ENDO Flashcards
Most common causes of hypothyroidism in areas of iodine sufficiency (2)
autoimmune
iatrogenic
Most common cause of neonatal hypothyroidism
Thyroid gland dysgenesis – 80–85%
3 Causes of neonatal hypothyroidism
o Thyroid gland dysgenesis – 80–85%
o Inborn errors of thyroid hormone synthesis – 10–15%
o TSH-R antibody-mediated – 5%
Treatment of congenital hypothyroidism with dose
T4 dose of 10–15 μg/kg per day
If transient congenital hypothyroidism is suspected or with unclear diagnosis, when can you stop the treatment?
treatment can be stopped at age 3 y.o then with further evaluation
2 thyroiditis that may be associated with goiter
o Hashimoto’s thyroiditis
o Goitrous thyroiditis
Thyroiditis that may be associated with minimal residual thyroid disease (at the later stages)
Atrophic thyroiditis
Symptomatic hypothyroidis usually occurs at what TSH level
> 10 mIU/L
Mean age at diagnosis of autoimmune hypothyroidism
60 years
Annual risk of developing clinical hypothyroidism is about 4% when subclinical hypothyroidism is associated with what antibodies?
Thyroid peroxidase (TPO) antibodies
Pathology of Hashimoto’s (5)
o Marked lymphocytic infiltration of the thyroid with germinal center formation o Atrophy of the thyroid follicles o Oxyphil metaplasia o Absence of colloid o Mild to moderate fibrosis
Pathology of atrophic thyroiditis (3)
o More extensive fibrosis
o Less lymphocyte infiltration
o Thyroid follicles are almost completely absent
Usually represents the end stage of Hashimoto’s thyroiditis rather than a separate disorder
Atrophic thyroiditis
The best documented genetic risk factors for autoimmune hypothyroidism
HLA-DR polymorphisms
Especially HLA-DR3, DR4, and DR5
2 risk factors of autoimmune thyroiditis
o High-iodine or low selenium intake – increased risk of autoimmune hypothyroidism
o Smoking cessation – transiently increases incidence
T or F: Alcohol intake is a risk factor for autoimmune hypothyroidism
false. protective
Clinically useful markers of thyroid autoimmunity
Antiboidies to TPO and thyroglobulin (Tg)
Usual clinical manifestation of hashimoto’s thyroiditis (2)
goiter
pain - rare
Describe the goiter in hashimoto’s thryoiditis
Irregular and firm in consistency
Stage of hashimoto’s thyroiditis that present with signs and symptoms of hypothyroidism, dry skin, decreased sweating, thinning of the epidermis, and hyperkeratosis of the stratum corneum
Atrophic thyroiditis
Sin thickening without pitting with puffy face with edematous eyelids due to increased dermal glycosaminoglycan content trapping water
Myxedema
Clinical manifestations of myxedema (6)
o Puffy face with edematous eyelids
o Nonpitting pretibial edema
o Pallor, often with yellow tinge to the skin due to carotene accumulation
o Nail growth retardation
o Hair is dry, brittle, difficult to manage and falls out easily (diffuse alopecia)
o Thinning of the outer third of the eyebrows
Describe the speech in myxedema
hoarse voice and clumsy speech
Cardiovascular manifestations of myxedema (4)
- reduced myocardial contractility
- bradycardia
- diastolic hypertension (increased peripheral resitance)
- pericardial effusion
Pericardial effusions occur in how many percent of myxedema patients
30%
Steroid-responsive syndrome associated with TPO antibodies, myoclonus, and slow-wave activity on EEG
Hashimoto’s encephalopathy
Relationship with hypothyroidism and thyroid autoimmunity has not been established
Screening test used in autoimmune hypothyroidism
TSH
T or F:o Normal TSH level excludes primary and secondary hypothyroidism
False. Normal TSH level excludes primary (but not secondary) hypothyroidism
If there is elevated TSH, what test should you do in order to confirm presence of clinical hypothyroidism ?
Unbound T4
These antibodies are found in in >95% of autoimmune hypothyroidism
TPO and Tg antibodies
Differentiate the ultrasound findings of multinodular goiter, thyroid carcinoma, and Hashimoto’s thyroiditis
- Multinodular goiter - multinodular
- Thyroid carcinoma -solitary lesion
- Hashimoto’s – heterogenous thyroid enlargement
In iatrogenic hypothyroidism, transient hypothyroidism in the first _______ after radioiodine treatment for Graves’ disease
3–4 months
Better measure of thyroid function than TSH in the months following radioiodine treatment
FT4
Cause of endemic goiter and cretinism
Iodine deficiency
T or F. Chronic iodine excess can also induce goiter and hypothyroidism
True
Psychiatric medication that can also cause iatrogenic hypothyroidism
Lithium
If there is no residual thyroid function, what is the dose of levothyroxine?
1.6 μg/kg body weight (typically 100–150 μg), ideally taken at least 30 min before breakfast
Dose of levothyroxine for iatrogenic hypothyroidism
Lower replacement doses (typically 75–125 μg/d)
Dose of levothyroxine in o adult patients under 60 years old without evidence of heart disease
50–100 μg levothyroxine (T4) daily
TSH monitoring should be done after how many month after instituting treatment of hypothyroidism
2 months
Patients treated with levothyroxine may experience full relief from symptoms only after ______
3-6 months after normal TSH levels are restored
T or F: Patients who miss a dose of levothyroxine can be advised to take two doses of the skipped tablets at once
True.Because T4 has a long half-life (7 days)
In the treatment of subclinical hypothyroidism, levothyroxine is recommended only in: (2)
o Woman who wishes to conceive or is pregnant
o TSH > 10 mIU/L
In subclinical hypothyroidism, trial of treatment with levothyroxine for TSH < 10mIU/L if with (3)
o Symptomatic
o Positive TPO antibodies
o Evidence of heart disease
In treatment of subclinical hypothyroidism, it is important to confirm that any elevation of TSH is sustained over a_____ period before treatment is given
3-month
Dose of levothyroxine in subclinical hypothyroidism
25–50 μg/d
Idiosyncratic reaction in children with levothyroxine treatment that occurs months after treatment has begun
Pseudomotor cerebri
In pregnant women or planning to conceive, thyroid function should be evaluated when?
- immediately after pregnancy is confirmed
- every 4 weeks during the first half of the pregnancy
- every 6–8 weeks after 20 weeks’ gestation (every 6–8 weeks depending on whether levothyroxine dose adjustment is ongoing)
In pregnant women or planning to conceive, levothyroxine dose may need to be increased by up to
45%
Mortality rate of myxedema coma
20-40%
Clinical manifestations of myxedema coma (3)
Reduced level of consciousness
Seizures
Hypothermia can reach 23°C (74°F)
Myedema coma is more common in this population
elderly
Causes of the clinical manifestations of myxedema coma (4)
- sepsis
- hypoventilation (leading to hypoxia and hypercapnia)
- hypoglycemia
- dilutional hyponatremia
Dose of levothyroxine in myxedema coma
A single IV bolus of 200–400 μg as loading dose
Daily oral dose of 1.6 μg/kg/d, reduced by 25% if administered IV
Supportive therapy for myxedema coma (8)
- external warming
- correct electrolytes
- IV hydrocortisone 50 mg q6
- treatment of precipitating factors
- broad spectrum antibiotics
- ventilatory syupport
- hypertonic saline
- IV glucose
State of thyroid hormone excess
Thyrotoxicosis
The result of excessive thyroid function
hyperthyroidism
T or F: Thyrotoxicosis is synonymous to hyperthyroidism
False
Accounts for 60–80% of thyrotoxicosis
Graves’ disease
Typical age of grave’s disease
20-50 years old
also occur in elderly
An important environmental factor contributing to Grave’s disease, presumably operating through neuroendocrine effects on the immune system
Stress
A minor risk factor for Graves’ disease and a major risk factor for the development of ophthalmopathy
Smoking
Occurrence of Graves’ disease in the postpartum period
threefold increase
The hyperthyroidism of Graves’ disease is caused by ________ that are synthesized in the thyroid gland as well as in bone marrow and lymph nodes
thyroid- stimulating immunoglobulin (TSI)
Thyroid stimulating Ig can be detected using what assay?
