Endocrinology Update Robert J. Rushakoff, MD Professor of Medicine - - PowerPoint PPT Presentation

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Endocrinology Update

Robert J. Rushakoff, MD

Professor of Medicine University of California, San Francisco

robert.rushakoff@ucsf.edu

Feedback control Golden Rule of Endocrinology

If overproduction is suspected, try to suppress production. If underproduction is suspected, try to stimulate production.

2 Pituitary Hormones and Their Function

Hormone Increased by Decreased by Excess Deficiency Notes ADH Thirst, high serum osmolality Low serum

• smolality,

low serum K+ SIADH DI ACTH CRH, Stress High cortisol Cushing’s syndrome Adrenal insufficiency Diurnal variation (peak at 3–4 a.m.) TSH TRH High T4 and/or T3 Hyperthyroidism Hypothyroidism LH/FSH GnRH Gonadal sex steroids Hypogonadism In men, inhibin inhibits FSH GH GHRH, hypoglycemia, dopamine Somatostatin Childhood: gigantism Adulthood: acromegaly Child: short stature Adult: poor sense

• f well-being

Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine

Pituitary Hormones and Their Function

Hormone Increased by Decreased by Excess Deficiency Notes

TSH TRH High T4 and/or T3 Hyper- thyroidism Hypo- thyroidism

Pituitary Hormones and Their Function

Hormone Increased by Decreased by Excess Deficiency Notes

ACTH CRH, Stress High cortisol Cushing’s syndrome Adrenal insufficiency Diurnal variation (peak at 3–4 a.m.)

Pituitary Hormones and Their Function

Hormone Increased by Decreased by Excess Deficiency Notes

GH GHRH, hypoglycemia, dopamine Somatostatin Childhood: gigantism Adulthood: acromegaly Child: short stature Adult: poor sense of well- being

3 Pituitary Hormones and Their Function

Hormone Increased by Decreased by Excess Deficiency Notes

Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine

• SOMATOSTATIN

Hypothalamus

TRH +

PIT TSH +

• T4

T3

Hormone Action

TSH (+)

T4, T3 (-) Thyroid Hormone Action

Thyroid

PITUITARY

T4, T3 (+)

Hormone Action

Thyroid Failure ↑↑TSH (+)

T4, T3 (-) Thyroid Hormone Action

Thyroid

PITUITARY

T4, T3 (+) X

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Hormone Action Primary Hyperthyroidism

↓ ↓ TSH (+)

↑ T4, T3

(-) Excess Thyroid Hormone Action

Thyroid

PITUITARY

↑ T4, T3

Thyroid Function Tests

Total Thyroid Hormone T4 T3 Free Thyroid Hormone direct and indirect measurement FT4, FT3 Tests for Thyroid hormone binding protein T3U TBG

TSH

Euthyroid Primary Hyperthyroid Primary Hypothyroid

normal

Radioactive Iodine Uptake

123I given orally Gamma counter over area of thyroid

measures radioactivity at 24 hours

Useful for differential diagnosis of

thyrotoxicosis

NOT A TEST FOR ASSESSMENT OF

THYROID FUNCTION

Dependent on iodine intake

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Radioactive Iodine Scanning

Image of thyroid obtained after the

administration of RAI

NOT A TEST FOR ASSESSMENT OF

THYROID FUNCTION

Useful for when thyrotoxic nodular disease

is suspected.

Thyroid Function and Oral Contraceptives Serum T4

Hyperthyroid Euthyroid

T3 Uptake Free T4 TSH T3 Uptake Patient ASBP Patient TDF Serum T4 Euthyroid Free T4 TSH Anabolic Steroids

Patient SF

FH + for mother with thyroid disease Medications: none Exam: Thin female, hyperactive Pulse regular at 120. BP: 98/60 HEENT: + stare, + lid lag at 98mm measure 17mm bilat

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Patient SF

Neck: thyroid enlarged 2X, beefy, no nodules Heart: + Means-Lerman systolic scratch (rubbing together of normal pleural and pericardial surfaces) Ext: fine tremor, no rash

Do you suspect that the patient has hyperthyroidism?

