased oxygen consumption•

Increased BP, HR• CVS – increased force of contraction and heart rate;

increased response to circulating catecholamines• Increased GIT motility• Increased appetite, but no or corresponding weight

gain• Increased DTR’s



Regulation of TH secretion – Level of hypothalamus

• modification of TRH secretion – (-)feedback of TH & TSH on TRH release; (+) ADH, exposure to cold, a

adrenergic catecholamines –

level of anterior pituitary• modification of TSH secretion

– (+) TRH, estrogen inc TRH binding sites; (-) feedback by T3/T4, (-) bysomatostatin, dopamine, glucocorticoids & chronic illness)

– level of thyroid gland – gland’s ability to modify function to adapt to changes in availability of

iodine independent of TSH – autoregulation of T3/T4 secretion

» (+) by TSH & TSH-R stimulating antibodies; (-) iodide excess,lithium , TSH-R blocking antibodies



Regulation of thyroid hormone



Plasma Hormone Levels

– Plasma- RIA• serum free thyroxine (FT 4)= 0.7-1.85 ng/dl• serum free T 3 = 70-132 ng/dl• TSH = 0.5-5 mU/ml• TSH= very sensitive to FT 4 levels• Thyroglobulin - <40 ng/ml in normal; 2 ng/ml in

complete thyroidectomized patient



Tests of Thyroid Function• Plasma hormone levels • Iodide metabolism assessment • Thyroid Imaging • Thyroid ultrasonography & MRI

– to assess thyroid size and nodules, differentiatesolid from cystic nodules

•

Thyroid Biopsy – Fine needle aspiration biopsy - of nodules to

determine benign from malignant thyroid disease



S/Sx: Hypothyrodism• thyroid hormone deficiency

• slow BMR, slow GIT peristalsis, decreased GFR withimpaired water load excretion, dec HR, dec RR, lowvoltage ECG waves, anemia

• cramps, muscle weakness,• lethargy, chronic fatigue, anovulatory cycles (due to

impaired conversion of estrogen precursors)•

deposition of glycoseaminoglycans in intracellularspaces particularly in skin and muscle= myxedema



Diagnosis: hypothyroidism

Patient takes t h y r o id h o r m o n e

Patien t does no t

t ak e t h y r o id h o r m o n e

S top meds 6 wks Serum FT4 & TSH

FT4 & TSH norm al FT4 low,TSH hig h

FT4 low, TSH norm al or low

eu thy ro id P r imary hypo thy ro id i sm

Secondary h y p o th y r o id i s m

TRH sup press ion tes t

If equivo cal

Excess ive r espons e

Pr im ary hypo thy ro id i sm

Normal r espon se

Hypo tha lamic les ion

No r e s p o n s e

Pi tu i tary les ion



Treatment: Hypothryroidism

– Levothyroxine : dosage• 0-6 months = 10-15 mg/kg/d• 7-11 mo = 6-8 mg/kg/d•

1-5 yr = 5-6 mg/kg/d• 6-10 yr= 4-5 mg/kg/d• 11-20 y/o =1-3 mg/kg/d• adult = 1-2 mg/kg/d

– Myexedema:• loading dose: 300-400 mg IV ff 50 mgIV/day• with HD = 0.025 mg/d x 2 wks increase q 2 wks until

0.075 mg is reached x 6 wks



Hyperthyroidism

• Thyrotoxicosis = due to inc levels of thyroidhormone, 2ndary to hyperactive thyroid gland(hyperthyroidism), ingestion of thyroidhormone, ectopic production of thyroidhormone – Grave’s disease = autoimmune, circulating

autoantibodies vs. thyroid gland TSH receptor=stimulation of TSH receptor inc. TH production



Grave’s disease • Diffuse toxic goiter• Clinical features :

• Eye signs: spasm of upper lids, soft tissue involvement withperiorbital edema, proptosis, muscle involvement(inferior rectus),corneal involvement (keratitis)

• skin: dermopathy= thickening of skin, deposition of glycosaminoglycans

Class Definition

0 No signs or symptoms

1 Only sings limited to upper eyelid retraction, stare, lid lag, no symptoms

2 Soft tissue involvement (with signs and symptoms)

3 Proptosis

4 Extraocular muscle involvement

5 Corneal involvement

6 Sight loss (optic nerve involvement)



Treatment: hyperthyroidism

–

Antithyroid drug therapy – PTU 100 mg /6 hrs and reduce to 50-200 mg (OD/BID) in 4-8 weeks,

partially inhibits T4 conversion to T3; – methimazole 40 mg/d x 1-2 months, reduce to 5-20 mg/d – maintain txt until normal T3/TSH values – monitor for agranulocytosis

– surgical treatment – subtotal thyroidectomy after preparation with antithyroid drugs in 6 wks – hypoparathyroidism & laryngeal nerve paralysis in 1% of cases