Thyrotropin-binding inhibitory immunoglobulin (TBII) assays
Antibodies that occur in up to 80% of cases of Grave’s disease (2)
thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies
Proposed pathogenesis of thyroid-associated ophthalmopathy
TSH-R is a shared autoantigen that is expressed in the orbit
In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with (2)
fatigue and weight loss
Type of thyrotoxicosis mostly seen in elderly that presents only as fatigue and weight loss
apathetic thyrotoxicosis
The most common cardiovascular manifestation of Grave’s disease
sinus tachycardia
Manifestations of high cardiac output in Grave’s disease (4)
Bounding pulse
Widened pulse pressure, Aortic systolic murmur
Worsening of angina or heart failure
Cardiac arrhythmia in Grave’s disease that is more common in patients >50 years of age
Atrial fibrillation
In Graves’ disease, the thyroid is usually_____ enlarged to ____ times its normal size. The consistency is____, but not_____.
diffusely
two to three
firm
nodular
PE finding in Grave’s disease that is due to the increased vascularity of the gland and the hyperdynamic circulation.
thrill or bruit, best detected at the inferolateral margins of the thyroid lobes
Clinical manifestation of ophthalmopathy in Graves’ disease (4)
lid retraction (staring appearance)
periorbital edema
conjunctival injection
marked proptosis
Thyroid-associated ophthalmopathy occurs in the absence of hyperthyroidism in___ of patients
10%
The earliest manifestations of thyroid-associated ophthalmopathy (3)
sensation of grittiness
eye discomfort
excess tearing
The most serious manifestation of thyroid-associated ophthalmopathy
compression of the optic nerve at the apex of the orbit, leading to papilledema; peripheral field defects; and, if left untreated, permanent loss of vision
Thyroid dermopathy occurs in ____ of patients with Graves’ disease, almost always in the presence of_____
<5%
moderate or severe ophthalmopathy
Most frequent involvement of thyroid dermopathy and the term associated with it
anterior and lateral aspects of the lower leg
pretibial myxedema
The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an “orange skin” appearance.
Refers to a form of clubbing found in <1% of patients with Graves’ disease
Thyroid acropachy
It is so strongly associated with thyroid dermopathy
For patients with thyrotoxicosis who lack the typical features of Grave’s, the diagnosis is generally established by a
radionuclide (99mTc, 123I, or 131I) scan and uptake of the thyroid
distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis, as well as diagnosing a toxic adenoma or toxic MNG
Group of drugs that inhibit the function of TPO, reducing oxidation and organification of iodide
Thionamides
PTU, carbimazole and methimazole (active metabolite)
Thionamide that has more adverse drug reaction especially hepatotoxicity
PTU
the U.S. Food and Drug Administration (FDA) has limited indications for its use to the first trimester of pregnancy, the treatment of thyroid storm, and patients with minor adverse reactions to methimazole
Dose of methimazole or carbimazole in Grave’s disease
10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored
Dose of PTU in Grave’s disease
100–200 mg every 6–8 h
Thyroid function tests and clinical manifestations are reviewed ____ after starting treatment for hyperthyroidism
4–6 weeks
TSH levels often remain suppressed for several months and therefore do not provide a sen- sitive index of treatment response
Most Grave’s disease patients do not achieve euthyroidism until _____ after treatment is initiated
6–8 weeks
Cholestasis is an adverse effect of thionamides that is more common in
Carbimazole or methimazole
Hepatotoxicity – PTU
Agranulocytosis is an ADR of thionamides that is seen in ____ of patient undergoing treatment
<1%
Rare but major side effects of thionamides (4)
Hepatitis
Vasculitis
Cholestasis
Agranulocytosis
It is essential that antithyroid drugs are stopped and not restarted if a patient develops major side effects
T or F. In patient on thionamide treatment for Grave’s disease, it is important to regularly monitor the blood counts to screen for agranulocytosis
False. It is not useful to monitor blood counts prospectively, because the onset of agranulocytosis is idiosyncratic and abrupt
Beta blockers used in Graves disease
Propranolol (20–40 mg every 6 h)
Atenolol - longer-acting selective β1 receptor blockers
may be helpful to control adrenergic symptoms
_____ causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs
Radioiodine
There is a small risk of thyrotoxic crisis after radioiodine, which can be minimized by
pretreatment with antithyroid drugs for at least a month before treatment
Carbimazole or methimazole must be stopped ____ before radioiodine administration to achieve optimum iodine uptake, and can be restarted ____ after radioiodine in those at risk of complications from worsening thyrotoxicosis.
2–3 days
3–7 days
Propylthiouracil appears to have a prolonged radioprotective effect and should be stopped for a longer period before radioiodine is given, or a larger dose of radioiodine will be necessary.
In general, patients who underwent radioiodine therapy need to avoid close, prolonged contact with children and pregnant women for _____ because of possible transmission of residual isotope and exposure to radiation emanating from the gland
5–7 days
Mild thyroid pain 1-2 weeks after radioiodine therapy
Radiation thyroiditis
Hyperthyroidism can persist for _____ before radioiodine takes full effect
2–3 months
β-adrenergic blockers or antithyroid drugs can be used to control symptoms during this interval
Persistent hyperthyroidism can be treated with a second dose of radioiodine, usually ____ after the first dose
6 months
Pregnancy and breast-feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely ____ after treatment
6 months
T or F. Radioiodine should generally be avoided in those with active moderate to severe thyroid-associated eye disease
True
Prednisone, 30 mg/d, at the time of radioiodine treatment, tapered over 6–8 weeks may prevent exacerbation of ophthalmopathy
_____ is an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine
Total or near-total thyroidectomy
The major complications of total or near-total thyroidectomy (4)
Bleeding
laryngeal edema
hypoparathyroidism
damage to the recurrent laryngeal nerves
unusual when the procedure is performed by highly experienced surgeons
Anti-thyroid drug that is used for hyperthyroid patient until 14-16 weeks AOG
PTU
Then converted to methimazole
Why is PTU preferred over Methimazole in pregnant women?
because of the association of rare cases of methimazole/ carbimazole embryopathy, including aplasia cutis and other defects, such as choanal atresia and tracheoesophageal fistulae
In euthyroid patients on low-dose PTU or methimazole that become pregnant, will you continue the medication?
No.
Recent recommendations suggest discontinuation of antithyroid medication in a newly pregnant woman with Graves’ disease, who is euthyroid on a low dose of methimazole (<5–10 mg/day) or PTU (<100–200 mg/day), after evaluating recent thyroid function tests, disease history, goiter size, duration of therapy, and TRAb measurement
What is the ratio of conversion from PTU to methimazole?
