✅ Endocrine

Question 1

Altered TBG 🔽 🔼 concentration

Answer 1

More than 99% of the circulating thyroid hormone pool is bound to 3 major transport proteins: TBG, transthyretin, and albumin. Only the free (ie, unbound) thyroid hormones are biologically active. Changes in binding protein levels can affect the total circulating pool of thyroid hormones, but if the hypothalamic-pituitary-thyroid axis is intact, free hormone levels are unchanged.

Increased TBG

• Estrogens (eg, pregnancy, OCs, HRT) & estrogenic medications (eg, tamoxifen)
• Acute hepatitis

High levels of estrogen (eg, pregnancy, oral contraceptive pills, hormone replacement therapy) increase the level of TBG by decreasing its catabolism and increasing its synthesis in the liver. As the additional TBG binds more thyroid hormone, thyroid hormone production increases to maintain a euthyroid state.

Decreased TBG

• Androgenic hormones
• High-dose glucocorticoids/hypercortisolism
• Hypoproteinemia (eg, nephrotic syndrome, starvation)
• Chronic liver disease

Dx: Slight elevation in total T4 level (free T4 level would be expected to be normal).

Question 2

🌋Thyroid nodule

Answer 2

Palpable thyroid nodules are common, occurring in about 5% of all adults. Thyroid sonography by itself cannot rule out malignancy in palpable nodules.

💉 FNA biopsy is recommended for any nodule greater than 1 cm in diameter that is solid and hypoechoic on ultrasonography and for any nodule 2 cm or greater that is mixed cystic-solid without worrisome sonographic characteristics.

🔪 Biopsy may be appropriate for smaller nodules (at least 5 mm in diameter) in patients with risk factors, such as a history of radiation exposure, a family or personal history of thyroid cancer, cervical lymphadenopathy, or suspicious ultrasound characteristics. FNA biopsy is not routinely recommended for thyroid nodules less than 1 cm in diameter.

☢ Radionucleotide imaging (scan): If a nodule takes up radiotracer, it is termed a “hot” nodule. Colloidal cysts and tumors do not take up tracer and are “cold” nodules. Therefore, “hot” nodules are more likely benign. Neurofibromas would also be “cold.” Definitive diagnosis can be made through needle aspiration.

Question 3

Thyroid Cancer

Answer 3

Papillary Thyroid Cancer (most common thyroid epithelial malignancy) is characterized by slow spread into local tissues and regional lymph nodes. Pathologic findings include large cells with ground glass cytoplasm; pale nuclei with inclusion bodies and central grooving; and grainy, lamellated calcifications known as psammoma bodies. Lymph node involvement is common. Tx: Surgical resection is the primary treatment for papillary thyroid cancer.

Follicular Thyroid Cancer is the second most common thyroid epithelial malignancy (after papillary cancer) and has a peak incidence at age 40-60. It typically presents with a firm thyroid nodule and is often discovered incidentally on examination or imaging for other purposes. Thyroid scintigraphy usually shows a nonmetabolically active (“cold”) nodule.

Diagnosis of FTC based on a limited tissue sample (eg, fine-needle biopsy) is not possible as the cytologic findings (large numbers of follicular cells arranged in microfollicles, clusters, and clumps, often categorized as “follicular neoplasm”) are similar in both FTC and benign follicular adenomas. However, in contrast to benign adenomas, FTC is characterized by invasion of the tumor capsule and/or blood vessels, a finding that is typically made on examination of a surgically excised nodule. This invasion pattern accounts for the tendency of FTC to metastasize via hematogenous spread to distant tissues (eg, bone, lung).

Thyroglobulin (Tg) is the precursor to active thyroid hormones (T3 and T4) and is produced by normal thyroid tissue or differentiated (papillary or follicular) thyroid cancer. Most Tg is stored in the thyroid gland, but some is released into the circulation. Patients who have undergone a total thyroidectomy and radioactive iodine treatment should have no residual normal thyroid tissue; therefore, a rising Tg level in these patients is likely due to recurrent differentiated thyroid cancer.

Patients who have undergone thyroidectomy for differentiated thyroid cancer require levothyroxine (T4) supplementation for 2 reasons:

• Levothyroxine replaces thyroid gland function.
• Levothyroxine suppresses pituitary release of TSH (negative feedback). Because TSH stimulates thyroid tissue growth, levothyroxine supplementation to suppress TSH (ie, by causing a mildly hyperthyroid state) may help prevent thyroid cancer recurrence.

In some patients, a “stimulated” Tg level can also be obtained to evaluate for recurrence. This test measures the Tg level after withdrawing levothyroxine supplementation (to increase pituitary release of TSH) or after giving recombinant TSH. If there is recurrent cancer, the increased TSH will cause increased Tg release from the cancer cells.

Question 4

🧪

• Serum TSH normally 0.5-5.0 µU/mL
• Serum free T4 (thyroxine) normally 0.9-2.4 ng/dL [Suspected thyroid dysfunction with concern for pituitary dysfunction, or evidence of TSH abnormality];
• Serum free T3** (triiodothryronine) normally 3.6-5.6 ng/L** [Rarely used except when T3 thyrotoxicosis is suspected]

_{<strong>Thyroiditis </strong>describes thyroid hormone release from a damaged thyroid gland. In thyroiditis, a decrease in 123I uptake will be observed.}

Answer 4

Symptoms

• Anxiety & insomnia
• Palpitations
• Heat intolerance
• Increased perspiration
• Weight loss without decreased appetite

Physical examination

• Goiter
• Hypertension
• Tremors involving fingers/hands
• Hyperreflexia
• Proximal muscle weakness 💈 💺 (thyrotoxic myopathy)
• Lid lag
• Atrial fibrillation

Dx:

High RAIU suggests de novo hormone synthesis due to Graves’ disease (diffusely increased uptake) or toxic nodular disease (nodular uptake).

Low RAIU suggests either release of preformed thyroid hormone (ie, thyroiditis) or exogenous thyroid hormone intake.

Cx:

☠ Thyrotoxicosis ❗ describes all forms of excess thyroid hormone, including both endogenous and exogenous causes.

• weight loss, tachycardia, tremor, and lid retraction
• Thyrotoxicosis can produce a number of 💔 cardiovascular complications directly through the effects of tri-iodothyronine (T3) on cardiac myocytes and blood vessels, as well as indirectly by increasing sensitivity to circulating catecholamines. Generally, thyrotoxicosis causes positive inotropic and chronotropic effects, leading to a hyperdynamic cardiovascular state characterized by tachycardia, systolic hypertension, and widened pulse pressure💦. Arrhythmias are common and may include sinus tachycardia, atrial fibrillation/flutter, and atrial and ventricular ectopy. Valvular abnormalities such as mitral valve prolapse 🏀and mitral or tricuspid regurgitation are also associated. Increased oxygen demand in thyrotoxicosis is due to increased cardiac output and increased systemic oxygen consumption; this can lead to anginal symptoms in patients with underlying coronary atherosclerosis. ⚓Angina may also occur due to coronary vasospasm (especially in young female patients). Thyrotoxicosis may also cause new-onset heart failure or decompensation of pre-existing heart failure.

Thyroid strom ⛈ (medical emergency):

The presence of fever, severe tachycardia, congestive heart failure, and
CNS changes (delirium, psychosis, seizure, or coma) help separate thyroid storm from uncomplicated hyperthyroidism. Other factors that point toward storm or impending
storm include atrial fibrillation, abdominal symptoms, jaundice, and the absence of a precipitating event. Even with treatment, the mortality of thyroid storm can be 10% to
20%, so admission to an intensive care unit for close monitoring is mandatory. Tx: Propranolol, methimazole, corticosteroids (if adrenal insuficency present).

Treatment includes beta blockers (eg, propranolol) for symptom control, thionamides (eg, propylthiouracil) to block new hormone synthesis, iodine solution to block thyroid hormone release (given at least an hour after propylthiouracil to prevent excess iodine incorporation into thyroid hormone), and glucocorticoids to decrease peripheral conversion of T4 to T3.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia in hyperthyroidism, occurring in 5%-15% of patients. Thyroid hormones cause an increase in beta-adrenergic receptor expression, which leads to an increase in sympathetic activity.

🎺 Beta blockers (eg, propranolol, atenolol) are recommended as initial therapy to control heart rate and hyperadrenergic symptoms. In addition, propranolol decreases conversion of T4 to T3 in peripheral tissues. The beta blocker should be initiated as soon as hyperthyroidism is diagnosed and should be continued until the hyperthyroidism is adequately treated with thionamides, radioiodine, and/or surgery.

Question 5

Graves Disease

Answer 5

Graves’ disease is an autoimmune disorder characterized by anti-thyroid antibodies, most prominently thyroid-stimulating immunoglobulin (TSI). TSI binds to TSH receptors in the thyroid and triggers release of thyroid hormones, leading to thyrotoxicosis.

Hyperthyroidism is associated with increased expression of beta-adrenergic receptors in various organs, and the subsequent hyperadrenergic state can cause:

Hx:

• Nervousness or emotional lability (99)
• Increased sweating (91)
• Heat intolerance (89)
• Palpitations (89) [Tachycardia]
• Fatigue (88)
• Weight loss (85)
• Hyperdefecation (33)
• Menstrual irregularity (22)

Px: Examination of the thyroid may reveal the classic smooth, rubbery, firm goiter, often associated with a bruit…

• Tachycardia or atrial fibrillation (100)
• Goiter (99)
• Tremor (97)
• Proptosis of the eyes or extraocular muscle palsy (40)
• Stare, lid lag, or signs of optic neuropathy (40)
• Pretibial myxedema (NA)

Dx: Low TSH; elevated T₃, and T₄

*Thyroid receptor antibodies: Serum TSI, Serum TBII, Antithyroid peroxidase antibodies

¹²³I uptake is diffusely 🔥 increased throughout the whole thyroid gland. *Over activation of the TSH receptor in the thyroid gland increases the iodine-trapping mechanism in the follicle cells.

Elevated thyroglobulin is consistent with endogenous thyroid hormone release

Tx:

Thioamides [propylthiouracil (PTU) and methimazole] may induce remission by blocking new thyroid hormone production via inhibition of the oxidation, organification and coupling steps (thyroid peroxidase) of thyroid hormone synthesis.

PTU (but not methimazole) also inhibits peripheral conversion of T4 to T3.

Cx: ❗ 🦴 Agranulocytosis is the most feared side effect, and is seen in approximately 0.3% of patients treated with antithyroid drugs. It is caused by immune destruction of granulocytes, and most cases occur within 90 days of treatment. Current recommendations state that once the patient complains of fever and sore throat, the antithyroid drug should be discontinued promptly and the WBC count measured. A total WBC count less than 1,000/cubic mm warrants permanent discontinuation of the drug.

Beta blockers (eg, propranolol, atenolol) are recommended as initial therapy to control heart rate and hyperadrenergic symptoms.

Radioactive iodine (RAI) therapy: RAI (¹³¹I) is taken up by the thyroid follicular cells in a manner similar to that of natural iodine, and the subsequent beta emission induces slow necrosis of the thyroid follicular cells. This leads to clinical and biochemical resolution of hyperthyroidism over the subsequent 6-18 weeks (not rapidly). The goal of RAI in Graves disease is to administer a sufficient dose of radiation to prevent recurrence of hyperthyroidism. However, the diffuse uptake of radioiodine eventually leads to permanent hypothyroidism within months in >90% of patients. Cx: Titers of TRAB increase significantly following RAI therapy, and RAI can cause worsening of ophthalmopathy. For this reason, administration of 🌚 glucocorticoids with RAI is often advised to prevent complications in patients with mild ophthalmopathy.

Cx: Graves ophthalmopathy Proptosis and impaired extraocular motion (decreased convergence, diplopia). Other common symptoms include irritation (eg, gritty or sandy sensation), redness, photophobia, pain, and tearing. In Graves disease, thyrotropin (TSH) receptor autoantibodies (TRAB) stimulate thyroid hormone production, resulting in hyperthyroidism. Thyroid hormone increases sensitivity to catecholamines, and thyrotoxicosis of any etiology may cause lid lag and retraction due to sympathetic activation and contraction of the superior tarsal muscle. However, true exophthalmos with impaired extraocular motion is seen only in Graves disease and is due to T cell activation and stimulation of orbital fibroblasts and adipocytes by TRAB, resulting in orbital tissue expansion and lymphocytic infiltration.​

Question 6

Toxic adenoma (TA), Multinodular Goiter (MNG)

Answer 6

TA and toxic multinodular goiter (MNG) are the second most common causes of hyperthyroidism and are most often caused by activating mutations in the TSH receptor. These disorders are characterized by TSH-independent thyroid hormone secretion and focal (TA) or multifocal (MNG) follicular hyperplasia.

Dx: Elevated RAIU 🔥 “hot nodule” which indicates endogenous production of thyroid hormones.