Symptoms of Hyperthyroidism

Palpitations nervousness fatigue hyperkinesia hyperdefication sweating Heat intolerance weight loss (with

increased appetite)

Neck swelling Neck pain Changes in eyes decrease in menstrual

periods

Symptoms of Hyperthyroidism

Palpitations nervousness fatigue hyperkinesia hyperdefication sweating Heat intolerance weight loss (with

increased appetite)

Neck swelling Neck pain Changes in eyes decrease in

menstrual periods

Patient SF

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Signs of Hyperthyroidism

Tachycardia Lid lag Stare exophthalmus

(Graves’ disease)

Tremor Thyroid enlargement Onycholysis

(separation of the nail from its bed)

brisk reflexes Dermopathy

(thickened skin, most

• ften pretibial)

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Is the patient thyrotoxic?

FT4 is 36 (nl 12-24) TSH is 0 (nl 0.5-5)

Laboratory Tests for Thyrotoxicosis

TSH FT4 Primary thyrotoxicosis TSH FT4 Secondary thyrotoxicosis

Laboratory Tests for Thyrotoxicosis

TSH FT4 ? T3 toxicosis TSH FT4 FT3 T3 toxicosis

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Laboratory Tests Not Usually Needed for Diagnosis

TSI Thyroid Antibodies

Causes of Thyrotoxicosis

Common Causes Graves’ Disease

autoimmune disease - B lymphocytes produce TSI Female:Male 5:1 Peak age 20-40

Toxic Multinodular Goiter (TMNG)

• lder patients with history of multinodular goiter

may be precipitated by iodine

Causes of Thyrotoxicosis

Common Causes Toxic Nodule (Plummer’s Nodule)

Single autonomous nodule (>3cm) Age usually > 40

Subacute thyroiditis

Young patient history of malaise, neck pain, viral infection thyroid may be slightly large and tender

Causes of Thyrotoxicosis

Less Common Causes Jod Basedow

iodine induced (usually in patient with underlying goiter)

Silent Thyroiditis factitious

excessive thyroid hormone ingested, usually for weight

control

Most often someone in medical field

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Causes of Thyrotoxicosis

Less Common Causes hypothalamic-pituitary post-partum

“postpartum depression” followed by hypothyroidism

molar pregnancy

high levels of hCG

Struma Ovarii teratoma of ovary containing thyroid tissue

Tests for Differential Diagnosis

Graves’ Disease Subacute Thyroiditis

TSH FT4 24h RAI uptake

Graves’ gland “beefy” Thyroiditis gland hard ESR high in Subacute thyroiditis

Tests for Differential Diagnosis

Graves’ Disease Subacute Thyroiditis

TSH FT4 24h RAI uptake

Graves’ gland “beefy” Thyroiditis gland hard ESR high in Subacute thyroiditis

Tests for Differential Diagnosis

TMNG Toxic Nodule

TSH FT4 FT3 24h RAI uptake

TMNG : feel a multinodular goiter, scan shows hot spots Toxic nodule: palpate a single large nodule, scan shows single hot spot

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Graves’ Disease Treatment

Antithyroid Drugs Radioactive iodine Surgery

Antithyroid Drug Therapy

Best in young patients with small gland

and mild disease

About 30% of patients have “remission”

after 6 months to several years

>60% relapse

Antithyroid Drug Therapy

Propylthiouracil (PTU) Initail dose 150-200 mg tid Methimazole (tapazole) Initial dose 20-30 mg qd Side effects rash in 5% - can often just treat with antihistamine agranulocytosis in <0.5% - patients told to stop drug and get WBC if fever and sore throat

Antithyroid Drug Therapy

• 1. Start Tapazole 20-30 mg per day
• 2. Start propranolol 20-40 mg tid and have patient

titrate to maintain pulse 60-90. Large doses may be required.

• 1. Follow FT4 monthly lowering Tapazole to

maintain in normal FT4. TSH will remain suppressed for months and will not be useful.

• 2. Titrate propranolol off as patient becomes

euthyroid.

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Surgical Treatment

Treatment of choice for patients with very

large goiters

Risk for hypoparathyroidism Risk for recurrent laryngeal nerve injury Surgeon will try to leave tissue so patient

remains euthyroid

Risk for late recurrence

Radioactive Iodine Treatment

For most patients treatment of choice Contraindicated in pregnancy, if

pregnancy anticipated in next year, and possibly if exophthalmus present (very controversial).