15–20 mg of propylthiouracil to 1 mg of methimazole
Antithyroid drugs given to the mother can be used to treat the fetus and may be needed for ___ after delivery, until the maternal antibodies disappear from the baby’s circulation
1–3 months
T or F. Breast-feeding is safe with low doses of antithyroid drugs
True
Rare and presents as a life-threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice
Thyrotoxic crisis, or thyroid storm
Most common causes of mortality in thyroid storm (3)
Cardiac failure
Arrhythmia
Hyperthermia
Thyrotoxic crisis is usually precipitated by (3)
- acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis)
- surgery (especially on the thyroid)
- radioiodine treatment of a patient with partially treated or untreated hyperthyroidism
Dose of PTU in thyroid storm
Propylthiouracil 500–1000 mg loading dose and 250 mg every 4 h
Alternative: Methimazole 20 mg every 6 h
Antithyroid drug of choice for thyroid storm
PTU
In the management of thyroid storm, ___ hour after the first dose of propylthiouracil, ____ is given to block thyroid hormone synthesis via the Wolff-Chaikoff effect
One stable iodide (5 drops SSKI every 6 h)
Dose of propranolol in thyroid storm
60–80 mg PO every 4 h; or 2 mg IV every 4 h
high doses of propranolol decrease T4 → T3 conversion, and the doses can be easily adjusted.
Dose of hydrocortisone in thyroid storm
300 mg IV bolus, then 100 mg every 8 h
Drugs that may be given to sequester thyroid hormones
Cholestyramine
Management of severe thyroid ophthalmopathy, with optic nerve involvement or chemosis resulting in corneal damage
- refer to ophthalmologist
- Pulse therapy with IV methylprednisolone (e.g., 500 mg of methylprednisolone once weekly for 6 weeks, then 250 mg once weekly for 6 weeks)
Typically presents with a short thyrotoxic phase due to the release of preformed thyroid hormones and catabolism of Tg
Destructive thyroiditis (subacute or silent thyroiditis)
True hyperthyroidism is absent, as demonstrated by a low radionuclide uptake
Amiodarone treatment is associated with thyrotoxicosis in up to ___ of patients, particularly in areas of low iodine intake
10%
A rare cause of thyrotoxicosis that is characterized by the presence of an inappropriately normal or increased TSH level in a patient with hyperthyroidism, diffuse goiter, and elevated T4 and T3 levels
TSH-secreting pituitary adenoma
Supports the diagnosis of TSH-secreting pituitary adenoma
Elevated levels of the α-subunit of TSH
released by the TSH-secreting adenoma
confirmed by demonstrating the pituitary tumor on MRI or CT scan
Ρare and due to suppurative infection of the thyroid
Acute thyroiditis
Μost common cause of acute thyroiditis ins children and young adults
presence of a piriform sinus
Such sinuses are predominantly left-sided
Remnant of the fourth branchial pouch that connects the oropharynx with the thyroid
piriform sinus
The patient presents with abrupt onset thyroid pain, often referred to the throat or ears, and a small, tender goiter that may be asymmetric. Fever, dysphagia, and erythema over the thyroid are common, as are systemic symptoms of a febrile illness and lymphadenopathy
Acute thyroiditis
In acute thyroiditis, thyroid function is low, normal, or high?
Normal
Other terms for subacute thyroiditis (3)
de Quervain’s thyroiditis
granulomatous thyroiditis
viral thyroiditis
Peak incidence of subacute thyroiditis and sex predilection
30–50 years
women are affected three times more frequently than men
The patient usually presents with a painful and enlarged thyroid, sometimes accompanied by fever. There may be features of thyrotoxicosis or hypothyroidism, depending on the phase of the illness. Malaise and symptoms of an upper respiratory tract infection may precede the thyroid-related features by several weeks.
Subacute thyroiditis
The patient typically complains of a sore throat, and examination reveals a small goiter that is exquisitely tender. Pain is often referred to the jaw or ear
Subacute thyroiditis
Usual outcome of subacute thyroiditis
Complete resolution
but late-onset permanent hypothyroidism occurs in 15% of cases, particularly in those with coincidental thyroid autoimmunity
In subacute thyroiditis, thyroid function tests characteristically evolve through three distinct phases over about____ : (1)____, (2)______, and (3) ____
6 months
thyrotoxic phase
hypothyroid phase
recovery phase
Cause of thyrotoxic phase in subacute thyroiditis
Discharge of hormones from damaged thyroid cells
Treatment of subacute thyroiditis
- Aspirin 600 mg every 4-6 h
- NSAIDs
sufficient to control symptoms in many cases. If not, may give glucocorticoids
Dose of glucocorticoids in subacute thyroiditis
15–40 mg of prednisone gradually tapered over 6–8 weeks. . If a relapse occurs during glucocorticoid withdrawal, the dosage should be increased and then withdrawn more gradually
Thyroid function monitoring in subacute thyroiditis during treatment
TSH and FT4 every 2-4 weeks
T or F. PTU and methimazole may be used in the thyrotoxic phase of subacute thyroiditis
False. antithyroid drugs play no role in treatment of the thyrotoxic phase
Treatment of hypothyroid phase of subacute thyroiditis
Levothyroxine replacement 50–100 μg daily
Low dose is given to allow TSH-mediated recovery
Painless thyroiditis
“silent” thyroiditis
Postpartum thyroidiris
“silent” thyroiditis
The condition occurs in up to 5% of women 3–6 months after pregnancy and is then termed postpartum thyroiditis
Silent thyroiditis is associated with the presence of ___ antibodies antepartum
TPO
Silent thyroiditis is three times more common in
women with type 1 diabetes mellitus
Difference between silent and subacute thyroiditis (4)
Silent:
- Painless
- Normal ESR
- Presence of TPO
- No response to glucocorticoids
Severe thyrotoxic symptoms of silent thyroiditis can be managed with
Brief course of propranolol, 20–40 mg three or four times daily
Thyroxine replacement may be needed for the hypothyroid phase of silent thyroiditis but should be withdrawn after ____, as recovery is the rule
6–9 months
Drug-induced thyroiditis is caused by (4)
- IFN-alpha
- IL-2
- TKI
- Amiodarone
The most common clinically apparent cause of chronic thyroiditis
Hashimoto’s thyroiditis
An autoimmune disorder that often presents as a firm or hard goiter of variable size
A rare disorder that typically occurs in middle-aged women and presents with an insidious, painless goiter with local symptoms due to compression of the esophagus, trachea, neck veins, or recurrent laryngeal nerves
Riedel’s thyroiditis
Goiter is hard, nontender, often asymmetric, and fixed, leading to suspicion of a malignancy
Dense fibrosis disrupts normal thyroid gland architecture and can extend outside the thyroid capsule. This is seen in
Riedel’s thyroiditis
Despite these extensive histologic changes, thyroid dysfunction is uncommon
Any acute, severe illness can cause abnormalities of circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease, making these measurements potentially misleading. This is called
Sick euthyroid syndrome
Unless a thyroid disorder is strongly suspected, the routine testing of thyroid function should be avoided in acutely ill patients.
The major cause of these hormonal changes is the release of cytokines most especially
IL-6
The most common hormone pattern in sick euthyroid syndrome (SES), also called nonthyroidal illness (NTI), is a decrease in _____ with normal levels of _____
Decrease total and unbound T3 levels (low T3 syndrome)
normal T4 and TSH
Which SES syndrome has poorer prognosis?
Low T4 syndrome – in very sick patients
dramatic fall in total T4 and T3 levels
Amiodarone is what type of antiarrhythmic drug?