Tx:

Initial treatment of TA and MNG includes a beta blocker to alleviate the symptoms of hyperthyroidism

Thionamide (eg, methimazole, propylthiouracil) to decrease thyroid hormone secretion. Options for definitive management of TA include surgery and radioiodine ablation.

Radioactive iodine (RAI) therapy: RAI (131I): The radioisotope is taken up only by the autonomous thyroid tissue, and the function of the remaining normal tissue is usually adequate to prevent permanent hypothyroidism.

Cx: If left untreated, patients with hyperthyroidism can develop rapid bone loss leading to osteoporosis and increased risk of fracture. Direct effects of the thyroid hormones cause increased osteoclastic bone resorption. Patients can also develop hypercalcemia and hypercalciuria due to increased bone turnover.

Question 7

Subacute thyroiditis (de Quervain’s thyroiditis) ❄

Answer 7

Subacute (de Quervain, subacute granulomatous) thyroiditis is thought to be due to a postviral inflammatory process and is often preceded by an upper respiratory illness.

Characterized by fever, neck pain, and thyroid tenderness. In most cases, hyperthyroid symptoms fade in <8 weeks as the thyroid gland becomes depleted of preformed hormone.

Thyrotoxicosis in subacute thyroiditis resolves spontaneously within a few weeks and may be followed by a hypothyroid phase lasting a few months. Most patients eventually recover to a euthyroid state.

Dx:

• Elevated ESR
• TSH triphasic (low, high, normal) over 2-4 mo
• Elevated Serum thyroglobulin (3-40 ng/mL): is consistent with endogenous thyroid hormone release

Tx: Symptomatic with 🎺beta blockers to control thyrotoxic symptoms and 🧯nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief. 🌑Glucocorticoids are used for severe thyroid pain not responding to NSAIDs.

Question 8

Factitious

Answer 8

Elevated thyroglobulin is consistent with endogenous thyroid hormone release

Decreased thyroglobulin suggests exogenous or factitious thyrotoxicosis.

Question 9

SECONDARY HYPERTHYROIDISM 🌱

Question 10

Pituitary Adenoma

Answer 10

Most TSH-secreting pituitary adenomas are macroadenomas.

Patients with this condition typically have a goiter due to the effect of TSH on growth of the thyroid follicles. However, they do NOT have the extrathyroidal manifestations of Graves disease such as infiltrative ophthalmopathy or pretibial myxedema.

Laboratory testing shows a high concentration of circulating thyroid hormone with an elevated or inappropriately normal TSH.

By contrast, patients with non-TSH-dependent hyperthyroidism (much more common) will have a suppressed TSH.

TSH is comprised of 2 subunits, an alpha-subunit (common to TSH, FSH, LH, and hCG) and a thyroid-specific beta-subunit. Many TSH-secreting pituitary adenomas overproduce the alpha-subunit, and an elevated ratio of alpha-subunit to TSH suggests a pituitary adenoma. These patients would have an elevated TSH, elevated free T4, and normal or increased RAIU.

Although the rarest of functional pituitary tumors, a TSH-producing adenoma can mimic Graves disease by causing hyperthyroidism with a diffuse goiter. A TSH-producing tumor does not cause infiltrative ophthalmopathy or pretibial myxedema, but these findings, helpful when present, are absent in over 50% of patients with Graves disease as well.

Question 11

Pituitary tumor apoplexy

Answer 11

Generally a neurosurgical emergency. On occasion, hemorrhagic infarction of a pituitary adenoma may be less urgent, especially in the absence of associated mass effect, and can be managed with conservative follow-up monitoring. In the setting of local mass effect and severe headache, however, neurosurgical decompression of the pituitary gland is necessary. Urgent 🌑 glucocorticoid administration is often required because of acute adrenocorticotropic hormone deficiency. The leading cause of death in patients with pituitary tumor apoplexy is adrenal insufficiency.

fatigue, weight gain, and erectile dysfunction and the laboratory finding of hyponatremia suggest panhypopituitarism, ❗ headache is consistent with hemorrhage.

Question 12

Tumors / Colloidal Cyst

Answer 12

Do not take up tracer and are “cold” nodules.

Neurofibromas would also be “cold.”

Definitive diagnosis can be made through needle aspiration.

Question 13

Ddx: Hypothyroidism:

Serum TSH normally 0.5-5.0 µU/mL

Serum free T4 (thyroxine) normally 0.9-2.4 ng/dL [Suspected thyroid dysfunction with concern for pituitary dysfunction, or evidence of TSH abnormality];

Serum free T3 (triiodothryronine) normally 3.6-5.6 ng/L [Rarely used except when T3 thyrotoxicosis is suspected

Answer 13

Hx: Sluggish affect or depression, Fatigue, Cold intolerance, Constipation, Weight gain, Alopecia.

Px: Dry, coarse skin and hair, Periorbital puffiness, Bradycardia, Slow movements and speech, Hoarseness, Diastolic hypertension, Goiter, Loss of the lateral portion of the eyebrow (NA), Delayed deep tendon reflexes.

Hypothyroidism can cause additional metabolic abnormalities such as hyperlipidemia, hyponatremia and asymptomatic elevations of creatinine kinase (usually <10x normal) and serum transaminases (aspartate aminotransferase and alanine aminotransferase).

Hypercholesteremia with high low-density lipoprotein (LDL) is due primarily to decreased surface LDL receptors (type 2a hyperlipidemia) and/or decreased LDL receptor activity. Hypothyroidism can also decrease lipoprotein lipase activity to cause hypertriglyceridemia.

Dx: Low T3 and T4, along with elevated TSH from the pituitary due to loss of negative of feedback. Titers of anti-thyroglobulin antibodies or anti-microsomal antibodies can also be elevated. Brief periods of hyperthyroidism (“Hashitoxicosis”) may also be seen during acute inflammation due to active destruction of thyroid follicles and release of pre-formed thyroid hormone.

Tx: Levothyroxine

Major drug interactions

↓ Levothyroxine absorption

• Bile acid binding agents (eg, cholestyramine)
• Iron, calcium, aluminum hydroxide
• Proton pump inhibitors, sucralfate

↑ TBG concentration

• Estrogen (oral), tamoxifen, raloxifene
• Heroin, methadone

↓ TBG concentration

• Androgens, glucocorticoids
• Anabolic steroids
• Slow-release nicotinic acid

↑ Thyroid hormone metabolism

• Rifampin
• Phenytoin
• Carbamazepine

Most patients with hypothyroidism have an increased requirement for levothyroxine after starting oral estrogen (estrogen replacement therapy or oral contraceptives). Oral estrogen formulations decrease clearance of thyroxine-binding globulin (TBG), leading to elevated TBG levels. TBG is synthesized and sialylated in the liver. Transdermal estrogen bypasses the liver and does not affect TBG levels.

Patients with normal thyroid function can readily increase thyroxine production to saturate the increased number of TBG binding sites, but hypothyroid patients are dependent on exogenous thyroid replacement and cannot compensate. This results in decreased free thyroxine and increased TSH. As a result, higher dosing of levothyroxine may be required. A rise in estrogen levels is also one of the main reasons for higher levothyroxine requirements during pregnancy.

Cx:

Myxedema coma is defined as severe hypothyroidism leading to decreased mental status, hypothermia, and other symptoms related to slowing of function in multiple organs. Unprovoked hypothermia is a particularly important sign. Myxedema coma constitutes a medical emergency; treatment should be started immediately. Should laboratory results fail to support the diagnosis, treatment can be stopped.

An intravenous bolus of levothyroxine is given (500 μg loading dose), followed by daily intravenous doses (50-100 μg). Impaired adrenal reserve may accompany myxedema coma, so parenteral hydrocortisone is given concomitantly. Intravenous fluids are also needed but are less important than thyroxine and glucocorticoids; rewarming should be accomplished slowly, so as not to precipitate cardiac arrhythmias. If alveolar ventilation is compromised, then intubation may also be necessary.

Question 14

Hypothyroid myopathy 🍗

Answer 14

Hypothyroid myopathy occurs in over one third of patients with hypothyroidism, and can range from an asymptomatic elevation in CK to myalgias, muscle hypertrophy, proximal myopathy, and rhabdomyolysis. Serum CK🍗 can be elevated for years before a patient develops clinical symptoms of hypothyroidism, and there is no clear correlation between the degree of CK elevation and severity of muscle disease. Inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein) may be normal or mildly elevated.

Dx: Initial testing should include TSH and free T4. If thyroid studies are normal, additional testing, including serologic markers (eg, antinuclear antibodies, anti-Jo-1 antibodies) and muscle biopsy, may be needed to rule out other causes of myositis

Question 15

Congenital Hypothyroidism 🚼

Answer 15

Clinical manifestations

• Initially normal at birth
• Symptoms develop after maternal T4 wanes:
  
  • Lethargy
  • Enlarged fontanelle
  • Protruding tongue
  • Umbilical hernia
  • Poor feeding
  • Constipation
  • Dry skin
  • Jaundice

Diagnosis

• ↑ TSH & ↓ free T4 levels
• Newborn screening

Treatment

• Levothyroxine

Jaundice, decreased activity, poor feeding, and hoarse cry are typical symptoms of congenital hypothyroidism. However, most infants with hypothyroidism are asymptomatic and identified through newborn screening. The most common cause of congenital hypothyroidism worldwide is thyroid dysgenesis (eg, aplasia, hypoplasia, ectopic gland). Prompt recognition and thyroid hormone replacement (eg, levothyroxine) is necessary to prevent permanent neurodevelopmental injury.

The most common cause is thyroid dysgenesis (i.e., aplasia, hypoplasia, or ectopic gland), which has been incriminated in 85% of cases. Other causes include inborn errors of thyroxin synthesis (10%), and transplacental maternal thyrotropin-receptor blocking antibodies (5%). Infants initially appear normal at birth, but gradually develop apathy, weakness, hypotonia, large tongue, sluggish movement, abdominal bloating, and an umbilical hernia. Other signs include pathologic jaundice, difficult breathing, noisy respiration, hypothermia, and refractory macrocytic anemia. Infants initially appear normal due to the presence of moderate amounts of maternal hormones in the infant’s circulation. For this reason, screening is mandated in all states at birth to allow for the early detection, treatment, and consequent improvement of the prognosis. Screening is done by measuring serum T4 and TSH levels. The treatment is levothyroxine (initial dose of 10 mcg/kg, then titrated accordingly).

Question 16

Subclinical Hypothyroidism

Answer 16

Defined as a serum thyroid-stimulating hormone (TSH) level greater than the reference range, with a concomitant serum free thyroxine (T4) level in the reference range.

Hx: Patients typically have mild or no symptoms of hypothyroidism.

Tx: Treatment is recommended when serum TSH levels are greater than 10 µU/mL. Levothyroxine also may be considered for patients who have marked symptoms, have a goiter, are pregnant or are planning to become pregnant, or have positive serum thyroid peroxidase antibody titers.

Monitor q1y

Question 17

Iatrogenic Hypothyroidism

Answer 17

Hx: Suspected surreptitious (gain) ingestion of thyroid hormone or analogues.

Dx: Excess thyroid hormone negatively feeds back on the pituitary, leading to decreased TSH. This decrease in thyroid activity manifests as decreased ¹²³I uptake, with thyroid gland atrophy.

Question 18

Hashimoto disease (Chronic autoimmune thyroiditis)

Answer 18

The most common cause of thyroiditis. Generally seen in middle-aged women, this generally presents with a palpable goiter most often there is associated tenderness.

TSH high; free T₃ and T₄ normal. positive family history for hypothyroidism; TPO antibodies present; slowly progressive

Dx: Antithyroblobulin antibodies / Antithyroid peroxidase antibodies (anti-TPO)

Tx: Levothyroxine (T₄), which should always be taken on an empty stomach 1 hour before or 2 to 3 hours after intake of food or other medications.

Cx:

Thyroid lymphoma is uncommon, but the incidence is approximately 60 times greater in patients with preexisting chronic lymphocytic (Hashimoto) thyroiditis (ie, chronic hypothyroidism, positive antithyroid peroxidase antibody). The typical presentation of thyroid lymphoma includes a rapidly enlarging, firm goiter associated with compressive symptoms (eg, dysphagia, hoarseness). As with other lymphomas, patients may have systemic B symptoms (eg, fever, night sweats, weight loss).

Mild pain and tenderness may be present, and the gland is frequently fixed to the surrounding structures and does not move up when swallowing. Retrosternal extension of the tumor is common and can result in venous compression with distended neck veins and facial plethora; raising the arms causes compression of the subclavian (and right internal jugular) vein between the clavicles and the enlarged thyroid, leading to more prominent venous distension and facial redness (Pemberton sign).

Inflammatory markers (eg, erythrocyte sedimentation rate) can be elevated but are nonspecific. CT imaging typically reveals diffuse enlargement of the thyroid around the trachea (doughnut sign). Core or excisional biopsy may be required, and flow cytometry can confirm monoclonal lymphoma cells.