Currently, usual treatment is to ablate

thyroid, then have patient take thyroid hormone

Treatment for Subacute Thyroiditis

Treatment of symptoms Treat with beta blocker titrated to lower

pulse

Antithyroid medications of no use ASA or NSAIA for pain toxic state should resolve in 2-3 months

Treatment for Subacute Thyroiditis

After toxic period, may have transient

hypothyroidism (in some patients permanent).

May choose to just watch patient during

this time and most will be euthyroid in another 2-4 months.

May start on levothyroxine and then stop

in a year to see if needed long term

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Patient LL

Patient is a 21 year old female who is preparing for finals. She complains of mild fatigue and heavy menstrual periods. She is

• n no medications (including birth control

pills). She has gained 15 lbs in past 2 years. Patient’s sister takes thyroid hormone. Physical exam is normal.

Do you suspect that the patient has hypothyroidism?

Symptoms of Hypothyroidism

Fatigue Cold intolerance Weight gain constipation heavy, frequent menstrual periods muscle cramps

Symptoms of Hypothyroidism

Fatigue Cold intolerance Weight gain constipation heavy, frequent menstrual periods muscle cramps

Patient LL

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Signs of Hypothyroidism

Dry skin puffy face and hands hoarse slow reflexes

Signs of Hypothyroidism

Dry skin puffy face and hands hoarse slow reflexes

Patient LL

Is the patient hypothyroid ?

TSH is 35 (nl .5-5).

Laboratory Tests for Hypothyroidism

TSH FT4 Primary hypothyroidism TSH FT4 Secondary hypothyrodism

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Laboratory Tests for Hypothyroidism

TSH FT4 Subclinical hypothyroidism Clinical significance not clear. Patients with TSH >20 or + thyroid antibodies have >80% chance to become clinically hypothyroid within 5 years

Etiology of Hypothyroidism

Primary Hashimoto’s Thyroiditis

automimmune +/- goiter

After RAI or surgery for Graves’ disease subacute thyroiditis inborn errors of thyroid hormone synthesis

Secondary

hypothalamic or hypopituitarism

Thyroid Hormone Preparations

Levothyroxine (T4) most physiologic treatment of choice daily dose t1/2 1 week average dose 0.125 mg/d

Thyroid Hormone Preparations

Liothyronine (T3) tid dosing not physiologic bypass normal T4 to T3 conversion t1/2 1 day

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Thyroid Hormone Preparations

Desiccated thyroid potency variable variable T4 and T3 levels monitoring difficult bypass normal T4 to T3 conversion 80% of patients on this preparation shown not to require any thyroid hormone replacement

Monitoring Thyroid Hormone Replacement

Goal is for normal TSH Minimal time after any change in thyroid hormone dose before rechecking TSH level is 6- 8 weeks. It takes this long to reach steady state. More frequent testing will be not only a waste of money but potentially misleading. Decreased Absorption:

– Drugs, supplements: calcium, iron, soy, Cholestyramine – Decreased gastric acid: H. pylori infection,

• meprazole

Monitoring Thyroid Hormone Replacement

TSH FT4 Subclinical hyperthyroidism Associated with decreased bone density. Associated with atrial arrhythmias in older patients. Patient needs decrease in thyroid hormone dose.

Thyroid Nodules

In experienced hands, thyroid US can be

first diagnostic test

Fine needle aspiration alternative first

diagnostic test

Experienced pathologist of key importance Thyroid radioactive scans not helpful to

determine if nodule is benign or malignant

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Hypopituitarism

Although primary organ failure is more common, hypopituitarism is in the differential diagnosis in cases of hypothyroidism, hypoadrenalism and hypogonadism GH, gonadotrophins, TSH, ACTH, Prolactin (loss in this order) ADH deficiency only if posterior pituitary involved

Etiologies – 9 I’s

Invasive – tumors, metastasis Infarction – Sheehan’s, apoplexy Iatrogenic –radiation, surgery Infiltrative – sarcoid, hemochromatosis, histiocytosis X Injury – head trauma (also can see DI) Immunologic – lymphocytic hypophysitis Infections – TB, syphilis or fungi Idiopathic Isolated – Kallman’s – GnRH deficiency with anosmia – X linked dominant – decreased expression of KAL 1