Type III
Amiodarone is structurally related to thyroid hormone and contains ___ iodine by weight
39%
Thus, typical doses of amiodarone (200 mg/d) are associated with very high iodine intake, leading to greater than fortyfold increases in plasma and urinary iodine levels
Moreover, because amiodarone is stored in adipose tissue, high iodine levels persist for >6 months after discontinuation of the drug
Amiodarone has the following effects on thyroid function
- acute, transient suppression of thyroid function
- hypothyroidism in patients susceptible to the inhibitory effects of a high iodine load
- thyrotoxicosis that may be caused by either a Jod-Basedow effect from the iodine load, in the setting of MNG or incipient Graves’ disease, or a thyroiditis-like condition
Iodide- dependent suppression of the thyroid is called
Wolff-Chaikoff effect
hyperthyroidism following administration of iodine or iodide, either as a dietary supplement or as iodinated contrast for medical imaging
Jod-Basedow phenomenon
Type of amiodarone-induced thyrotoxicosis that is associated with an underlying thyroid abnormality (preclinical Graves’ disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure (Jod-Basedow phenomenon)
Type 1 AIT
Increased vascularity
Type of amiodarone-induced thyrotoxicosis that occurs in individuals with no intrinsic thyroid abnormalities and is the result of drug-induced lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative amiodarone dosage increases
Type 2 AIT
Decreased vascularity
Treatment of type 1 AIT (3)
- discontinuation of amiodarone
- potassium perchlorate 200 mg every 6 h - reduce thyroidal iodide content
- Near-total thyroidectomy
Treatment of type 2 AIT (4)
- discontinuation of amiodarone
- glucocorticoids – modest benefit
- Lithium
- Near-total thyroidectomy
An autosomal dominant syndrome that causes inappropriate PTH secretion and increased renal tubular calcium reabsorption
Familial hypocalciuric hypercalcemia (FHH)
Familial hypocalciuric hypercalcemia that involve inactivating mutations in the calcium sensor receptor (CaSR)
FHH type 1
Familial hypocalciuric hypercalcemia that involve mutations in the G11 protein (GNA11)
FHH type 2
Familial hypocalciuric hypercalcemia that involve mutation in the adaptor-related protein complex 2, -2 subunit (AP2S1)
FHH type 3
Many solid tumors produce this protein that mimick effects of PTH on bone and the kidney
PTH-related peptide (PTHrP)
PTH levels are suppressed by the high serum calcium levels
Value of mild hypercalcemia
up to 11–11.5 mg/dL
Value of severe hypercalcemia
> 12–13 mg/dL
May result in lethargy, stupor, or coma, gastrointestinal symptoms (nausea, anorexia, constipation, or pancreatitis
ECG changes in hypercalcemia (3)
- Bradycardia
- AV block
- Short QT interval
First step in the approach to hypercalcemia
Ensure that the alteration in serum calcium levels is not due to abnormal albumin concentrations
About 50% of total calcium is ionized – may be directly measured but may be influenced by collection methods and other artifacts. The rest is bound principally to albumin
Corrected calcium formula if with low albumin
Total calcium + (0.2 mM (0.8 mg/dL) * every decrement in serum albumin of 1.0 g/dL below the reference value of 4.1 g/dL for albumin
Most common cause of chronic hypercalcemia
Primary hyperparathyroidism
Second most common cause of hypercalcemia
Hypercalcemia of malignancy
Second most important laboratory test once true hypercalcemia is established
PTH level
PTH, Ca, and phosphorus are low or high in primary hyperthyroidism
Increased PTH, elevated calcium, low phosphorus
Calcium/creatinine clearance ratio that suggest FHH
<0.01
Calcium/creatinine clearance ratio – urine/serum Ca divided by urine/serum crea
Most common cause of low PTH, elevated Ca
Malignancy
Hypercalcemia in granulomatous disorders is caused by
Increased Serum 1,25(OH)2D levels
Initial therapy of significant, symptomatic hypercalcemia
volume expansion
4–6 L of IV saline may be required over the first 24 h
Underlying comorbidities may require the use of loop diuretics to enhance Na and Ca excretion
Commonly used drug for the treatment of hypercalcemia of malignancy
Bisphosphonates
- Zoledronic acid – 4 mg IV over 30 mins
- Pamidronate – 60-90 mg IV over 2-4 h
- Ibandronate – 2 mg IV over 2 h
Potent inhibitor of bone resorption that treat hypercalcemia that is refractory to bisphosphonates
Denosumab – 120 mg SQ on days 1, 8, 15, and 29 and then every 4 weeks
Preferred therapy in patients with 1,25(OH)2D-mediated hypercalcemia
Glucocorticoids
- IV hydrocortisone – 100-300 mg daily
- Oral prednisone – 40-60 mg daily for 3-7 days
Low calcim, high PTH
secondary hyperparathyroidism
Most common causes of hypocalcemia (2)
Impaired PTH production
Impaired Vitamin D production
Twitching of the circumoral muscles in response to gentle tapping of the facial nerve just anterior to the ear
Chvostek’s sign
Carpal spasm induced by inflation of a blood pressure cuff to 20 mmHg above the patient’s systolic blood pressure for 3 min
Trousseau’s sign
Treatment of acute, symptomatic hypocalcemia
Calcium gluconate – 10 mL 10% wt/vol (90 mg or 2.2 mmol) IV, diluted in 50 mL of 5% dextrose or 0.9% sodium chloride, given intravenously over 5 min
May need constant IV infusion if with continuing hypocalcemia 10 amp of Ca gluconate or 900 mg of calcium in 1 L of 5% dextrose or 0.9% sodium chloride administered over 24 h
Magnesium supplement – if with hypomagnesemia
Recently been approved by the FDA for the treatment of refractory hypoparathyroidism
PTH (1-84) (Natpara)
Dose of vitamin D supplementation if vitamin D deficiency is due to nutritional deficiency
Vitamin D 50,000 U, 2–3 times per week for several months
Dose of vitamin D supplementation if vitamin D deficiency is due to malabsorption of Vit D
Vitamin D 100,000 U/d or more
Primary hyperparathyroidism often presents in its severe form with skeletal complications
osteitis fibrosa cystica
Long-term stimulation of PTH secretion in renal insufficiency
Tertiary hyperparathyroidism
Neurohypophysis is also known as the
Posterior pituitary
Neurohypophysis produces two hormones
- arginine vasopressin (AVP)
2. oxytocin
A deficiency of AVP secretion or action causes
diabetes insipidus (DI)
A syndrome characterized by the production of large amounts of dilute urine
diabetes insipidus
AVP secretion is regulated primarily by the
“effective” osmotic pressure of body fluids
Specialized hypothalamic cells which are extremely sensitive to small changes in the plasma concentration of sodium and its anions but normally are insensitive to other solutes such as urea and glucose
osmoreceptors
The average threshold, or set point, for AVP release corresponds to a plasma osmolarity of ____ and sodium level of ________
280 mosmol/L
135 meq/L
levels only 2–4% higher normally result in maximum antidiuresis
The set point of the osmoregulatory system can be lowered by (4)
- Pregnancy
- Menstrual cycle
- Estrogen
- Relatively large, acute reductions in blood pressure or volume
Stimuli that is extremely potent that they typically elicit immediate, 50- to 100-fold increases in plasma AVP
Nausea / emesis
act via the emetic center in the medulla
AVP secretion also can be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia
The most important, if not the only, physiologic action of AVP is to
reduce water excretion by promoting concentration of urine
AVP acts on what part of the kidney (2)
distal tubule and medullary collecting ducts
In the absence of AVP, these cells are impermeable to water and reabsorb little, if any, of the relatively large volume of dilute filtrate that enters from the proximal nephron
In the presence of AVP, these cells become selectively permeable to water, allowing the water to diffuse back down the osmotic gradient created by the hypertonic renal medulla
Like AVP, thirst is regulated primarily by an osmostat that is situated in the _______ and is able to detect very small changes in the plasma concentration of sodium and its anions.