Question 19

Silent /Painless (lymphocytic) thyroiditis

Answer 19

Painless thyroiditis is associated with thyroid peroxidase autoantibodies and is considered a variant of chronic lymphocytic (Hashimoto) thyroiditis. It is similar to postpartum thyroiditis but by definition excludes patients within a year of pregnancy.

Hx: Painless

Dx: Following a self-limited hyperthyroid phase, patients often develop a hypothyroid phase, which may persist or return to a euthyroid state.

In patients with subacute, silent, or postpartum thyroiditis or exposure to exogenous thyroid hormones, the radioactive iodine uptake ❄ (RAIU) will be very LOW (<5% at 24 hours), which indicates very little endogenous thyroid production.

Tx: Painless thyroiditis does not require specific therapy. However, as hyperthyroidism causes adrenergic overstimulation, a beta blocker (eg, propranolol) may be prescribed to control symptoms, especially palpitations or tremulousness.

Question 20

🤰🏼Postpartum thyroiditis

Answer 20

Patients can have a brief hyperthyroid phase due to release of preformed thyroid hormone but frequently have only mild, nonspecific symptoms (eg, anxiety, palpitations). The subsequent hypothyroid phase (eg, fatigue, weight gain despite normal appetite, constipation) often brings patients to medical attention. Examination typically shows a nontender goiter, bradycardia, diastolic hypertension, lower extremity edema, and other findings (eg, coarse facies, delayed deep tendon reflex relaxation). In the hypothyroid phase, TSH will be elevated and free T4 levels will be low. Other laboratory findings associated with hypothyroidism include hypercholesterolemia (due to thyroid effects on lipid metabolism) and hyponatremia.

Hx: A subset of painless autoimmune thyroiditis and can occur up to 12 months after parturition. It affects 5% to 8% of pregnant women in the United States and can recur with each pregnancy.

Postpartum thyroiditis is similar to painless (silent) thyroiditis, but by convention the latter is not diagnosed within a year of childbirth. Both may be considered variants of chronic lymphocytic (Hashimoto) thyroiditis and are associated with elevated titers of anti-thyroid peroxidase autoantibodies. However, whereas Hashimoto thyroiditis frequently leads to permanent hypothyroidism, postpartum and painless thyroiditis are usually self-limited, and patients return to a euthyroid state over several months.

The disorder usually follows a classic course of approximately 6 weeks of thyrotoxicosis, a shorter period of euthyroidism, 4 to 6 weeks of hypothyroidism, and then restoration of euthyroidism.

Dx: TSH triphasic (low, high, normal) over 2-4 mo but often ultimately elevated; recent pregnancy.

Thyroiditis is associated with elevated serum free thyroxine (T4) and triiodothyronine (T3) levels and a low serum thyroid-stimulating hormone (TSH) level.

Question 21

Iodine deficiency

Answer 21

TSH high; iodine-deficient area; rare in United States

Question 22

Pituitary/hypothalamic mass or radiation

Answer 22

“Central hypothyroidism”

Hx: Headaches; most often a pituitary or sellar lesion noted on MRI/CT scan or evidence of prior pituitary surgery

Dx: TSH low or normal; free T4 low

Serum thyroglobulin

3-40 ng/mL

Suspected subacute thyroiditis or suspected surreptitious ingestion of thyroid hormone or analogues; followed as a tumor marker in patients with well-differentiated thyroid cancer

Question 23

Pregnancy (treated)

Answer 23

Pregnancy is known to increase levothyroxine requirements in most patients receiving thyroid replacement therapy, and this expected increase should be anticipated by increasing the levothyroxine dose. This is typically increased in the first (and sometimes in the second) trimester of pregnancy, with a possible total increase of 30% to 50%, and an increase in levothyroxine dose in this range to maintain the thyroid-stimulating hormone (TSH) level between approximately 0.1 and 2.5 µU/mL is associated with fewer maternal and fetal complications. The fetus is largely dependent on transplacental transfer of maternal thyroid hormones during the first 12 weeks of gestation, and the presence of maternal subclinical or overt hypothyroidism may be associated with subsequent fetal neurocognitive impairment, increased risk of premature birth, low birth weight, increased miscarriage rate, and even an increased risk of fetal death. In pregnant women with hypothyroidism, thyroid function testing should be frequent, preferably every 4 weeks, to protect the health of mother and fetus and to avoid pregnancy complications.

TSH levels generally should range from 0.1 to 2.5 µU/mL (0.1-2.5 mU/L) in the first trimester, 0.2 to 3.0 µU/mL (0.2-3.0 mU/L) in the second trimester, and 0.3 to 3.0 µU/mL (0.3-3.0 mU/L) in the third trimester.

Question 24

Subacute lymphocytic thyroiditis

Answer 24

Less common, and although an acute increase in thyroid size is seen, it is generally nontender.

Question 25

Subacute granulomatous thyroiditis

Answer 25

Usually follows a viral illness and is also associated with a mildly painful gland.

Question 26

Invasive fibrous thyroiditis

Answer 26

Presents as a gradually increasing gland that is firm, but is nontender.

Question 27

EUTHYROID

Question 28

Suppurative (infectious) thyroiditis

Answer 28

Rare, and is associated with fever, a swollen thyroid, and clinical manifestations of a bacterial illness.

The thyroid gland may be palpably enlarged due to abscess formation. However, patients are usually euthyroid as the involvement of the thyroid gland is focal.

Question 29

Euthyroid sick syndrome

Answer 29

This condition, often referred to as euthyroid sick syndrome, or “low T3 syndrome,” is thought to be a result of decreased peripheral 5’-deiodination of T4 due to caloric deprivation, elevated glucocorticoid and inflammatory cytokine levels, and inhibitors of 5’monodeiodinase (eg, free fatty acids, certain medications). There is a rough correlation between the severity of the underlying, non-thyroidal illness and the fall in T3 levels. If the non-thyroidal illness continues, serum T4 and TSH levels may eventually decrease as well.

• Low serum (total) T3
• Normal serum (total) T4
• Normal TSH

In the setting of acute illness (eg, ulcerative colitis flare treated with glucocorticoids).

T4 is produced exclusively in the thyroid gland, whereas T3 is produced mainly by peripheral conversion of T4 by deiodination. ESS encompasses a variety of alterations in thyroid physiology, the most common of which is termed “low T3 syndrome” and is thought to be the result of decreased conversion of T4 to T3. Factors in acute illness that inhibit peripheral deiodination include high endogenous cortisol levels, inflammatory cytokines (eg, tumor necrosis factor), starvation, and certain medications (eg, glucocorticoids, amiodarone).

TSH and T4 levels are often normal in ESS, although they also may fall in severe or prolonged cases; thus, ESS may represent a transient central hypothyroidism rather than a true euthyroid state. In light of these changes, thyroid function tests must be interpreted with caution in acutely ill patients. ESS does not usually require treatment, and abnormal results should be followed up with repeat testing once the patient has returned to baseline health.

Question 30

T1DM

Answer 30

Type 1 diabetes mellitus (T1DM) is primarily a disease of β-cell failure resulting in lack of circulating insulin; insulin sensitivity usually remains normal, with insulin doses required to treat patients being similar to a healthy individual’s daily endogenous insulin production (30-60 U/day).

Patients with type 1 diabetes are typically diagnosed at the time of disease onset based on the occurrence of symptomatic hyperglycemia or ketoacidosis. Since microvascular complications in patients with type 1 diabetes typically occur after the onset of puberty and/or 5 to 10 years after the initial diagnosis, screening for these complications is delayed until that time. Because patients with type 1 diabetes have a higher risk of early cardiovascular disease, screening is typically done early in the disease course. The American Diabetes Association (ADA) recommends that such patients have a fasting lipid panel performed after puberty or at diagnosis if the diagnosis is established after puberty.

The ADA recommends screening for nephropathy (such as a urine albumin-creatinine ratio) once a patient with type 1 diabetes is 10 years of age or older and has been diagnosed with diabetes for 5 or more years. The first dilated funduscopic examination should be obtained once the child is 10 years of age or older and has been diagnosed with type 1 diabetes for 3 to 5 years. This patient only needs a fasting lipid profile since she was diagnosed with type 1 diabetes 2 years ago and is postpubertal.

Question 31

T2DM

Answer 31

Screening

• Asymptomatic adults with sustained blood pressure (BP; treated or untreated) >135/80 mm Hg.
• Overweight or obese (body mass index >25 kg/m2) and who have risk factors (eg, BP >140/90 mm Hg, dyslipidemia [high-density lipoprotein levels <35 mg/dL and/or triglyceride levels >250 mg/dL], first degree relative with diabetes or member of a high-risk ethnic group, or polycystic ovary syndrome).
• Asymptomatic patients without risk factors should consider screening at age 45 years.

The National Kidney Foundation and the American Diabetes Association recommend:

Screen annually for diabetic nephropathy with annual testing with a spot urine test (urine albumin–creatinine ratio) for moderately increased albuminuria (microalbuminuria). [In patients with type 1 diabetes of 5 years’ duration and in all patients with type 2 diabetes starting at the time of diagnosis]

Glycemic control should be monitored with HbA1c measurements every 3 to 6 months.

Obtain an annual fasting lipid profile, including LDL-C, triglyceride, high-density lipoprotein cholesterol, and total cholesterol levels, and adjust treatment to meet goals.

Perform a foot examination at each visit.

Obtain an annual dilated funduscopic examination from a specialist, unless otherwise dictated by the specialist.

Dx: Glomerular hyperfiltration is believed to be the earliest renal abnormality present in patients with diabetes mellitus. It can be detected as early as several days after the diagnosis of diabetes was made. Moreover, glomerular hyperfiltration is the major pathophysiologic mechanism of glomerular injury in these patients. It creates intraglomerular hypertension leading to progressive glomerular damage and renal function loss. You should remember that effectiveness of ACE inhibitors in diabetic nephropathy is related to their ability to reduce intraglomerular hypertension and, thereby, decrease glomerular damage.

Tx:

Reduce the dose of insulin and carefully monitor the blood glucose level for 1 week so that it does not become less than 100 mg/dL. This intervention allows the body to reset its adrenergic responses.

Improved control of blood glucose levels has been shown to reduce the incidence of microvascular complications, however, there is conflicting evidence about whether improving glucose levels also benefits macrovascular complications (myocardial infarction, stroke, and peripheral arterial disease).

Ideally, the HbA1c value should be < 7.0% (reference range, 4.0% - 6.0%). In patients with a shorter duration of diabetes and no significant cardiovascular disease or hypoglycemia, it may be reasonable to attempt an HbA1c goal of 6.5%. For patients with a history of hypoglycemia, a limited life expectancy, and advanced macrovascular complications, a target HbA1c goal of 8.0% may be reasonable.

The desired fasting glucose and postprandial glucose levels are 70 to 130 mg/dL (3.9-7.2 mmol/L) and < 180 mg/dL (10.0 mmol/L), respectively.

Type 2 diabetes is conventionally treated first with diet, weight loss (for overweight or obese patients), and exercise. These changes include 30 minutes of exercise most days of the week and a calorie-restricted diet to achieve weight reduction of approximately 7% of body weight. Glycemic control is dependent on the total caloric intake, not the type of calorie taken in. Increased fiber does improve glycemic control.

Biguanides [Metformin] act to decrease glucose output from the liver, and can decrease hemoglobin A1c by 1.5% to 2%. Should not be used if creatinine is higher than 1.5 mg/dL or with known liver disease or alcohol abuse. Metformin must be discontinued before receipt of radiocontrast agents. Patients should be counseled about the risk of loose stools, bloating, gas, or other gastrointestinal side effects.

Sulfonylureas can be given as first-line agents or in combination with metformin. Sulfonylureas are well tolerated and have few contraindications, although they can cause hypoglycemia and should be used with caution in the elderly, especially in the presence of chronic kidney disease. Glipizide has fewer hypoglycemically active metabolites and has a shorter half-life than glyburide, it also frequently causes hypoglycemia, particularly in older patients.

Incretin-based therapy:

Glucagon-like peptide-1 (GLP-1)[Exenatide] receptor agonists gut-derived incretin hormones that stimulate insulin and suppresses glucagon secretion, delays gastric emptying, and reduces appetite and food intake. Glucagon-like peptide-1 agonists improve glycemic control without increasing the risk of hypoglycemia or weight gain and, in some patients, may promote modest weight loss. However, side effects include significant nausea, diarrhea, vomiting, and bloating. In addition, these agents require injections and are significantly more expensive than other medications. This class of drug can reduce HbA1c by approximately 0.5% to 1.5%.

Dipeptidyl peptidase-4 (DPP-4) inhibitors [Sitagliptin] prolong the activity of endogenously released GLP-1.Dipeptidyl peptidase-4 inhibitors are oral agents that can similarly reduce HbA1c, although without changes in body weight.