Hypopituitarism: Dx and Tx

In general, treat underlying cause Central hypothyroidism

– TSH is not reliable for screening or for monitoring – Diagnosis depends on low Free T4 – Tx: LT4 therapy, but do not start until adrenal insufficiency has been ruled out

Hypopituitarism: Dx and Tx cont’d

Central adrenal insufficiency

– Aldosterone secretion intact so no hyperkalemia – Hyponatremia due to decreased GFR & inability to excrete water load (+ increased ADH secretion +/- hypothyroidism) – Dx: cosyntropin stimulation test (random cortisol or ACTH level not useful) – Tx: hydrocortisone 20-30 mg/d, 2/3 in the morning and 1/3 in the evening.

Prolactin deficiency – inability to lactate

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Pituitary tumors

Microadenomas are < 1cm

Macroadenomas are >1cm Types of tumors

– 60% prolactinomas – 20% GH producing – 10% ACTH producing – 10% non-functioning – Rare: TSH, LH/FSH or α-subunit producing

Pituitary tumors - Presentation

Symptoms/Exam:

–Neurological syx (h/a, visual field cuts, nerve palsies) –Hormonal excess or deficiency –Incidental discovery on imaging study

up to 10% general population have pituitary incidentalomas

Pituitary tumors - Evaluation

Once tumor is identified, must determine if functional or not:

– TSH, FT4 – Prolactin – ACTH, cortisol

Cosyntropin stimulation test if suspect deficiency 24 hr urinary cortisol or dexamethasone suppression test if suspect excess

– LH/FSH + testosterone in men

Pituitary tumors - Treatment

Surgery: transsphenoidal approach is successful in approximately 90% of patients with microadenomas Medical:

– Dopamine agonists for prolactinomas – Somatostatin analogues for GH producing tumors

Radiotherapy after surgery and/or medical therapy fails or poor surgical candidates:

– Conventional XRT or – Gamma knife

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Hyperprolactinemia Hyperprolactinemia

Physiologic:

– Pregnancy (prolactin can reach 200 ng/ml in 2nd trimester) – Lactation – Nipple stimulation – Exercise – Coitus – Stress – Sleep

Pathologic:

– Pituitary tumors – mostly microadenomas – Pituitary stalk lesions – Hypothalamic lesions – Chest wall /spinal cord lesions – Hypothyroidism – Chronic kidney disease – Cirrhosis

Hyperprolactinemia Cont’d

Pharmacologic:

– Estrogen – Dopamine antagonists (phenothiazines, haloperidol, risperidone, metoclopramide, methyldopa, opioids, amoxapine) – Monoamine oxidase inhibitors – Cimetidine and Ranitidine – SSRI’s – Tricyclic antidepressants – Verapamil – Liquorice

Hyperprolactinemia: Syx/exam

Women galactorrhea, amenorrhea

• r oligomenorrhea with

anovulation and infertility in 90% Amenorrhea: 18% prolactinoma Galactorrhea: 37% Prolactinoma Both: 75% Prolactinoma Microadenoma: 64% Men impotence, decreased libido, galactorrhea (very rare) 91% macroadenoma Both local tumor extension symptoms - headache, visual field cuts, hypopituitarism

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Hyperprolactinemia: Diagnosis

Elevated prolactin:

– PRL >200 ng/ml virtually diagnostic of prolactinoma – PRL 100-200 usually prolactinoma – PRL 20-100 may be microadenoma but exclude other causes

Normal TFT’s and negative pregnancy test MRI of pituitary

Hyperprolactinemia: Treatment

Medical – 1st line in most cases

– Dopamine agonists: bromocriptine or cabergoline

SE: nausea, fatigue, nasal stuffiness and postural hypotension

– Restores fertility and gonadal function in most patients – Leads to tumor shrinkage – During pregnancy, risk of growth is <5% for microprolactinomas and 20-40% for macroprolactinomas

Surgical:

– For patients intolerant or resistant to medications – If need urgent decompression of the sella turcica for visual field defects unresponsive to trial of dopamine agonists

Hyperprolactinemia: Treatment Pituitary Tumors: GH Tumors

80% are macroadenomas 15% co-secrete prolactin Very rarely (<1% cases), acromegaly due to ectopic GH or GHRH production

– Lung CA, carcinoid, or pancreatic islet cell tumors

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Pituitary Tumors: GH Tumors

Clinical features due to excess IGF-I and mass effect of the tumor.

