Endocrinology Update Robert J. Rushakoff, MD Professor of Medicine - - PowerPoint PPT Presentation
Feedback control Endocrinology Update Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Golden Rule of Endocrinology If overproduction is suspected, try to suppress production.
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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.
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Hypothalamus
TRH +
PIT TSH +
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
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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.
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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
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
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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
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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
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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)
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
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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
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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
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
pills). She has gained 15 lbs in past 2 years. Patient’s sister takes thyroid hormone. Physical exam is normal.
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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
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Signs of Hypothyroidism
Dry skin puffy face and hands hoarse slow reflexes
Patient LL
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
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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 – 1.6 mcg/kg
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
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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,
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
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
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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 α-subunit producing
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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
Hyperprolactinemia
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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
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
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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
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
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Pituitary Tumors: GH Tumors Gigantism
Identical twins, 22 years old, excess GH secretion
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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
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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)
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
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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:
Idiopathic hyperaldosteronism (1/3) Adenoma (60-65% ) Glucocorticoid suppressible (~1%) Cancer (<1% )
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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
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
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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
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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
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
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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!