Thiazolidinediones (pioglitazone, rosiglitazone) decrease insulin resistance in the periphery and are an excellent choice for those with insulin insensitivity. When used as monotherapy, they can decrease the HbA 1 C by about 1 to 2 percentage points. When added to the regimen of patients on insulin, it can reduce the insulin dosage by 30% to 50%.

Rosiglitazone is associated with increased cardiovascular adverse events, and its use has been significantly restricted by the US Food and Drug Administration. These medications are contraindicated in patients with heart failure or liver dysfunction and have been associated with increased risk of bladder cancer and osteoporotic fracture. They may have a role in unique circumstances, although risks and benefits must be carefully weighed and discussed with the patients in advance.

Acarbose is an α-glucosidase inhibitor that impairs polysaccharide absorption in the intestine, does not cause hypoglycemia, and is relatively weight neutral. However, it has resulted in an approximately 25% RRR for development of diabetes, which is inferior to that obtained with diet and exercise.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (eg, canagliflozin, empagliflozin) cause increased renal excretion of sodium and glucose. In addition to lowering blood glucose, these agents induce a mild diuresis, leading to decreased blood pressure and decreased risk of heart failure and cardiovascular events. Minor weight loss is common. Notable adverse effects include hypotension and urinary tract infection.

Insulin is critical for intracellular potassium movement and Insulin therapy will stimulate transfer of potassium from the extracellular to the intracellular space. Use insulin if the desired level of glycemic control is not achieved with these other strategies.

The most popular method is to begin with a single nighttime injection of basal (long-acting) insulin because this simple approach minimizes the risk of hypoglycemia. Basal insulin, although effective in many patients, does not address postprandial glucose excursions. To address this, a short- or rapid-acting insulin (bolus) is added before each meal.

Another method is twice-daily use of a premixed product that contains both intermediate- and short- or rapid-acting insulin in fixed ratios. Some oral agents can be continued with the initiation of basal insulin, although insulin secretagogues (sulfonylureas and glinides) are usually discontinued because of the additive risk for hypoglycemia. Regardless, patients should be counseled that consistency in their routine (both timing of insulin administration and eating patterns) is paramount to success in managing their diabetes. Insulin therapy is also considered the standard of care for treating diabetes during pregnancy, although some recent studies suggest certain oral agents may prove to be safe.

The ADA recommends premeal blood glucose targets to be <140 mg/dL and random blood glucose to be <180 mg/dL.

“Sliding scale” insulin has fallen out of favor, it is reactive rather than proactive and often leads to wide fluctuations and inadequate glucose control.

“Sensitive, resistant, or XR”

In critically ill patients:

Initiate insulin therapy with persistent hyperglycemia >200 mg/dL and aim for a target goal of 140 to 200 mg/dL.

🐇Rapid: “Girls And Lads” O[15-30 min]D[3 to 5 hours]

Glulisine (Apidra), Aspart (Novolog🌲)[4], Lispro** 🏌🏽‍♂️(Humalog🌲)[4]** is a regular insulin molecule chemically modified to remove the disulfide bond between the amino acids lysine and proline, thus allowing for very rapid absorption from the subcutaneous space to the intravascular space.

Intermediate

“Rest Now”

Neutral protamine Hagedorn (NPH) insulin is a pentamer of the insulin molecule covalently bound to protamine, which inhibits free insulin release, leading to a long onset of action and prolonged duration of insulin release. P[4 to 8 hours]D[10 to 20 hours]

Patients with type 2 diabetes may require insulin therapy if diet, exercise, and oral hypoglycemic agent do not provide appropriate control. A low dose of NPH is commonly used, estimating 0.1 U/kg of body weight, as an addition to the current regimen.

Regular insulin administered intravenously, directly into the circulation, will interact with the insulin receptor almost immediately. As with almost all small peptides, the half-life of insulin is very short, with regular insulin having a half-life of 9 minutes. Therefore, it must be provided as a continuous infusion as opposed to bolus administration O[30-60 min]P[2 to 3 hours]D[4 to 12 hours]

Novolin (70/30), Humalin (50/50)

🐢 ❕Long: [1 to 2 hours]D[24 hours]

“Don’t Go”

Levemir🔍 (Detemir🔍)[12-16], Lantus (❕Glargine)[18-24], 🎴 Degludec (36h)

🎯 150 - 188

QHS (night)➡ AM > 20 and (QHS > AM) = (⬇ Basal bolus)

QHS ➡ AM < 20 ✅

QHS ➡ AM > 20 (QHS < AM) = (⬆ Basal bolus)

DM 1 0.2 - 0.4 U/kg/day

DM 2 0.6 - 0.8 U/kg/day

Moderate-intensity statin therapy (to lower the low-density lipoprotein cholesterol [LDL-C] concentration by 30% to <50%) in patients with diabetes, and high-intensity statin therapy (to lower the LDL-C concentration by ≥50%) if the 10-year cardiovascular risk is ≥7.5% in patients aged 40 to 75 years.

Aspirin for secondary prevention in patients with a history of myocardial infarction, vascular bypass, stroke or transient ischemic attack, peripheral arterial disease, claudication, or angina.

Aspirin is also recommended for primary prevention in patients with diabetes and a 10-year risk of cardiovascular disease >10% (based on the Framingham risk score), which would include most men aged >50 years and women aged >60 years who have at least 1 additional cardiovascular risk factor.

Ace Inhibitors: Indicated for diabetics with systolic blood pressures greater than 100 mm Hg.

Cx:

In some patients with long-standing type 2 diabetes mellitus, glucose counterregulation may be altered by shifting the sympathoadrenal response to hypoglycemia to a lower blood glucose level, leading to episodes of severe hypoglycemia that may not be recognized by the patient (hypoglycemic unawareness).

Complications and their management:

Preipheral Neuropathy:

Neuronal injury in diabetes is due to a number of factors, including microvascular injury, demyelination, oxidative stress, and deposition of glycation end products. The use of metformin, which decreases intestinal absorption of vitamin B12, can also contribute. This leads to a length-dependent axonopathy, with clinical features occurring first in the longest nerves (eg, feet).

Symmetric distal sensorimotor polyneuropathy is the most common neuropathy in patients with diabetes; the clinical features depend on the type of nerve fibers involved.

Small fiber injury is characterized by predominance of positive symptoms (eg, pain, paresthesias, allodynia) .

Large fiber involvement is characterized by predominance of negative symptoms (eg, numbness, loss of proprioception and vibration sense, diminished ankle reflexes).

Microvascular complications:

Diabetic Nephropathy: To screen for nephropathy, it is recommended that all patients with T1DM and T2DM be tested for urine albumin excretion with a spot urine sample for albumin-creatinine ratio. The presence of moderately increased albuminuria (approximately 30-300 mg/g) should prompt initiation of an angiotensin-converting enzyme inhibitor (ACE) or angiotensin-receptor blocker (ARB) for its renoprotective effects. Tx: In patients with type 2 diabetes, intensive blood pressure control is associated with reduced progression of DN; the ideal blood pressure (BP) is uncertain, although a target of <130/80 mm Hg is reasonable and achievable for most patients.

Diabetic retinopathy: The leading cause of blindness in the United States. The highly vascular retina is often affected in patients with long-standing diabetes mellitus. The risk increases with the length of time that the patient has had diabetes, and the condition worsens with increasing hemoglobin A 1C levels. Px: Hard exudates, microaneurysms, and minor hemorrhages (background diabetic retinopathy) are among the early changes. Although diabetic background retinopathy is not typically associated with any decline in visual acuity, it is associated with retinal infarcts and growth of abnormally fragile blood vessels (neovascularization) that predispose to retinal and vitreous hemorrhage resulting in visual loss. Macular edema may also occur. Tx: Laser photocoagulation can preserve sight in these individuals. In addition, BP reduction and glycemic control slow the progression of eye disease.

Diabetic Neuropathy: Foot ulcer: patients must be educated about daily foot inspections, appropriate footwear and avoiding barefoot activities, and testing water temperature before bathing. Orthotic footwear should be prescribed for patients with foot deformities to cushion high-pressure areas. Testing sensation using a 5.07/10-g monofilament has been shown to predict ulcer and amputation risk and have superior predictive value, compared with other sensory test modalities (tuning fork, pinprick, and cotton wisps), for the presence or absence of neuropathic symptoms.

Others:

Cardiovascular autonomic neuropathy is an often underdiagnosed autonomic neuropathy in diabetic patient that may present with nonspecific symptoms such as exercise intolerance, orthostatic hypotension, or cardiovascular lability. While often difficult to identify, cardiovascular autonomic neuropathy is associated with increased risk of silent myocardial ischemia and mortality.

Gastrointestinal neuropathy, often manifesting as gastroparesis, is another cause of frequent hospitalization in patients with advanced diabetes. Gastroparesis should be suspected in a diabetic patient who has erratic glucose control with nonspecific gastrointestinal complaints and no other identifiable cause.

Autonomic neuropathy can also involve the genitourinary tract, resulting in neurogenic bladder and, in men, erectile dysfunction and retrograde ejaculation. Erectile dysfunction has been reported to affect up to 35% to 75% of men with diabetes and is usually a marker for development of other microvascular complications. Like many other complications of diabetic patients, optimal glycemic control can prevent the development of neuropathies. However, once neuropathies are present, glycemic control can only slow progression but not reverse the disease process.

Somogyi effect develops in response to excessive insulin administration. An adrenergic response to hypoglycemia results in increased glycogenolysis, gluconeogenesis, and diminished glucose uptake by peripheral tissues.

Oculomotor nerve (CN III) palsy The most common cause of CN III palsy in adults is ischemic neuropathy due to poorly controlled diabetes mellitus.

CN III has 2 major components as follows:

Inner somatic fibers - innervate the levator muscle of the eyelid and 4 of the extraocular muscles (EOMs) (superior rectus, medial rectus, inferior rectus, inferior oblique)

Superficial parasympathetic fibers - innervate the sphincter of the iris and the ciliary muscles (controlling pupil constriction).

Because the inner somatic fibers are farther from the blood supply, they are more susceptible to ischemic injury. Therefore, patients with ischemic CN III palsy typically have paralysis of the levator muscle (ptosis) and 4 EOMs (“down-and-out-gaze”) with preserved pupillary response.

Question 32

DKA

Answer 32

Diabetic ketoacidosis develops when significant insulin deficiency is coupled with excess circulating levels of counter-regulatory hormones, including glucagon. Insufficient insulin prevents glucose uptake by muscle and liver cells, resulting in profound hyperglycemia and excessive hepatic glucose production. The hyperglycemia is responsible for osmotic diuresis and hypovolemia. The excess glucose is metabolized via the fatty acid degradation pathway to free fatty acids that are converted to β-hydroxybutyrate and acetoacetate by the liver, resulting in ketoacidosis, ketonuria, and electrolyte abnormalities.

Hx: DKA is most commonly caused by omission of insulin therapy, but both conditions may occur with concomitant infection or rarely with other clinical events such as silent myocardial infarction or cerebrovascular accident. Pancreatitis, trauma, alcohol abuse, and illicit drug (cocaine) use are other possible causes. Less often, drugs that affect carbohydrate metabolism may lead to DKA or HHS. These include the use of glucocorticoids, thiazide diuretics, sympathomimetic agents, or second-generation antipsychotics. In elderly patients, restricted access to water intake or altered thirst response increases risk of dehydration and, therefore, HHS.

🍌Hyperkalmeia due to extracellular potassium shifts caused by acidosis, but total body potassium stores are often depleted because of urinary losses. Acidosis and dehydration contribute to hyperkalemia. This is compounded by a lack of circulating insulin, which is critical for intracellular potassium movement. Together, these changes frequently produce serum potassium values ranging from 6.0 to 7.0 mEq/L at the time of presentation. Because of the presence of hyperkalemia, cardiac monitoring is required.

Tx: For almost all patients with diabetic ketoacidosis, effective therapy requires adding potassium to the intravenous fluid when serum potassium concentrations decline to 4.0 to 4.5 mEq/L. Without potassium supplementation, dangerous levels of hypokalemia may occur.

Hyponatremia due to the hyperglycemia-induced osmotic shifts of fluid into the vascular system.

Symptoms of DKA include polyuria, polydipsia, blurred vision, nausea, vomiting, and abdominal pain. If DKA is severe, patients may have altered mental status or be unresponsive.

Px: Signs of hypovolemia, including tachycardia, hypotension, dry mucous membranes, and poor skin turgor. Kussmaul respiration (deep and frequent breathing) is a sign of metabolic acidosis, and a fruity breath odor is often noted due to acetone elimination by the lungs.

Dx: Triad of hyperglycemia (blood glucose level >250 mg/dL), increased anion gap metabolic acidosis (arterial pH <7.30; serum bicarbonate <15 meq/L), and positive serum or urine ketones. Blood urea nitrogen and serum creatinine levels are usually elevated secondary to hypovolemia.