–

radioactive iodine therapy – 80-150 mCi/g thyroid weight in patients > 21 y/o, w/o heart disease – hypothyroidism in 80% patients



Thyrotoxic crisis: thyroid storm•

Usually occurs in severe form after surgery of apatient who has inadequate control of thyrotoxicosis or hyperthyroidism

• May also occur in patient in severe stressful illness eg.Uncontrolled DM, MI, trauma, acute infection

• Pathogenesis: T3/T4 levels are not higher thanthyrotoxicosis patients but increased bindingsites for catecholamines, decreased bindingwith TBG, with elevation of T3/T4 levels

– Acute illness, surgical stress causes increased CA releasewhich in association with high T3/T4 levels precipitates theacute problem



Cancers of the thyroid – Malignant thyroid tumors: – papillary carcinoma = 75%

– Single layer of thyroid cells arranged in vascular stalks withpapillary projections into cyst like spaces; secrete thyroglobulin

– With “psammoma bodies” (laminated calcified spheres 40% of cases)

– Slow growing, late metastasis – follicular carcinoma = 16%

• Small follicles with little colloid formation – medullary carcinoma = 5%- C cells, more aggressive than

first 2; – 20% cases associated with familial patterns: MEN 2A (medullary

carcinoma, pheochromocytoma, hyperparathyroidism); MEN 2B(medullary carcinoma, pheochromocytoma & multiple mucosalneuromas

– undifferentiated = 3%- most aggressive – miscellaneous (lymphoma, metastatic, etc)= 1%



Regulation of cortisol

secretionCRH and ACTHcircadian rhythm - high in AM, low in PMstress response- stress (+) CRH, ACTHglucocorticoid (-) feedback (fast feedback - rate ofcortisol change; slow feedback - absolute cortisolconcentrationnormal secretion:



ests of CRH-ACTH-adrenal cortex function

Rapid ACTH stimulation (cosyntropin)synthetic ACTH 250 mg IV; measure plasma cortisol at 0, 30 min or at0, 60 min;normal response: peak plasma cortisol > 18-20 mg/dl

Insulin induced hypoglycemia

0.1 to 0.15 unit/kg insulin (0.2- 0.3 unit/kg if obese, Cushing’s oracromegaly); measure plasma glucose every 15 min; GH at 0, 30, 45,60, 75 & 90 minresponse: hypoglycemia < 40 mg/dl will inc GH > 10 ng/ml; cortisol> 18-20 mg/dl

metapyrone stimulationoral metapyrone30 mg/kg at 11-12 PM; measure plasma 11deoxycortisol and cortisol at 8 AM next dayresponse: 11-deoxycortisol inc > 7 mg/dl; cortisol <10 mg/dl



Comparison of normal & pathologic effects

Target Physiologic Cushing’s disease Addison’s disease

Liver Inc.gluconeogenesis

Inc. hepatic glucoseoutput; + insulin= inchepatic glucosestorage

Dec. hepatic glucose output & glycogestores

Adiposetissue

Elevated FFAto fuelgluconeogenesis

Central obesity (+insulin effect),truncal obesity,buffalo hump, moonfacies

Dec. adiposity; dec. lipolysis

Skeletalmuscle

Degradation of muscle proteins

Muscle weakness &wasting (Proximal);inc N2 excretion

Muscle weakness, dec glycogen stores,N2 excretion

Plasmaglucose

Maintainsglucose infasting state;inc duringstress

Impaired glucosetolerance, insulinresistsnt DM

Hypoglaycemia, inc insulin sensitivity



Comparison of normal & pathologic effectsTarget Physiologic Cushing’s disease Addison’s disease

Thymus,lymphocytes Causes Age-relatedinvolution of thymus Immunocompromisedstate;lymphocytopenia

Relativelymphocytosis inperipheral blood

Monocytes Inhibits proliferation,Ag presentation, decIL-1,6; TNFa

Monocytopenia inperipheral blood

Monocytosis inperipheral blood

Granulocytes Demargination of neutrophils

Peripheral bloodgranulocytosis,eosinopenia

Peripheral bloodgranulocytopenia,eosinophilia

Inflammatoryresponse

(-) inflammation by (-)PLA, decleukotrienes, PG; (-)COX-2 expression

Erythrocytes No effect Inc Hg and Hct due toACTH mediated inc inandrogens

Anemia pronouncedin women; due totargeting of parietalcells (GIT)

f l h l



Comparison of normal & pathologiceffects

Target Physiologic Cushing’sDisease

Addison’sdisease

Skin &connectivetissue

Antiproliferative for fibroblasts& keratinocytes

Easybruisability dueto dermalatrophy, striaein sites of hightension/accumulation of fat,hirsutism &acne due to incACTH mediatedadrenalandrogens;hyperpigmentation due toACTH effect onmelanocortinreceptors