anteromedial hypothalamus
The thirst osmostat appears to be “set” about ____ higher than the AVP osmostat
3%
This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/sodium starts to exceed the defensive capacity of the antidiuretic mechanism
A decrease of _____ in the secretion or action of AVP usually results in DI
75% or more
In DI, the 24-h urine volume exceeds______, and the osmolarity is ______
40 mL/kg body weight
<300 mosmol/L
A primary deficiency of AVP secretion usually results from agenesis or irreversible destruction of the neurohypophysis. It is referred to as
central DI
Also known as neurohypophyseal DI, neurogenic DI,
pituitary DI, cranial DI,
usually idiopathic
Pituitary DI caused by surgery in or around the neurohypophysis usually appears within
24 h
After a few days, it may transition to a 2- to 3-week period of inappropriate antidiuresis, after which the DI may or may not recur permanently
Most common genetic form of DI is an autosomal _____ and is caused by diverse mutations in the coding region of one allele of the ____
Dominant
AVP– neurophysin II (or AVP-NPII) gene
Form of pituitary DI that is caused by mutations of the WFS 1 gene
Wolfram’s syndrome
Wolfram’s syndrome is composed of (4)
DIDMOAD
DI
Diabetes Mellitus
Optic Atrophy
Neural Deafness
A primary deficiency of plasma AVP also can result from increased metabolism by an N-terminal aminopeptidase produced by the placenta
gestational DI
signs and symptoms manifest during pregnancy and usually remit several weeks after delivery
Secondary deficiencies of AVP secretion result from inhibition by excessive intake of fluids. This is called
primary polydipsia
3 categories of primary polydipsia
dipsogenic DI
psychogenic polydipsia
iatrogenic polydipsia
Form of DI characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, and multiple sclerosis but is often idiopathic.
dipsogenic DI
Primary deficiencies in the antidiuretic action of AVP
nephrogenic DI
Most common genetic form of nephrogenic DI
semirecessive X-linked caused by mutation in the coding region of the the V2 receptor
When will hypernatremia and other overt physical or laboratory signs of dehydration develop in patients with DI?
If patient also has a defect in thirst or fails to increase fluid intake for some other reason
polyuria results in a small (1–2%) decrease in body water and a commensurate increase in plasma osmolarity and sodium that stimulates thirst and a compensatory increase in water intake
In the approach to patients with DI, if basal plasma osmolarity and sodium are within normal limits, the traditional approach is to determine the effect of (2) ______ on urine osmolarity
fluid deprivation
injection of antidiuretic hormone
Test that differentiate pituitary and nephrogenic DI once primary polydipsia has been ruled out
2 μg of the AVP analogue, desmopressin
this approach is of little or no diagnostic value if fluid deprivation results in concentration of the urine because the increases in urine osmolarity achieved both before and after the injection of desmopressin are similar in patients with partial pituitary DI, partial nephrogenic DI, and primary polydipsia
Effect of fluid deprivation in DI
raises plasma osmolarity and sodium without inducing concentration of the urine
A simpler, and less stressful, but equally reliable way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is measure
Basal plasma AVP and urine osmolarity under conditions of unrestricted fluid intake
If AVP is normal or elevated (>1 pg/mL) and the concurrent urine osmolarity is low (<300 mosm/L)
nephrogenic DI
If basal plasma AVP is low or undetectable (<1 pg/mL), what is the next step?
MRI of the brain
to differentiate pituitary DI from primary polydipsia
Difference in the MRI of primary polydipsia and pituitary DI
primary polydipsia – presence of bright spot (normal)
pituitary DI – absent or abnormally small bright spot
Medical treatment of pituitary DI
desmopressin (DDAVP)
DDAVP acts selectively at ___receptors to ______ urine concentration and _____ urine flow in a dose- dependent manner
V2
Increase
Decrease
Onset of antidiuresis of IV DDAVP and oral DDAVP
Rapid.
15 min after IV
60 min after oral
Effect of desmopressin test if the diagnosis is primary polydipsia
Hyponatremia
T or F. Primary polydipsia can be treated with desmopressin
False. Primary polydipsia cannot be treated safely with DDAVP or any other antidiuretic drug because eliminating the polyuria does not eliminate the urge to drink. Therefore, it invariably produces hyponatremia and/or other signs of water intoxication, usually within 8–24 h if urine output is normalized completely
Management of nephrogenic DI (3)
Management of nephrogenic DI (3)
The most common cause of an increase in total body sodium
primary hyperaldosteronism
form of hypernatremia due to a primary defect in the thirst mechanism
hypodipsic hypernatremia
a syndrome characterized by chronic or recurrent hypertonic dehydration
hypodipsic hypernatremia
Most common cause of hypodipsia
hypogenesis or destruction of the osmoreceptors in the anterior hypothalamus that regulate thirst
These defects can result from various congenital malformations of midline brain structures or may be acquired due to diseases such as occlusions of the anterior communicating artery, primary, or metastatic tumors in the hypothalamus, head trauma, surgery, granulomatous diseases such as sarcoidosis and histiocytosis, AIDS, and cytomegalovirus encephalitis
Management of hypodipsic hypernatremia
- oral water
2. hypotonic IV fluids
An increase in total body water that exceeds the increase in total body sodium
hypervolemic hyponatremia (type 1)
A decrease in body sodium greater than the decrease in body water
hypovolemic hyponatremia (type 2)
an increase in body water with little or no change in body sodium
euvolemic hyponatremia (type 3)
Causes of hypervolemic hyponatremia (2)
- severe congestive heart failure
2. cirrhosis
Causes of hypovolemic hyponatremia (3)
- severe diarrhea
- diuretic abuse
- mineralocorticoid deficiency
Causes of euvolemic hyponatremia
- defect in the osmotic suppression of AVP
Defect in the osmotic suppression of AVP can have either of two causes
- nonhemodynamic stimulus such as nausea or a cortisol deficiency, which can be corrected quickly by treatment with antiemetics or cortisol
- primary defect in osmoregulation caused by another disorder such as malignancy, stroke, or pneumonia that cannot be easily or quickly corrected (SIADH)
primary defect in osmoregulation caused by another disorder such as malignancy, stroke, or pneumonia
SIADH
In acute symptomatic SIADH, the aim of therapy should be to ______ plasma osmolarity and/ or plasma sodium at a rate ____ an hour until they reach levels of _____ or_____, respectively
Raise
~1%
~270 mosmol/L
130 meq/L
Medical treatment of acute, symptomatic SIADH
AVP receptor-2 antagonist (vaptan)
Vaptan that has a combined V2/V1a antagonist action that has been approved for short-term, in-hospital IV treatment of SIADH
Conivaptan
Oral vaptan
Tolvaptan
Acute, potentially fatal neurologic syndrome characterized by quadriparesis, ataxia, and abnormal extraocular movements that occurs during correction of hyponatremia when Na is raised faster than 1mEq/L per hour
central pontine myelinolysis
In chronic and/or minimally symptomatic SIADH, the hyponatremia can and should be corrected more gradually by restricting total fluid intake to less than the sum of urinary and insensible losses. The aim should be to reduce total discretionary intake (all liquids) to _____ less than urinary output
~500 mL
Because the water derived from food (300–700 mL/d) usually approximates basal insensible losses in adults, t
The best approach for treatment of chronic SIADH is the administration of
Tolvaptan (oral vaptan)
Other drugs:
Demeclocycline
fludrocortisone
A selective AVP V2 antagonist that also increases urinary water excretion by blocking the antidiuretic effect of AVP
Tolvaptan
Treatment of hyponatremia in SIAD due to an activating mutation of the V2 receptor
osmotic diuretic such as urea
When diffuse enlargement of the thyroid occurs in the absence of nodules and hyperthyroidism, it is referred to as
diffuse nontoxic goiter
diffuse nontoxic goiter is also known as (2)
simple goiter(absence of nodules) colloid goiter (presence of uniform follicles that are filled with colloid)
Diffuse goiter is termed as endemic goiter when it affects ____ of the population
> 5%
Thyroid enlargement in teenagers
juvenile goiter
Examples of environmental goitrogens
- cassava root (contains thiocyanate)