Tx:

Diabetic ketoacidosis is a life-threatening condition. Patients require hospitalization, often in an intensive care unit. The goals of treatment are the resolution of ketosis (anion gap normalization), volume repletion, and restoration of electrolyte abnormalities.

IV fluids

• High-flow 0.9% normal saline is initially recommended
• Add dextrose 5% when serum glucose is ≤200 mg/dL

Insulin

• Initial continuous IV insulin infusion
• Switch to SQ (basal bolus) insulin for the following: Able to eat, glucose <200 mg/dL, anion gap <12 mEq/L, serum HCO3 ≥15 mEq/L
• Overlap SQ & IV insulin by 1-2 hours

Potassium

• Add IV potassium if serum K+ ≤5.2 mEq/L
• Hold insulin for serum K+ <3.3 mEq/L
• Nearly all patients K+ depleted, even with hyperkalemia

Bicarbonate

• Consider for patients with pH <6.9

Phosphate

• Consider for serum phosphate <1.0 mg/dL, cardiac dysfunction, or respiratory depression
• Monitor serum calcium frequently

An intravenous (IV) infusion of 0.9% saline is started immediately, along with IV regular insulin. From 2 to 6 L of IV fluid may be required to achieve euvolemic status. An initial IV bolus of regular insulin is administered, followed by a continuous IV infusion of approximately 0.1 U/kg/h.

In HHS, Regular insulin by intravenous infusion is the most appropriate therapy

Blood glucose is monitored hourly, targeting a reduction in serum glucose of 50-100 mg/dL per hour. When the serum glucose reaches 250 mg/dL, the IV solution is typically changed to 0.45% saline with 5% or 10% dextrose to avoid hypoglycemia. The insulin infusion is continued until the anion gap has normalized and ketones are no longer present. Premature discontinuation of insulin may lead to rebound acidosis. Once ketones are cleared and the anion gap is normalized, patients are started on subcutaneous insulin with a 2- to 6-hour period of overlapping subcutaneous and IV insulin before IV insulin is discontinued.

Measure serum potassium every 1 to 2 hours and to replace potassium intravenously. Phosphate repletion is typically not required. Bicarbonate therapy is reserved for severe acidosis (pH <6.9).

Intravenous insulin therapy can lower serum glucose by 50-75 mg/dL per hour but ketosis and acidosis resolve more slowly.

The best markers indicating resolution of ketonemia are the serum anion gap and direct assay of beta-hydroxybutyrate (BH), which is the predominant ketone in DKA. The anion gap estimates the unmeasured anion concentration in the blood and returns to normal with the elimination of ketoacid anions. BH is converted to acetoacetate and acetone, which can be measured by the commonly used nitroprusside test, but this test does not detect BH itself. Therefore, either calculation of the anion gap or direct assay of serum BH is recommended to follow ketonemia. A rise in serum bicarbonate and arterial pH provides further confirmation of the improvement in acidosis.

Cx: The most dangerous complication of DKA treatment is the rare development of cerebral edema, signaled by symptoms of headache and altered mental status, which is most common during the treatment of children and can be fatal. The exact cause is unknown but may be due in part to aggressive hydration with hypotonic fluids.

Question 33

[HHS] Hyperglycemic hyperosmolar syndrome

Answer 33

Patient characteristics

• Type 2 diabetes usually
• Older age

Clinical symptoms

• More pronounced altered mentation
• Gradual onset of hyperglycemic symptoms
• Hyperventilation & abdominal pain less common

Laboratory studies

• Glucose >600 mg/dL (33.3 mmol/L)
• Bicarbonate >18 mEq/L (18 mmol/L)
• Normal anion gap
• Negative or small serum ketones
• Serum osmolality >320 mOsm/kg (320 mmol/kg)

HHS is characterized by severe hyperglycemia and high serum osmolality due to relative insulin deficiency and/or elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone). Common precipitating factors include:

Infection (most common)

Medications (eg, glucocorticoids, thiazide diuretics, pentamidine, atypical antipsychotics)

Interruption of insulin therapy

Trauma or acute illness (eg, stroke, myocardial infarction)

Severe hyperglycemia causes glycosuria and osmotic diuresis, resulting in hypovolemia and dehydration. As hypovolemia worsens, the glomerular filtration rate declines (GFR), leading to reduced renal glucose excretion and worsening hyperglycemia. Elderly individuals are at increased risk due to altered perception of thirst and restricted fluid intake. Neurologic symptoms ranging from confusion to coma (nonketotic coma) are common and are primarily due to the high serum osmolality (usually >320 mOsm/kg). In contrast to diabetic ketoacidosis, which typically develops rapidly over hours, HHS develops over a few days to weeks.

Dx: Diagnostic criteria for HHS include plasma glucose >600 mg/dL; arterial pH > 7.30; serum bicarbonate > 15 meq/L; serum osmolality >320 mOsm/kg; and absent urine or serum ketones. The anion gap is usually normal but can be increased in the setting of hypovolemia-induced prerenal azotemia. Although HHS shares similar pathophysiology to DKA, residual circulating insulin precludes the onset of ketosis; therefore, acidosis does not occur despite severe hyperglycemia. This may lead to marked blood glucose elevation (plasma levels frequently >800 mg/dL) due to progressive dehydration that further stimulates compensatory hormone secretion (such as catecholamines), leading to even greater hyperglycemia.

Most patients with HHS or DKA have normal or elevated serum potassium levels at initial evaluation. This is due to the combined effects of insulin deficiency and hyperosmolality, which promote the movement of potassium out of cells into the extracellular space. Despite normal serum levels, patients with HHS or DKA have a total body potassium deficit (3–5 mg/kg) due to excessive urinary loss caused by osmotic diuresis induced by hyperglycemia.

Tx: Patients with HHS are often hemodynamically unstable and usually require care in an intensive care unit. The mainstay of treatment is correction of hypovolemia with 0.9% saline, infusing at least 1 L before the initiation of insulin. Half of the fluid deficit should be replaced during the first 24 hours, with the remainder replaced during the following 2 to 3 days. Intravenous insulin is initiated with a bolus of 0.1 U/kg and continued at a rate of 0.1 U/kg/h. The goal is to decrease serum glucose by 50-100 mg/dL per hour until glucose is <200 mg/dL and the patient is eating, at which point the patient is changed to subcutaneous insulin.

Potassium is monitored closely, as patients may become hypokalemic. Intravenous or oral potassium is provided to maintain serum potassium concentrations between 4.0 and 5.0 meq/L (4-5 mmol/L). Bicarbonate therapy is typically not required. Serum osmolality is monitored, with a goal of decreasing it by <3 mOsm/kg (3 mmol/kg) per hour.

Question 34

LADA

Answer 34

Late onset autoimmune diabetes of adults (LADA) typically occurs in nonobese adults, often without a family history of diabetes. It is slower in onset and less ketosis prone than type 1 diabetes, but responds poorly to agents such as metformin that improve insulin sensitivity. Autoantibodies (anti-GAD antibodies being the most sensitive and specific) characterize LADA as well as type 1 DM. An important aspect of LADA is that early use of insulin is necessary to adequately control the blood glucose levels.

Question 35

🌚 Cortisol

Answer 35

Endogenous: 🌱 Pituitary adenoma (ACTH-secreting in 60%-65% of patients)

Ectopic ACTH secretion by tumors, such as small cell carcinoma of the lung, bronchial carcinoid tumor, pheochromocytoma, and medullary thyroid carcinoma tumors (10%-15% of patients)

CRH-secreting tumors (rare)

Exogenous:

Prolonged administration of supraphysiologic doses of glucocorticoid therapy (such as prednisone, dexamethasone, or hydrocortisone)

Administration of drugs with glucocorticoid activity (progestational agents, such as megestrol, intra-articular injections and inhaled GC therapy)

Systemic Glucocorticoid use causes a leukocytosis due to the following:

• Mobilization of marginated neutrophils into the bloodstream (predominant mechanism): Marginated neutrophils are attached to the endothelium of blood vessels; glucocorticoid-induced mobilization of these neutrophils leads to a higher number of circulating neutrophils
• Stimulation of release of immature neutrophils from the bone marrow (as evidenced by the 3% band forms in this patient)
• Inhibition of neutrophil apoptosis

In contrast, glucocorticoids decrease the number of circulating lymphocytes and eosinophils through a combination of increased apoptosis, increased emigration into the tissues, and decreased production.

Other: Adrenal Incindentaloma

Question 36

Cushing Syndrome

Answer 36

Exogenous glucocorticoid intake or ectopic ACTH production (SCLC)[Cushing syndrome]

ACTH-secreting pituitary adenoma (Cushing disease)

Hx: Weight gain, proximal muscle weakness, and hypertension are common presenting findings. Patients can experience easy bruisability, dermal atrophy, and wide purple striae due to the catabolic effects of cortisol on connective tissue; however, platelet function and coagulation proteins are normal.

Dermatologic signs may include facial plethora, hyperpigmentation (in ACTH-dependent Cushing syndrome) and increased incidence of cutaneous fungal infections (eg, tinea versicolor, onychomycosis). Women can have features of hyperandrogenism (eg, menstrual irregularities, acne, hirsutism) due to co-secretion of adrenal androgens with cortisol.

Hyperglycemia is common (due to peripheral insulin resistance and hypercortisolism-induced gluconeogenesis). Hypokalemia and alkalosis may be present (due to the partial mineralocorticoid effects of cortisol) if cortisol levels are very high.

Px: Abnormal fat distribution (not just the presence of adipose tissue), particularly in the supraclavicular and temporal areas, proximal muscle weakness, or wide (>1 cm) purple striae.

Dx: 24-hour urine free cortisol (>3 times normal), overnight 1-mg dexamethasone suppression test (failure to suppress cortisol), or nighttime salivary cortisol level. Typically, 2 to 3 of these tests are performed to confirm the diagnosis.

Basal ACTH levels <6 pg/mL are found in adrenal forms of Cushing syndrome, while levels >6 pg/mL occur in ACTH-dependent disease. An adrenal computed tomography (CT) or MRI scan should be obtained to localize lesions in patients with suppressed ACTH values. In patients with nonsuppressed ACTH levels, a pituitary MRI scan should be obtained.

Tx: 🔪 Surgical resection of an identified tumor (adrenal, pituitary, or ectopic) is the optimal therapy for Cushing syndrome. Pituitary radiation (“gamma knife”) therapy can be used for patients with persistent or recurrent Cushing disease after transsphenoidal surgery or for those in whom pituitary surgery is contraindicated.

Rx: Drugs are used adjuvantly in patients undergoing surgery and as sole therapy for those with occult ectopic ACTH secretion or metastatic adrenal cancer to reduce cortisol production. Ketoconazole, mitotane, metyrapone, and aminoglutethimide reduce endogenous cortisol production and reverse most signs and symptoms of Cushing syndrome.

Question 37

Cushings Myopathy

Answer 37

Regardless of etiology, myopathy in Cushing syndrome is typically characterized by weakness predominantly involving the proximal muscles and may be severe enough to interfere with daily activities. It is due to the direct catabolic effects of cortisol on skeletal muscle, which leads to muscle atrophy.

Glucocorticoid-induced muscle atrophy is thought to be mediated by the inhibition of Akt-1, an intracellular signaling molecule with serine/threonine kinase activity. Interference of insulin-like growth factor 1 signaling may also contribute. Furthermore, glucocorticoids may decrease muscle cell differentiation and protein synthesis.

Question 38

Ectopic ACTH Secretion

Answer 38

Tumors, such as small cell carcinoma of the lung, bronchial carcinoid tumor, pheochromocytoma, and medullary thyroid carcinoma tumors (10%-15% of patients).

Hx: Weight loss, muscle weakness, and profound hypokalemia may predominate.

Dx: Chest MRI or CT scan. If negative, an abdominal CT or MRI scan should be obtained to look for a pancreatic tumor or other mass; bilateral adrenal enlargement;

Tx: Surgical resection of an identified tumor (adrenal, pituitary, or ectopic) is the optimal therapy for Cushing syndrome. Pituitary radiation (“gamma knife”) therapy can be used for patients with persistent or recurrent Cushing disease after transsphenoidal surgery or for those in whom pituitary surgery is contraindicated.

Rx: Drugs are used adjuvantly in patients undergoing surgery and as sole therapy for those with occult ectopic ACTH secretion or metastatic adrenal cancer to reduce cortisol production. Ketoconazole, mitotane, metyrapone, and aminoglutethimide reduce endogenous cortisol production and reverse most signs and symptoms of Cushing syndrome.

Question 39

Adrenal Incendentaloma

Answer 39

Given the frequency of abdominal CT and MRI scanning, adrenal nodules are commonly incidentally noted on these images. When imaged for other conditions, 1% to 7% of patients are found to have adrenal “incidentalomas,” and the incidence increases with age.

