feedback control endocrinology update€¦ · endocrinology update robert j. rushakoff, md...
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Endocrinology Update
Robert J. Rushakoff, MDProfessor of Medicine
University of California, San [email protected]
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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- SOMATOSTATIN
Hypothalamus
TRH +PIT
TSH +-
-
T4
T3
Hormone Action
TSH (+)
T4, T3 (-)
Thyroid HormoneAction
ThyroidPITUITARY
T4, T3(+)
Hormone ActionThyroid Failure
↑↑TSH (+)
T4, T3 (-)
Thyroid HormoneAction
ThyroidPITUITARY
T4, T3(+)
X
Hormone ActionPrimary Hyperthyroidism
↓ ↓ TSH(+)
↑ T4, T3
(-)Excess Thyroid HormoneAction
ThyroidPITUITARY
↑ 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
EuthyroidPrimary
HyperthyroidPrimary
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 ASBPPatient 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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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 often 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
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 TSIFemale:Male 5:1Peak 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 pregnancyhigh levels of hCG
�Struma Ovariiteratoma 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 hardESR high in Subacute thyroiditis
Tests for Differential Diagnosis
Graves’ Disease
Subacute Thyroiditis
TSH FT4 24h RAI uptake
Graves’ gland “beefy”Thyroiditis gland hardESR 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 spotsToxic 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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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
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 on 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.
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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
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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
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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 TSHMinimal 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,
omeprazole
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
HypopituitarismAlthough 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’sInvasive – tumors, metastasisInfarction – Sheehan’s, apoplexyIatrogenic –radiation, surgeryInfiltrative – sarcoid, hemochromatosis, histiocytosis XInjury – head trauma (also can see DI)Immunologic – lymphocytic hypophysitisInfections – TB, syphilis or fungiIdiopathic 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 deficiency24 hr urinary cortisol or dexamethasone suppression test if suspect excess
– LH/FSH + testosterone in men
Pituitary tumors - TreatmentSurgery: transsphenoidal approach is successful in approximately 90% of patients with microadenomasMedical: – 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’dPharmacologic:– 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
Womengalactorrhea, amenorrhea or oligomenorrhea with anovulation and infertility in 90%Amenorrhea: 18% prolactinomaGalactorrhea: 37% ProlactinomaBoth: 75% ProlactinomaMicroadenoma: 64%
Menimpotence, decreased libido, galactorrhea (very rare)91% macroadenoma
Bothlocal tumor extension symptoms - headache, visual field cuts, hypopituitarism
Hyperprolactinemia: DiagnosisElevated 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
cabergolineSE: 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 TumorsClinical 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 TumorsDiagnosis:– Elevated IGF-1 is the hallmark– Dx: oral glucose tolerance test
100 g glucose given60 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: EtiologiesPrimary 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: DiagnosisLabs: 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 ACTHInject Cortrosyn 250 µg IM or IVCheck cortisol level 45-60 minutes laterNormal 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 SyndromeExogenous steroids: #1 causeEndogenous:– Cushing’s disease (70%): due to ACTH
secretion from pituitary adenoma– Ectopic ACTH (15%): from non pituitary
tissue making ACTHSmall cell lung CA most commonBronchial carcinoids
– Adrenal (15%):AdenomaCarcinomaNodular 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:
Idiopathichyperaldosteronism (1/3)
Adenoma (60-65%)
Glucocorticoidsuppressible (~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 tumorsProduce epinephrine and/or norepinephrineSymptoms:– 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 HPTFHHLithium
HIGH
LOW
↑ PTHrPSolid tumorsT cell lymphoma
Malignancy
−1,25 Vit Dlymphoma Local osteoclastic
LesionsMyeloma, leukemiaLymphoma
OthersMilk-alkali syndromeImmobilization
EndocrineThyroid, adrenal,Pheo, VIPOMAAcromegaly
Granulomas↑ 1,25 Vit DSarcoid, 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 HyperparathyroidismTreatment: – Surgery if
Serum Ca >1.0 mg/dl above NL24 hr urine Calcium>400 mg/dCrCl reduced by > 20%
BMD T-score <-2.5 at any siteAge <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 HypocalciuricHypercalcemia (FBHH)
Mutation in calcium sensorAutosomal dominant inheritanceLifelong asymptomatic hypercalcemiaUrine Ca < 50 mg/24 hrCalcium creatinine clearance ratio < 0.01
urine Ca X Serum Creatserum Ca X Urine Creat
No need for treatment!