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

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.

• 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

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

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.

Patient BCP

She is not sure, but her mother may take thyroid hormone. You ask “are you taking any medications?” and she replies “no.” Physical exam is completely normal

Patient BCP

• A total T4 is high at 16 (nl 4.5-12.5 )
• You believe BCP may have an atypical

presentation of hyperthyroidism, order multiple tests and refer patient to an endocrinologist.

Patient BCP

Patient BCP turns out to have no thyroid problem but actually started BIRTH CONTROL PILLS just prior to starting college. BCP did not consider the birth control pills “medication.” The birth control pills have altered the thyroid function tests

Thyroid Function and Oral Contraceptives Serum T4

Hyperthyroid Euthyroid

T3 Uptake Free T4 TSH

Patient TDF

Patient TDF is a 38 year old male, ER physician who you bike with on weekends. He tells you he feels a bit fatigued recently. He also tells you, by the way, he has had decreasing testicular size and thinks he may need testosterone He denies taking any drugs, legal or illegal.

Patient TDF

Total T4 level is low at 3 (nl 4.5-12.5 ) Patient is thought to have polyglandular failure and $10,000 of tests are ordered.

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

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

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)

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)

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

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)
• older 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

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

Tests for Differential Diagnosis

Factitious

TSH FT4 24h RAI uptake

Factitious: low thyroglobulin

Graves’ Disease Treatment

Antithyroid Drugs Radioactive iodine Surgery

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

Apathetic Hyperthyroidism

• Placid
• Apathetic facies
• Small Goiter
• Depression or Lethargy
• No eye changes
• Muscular weakness and wasting
• Excessive weight loss
• Cardiovascular dysfunction with atrial fibrillation

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

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

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

What is the appropriate cutoff for a “normal” TSH?

Proposal: Lowering the upper limit of normal for the serum TSH level from 5.0 to 3 .0 or even 2.5 mIU/L

– 22 to 28 million more Americans would be diagnosed with hypothyroidism without any clinical or therapeutic benefit from this – No clear evidence supports a benefit for intervening at these levels of TSH. – lowering of the level of TSH from the upper limit of normal to lower normal range by adjustment of levothyroxine dose does not improve sense of well- being and nonspecific complaints

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/day
• Formula: 1.6 mcg/kg/day

Thyroid Hormone Preparations

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

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

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer THYROID 26: 1, 2016

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

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 a-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

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

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

Surgical:

– For patients intolerant or resistant to medications

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

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

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

Hyperpigmentation characteristic of primary adrenal insufficiency

AI: Diagnosis

Labs: hyponatremia, hyperkalemia, eosinophilia,

mild metabolic acidosis, hypercalcemia

Step 1: confirm diagnosis

– Any random cortisol  18 mg/dl rules out AI – Cortrosyn stimulation test

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

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

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

Primary Aldosteronism (PA)

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

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

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?

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)

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

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!