Hx: Greater than 90% of incidentalomas are nonfunctional, but all patients should be screened for Cushing syndrome and pheochromocytoma. Patients with hypertension or spontaneous hypokalemia should be screened for hyperaldosteronism. If the patient is virilized (voice deepening or clitoral enlargement), DHEA, DHEAS, and testosterone levels should be checked.

If the nodule is >6 cm, the risk of malignancy is approximately 25%, and surgical resection is recommended. If the nodule is <4 cm, the risk of malignancy is approximately 2%, and surgery is not recommended. Certain imaging characteristics of an adrenal nodule can indicate a higher or lower risk of malignancy (metastatic disease or primary adrenal cancer). If the patient has a history of malignancy, an incidentally noted adrenal nodule is likely to represent metastatic disease, especially if bilateral nodules are present. Irregular borders or intranodular necrosis are especially worrisome for malignancy. To avoid hypertensive crisis, biopsy of an adrenal nodule should never be attempted until pheochromocytoma has been ruled out. Follow-up recommendations include repeat biochemical testing at 1 year, with additional testing if signs or symptoms of hormonal functionality develop, and repeat adrenal imaging (CT or MRI) at 6 to 12 months to assess for change in the size and imaging characteristics of the nodule, with additional imaging if a significant change is detected.

Testing is usually necessary to identify functional tumors secreting catecholamines, cortisol, or aldosterone.

Dx: Initial laboratory tests should include:

• Overnight dexamethasone suppression test
• 24-hour urine collection for metanephrines
• Measurement of plasma renin activity
• Serum aldosterone level

Question 40

🔑 Hyperaldosteronism

Answer 40

Once thought to be a rare cause of hypertension, hyperaldosteronism (also called aldosteronism) has been recognized in up to 14% of unselected hypertensive patients. Depending on the cause, hyperaldosteronism is amenable to medical or surgical treatment.

Hx: Difficult-to-control or worsening hypertension despite multiple antihypertensive agents, spontaneous hypokalemia, severe hypokalemia after institution of low-dose diuretic therapy, or hypertension at a young age. Hypokalemia results when hyperaldosteronism causes excess distal renal tubule exchange of sodium for potassium.

Serum potassium may be normal initially in patients with PH, but treatment with diuretics may trigger severe, symptomatic hypokalemia. Although aldosterone causes increased renal reabsorption of sodium, most patients with PH do not have edema or clinically significant hypernatremia due to aldosterone escape.

Dx: In the presence of an elevated aldosterone and suppressed renin level, a midmorning ambulatory plasma aldosterone concentration (PAC)/PRA ratio >20 to 30 suggests primary hyperaldosteronism. If 2 screening PAC/PRA ratios are positive, a confirmatory test should be performed, such as assessing for serum aldosterone suppression after dietary or intravenous sodium loading; if aldosterone secretion is not suppressed, hyperaldosteronism is confirmed.

Once unequivocal excess aldosterone production is proven, a dedicated adrenal CT scan should be obtained.

Tx:

Adrenalectomy is the treatment of choice for aldosteronoma.

Question 41

Primary hyperaldosteronism (Conn’s syndrome)

Answer 41

Conn’s syndrome is usually due to an adrenal adenoma or bilateral adrenal hyperplasia.

Hx: Patients typically develop hypertension, mild hypernatremia, hypokalemia, and metabolic alkalosis. The elevated aldosterone leads directly to decreased renin through a feedback inhibition. The hypokalemia can cause muscle weakness and decreased exercise tolerance in some patients.

Difficult-to-control or worsening hypertension despite multiple antihypertensive agents, spontaneous hypokalemia, severe hypokalemia after institution of low-dose diuretic therapy, or hypertension at a young age. Hypokalemia results when hyperaldosteronism causes excess distal renal tubule exchange of sodium for potassium.

Dx: In the presence of an elevated aldosterone and suppressed renin level, a midmorning ambulatory plasma aldosterone concentration (PAC)/PRA ratio >20 to 30 suggests primary hyperaldosteronism. If 2 screening PAC/PRA ratios are positive, a confirmatory test should be performed, such as assessing for serum aldosterone suppression after dietary or intravenous sodium loading; if aldosterone secretion is not suppressed, hyperaldosteronism is confirmed.

Once unequivocal excess aldosterone production is proven, a dedicated adrenal CT scan should be obtained.

Tx: Adrenalectomy is the treatment of choice for aldosteronoma.

Question 42

Bilateral adrenal hyperplasia

Answer 42

Bilateral adrenal hyperplasia (also termed idiopathic primary hyperaldosteronism) is the most common cause of primary hyperaldosteronism, followed by unilateral aldosteronoma (Conn syndrome), and more rarely, unilateral hyperplasia or adrenal carcinoma.

Tx:

Bilateral adrenal resection is NOT indicated for bilateral adrenal hyperplasia because of the risks associated with possible primary adrenal insufficiency. Hypokalemia usually resolves following surgery, but hypertension does not always resolve; long-standing hypertension results in permanent vascular changes, making normalization of BP difficult.

Spironolactone is the treatment of choice for idiopathic hyperaldosteronism, bilateral adrenal hyperplasia, and nonsurgical candidates with aldosteronoma. A more selective mineralocorticoid receptor antagonist, eplerenone, can be used in patients unable to tolerate side effects from spironolactone, such as decreased libido, impotence, or gynecomastia. Dietary sodium restriction will decrease urinary potassium wasting and help potentiate the effect of antihypertensive therapy.

Question 43

Medullary Thyroid Cancer (MTC) 👨🏽👨🏽

Answer 43

Medullary Thyroid Cancer (MTC) is a calcitonin-producing tumor arising from neuroendocrine parafollicular C cells of the thyroid gland. Although most MTC is sporadic, approximately one third of MTC is inherited as a component of multiple endocrine neoplasia (MEN) types 2A (Parathyroid hyperplasia) and 2B (Mucosal Neuroma).

MTC most commonly presents as an asymptomatic thyroid nodule. A minority of patients have diarrhea and flushing (due to hormone secretion by the tumor). Dx: The diagnosis of MTC is confirmed with fine-needle aspiration.

Tx: Primary treatment is total thyroidectomy, and therefore postoperative thyroid replacement therapy (ie, levothyroxine) is necessary.

MEN Type 2A

• Medullary thyroid cancer (calcitonin)
• Pheochromocytoma
• Primary hyperparathyroidism (parathyroid hyperplasia)

MEN Type 2B

• Medullary thyroid cancer (calcitonin)
• Pheochromocytoma
• Mucosal neuromas/marfanoid habitus

Dx: MEN 2A and 2B (usually due to RET proto-oncogene mutations) are also associated with pheochromocytoma, which can be asymptomatic at the time of diagnosis but cause life-threatening hypertensive crisis during surgical procedures (eg, thyroidectomy). In light of this risk, most patients with MTC should undergo RET mutation testing and screening for pheochromocytoma with a plasma fractionated metanephrine assay. If found, pheochromocytoma should be resected prior to thyroidectomy.

Serum calcitonin levels correlate with the risk of metastasis and are measured at the time of diagnosis; they also correlate with risk of recurrence and are therefore measured serially following surgery. Carcinoembryonic antigen also correlates with disease progression and is typically measured with calcitonin.

Question 44

Pheochromocytoma

Answer 44

Pheochromocytomas are paraganglioma tumors that arise in the chromaffin cells of the adrenal medulla. The tumors can produce, store, and secrete catecholamines (norepinephrine, epinephrine, and/or dopamine); most produce norepinephrine; accounts for a small number of cases of secondary hypertension (0.1%-0.6%).

“Ten percent” of pheochromocytomas are extra-adrenal, 10% are malignant, 10% recur, and 10% are asymptomatic. Up to 25% of pheochromocytomas are familial. These familial tumors are more likely to occur at a young age; to be bilateral, extra-adrenal, and malignant; and to recur. Genetic testing should be considered in suspected familial cases.

Hx: Pheochromocytoma should be considered in patients with moderate-to-severe hypertension (sustained or paroxysmal) coupled with the classic triad of episodes of severe headache, diaphoresis, and palpitations.

Hyperglycemia as a result of a catecholamine effect of insulin suppression and stimulation of hepatic glucose output.

Dx: Initial evaluation is by measurement of 24-hour urine catecholamine and metanephrine excretion or plasma free metanephrine level.

Plasma catecholamine measurement (high false-positive rates) and urine vanillylmandelic acid (requires a special diet prior to collection) should be avoided. Testing should be avoided in the setting of acute illness, as catecholamine production is increased. Patients under marked psychological stress, or with anxiety or panic disorder, may have increased catecholamine production, but measured levels should be less than 2 to 4 times the upper limit of normal.

When the diagnosis of pheochromocytoma is biochemically proven, a dedicated adrenal CT or MRI scan should be obtained to localize the tumor. Intravenous contrast is contraindicated, as it can precipitate hypertensive crisis. If no adrenal abnormality is seen, CT scans of the chest, abdomen, and pelvis should be obtained to look for paragangliomas along the sympathetic chain.

Tx: Surgical resection is the treatment of choice for pheochromocytoma. Patients must receive full α-adrenergic blockade prior to surgery to avoid a hypertensive emergency during the procedure. Phenoxybenzamine is a long-acting irreversible nonselective α-blocker that is classically used for preoperative management, but shorter-acting selective α1-adrenergic antagonists (eg, terazosin, prazosin, or doxazosin) can also be used. If needed, β-blockade can follow α-blockade for additional control of BP (goal of ≤120/80 mm Hg) and heart rate (<100 beats per minute). β-Blockade prior to α-blockade is contraindicated because of the dangers of unopposed α-adrenergic activity.

Question 45

Congenital adrenal hyperplasia (CAH)

Answer 45

Due to 21-hydroxylase deficiency causes elevated androgen precursors (eg, 17-hydroxyprogesterone). Female infants with classic CAH present at birth with ambiguous genitalia. In contrast, women with nonclassic CAH due to partial 21-hydroxylase deficiency develop hyperandrogenism from late childhood to early adulthood. However, symptoms are typically slowly progressive over years. Initial testing is with a basal 17-hydroxyprogesterone level; an ACTH stimulation test may be performed in patients with a moderately elevated basal screening for diagnosis.

Question 46

🥇 Primary Adrenal Insufficency (👨🏿Addison’s Disease )

Answer 46

Etiology

• Autoimmune
• Infections (eg, tuberculosis, HIV, disseminated fungal)
• Hemorrhagic infarction
• Metastatic

Clinical presentation

• Fatigue, weakness, anorexia/weight loss, salt craving
• Gastrointestinal symptoms
• Postural hypotension
• Hyperpigmentation or vitiligo
• Hyponatremia, hyperkalemia
• May lead to acute adrenal crisis (abdominal pain, shock, fever, altered mental status)

Diagnosis

• ACTH, serum cortisol & high-dose (250 µg) ACTH stimulation test
• Primary adrenal insufficiency: Low cortisol, high ACTH
• Secondary/tertiary adrenal insufficiency: Low cortisol, low ACTH

Primary adrenal insufficiency (Addison’s disease) is characterized by decreased cortisol, adrenal sex hormone, and aldosterone secretion. Aldosterone normally acts on the distal renal tubules to increase sodium reabsorption (saves sodium) and secrete potassium and hydrogen ions. If aldosterone is deficient, the kidney inappropriately loses sodium while retaining excessive potassium and hydrogen ions. This results in a normal anion gap and hyperkalemic and hyponatremic metabolic acidosis.

Autoimmune adrenalitis: Autoimmune adrenalitis is responsible for >90% of cases of PAI in developed countries. It is due to autoantibodies against adrenal enzymes that are responsible for corticosteroid synthesis. Autoimmune adrenalitis can occur as an isolated disorder or in association with other autoimmune syndromes (eg, hypothyroidism, vitiligo).

Hx: Unexplained weight loss, anorexia, weakness, nausea, abdominal pain, arthralgias, fatigue, and malaise should be observed in most patients with adrenal insufficiency.

• Orthostatic hypotension and salt craving can be prominent in primary insufficiency due to aldosterone deficiency leading to profound volume depletion.
• Hyperpigmentation 👨🏿 due to cosecretion of melanocyte-stimulating hormone with ACTH (both are derived from proopiomelanocortin), which is increased in response to cortisol deficiency.
• Loss of mineralocorticoid production can cause ^🍌hyperkalemia, _🥜hyponatremia, and hypotension.
• Eosinophilia and hyperplasia of lymphoid tissue (eg, tonsils) are common but nonspecific findings.
• TB is a common cause of chronic primary adrenal insufficiency in endemic areas. Patients typically develop gradual fatigue, weakness, borderline hypotension, and electrolyte abnormalities.

Dx: A cosyntropin (ACTH) stimulation test establishes the diagnosis of adrenal insufficiency.