- cruciferous vegetables (Brussels sprouts, cabbage, and cauliflower)
- milk from regions where goitrogens are present in grass
Examination reveals a symmetrically enlarged, nontender, generally soft thyroid gland without palpable nodule, with a lateral lobe with a volume greater than the thumb of the individual being examined
Diffuse nontoxic goiter
On ultrasound, total thyroid volume exceeding ____ is considered abnormal
30 mL
Goiter that may obstruct the thoracic inlet
Substernal goiter
Refers to facial and neck congestion due to jugular venous obstruction when the arms are raised above the head, a maneuver that draws the thyroid into the thoracic inlet
Pemberton’s sign
A low TSH with a normal free T3 and free T4, particularly in older patients, suggests the possibility of thyroid autonomy or undiagnosed Graves’ disease, and is termed
subclinical thyrotoxicosis
T or F. Treatment of subclinical hyperthyroidism is not recommended in the elderly
False. Increasingly recommended to reduce the risk of atrial fibrillation and bone loss
Usual reason for surgery in diffuse nontoxic goiter (2)
- Compressive symptoms or obstruction of the thoracic inlet
- Cosmetic reasons
Surgery is rarely indicated for diffuse goiter
Subtotal or near-total thyroidectomy
Aim of levothyroxine treatment post surgery of DNTG
keep the TSH level at the lower end of the reference interval to prevent regrowth of the goiter
Usual clinical manifestation of multinodular goiter
asymptomatic and euthyroid
Sudden pain in an MNG is usually caused by (2)
- hemorrhage into a nodule
2. Possibility of invasive malignancy
Hoarseness, reflecting laryngeal nerve involvement, in MNG suggests
malignancy
In MNG, tracheal deviation is common, but compression must usually exceed ____ of the tracheal diameter before there is significant airway compromise
70%
T or F. The risk of malignancy in MNG is similar to that in solitary nodules
True
Medication that may cause acute, subacute or chronic thyroiditis
Amiodarone
Most common bacteria associated with acute thyroiditis (3)
Staphylococcus, Streptococcus, and Enterobacter
In MNG, contrast agents and other iodine-containing substances should be avoided because of the risk of inducing the
Jod-Basedow effect
enhanced thyroid hormone production by autonomous nodules
Toxic MNG is more common in what population
Elderly
May present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or weight loss
Thyroid scan of toxic MNG shows
heterogeneous uptake with multiple regions of increased and decreased uptake
“Cold” nodules in thyroid scan
Decreased uptake
If present, fine-needle aspiration (FNA) may be indicated based on sonographic patterns and size cutoffs
“Hot” nodules in thyroid scan
Increased uptake
Usually benign
Treatment of choice for toxic MNG
Radioiodine
it treats areas of autonomy as well as decreasing the mass of the goiter by ablating the functioning nodules. Sometimes, however, a degree of autonomy may persist, presumably because multiple autonomous regions may emerge after others are treated, and further radioiodine treatment may be necessary
Definitive treatment of underlying thyrotoxicosis as well as goiter in toxic MNG
Surgery
Patients should be rendered euthyroid using an antithyroid drug before operation
A solitary, autonomously functioning thyroid nodule is referred to as
toxic adenoma
Most patients with solitary hyperfunctioning nodules have acquired somatic, activating mutations in the
TSH-R
Less commonly, somatic mutations are identified in G.Sα, same mutations with McCune-Albright syndrome.
In most series, activating mutations in either the TSH-R or the GSα subunit genes are identified in >90% of patients with solitary hyperfunctioning nodules.
Thyrotoxicosis in solitary hyperfunctioning nodule is usually mild and is generally only detected when the size of the nodule is
> 3 cm
Provides a definitive diagnostic test for hyperfunctioning solitary nodule
Thyroid scan
Demonstrating focal uptake in the hyperfunctioning nodule and diminished uptake in the remainder of the gland, as activity of the normal thyroid is suppressed
usually the treatment of choice for hyperfunctioning solitary nodule
Radioiodine ablation
131I is concentrated in the hyperfunctioning nodule with minimal uptake and damage to normal thyroid tissue
Surgery for hyperfunctioning solitary nodule
Lobectomy
preserving thyroid function and minimizing risk of hypoparathyroidism or damage to the recurrent laryngeal nerves
Thyroid nodules that reflect a combination of both macro- and microfollicular architecture and appear as mixed cystic/ solid or spongiform lesions on ultrasound
Hyperplastic
Thyroid nodules that generally have a more monotonous microfollicular pattern
neoplastic, encapsulated adenomas
If the thyroid adenoma is composed of oncocytic follicular cells arranged in a follicular pattern, this is termed
Hürthle cell adenoma
The definition of spongiform requires the presence of microcystic areas comprising ____ of the thyroid nodule volume, with the concept that this microcystic sonographic pattern recapitulates the histology of ______
> 50%
macrofollicles containing colloid
T or F. Majority of solid thyroid nodules (whether hypo-, iso-, or hyperechoic) are benign
True
Diagnostic procedure of choice to evaluate thyroid nodules
Ultrasound-guided FNA
In relative iodine deficiency, both ____ and ____ therapy have been demonstrated to decrease thyroid nodule volume
Iodine
Levothyroxine
If the nodule has not decreased in size after 6–12 months of therapy, treatment should be discontinued because little benefit is likely to accrue from long-term treatment
TSH suppression with levothyroxine therapy does not decrease thyroid nodule size in iodine-sufficient populations.
Most common malignancy of the endocrine system
Thyroid carcinoma
T or F. Thyroid cancer is twice as common in women as men and is associated with a worse prognosis in women
False. Thyroid cancer is twice as common in women as men, but male gender is associated with a worse prognosis
Serum markers used to detect residual or recurrent medullary thyroid CA
Calcitonin
T or F. Higher serum TSH levels, even within normal range, are associated with increased thyroid cancer risk in patients with thyroid nodules
True. These observations provide the rationale for T4 suppression of TSH in patients with thyroid cancer
RET/PTC and PAX8-PPARg1 rearrangements, are relatively specific for
thyroid neoplasia.
Activation of the _______ is seen in up to 70% of papillary thyroid carcinomas
RET-RAS-BRAF signaling pathway
simultaneous RET, BRAF, and RAS mutations rarely occur in the same tumor, suggesting that activation of the MAPK cascade is critical for tumor development, independent of the step that initiates the cascade
Most common genetic alteration in PTC
BRAF V600E mutations
Mutations in_____ , occur in about two-thirds of ATCs, but not in PTC or FTC
CTNNB1, which encodes β-catenin
Mutations of the tumor-suppressor ____ play an important role in the development of ATC
P53
Because P53 plays a role in cell cycle surveil- lance, DNA repair, and apoptosis, its loss may contribute to the rapid acquisition of genetic instability as well as poor treatment responses
Medullary thyroid carcinoma, when associated with multiple endocrine neoplasia (MEN) type 2, harbors an inherited mutation of the
RET gene
Unlike the rearrangements of RET seen in PTC, the mutations in MEN 2 are point mutations that induce constitutive activity of the tyrosine kinase
The most common type of thyroid cancer
Papillary thyroid carcinoma
80–85% of well-differentiated thyroid malignancies
Large, clear nuclei with powdery chromatin with nuclear grooves and prominent nucleoli seen in FNA of thyroid. What do you call this feature and what disease do you see this feature?
orphan Annie eye” appearance
Papillary thyroid carcinoma
The histologic finding of these cells arranged in either papillary structures versus follicles distinguishes the classic and follicular variants of PTC, respectively
PTC has a propensity to spread via the lymphatic system but can metastasize hematogenously as well, particularly to
Bone and lung
Because of the relatively slow growth of the tumor, a significant burden of pulmonary metastases may accumulate, sometimes with remarkably few symptoms
Micrometastases of PTC is defined as ____ of cancer in a lymph node
<2 mm
do not affect prognosis
Gross PTC metastatic involvement of multiple ____ lymph nodes indicates a 25–30% chance of recurrence, and may increase mortality in older patients
2–3 cm
Follicular thyroid CA is more common in iodine-deficient or sufficient areas?