– Hypertension – Glucose intolerance or DM – Increased colonic polyp frequency – Soft tissue proliferation: coarsening of facial features, hand and feet enlargement – Sweaty palms and soles – Carpal Tunnel Syndrome – Hypogonadism – Visual field cuts and h/a’s

Pituitary Tumors: GH Tumors

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Gigantism

Identical twins, 22 years old, excess GH secretion

Pituitary Tumors: GH Tumors

Diagnosis:

– Elevated IGF-1 is the hallmark – Dx: oral glucose tolerance test

100 g glucose given 60 minutes GH<1 ng/ml rules out acromegaly

– Random GH level not helpful

Therapy:

– Surgery: curative in 60-80% – Radiation therapy: adjuvant therapy – Medical:

Octreotide LAR (SS analog) Pegvisomant (GH receptor antagonist)

Adrenal Insufficiency: Etiologies

Primary AI:

– Autoimmune – Metastatic malignancy & lymphoma – Hemorrhage: pregnancy, anticoagulation, antiphospholipid antibody syndrome – Infiltrative disorders: amyloid, hemochromatosis – Drugs: ketoconazole, metyrapone, aminoglutethimide, trilostane, mitotane, etomidate – Rare: congenital adrenal hyperplasia, adrenal leukodystrophy

Secondary AI:

– Iatrogenic: glucocorticoids & anabolic steroids – Pituitary or hypothalamic tumors

Vague syx:

– Weakness – Fatigue – Anorexia – Weight loss – Nausea – Vomiting – Diarrhea – Unexplained abdominal pain – Postural lightheadedness

AI: Clinical Features

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Hyperpigmentation characteristic of primary adrenal insufficiency

AI: Diagnosis

Labs: hyponatremia, hyperkalemia, eosinophilia,

mild metabolic acidosis, hypercalcemia

Step 1: confirm diagnosis

– Any random cortisol ≥ 18 µg/dl rules out AI – Cortrosyn stimulation test

Obtain baseline cortisol and ACTH Inject Cortrosyn 250 µg IM or IV Check cortisol level 45-60 minutes later Normal if post stimulation cortisol ≥ 18 µg/dl

Step 2: distinguish 1o from 2o Step 3: evaluate cause (CT abdomen or MRI pituitary)

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AI: Treatment

Hydrocortisone 20-30 mg/day

– 2/3 in the morning – 1/3 in evening

Stress doses:

– Minor stress – double usual dose – Major stress: 50 mg IV q 6-8 hrs, and taper

For 1o AI, also need:

– Fludrocortisone 0.05-0.1 mg/day

Cushing’s Syndrome

Exogenous steroids: #1 cause Endogenous:

– Cushing’s disease (70%): due to ACTH secretion from pituitary adenoma – Ectopic ACTH (15%): from non pituitary tissue making ACTH

Small cell lung CA most common Bronchial carcinoids

– Adrenal (15%):

Adenoma Carcinoma Nodular adrenal hyperplasia

Cushing’s Diagnosis

ACTH Adrenal Pituitary or Ectopic CT Adrenals MRI pituitary

Petrosal Sinus ACTH

Ectopic ACTH-producing tumor Pituitary source

Low (<5) High (>10 pg/ml)

+

Central

_

Peripheral

24 h Urine Cortisol

+ _

Normal

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Primary Aldosteronism (PA)

Accounts for 0.5-10% cases htn Results from autonomous aldosterone prdctn, due to:

Idiopathic hyperaldosteronism (1/3) Adenoma (60-65% ) Glucocorticoid suppressible (~1%) Cancer (<1% )

Primary Aldosteronism: Features

Hypertension Hypokalemia

– May be absent – Exacerbated by diuretics

Paresthesias if severe hypokalemia Mild alkalosis on laboratories

Primary Aldosteronism: Dx

Screening:

– Must first replete potassium – Plasma aldosterone (PA)/ Plasma Renin Activity (PRA) ratio >20-25 suggestive

Confirmatory test:

– Salt load: 1 g NaCl tid for 3 days – 24 hr urine aldosterone>12 mcg/24 hr with concomitant 24 hr urine Na>200 mmol/d

Primary Aldosteronism cont’d

CT

– Unilateral lesion – Bilateral Hyperplasia, or no lesion seen:

Adrenal vein sampling – measure cortisol and aldosterone to lateralize source of aldosterone excess

Management:

– Unilateral lesion resect – Bilateral hyperplasia or no lesion medical rx with spironolactone or eplerenone

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Pheochromocytoma

Rare tumors Produce epinephrine and/or norepinephrine Symptoms:

– Episodic throbbing in the chest, trunk and head – Headaches – Diaphoresis – Palpitations – Tremor, anxiety, nausea, vomiting, fatigue – Abdominal or chest pain – Weight loss – Cold hands and feet

Pheochromocytoma cont’d

In ¼ of cases, hypertension is episodic Orthostasis usually present Rule of 10’s:

– 10% normotensive – 10% occur in children – 10% are bilateral – 10% are malignant – 10% are extra-adrenal (called paragangliomas)

Pheochromocytoma cont’d

First – make BIOCHEMICAL dx:

– 24-hr urinary metanephrine and normetanephrine or plasma free metanephrine (levels usually 2-3 x normal)

If biochemical diagnosis made, localize:

– CT or MRI of the adrenal – If CT or MRI negative, can use 123I-MIBG to localize extra-adrenal pheo and mets

Adrenal Incidentalomas

Found in ~10% of autopsies Prevalence increases with age 2 questions for evaluation:

– Is lesion functioning or not? – Is lesion benign or malignant?

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Incidentaloma: is it functional?

In all patients: Screen for pheochromocytoma:

– 24 hr urine for metanephrines or Plasma metanephrines

Screen for subclinical Cushing’s

– 1 mg overnight dexamethasone suppression test – 24 hour urine cortisol

In patients with hypertension: Screen for primary aldosteronism:

– PA/PRA ratio

Incidentaloma: Benign or not?

More likely to be BENIGN if: <4 cm Low density on unenhanced CT (<10 HU) It contains fat (suggests myelolipoma)

Incidentaloma: Management

Yes No Functional? Size on CT >4 cm <4 cm Adrenalectomy Re-image at 6, 12 and 24 mos No further f/u if no change in size

Increase in size >1 cm

Adrenalectomy

Hypercalcemia PTH Primary HPT FHH Lithium HIGH LOW ↑ PTHrP Solid tumors T cell lymphoma Malignancy −1,25 Vit D lymphoma Local osteoclastic Lesions Myeloma, leukemia Lymphoma Others Milk-alkali syndrome Immobilization Endocrine Thyroid, adrenal, Pheo, VIPOMA Acromegaly Granulomas ↑ 1,25 Vit D Sarcoid, TB, Cocci, Histo, pulm eosinophilia

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Primary Hyperparathyroidism

PTH, Ca, Phos

0.4% women over 60; 2-3Xs the rate in men Single adenoma 80 %, rest hyperplasia Associated with MEN1, MEN 2A, isolated familial Tx: Surgical if indicated

Primary Hyperparathyroidism

Treatment:

– Surgery if

Serum Ca >1.0 mg/dl above NL 24 hr urine Calcium>400 mg/d CrCl reduced by > 20% BMD T-score <-2.5 at any site Age <50 yrs

– If no surgery, follow with:

Ca 2x/yr, Cr q yr BMD q yr

– Medication:

Cinacalcet: oral calcimimetic agent decreasing PTH and calcium

Familial Benign Hypocalciuric Hypercalcemia (FBHH)

Mutation in calcium sensor Autosomal dominant inheritance Lifelong asymptomatic hypercalcemia Urine Ca < 50 mg/24 hr

Calcium creatinine clearance ratio < 0.01 urine Ca X Serum Creat serum Ca X Urine Creat

No need for treatment!