Low basal serum cortisol level (<5 µg/dL) with suboptimal response (Cortisol and ACTH values are obtained at baseline and at 30 and 60 minutes following administration of cosyntropin. A rise of serum cortisol by ≥18 µg/dL rules out adrenal insufficiency) to cosyntropin; high plasma ACTH level (in primary disease only)

In primary adrenal insufficiency, ACTH is 👆🏽elevated by >100 pg/mL

To distinguish primary from secondary adrenal insufficiency, plasma ACTH and cortisol levels should be measured at 8 AM.

Tx: If acute adrenal crisis is suspected, serum ACTH and cortisol levels should be obtained immediately. While awaiting results, high-dose GC (Dexamethasone; Fludrocortisone) and large-volume intravenous saline should be given. Dexamethasone is the preferred GC therapy because it does not interfere with serum cortisol assays. For less critically ill patients, oral GC should be promptly administered for primary or secondary adrenal insufficiency; delay is potentially life threatening.

Fludrocortisone is required in primary but not secondary insufficiency, but stress dosing is not required; in the acute phase, intravenous saline is required because several days of therapy are necessary for the effects of fludrocortisone to be seen.

Mild stress (eg, fever or gastroenteritis) requires doubling or tripling of the daily GC dose, and severe illness requires hospitalization for high-dose intravenous GC therapy. Oral GC used for daily replacement therapy are prednisone, hydrocortisone, and dexamethasone.

Ddx: Autoimmune adrenalitis, Infection (tuberculosis, mycosis, bacterial, or human immunodeficiency virus-associated), Metastatic cancer, adrenal hemorrhage (acute disease), Medications (etomidate, ketoconazole, mitotane, and metyrapone).

Question 47

🥈Central (Secondary / Pituitary🌱) Adrenal Insufficency

Answer 47

Chronic glucocorticoid therapy

• Most common cause of central/secondary adrenal insufficiency due to suppression of endogenous CRH and ACTH production.
• Patients with >3 weeks of GC therapy will require tapering to allow for recovery of the HPA axis.
• Chronic suppression (>1 year) of the HPA axis by exogenous GC therapy may eventually lead to atrophy of the zonae fasciculata and reticularis, which requires lifelong daily GC replacement therapy.

Hx: Exogenous glucocorticoid therapy (oral, intramuscular, intra-articular, inhaled, or intravenous); hypoglycemia and eosinophilia.

Dx: To distinguish primary from secondary adrenal insufficiency, plasma ACTH and cortisol levels should be measured at 8 AM.

In central adrenal insufficiency, ACTH is low 👇🏽 or inappropriately normal.

A pituitary magnetic resonance imaging (MRI) scan should be obtained in secondary insufficiency, and other pituitary axes, such as thyroid and reproductive function, should be assessed.

Secretion of melanocyte-stimulating hormone is NOT increased so patients do not display ❌ hyperpigmentation. Also, mineralocorticoid production is controlled by the renin-angiotensin system; aldosterone levels are normal and ❌ hyperkalemia is NOT seen with exogenous glucocorticoid use.

Tx: 🌑Hydrocortisone (overreplacement: check for signs or symptoms of Cushing syndrome such as weight gain, hyperglycemia, hypertension, striae, and abnormal fat distribution).(underreplacement: nausea, vomiting, malaise, hypotension, weight loss, hyponatremia, or hypoglycemia).

Physiologic daily dosing

• 15 mg/d orally in 2 divided doses at 8 AM (10 mg) and at 3 PM (5 mg)

Minor stress (such as cold symptoms)

• 30-50 mg/d orally in 2 to 3 doses for 2-3 days

Moderate stress (such as a minor/moderate surgical procedure)

• 45-75 mg/d orally or IV in 3 to 4 divided doses for 2-3 days

Severe stress (such as a major surgical procedure, or sepsis)

• 100-150 mg/d IV in 3 to 4 divided doses for 1 day; taper to physiologic dose over 3-5 days once patient is stable and recovering

Septic shock, severe inflammatory process

• 150-200 mg/d IV in 3 to 4 divided doses; taper as clinically tolerated

Question 48

🌱 PITUITARY

Answer 48

Ddx:

Nonpituitary sellar and parasellar lesions

• Craniopharyngioma
• Hypothalamic disease (sarcoidosis, Langerhans cell histiocytosis, lymphoma)
• Metastatic tumors to pituitary/hypothalamus
• Meningiomas
• Dysgerminomas
• Irradiation

Neurogenic

• Chest wall or spinal cord disease
• Breast stimulation/lesions

Drugs

• Psychotropic agents (butyrophenones and phenothiazines, monoamine oxidase inhibitors, tricyclic antidepressants, fluoxetine, molindone, risperidone, cocaine)
• Antihypertensive agents (verapamil, methyldopa, reserpine)
• Metoclopramide
• (Estrogen in conventionally used doses does not cause hyperprolactinemia.)

Other

• Pregnancy
• Physiologic cause (coitus, nipple stimulation, strenuous exercise, stress)
• Hypothyroidism
• Chronic kidney failure
• Cirrhosis
• Macroprolactinoma
• Idiopathic
• Adrenal insufficiency
• Ectopic secretion

Question 49

Pituitary microadenoma

Answer 49

(<10 mm) associated with galactorrhea and symptoms of low estrogen (eg, amenorrhea, vaginal dryness).

Any mass lesion in the pituitary gland can cause a mild elevation in prolactin due to disruption of the normal inhibitory dopaminergic regulation of prolactin secretion. However, significant elevations in the prolactin level (eg, serum prolactin level >200 ng/mL or repeat level >100 ng/mL) suggest a prolactin-secreting tumor (prolactinoma).

Elevated prolactin levels suppress gonadotropin-releasing hormone, LH, and estradiol, leading to oligo-amenorrhea in premenopausal females. Men and postmenopausal women often have minimal early symptoms and are more likely to seek evaluation when a large tumor (>1 cm, macroadenoma) causes mass-effect symptoms (eg, headache, visual field defects).

Tx: Asymptomatic patients with an incidental finding of a microprolactinoma may be observed over time .

Patients with macroprolactinomas or symptomatic tumors of any size should be treated with dopaminergic agonists (eg, 🦝 cabergoline, 🧹bromocriptine), which can normalize prolactin levels and reduce tumor size.

Patients who fail to respond or who have very large tumors (>3 cm) should be referred for transsphenoidal resection.

Question 50

Empty sella syndrome

Answer 50

Empty sella syndrome is enlargement of the sella turcica from CSF pressure compressing the pituitary gland. It is most common in obese, hypertensive women. There are no focal findings. Some patients have chronic headaches; others are asymptomatic. MRI will distinguish this syndrome from a pituitary tumor. These patients have normal pituitary function, the rim of pituitary tissue being fully functional.

Question 51

🦴 Osteoporosis

Answer 51

The recommended age for osteoporosis screening (age 65 years in average-risk women), her risk factors (family history, low body mass index, and smoking history) are indications for bone mineral density testing.

Dx: Osteoporosis is diagnosed by a DEXA T-score of less than –2.5 OR the presence of fragility fractures; a fragility fracture (fracture sustained in a fall from a standing height) defines osteoporosis regardless of bone mineral density results.

Fracture Risk Assessment Tool (FRAX)

Tx: The National Osteoporosis Foundation (NOF) recommends antiosteoporotic therapy for persons whose risk of major osteoporotic fracture over the next 10 years is 20% or greater or whose risk of hip fracture over the next 10 years is 3% or greater.

Bisphosphonates: Alendronate is approved for both osteoporosis prevention and treatment by the Food and Drug Administration (FDA).

Zoledronic acid (IV bisphosphonate) is preferred for women with postmenopausal osteoporosis who are unable to take oral bisphosphonates (❗gastroesophageal reflux disease) or who desire the convenience of less frequent dosing.

Raloxifene, a selective estrogen receptor modulator, is also approved for osteoporosis prevention by the FDA. However, vasomotor symptoms are highly associated with its use.

Teriparatide, or recombinant human parathyroid hormone (1-34), is an anabolic agent that increases bone density and decreases fracture risk. However, it is considered second-line therapy to bisphosphonates, is expensive, and has been associated with an increased risk of osteosarcoma.

Low bone mass​

Low bone mass is defined as a bone mineral density score that is between 1.0 and 2.5 SD below the young adult mean.

🧪 Dx: Screening guided by history and physical examination findings may include testing for hypogonadism, vitamin D deficiency, primary hyperparathyroidism, calcium malabsorption, and multiple myeloma. Calcium malabsorption may occur in patients with celiac disease and may cause “secondary osteoporosis”.

Tx: Initiation of therapy, such as the bisphosphonate alendronate, can be considered after the evaluation for secondary causes is completed and his fracture risk is assessed.

Osteomalacia

Osteomalacia is a generalized disorder of bone resulting in decreased mineralization of newly formed osteoid at sites of bone turnover.

Although it may be asymptomatic, osteomalacia may present with diffuse bone and joint pain, muscle weakness, and difficulty walking. It most commonly occurs in patients with low vitamin D, hypophosphatemia, hypocalcemia, and increased serum parathyroid hormone and alkaline phosphatase levels.

Paget disease of bone

Paget disease of bone is a focal disorder of bone metabolism characterized by an accelerated rate of bone remodeling that results in overgrowth of bone at a single or multiple sites and impaired integrity of affected bone. Although Paget disease is usually asymptomatic, if symptoms are present they are usually due to overgrowth of the affected bone, either in the bone itself or from bony overgrowth due to fracture or nerve impingement. The serum alkaline phosphatase level is typically elevated, and radiographs show increased bone density in involved areas.

Secondary Causes

Hypogonadism, vitamin D deficiency, primary hyperparathyroidism, calcium malabsorption (celiac disease), and multiple myeloma.

Celiac sprue is relatively common (as high as 1% of the Caucasian population) and often presents with mild symptoms. A tissue transglutaminase or antiendomysial antibody test will provide important diagnostic information.

Question 52

Paget Disease of Bone

Answer 52

Clinical features

• Most patients are asymptomatic
• Bone pain & deformity
  
  • Skull: headache, hearing loss
  • Spine: spinal stenosis, radiculopathy
  • Long bones: bowing, fracture, arthritis of adjacent joints
• Giant cell tumor, osteosarcoma

Pathogenesis

• Osteoclast dysfunction
• Increased bone turnover

Laboratory testing

• Elevated alkaline phosphatase
• Elevated bone turnover markers (eg, PINP, urine hydroxyproline)
• Calcium & phosphorus are usually NORMAL

Imaging

• X-ray: osteolytic or mixed lytic/sclerotic lesions
• Bone scan: focal increase in uptake

Treatment

• Bisphosphonates

Paget disease is characterized by disordered osteoclastic bone resorption of uncertain etiology. Paget disease is the most common bone disorder after osteoporosis, affecting approximately 3% of adults age >40. It is characterized by a focal increase in bone turnover, in which osteoclast dysfunction leads to bone breakdown and a compensatory increase in bone formation. The pelvis, skull, spine, and long bones are most commonly involved. Microscopic findings include increased numbers of abnormal-appearing osteoclasts, with a disorganized “mosaic” pattern of lamellar bone. Early-stage lesions will have a predominance of osteoclast activity, later progressing through a mixed osteoclastic/osteoblastic phase, a predominantly osteoblastic phase, and a residual sclerotic phase.

Most patients with Paget disease are asymptomatic and are identified incidentally by radiographic findings or elevated alkaline phosphatase levels. Symptoms may include skeletal deformities, bone or joint pain, and fractures. Enlarging cranial bones may lead to increased hat size, headaches, and 👂🏽hearing loss due to entrapment of cranial nerve VIII or encroachment on the cochlea. Additional complications include benign giant cell tumors of bone and osteosarcoma. Bone pain, hearing loss, bony deformity, congestive heart failure, hypercalcemia, and repeated fractures are all indications for specific therapy beyond just symptomatic treatment for pain.

Due to the increased bone turnover, serum alkaline phosphatase (bone isoenzyme) is elevated, often >10 times the upper limit of normal. Paget disease is the most common cause of an asymptomatic elevation in alkaline phosphatase in older patients and is often discovered on routine laboratory testing. Urine hydroxyproline is derived almost exclusively from the breakdown of collagen, and levels will be increased in Paget disease as well. Urine calcium may be increased. However, serum calcium and phosphorus levels will usually be normal in the absence of other complicating factors (eg, prolonged immobility, concurrent hyperparathyroidism).

Tx: Bisphosphonates bind to hydroxyapatite crystals to decrease bone turnover; they are now recommended as the treatment of choice for symptomatic Paget disease. Newer bisphosphonates such as alendronate and risedronate have replaced etidronate because they are more potent and do not produce mineralization defects. The recommended dose in Paget disease is higher than the bisphosphonate dose used to treat osteoporosis. Subcutaneous injectable calcitonin is still used in patients who cannot tolerate the GI side effects of bisphosphonates.