Deficient
Follicular carcinoma is different histologically to follicular adenoma because of the presence of
capsular and/or vascular invasion
FTC tends to spread by hematogenous routes leading to this most common sites (3)
bone, lung, and central nervous system
Poor prognostic features of FTC (5)
- distant metastases
- age >50 years
- primary tumor size >4 cm
- Hürthle cell histology
- Marked vascular invasion
All well-differentiated thyroid cancers with the size of ____ should be surgically excised although active surveillance may be an option for _______ without metastases
> 1cm (T1b or larger)
small intrathyroidal micropapillary thyroid cancers (T1a)
Initial surgical procedure for patients with intrathyroidal cancers >1 cm and <4 cm (T1b and T2 tumors) in the absence of metastatic disease
unilateral (lobectomy) or bilateral (near total thyroidectomy)
Surgey for thyroid tumors >4 cm or in the presence of metastases or clinical evidence of extrathyroidal invasion
near-total thyroidectomy
For patients at high risk for recurrence, bilateral surgery allows administration of radioiodine for remnant ablation and potential treatment of iodine-avid metastases, if indicated, as well as for monitoring of serum Tg levels
Medical therapy that is a mainstay of thyroid cancer treatment
levothyroxine suppression of TSH
Because most tumors are still TSH-responsive
In thyroid caner, or patients at low risk of recurrence, TSH should be maintained at the ______. For patients either at intermediate or high risk of recurrence, TSH levels should be kept to _____ and____, respectively, if there are no strong contraindications to mild thyrotoxicosis. TSH should be _____ for those with known metastatic disease
Low-risk: lower normal limit (0.5–2.0 mIU/L)
Intermediate: 0.1 to 0.5 mIU/L
High: <0.1 mIU/L
Metastatic: <0.1 mIU/L
After near-total thyroidectomy, ____of thyroid tissue remains in the thyroid bed. This residual thyroid is eliminated by ____
<1 g
Postsurgical radioablation
use 131I for thyroid ablation should be coordinated with the surgical approach, because radioablation is much more effective when there is minimal remaining normal thyroid tissue.
Indications of radioablation therapy of well-differentiated thyroid CA (5)
- larger tumors
- more aggressive variants of papillary cancer
- tumor vascular invasion
- extrathyroidal invasion
- presence of large-volume lymph node metastases
Radioiodine is administered after (what diet) and in the presence of _______to stimulate uptake of the isotope into both the remnant and potentially any residual tumor
iodine depletion (patient follows a low-iodine diet for 1–2 weeks)
elevated serum TSH levels
To achieve high serum TSH levels prior to radioablation, there are two approaches:
- withdraw thyroid hormone
2. treat with liothyronine 25 μg qd or bid followed by thyroid hormone withdrawal for 2 weeks
A sensitive marker of residual/recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue
Serum thyroglobulin
When do you perform neck ultrasound after thyroid ablation?
After 6 months
Because the vast majority of PTC recurrences are in cervical lymph nodes
Aside from radioiodine, this therapy can also be used to treat gross residual neck disease or specific metastatic lesions, particularly when they cause bone pain or threaten neurologic injury
external beam radiotherapy
Group of drugs that are being explored as a means to target pathways known to be active in thyroid cancer, including the RAS, BRAF, RET, EGFR, VEGFR, and angiogenesis pathways
Kinase inhibitors
Sorafenib
Poorly differentiated and aggressive thyroid cancer
Anaplastic Thyroid Cancer
The prognosis of ATC is poor, and most patients die within ____ of diagnosis
6 months
Because of the undifferentiated state of these tumors, the uptake of radioiodine is usually_____
Negligible
but it can be used therapeutically if there is residual uptake
Lymphoma in the thyroid gland often arises in the background of
Hashimoto’s thyroiditis
A rapidly expanding thyroid mass that occurs with Hashimoto’s thyroiditis is suggestive of
Thyroid Lymphoma
Most common type of lymphoma in the thyroid
Diffuse large-cell lymphoma
Thyroid biopsies reveal sheets of lymphoid cells that can be difficult to distinguish from small-cell lung cancer or ATC.
Thyroid Lymphoma
Treatment of thyroid lymphoma
External beam radiation
Surgical resection should be avoided as initial therapy because it may spread disease that is otherwise localized to the thyroid. If staging indicates disease outside of the thyroid, treatment should follow guidelines used for other forms of lymphoma
3 familial forms of medullary thyroid carcinoma
MEN 2A
MEN 2B
Familial MTC without other features of MEN
Which is more aggressive? MTC secondary to MEN2B or MEN 2A? And familial or sporadic?
MEN2B > MEN 2A
Familial > sporadic MTC
All patients with MTC should be tested for what mutations
RET mutations
because genetic counseling and testing of family members can be offered to those individuals who test positive for mutations.
Management of MTC is primarily
Surgical
External radiation treatment and targeted kinase inhibitors may provide palliation in patients with advanced disease
Prior to surgery for MTC, this condition should be excluded in all patients with a RET mutation
pheochromocytoma
Does MTC tumors take up radioiodine?
No. Unlike tumors derived from thyroid follicular cells, these tumors do not take up radioiodine.
First diagnostic test in thyroid nodules
TSH
If TSH is suppressed in thyroid nodule, what is the next step?
radionuclide scan
determine if the identified nod- ule is “hot,” as lesions with increased uptake are almost never malignant and FNA is unnecessary
2015 ATA guidelines do not recommend FNA for any thyroid nodule ____ unless metastatic cervical lymph nodes are present
<1 cm
Widely used to provide more uniform terminology for reporting thyroid nodule FNA cytology results
Bethesda System
Grayscale sonographic features associated with thyroid cancer (6)
- Hypoechoic compared with surrounding thyroid
- Marked hypoechogenicity
- Microcalcifications
- Irregular, microlobulated margins
- Solid consistency
- Taller than wide shape on transverse view
If TSH is normal or high in thyroid nodule, what is the next step?
Ultrasound for LN assessment
If thyroid nodule is not functional on radionuclide scan with suppressed TSH, what is the next step?
Ultrasound for LN assessment
After ultrasound with confirmation of presence of thyroid nodules, what is the next step?
FNA based on features and cutoffs
If initial FNA of thyroid nodule is not diagnostic, what is the next step?
Repeat USD-guided FNA
If FNA of thyroid nodule is suggestive of follicular neoplasm, what is the next step?
Molecular testing
If FNA of thyroid nodule is suggestive of atypia or follicular lesion of undetermined significance, what is the next step?
Repeat USD-guided FNA or consider molecular testing
If FNA of thyroid nodule is suggestive of benign lesion, what is the next step?