Darkening skindue to ACTHmediatedstimulation of epinermalmelanocortinreceptors,vitiligo mayoccur due toautoimmunedestruction of melanocytes



Comparison of normal and pathologiceffects

Target physiologic Cushing’s disease Addison’s disease

Breast Mandatoryrequirement for

devpt

May be associatedwith galactorrhea

Not associatedwith galactorrhea

Lung Stumulationsurfactantproduction

CVS Heart- Inc

contractility;BV = increactivity tovasoconstrictions

Hypertension Lower peripheral

resistance;orthostatichypotension; lowvoltage ECG

C i f l & th l gi ff t



Comparison of normal & pathologic effectsTarget Physiologic Cushing’s

diseaseAddison’sdisease

Mood Eucotisolemiamaintainsemotionalbalance

Initiallyeuphroia, longterm-depression

Depression

Appetite Increasesappetite

Hyperphagia Decreasedappetite inspiteof improved tasteand smell

Sleep Suppression of REM sleep

Sleepdisturbances

Memory Sensitizeshippocampla

glutamatereceptors;induces atrophyof dendritees

Impairedmemory,

bilateralhippocampalatrophy

Eye Inc intraocular pressure

Cataractformation, incintraocular pressure

Dec intraocular pressure



Primary Adrenocortical Insufficiency(Addison’s disease)

Etiology:infectious (TB,CMV, fungi); adrenal he, autoimmune,metastatic CA, infiltrative disorders (amyloid)

Lab:hyponatremia, hyperkalemia, anemia, neutropenia,eosinophilia, relative lymphocytosis; calcification (TB)on x-ray of abdomen

S/Sxweakness, malaise, fatigue, anorexia & wt loss;hyperpigmentation, hypotension, GIT disturbance,salt craving, hyponatremia, hypoglycemia,hyperkalemia



Secondary Adrenocortical insufficiencyEtiology

ACTH deficiency due to pituitary/hypothalamicdisorder

S/Sx - usually chronic, nonspecific manifestations;deficiency of ACTH= no hyperpigmentation;mineralocorticoid secretion usually normal(no volumedepletion, dehydration & hyperkalamia)Lab:

normochromic,normocytic anemia, neutropenia,lymphocytosis; hyponatremia due to absence of (-)feedback on AVPsubnormal response to low dose ACTH, insulininduced hypoglycemia or metapyrone test



Approach to patient withadrenocortical insufficiency

Adrenoco r t ical in su ff ic iency su spec ted

Rapid ACTH s t im ulat ion tes t

abnormal n o r m a l Adrena l a trophy exc luded ,decreased ACTH reserve no t exc luded Adrenocor t ica l

in su ff ic iency

Plasm a ACTH level

Inc ACTH Normal/ low

Pr imary

adrenocor t ica l in su ff ic iency

Secondary

adrenocor t ica l in su ff ic iency

Exc ludes p r imary ad renoco r t ical in su ff ic iency

Metapyron e or

i n s u l in h y p o g ly cem ia test

ab n o r m a l n o r m a l

Exc ludes 2 o ad reno-

co r t ica l in su ff ic iency



Cushing’s Syndrome S/Sx:

obesity, hypertension, skin (striae, hirsutism, plethora,acne, bruising, hyperpigmentation in ectopic ACTHsyndromes only), musculoskeletal (osteopenia,weakness), neuropsychiatric (emotional lability,euphoria, depression, psychosis), gonadaldysfunction(amenorrhea, impotence), metabolic(glucose intolerance, diabetes, hyperlipidemia,polyuria, kidney stones

EtiologyACTH dependent= pituitary adenoma (Cushing’sdisease); nonpituitary neoplasm (ectopic ACTH)ACTH independent = iatrogenic glucocorticoid txt,adrenal neoplasm, nodular adrenal hyperplasia



http://www.netterimages.com/images/vpv/000/00

0/005/5765-0550x0350.j

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Approach to Dx: glucocorticoid excess



Synthesis of adrenal medullary hormones

Di d d l



Disorders: adrenalmedulla

Hypofunctioninterruption of afferent, central or efferentcomponents of the autonomic NS = autonomicinsufficiency ; rare

hyperfunctionpheochromocytoma - paroxyms of hypertensionwith - headaches, sweating, tachycardia, anxiety,tremor, fatigue, abdominal or chest pain, visualdisturbancesinc sweating, cold hands and feet, weight loss,constipation



Normal values (urine): epi =0.02 mg/24 hr; NE = 0.08 mg/24 hr metanephrine = 0.4 mg/24 hr; normetaneprhine= 0.9 mg/

thyroid and adrenal cortex handout

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