Follow-up
Diagnostic categories of Bethesda Classification for Thyroid Cytology and the risk of malignancy. (6)
I. Nondiagnostic or unsatisfactory - 1–5%
II. Benign - 2–4%
III. Atypia or follicular lesion of unknown significance (AUS/FLUS) - 5–15%
IV. Follicular neoplasm - 15–30%
V. Suspicious for malignancy – 60-75%
VI. Malignant - 97–100%
ACTH-producing corticotrope adenoma of the pituitary
Cushing’s disease
Majority of patients with Cushing’s disease
Most common cause of Cushing’s syndrome
Medical use of glucocorticoids
hyperpigmentation of the knuckles, scars, or skin areas exposed to increased friction due to stimulation of melanocyte pigment production
ectopic ACTH syndrome
Weight gain, central obesity, rounded face, fat pad on back of neck (“buffalo hump”), Facial plethora, thin and brittle skin, easy bruising, broad and purple stretch marks, acne, hirsutism, Osteopenia, osteoporosis (vertebral fractures), decreased linear growth in children are symptoms of
Cushing’s syndrome
Myopathy in Cushing’s syndrome
proximal
prominent atrophy of gluteal and upper leg muscles with difficulty climbing stairs or getting up from a chair
Diagnostic tests for Cushing’s syndrome
Increased 24-h urinary free cortisol excretion in three separate collections
Failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone
Evidence of loss of diurnal cortisol secretion with high levels at midnight
T or F. Imaging should only be used after it is established whether the cortisol excess is ACTH-dependent or ACTH-independent
True
If with confirmed ACTH-independent cortisol excess
Adrenal imaging is indicated with unenhanced CT scan (helps to distinguish between benign and malignant adrenal lesions)
Used in diagnosis of glucocorticoid excess
Dexamethasone Suppression Test
If cortisol production is autonomous, what is the effect of dexamethasone
Little additional effect
If cortisol production is driven by an ACTH-producing pituitary adenoma, what is the effect of dexamethasone
Ineffective at low doses but usually induces suppression at high doses.
If cortisol production is driven by an ectopic source of ACTH, what is the effect of dexamethasone
Resistant to dexamethasone suppression
Diagnostic test for ectopic ACTH syndrome:
High-resolution, fine-cut CT scanning of the chest and abdomen (for scrutiny of the lung, thymus, and pancreas)
Treatment of choice for Cushing’s disease
Selective removal of the pituitary corticotrope tumor (endoscopic transsphenoidal approach)
Drugs used in Cushing’s syndrome that inhibits cortisol synthesis at the level of 11β-hydroxylase
Metyrapone 500 mg/tab TID (maximum dose, 6 g)
Antifungal drug used in Cushing’s syndrome that inhibits the early steps of steroidogenesis.
ketoconazole
A derivative of an insecticide which is an adrenolytic agent used in adrenocortical carcinoma
Mitotane
Ectopic ACTH production is predominantly caused by
occult carcinoid tumors, most frequently in the lung
but also in thymus or pancreas
Advanced small-cell lung cancer can cause ectopic ACTH production. In rare cases, ectopic CRH and/or ACTH production has been found to originate from medullary thyroid carcinoma or pheochromocytoma
A rare cause of ACTH-independent Cushing’s that is also associated with polyostotic fibrous dysplasia, unilateral cafe-au-lait spots, and precocious puberty
McCune-Albright syndrome,
Caused by activating mutations in the stimulatory G protein alpha subunit 1, GNAS-1.
McCune-Albright syndrome,
The most important first step in the management of patients with suspected Cushing’s syndrome
establish the correct diagnosis
the time of the physiologically lowest secretion of cortisol
midnight
For ACTH-dependent cortisol excess, the imaging of choice is
MRI of the pituitary
If dexamethason suppression and CRH responsiveness test show discordant results, the differential diagnosis for Cushing’s can be further clarified by performing
bilateral inferior petrosal sinus sampling (IPSS) with concurrent blood sampling for ACTH in the right and left inferior petrosal sinus and a peripheral vein
Another test that can be done in in ectopic ACTH syndrome is the_____ which can be helpful in some cases because ectopic ACTH-producing tumors often express somatostatin receptors.
octreotide scintigraphy
an anesthetic agent, can be used to lower cortisol in severe cases of cortisol excess
etomidate
by continuous IV infusion in low, nonanesthetic doses.
Primary adrenal insufficiency is most commonly caused by
autoimmune adrenalitis
transmitted in an autosomal recessive manner and is caused by mutations in the autoimmune regulator gene AIRE
autoimmune polyglandular syndrome 1
APS2 is much more prevalent and is of polygenic inheritance, with confirmed associations with the HLA-DR3 gene region in the major histocompatibility
complex and distinct gene regions involved in immune regulation.
Cause of primary adrenal insufficiency characterized by alacrima, achalasia, and neurologic impairment
Triple A syndrome
Cause of primary adrenal insufficiency characterized by progressive external ophthalmoplegia, pigmentary retinal degeneration, cardiac conduction defects, gonadal failure, hypoparathyroidis and type 1 diabetes
Kearns-Sayre syndrome
mitochondrial DNA deletions
Characterized by the abrupt onset of fever, petechiae, arthralgia, weakness, and myalgias, followed by acute hemorrhagic necrosis of the adrenal glands and severe cardiovascular dysfunction
Waterhouse-Friderichsen syndrome
primary adrenal insufficiency is also known as
Addison’s disease
Adrenal insufficiency where there is loss of both glucocorticoid, mineralocorticoid secretion, and androgen secretion
Addison’s disease
In secondary adrenal insufficiency, on the other hand, only glucocorticoid deficiency is present, as the adrenal itself is intact and thus still amenable to regulation by the RAA system. Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency.
A distinguishing feature of primary adrenal insufficiency
hyperpigmentation
caused by excess ACTH stimulation of melanocytes. It is most pronounced in skin areas exposed to increased friction or shear stress. It is also increased by sunlight.
On the other hand, in secondary adrenal insufficiency, the skin has an alabaster-like paleness due to lack of ACTH secretion.
a characteristic biochemical feature in primary adrenal insufficiency and is found in 80% of patients at presentation
hyponatremia
Hyperkalemia is present in 40% of patients at initial diagnosis.
The diagnosis of adrenal insufficiency is established by
short cosyntropin test
ACTH stimulation of cortisol production
administration of cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0, 30, and 60 min for cortisol
A normal response to cosyntropin test is defined as a cortisol level _______ 30–60 min after cosyntropin stimulation
> 20 μg/dL (>550 nmol/L)
During the early phase of HPA disruption or within 4 weeks of pituitary insufficiency, patients may still respond to exogenous ACTH stimulation. In this circumstance, the _______ is an alternative choice but is more invasive.
Insulin tolerance test
It involves injection of insulin to induce hypoglycemia, which represents a strong stress signal that triggers hypothalamic CRH release and activation of the entire HPA axis. The ITT involves administration of regular insulin 0.1 U/kg IV (dose should be lower if hypopituitarism is likely) and collection of blood samples at 0, 30, 60, and 120 min for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is administered after the patient has achieved symptomatic hypoglycemia
(usually glucose <40 mg/dL).
A normal response to Insulin tolerance test
is defined as a cortisol ____ and GH _______
> 20 μg/dL
> 5.1 μg/L
Once adrenal insufficiency is confirmed, measurement of _____ is the next step
plasma ACTH
with increased levels defining primary and inappropriately low levels defining the secondary origin of disease
Management of acute adrenal insufficiency (3)
- hydration
- bolus injection of 100 mg hydrocortisone, followed by the administration of 100–200 mg hydrocortisone over 24
- mineralocorticoid (once hydrocortisone dose is given at <50mg
Glucocortcoid replacement in chronic adrenal insufficiency
15–25 mg hydrocortisone in two to three divided doses
Long-acting glucocorticoids such as prednisolone or dexamethasone are not preferred because they result in increased glucocorticoid exposure due to extended glucocorticoid receptor activation at times of
physiologically low cortisol secretion.
Mineralocorticoid replacement in primary adrenal insufficiency
100–150 μg fludrocortisone
In patients living or traveling in areas with hot or tropical weather conditions, the fludrocortisone dose should be increased by 50–100 μg during the summer. Mineralocorticoid dose may also need to be adjusted during pregnancy, due to the anti-mineralocorticoid activity of progesterone, but this is less often required than hydrocortisone dose adjustment