Question 53

Osteomalacia

Answer 53

Causes

• Malabsorption
• Intestinal bypass surgery
• Celiac sprue
• Chronic liver disease
• Chronic kidney disease

Symptoms/signs

• May be asymptomatic
• Bone pain & muscle weakness
• Muscle cramps
• Difficulty walking, waddling gait

Diagnosis

• ↑ Alkaline phosphatase, ↑ PTH
• ↓ Serum calcium & phosphorus, ↓ urinary calcium
• ↓ 25 OH-D levels
• X-rays may show thinning of cortex with reduced bone density
• Bilateral & symmetric pseudofractures (looser zones) are characteristic radiologic findings

Osteomalacia is due to defective mineralization of the organic bone matrix. During new bone formation and remodeling, osteoclasts create a cavity at the bone surface that osteoblasts fill with organic matrix (osteoid). Calcium and phosphorus then deposit in the matrix to provide adequate mineralization. As a result, calcium or phosphorus deficiency at the mineralization front will lead to inadequate mineralization of the organic matrix.

Osteomalacia can occur in both children and adults (rickets - defective mineralization of the growth plate - occurs only in children). Osteomalacia is most commonly due to severe vitamin D deficiency, which may be caused by malabsorption, intestinal bypass surgery, celiac sprue, or chronic liver or kidney disease. Osteomalacia may also be caused by renal tubular acidosis (proximal, type 2) and inadequate calcium intake.

Patients can be asymptomatic or present with bone pain, muscle weakness or cramps, and difficulty walking.

Vitamin D deficiency leads to decreased intestinal calcium and phosphorus absorption, resulting in hypocalcemia and hypophosphatemia. Hypocalcemia and low vitamin D levels lead to secondary hyperparathyroidism, which brings the serum calcium levels to normal or near-normal by increasing bone calcium resorption and renal calcium reabsorption. Also, high parathyroid hormone increases urinary phosphate excretion to worsen the hypophosphatemia. As a result, vitamin D deficiency causes more marked hypophosphatemia than hypocalcemia, especially in the early stages. X-ray findings include decreased bone density with thinning of cortex, eventual codfish vertebral bodies (concave shape), and pseudofractures (Looser zones).

Question 54

🥛 Hypercalcemia

Answer 54

Causes of hypercalcemia can be categorized on the basis of parathyroid hormone (PTH) levels as PTH-dependent or PTH-independent:

• PTH-independent hypercalcemia (suppressed PTH) is usually due to malignancy, vitamin D toxicity, or extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in granulomatous diseases (eg, sarcoidosis).
• PTH-dependent hypercalcemia (elevated or inappropriately normal PTH) is usually due to primary hyperparathyroidism (PHPT).

Question 55

Sarcoidosis

Answer 55

A chronic multisystem disorder due to noncaseating granulomatous inflammation. It typically occurs in young adults, is 3-4 times more common in African Americans, and affects more women than men.

Cough, dyspnea, fever, fatigue, and weight loss.

Dx:

CRX with bilateral hilar adenopathy (first manifestation of disease in 50% of patients).

Bronchoscopy with transbronchial biopsy is often performed to obtain tissue diagnosis (looking for noncaseating granulomas). If there is evidence of systemic involvement, more accessible sites such as peripheral lymph nodes or cutaneous lesions can be biopsied.

Cx: Infiltration of noncaseating granulomas leads to surrounding inflammation and can result in conduction defects (complete AV block is most common), restrictive cardiomyopathy (early manifestation), dilated cardiomyopathy (late manifestation), valvular dysfunction, and heart failure. Sudden cardiac death can occur due to complete AV block or ventricular arrhythmia.

Cardiac sarcoidosis should be suspected in any young patient (age <55) with unexplained second- or third-degree heart block or when ECG changes occur in a patient with known or suspected systemic sarcoidosis. Definitive diagnosis can be challenging due to poor sensitivity of endomyocardial biopsy, but a combination of imaging findings, ECG findings, and history often strongly suggests the diagnosis.

Question 56

Humoral hypercalcemia of malignancy

Answer 56

Hypercalcemia of malignancy may be due to local osteolytic hypercalcemia or to humoral hypercalcemia of malignancy, in which a tumor that does not involve the skeleton secretes a circulating factor that activates bone resorption.

Dx: Usually due to secretion of PTH-related protein (PTHRP) and is characterized by severe hypercalcemia (typically >14 mg/dL) and a suppressed PTH level.

Normal or low phosphate (elevated if GFR <35 mL/min/1.73 m2), normal or elevated PTHrP (not needed for diagnosis), normal or elevated alkaline phosphatase, and elevated urine calcium.

Tx: Control of the tumor with chemotherapy.

Question 57

Milk-alkali syndrome

Answer 57

Excessive ingestion of calcium carbonate to treat osteoporosis or dyspepsia can result in hypercalcemia, metabolic alkalosis, and kidney insufficiency. Metabolic alkalosis stimulates the distal tubule to reabsorb calcium, contributing to hypercalcemia.

Hx: Excessive ingestion of calcium-containing antacids may be present.

Dx: Associated with elevated calcium, elevated phosphate, elevated creatinine, normal alkaline phosphatase, elevated bicarbonate, and variable urine calcium. Suppressed PTH

Question 58

◻ 🎀 ◻ Primary Hyperparathyroidism

Answer 58

Etiology

• Parathyroid adenoma (most common), hyperplasia, carcinoma
• Increased risk in MEN types 1 & 2A

Symptoms

• Asymptomatic (most common)
• Mild, nonspecific symptoms (eg, fatigue, constipation)
• Abdominal pain, renal stones, bone pain, neuropsychiatric symptoms

Diagnostic findings

• Hypercalcemia
• Elevated or inappropriately normal PTH
• Elevated 24-hour urinary calcium excretion

Indications for parathyroidectomy

• Age <50
• Symptomatic hypercalcemia
• Complications: Osteoporosis (T-score <−2.5, fragility
• fracture), nephrolithiasis/calcinosis, CKD (GFR <60 mL/min)
• Elevated risk of complications: Calcium >1 mg/dL above normal, urinary calcium excretion >400 mg/day

Excess parathyroid hormone causes hypercalcemia due to increased renal calcium reabsorption, gastrointestinal calcium absorption, and bone resorption.

Hx: Most patients with PHPT present with mild, asymptomatic hypercalcemia, but potential clinical features include nephrolithiasis, osteoporosis, nausea, constipation, and neuropsychiatric symptoms (“stones, bones, abdominal moans, psychic groans”). Serum phosphorus is often normal but can be low in moderate-to-severe PHPT.

The majority (80%) of PHPT cases are due to parathyroid adenoma.

Dx: Urine calcium excretion can be more precisely assessed using the urine calcium/creatinine clearance ratio (UCCR):

UCCR = (Caurine/Caserum)/(Creaturine/Creatserum)

UCCR is usually >0.02 in primary hyperparathyroidism

Question 59

Parathyroid adenoma 👨🏽

Answer 59

???

MEN Type 1

An autosomal dominant condition characterized by the “3 Ps”. PHPT is present in >90% of patients with MEN Type 1. It usually occurs by age 40, and results from multiglandular parathyroid adenomas or parathyroid hyperplasia.

Pituitary adenomas (10%-20%)

• Secretion of prolactin, growth hormone, ACTH (or “nonfunctioning” tumors)
• Mass effects (eg, headache, visual field defects)

Parathyroid adenomas/hyperplasia

• Multiple parathyroid adenomas or parathyroid hyperplasia
• Hypercalcemia (constipation, polyuria, kidney stones, decreased bone density)

Present in >90% of patients with MEN1, usually occurs by age 40, and results from multiglandular parathyroid adenomas or parathyroid hyperplasia.

Pancreatic/gastrointestinal neuroendocrine tumors (60%-70%)

• Gastrinoma - recurrent peptic ulcers
• Insulinoma - hypoglycemia
• VIPoma - secretory diarrhea, hypokalemia, hypochlorhydria
• Glucagonoma - weight loss, necrolytic migratory erythema, hyperglycemia

Burning upper abdominal pain that is only partially responsive to ranitidine and antacids and associated with occult gastrointestinal bleeding is concerning for Zollinger-Ellison syndrome, characterized by severe and refractory peptic ulcer disease due to gastrin-producing tumors (gastrinomas).

Question 60

Familial hypocalciuric hypercalcemia

Answer 60

FHH is a benign autosomal dominant disorder caused by a mutation of the calcium-sensing receptor (CaSR).

• In FHH, higher calcium concentrations are required to suppress PTH release resulting in an elevated PTH level.
• Concurrently, the defective CaSR leads to increased reabsorption of calcium in renal tubules.
• Very low urinary calcium levels (typically <100 mg/24 hr).

Urine calcium excretion can be more precisely assessed using the urine calcium/creatinine clearance ratio (UCCR):

• UCCR = (Caurine/Caserum)/(Creaturine/Creatserum)
• UCCR is usually <0.01 in FHH

Question 61

Lithium

Answer 61

🔘 Lithium [first line]

Indications

• Acute mania, bipolar maintenance

❌ Contraindications

• Chronic kidney disease
• Heart disease
• Hyponatremia or diuretic use

Baseline studies

• Blood urea nitrogen (BUN)[yearly], creatinine, calcium, urinalysis
• TSH (Thyroid function tests) q6 months; T₃RU (yearly)
• ECG in patients with coronary risk factors

☠ Adverse effects

Acute

• Tremor, ataxia, weakness
• Polyuria, polydipsia
• GI: Nausea, vomiting, diarrhea 💩
• Cognitive impairment (confusion, agitation)

In addition to hyperparathyroidism, potential long-term side effects include nephrogenic diabetes insipidus, chronic kidney disease, and thyroid dysfunction (most often hypothyroidism). Furthermore, first-trimester lithium exposure is associated with teratogenic effects (eg, Ebstein anomaly). Current guidelines recommend a baseline basic metabolic panel (including blood urea nitrogen and creatinine), calcium, urinalysis, pregnancy test in women of childbearing age, and thyroid function tests before lithium is prescribed.

Chronic

• Nephrogenic diabetes insipidus: lithium antagonizes the effects of ADH in the distal kidney. The primary treatment is discontinuation of treatment or addition of 🦵 HCTZ (thiazide diuretic). Thiazides, in addition to effects on Na in the proximal kidney, increase expression of distal aquaporins, thus reversing the effects of lithium. Because HCTZ decreases NA reabsorption, it ultimately leads to increased lithium absorption (a positive ion) and can be associated with lithium toxicity. Thus lithium coadministered with HCTZ must be decreased in dose.
• Chronic kidney disease
• Thyroid dysfunction: Approximately 25% of patients treated with lithium will develop hypothyroidism (fatigue, constipation, myalgias, and bradycardia). A much smaller percentage will experience hyperthyroidism. Tx: Patients who develop hypothyroidism are generally managed symptomatically with addition of T4 (eg, levothyroxine) rather than discontinuation of lithium.
• Hyperparathyroidism

Weight gain, metallic taste, acne, and polyuria,

Drug interactions

• 🦵 Thiazide diuretics can cause a decrease in the renal clearance of lithium and lead to lithium toxicity. The risk of lithium toxicity is higher in patients with dehydration from any cause (eg, vomiting, diarrhea, fever, diuresis) and in elderly patients due to a lower glomerular filtration rate and reduced volume of distribution.
• NSAIDs (not aspirin)
• ACE inhibitors
• Tetracyclines, metronidazole

ECG is also recommended in patients with coronary artery disease risk factors (eg, diabetes, hypertension, smoking) as lithium may cause dysrhythmias in these patients. These studies should also be reassessed periodically after starting the medication.

The lithium level considered effective for acute mania is between 1 and 1.5 meq/L. Since the half-life of lithium is about 20 hours, equilibrium is reached after 5 to 7 days of regular intake. Mild lithium toxicity (serum levels below 3 meq/L with symptoms of tremor, mild confusion, and gastrointestinal distress); severe toxicity requires dialysis

💀Toxicity

Neurologic (eg, altered mental status, seizure, fasciculations, tremor) and gastrointestinal (eg, vomiting, diarrhea) signs are common in cases of acute intoxication. Tx: Although mild overdoses can frequently be managed supportively with hydration and monitoring, hemodialysis is the treatment of choice for patients with lithium levels >2.5 mEq/L and prominent signs of toxicity. Patients with levels >4 mEq/L and creatinine >2.0 mg/dL should generally be prescribed dialysis regardless of symptoms.

Because lithium is renally excreted, common precipitants of toxicity include medications that affect the excretion rate (eg, nonsteroidal anti-inflammatory drugs, ACE inhibitors, angiotensin receptor blockers) as well as dehydration by any cause (eg, diuretics, gastrointestinal illness). Intentional overdose should also always be on the differential.

Carbamazepine: can cause 🦴 aplastic anemia, agranulocytosis, thrombocytopenia, and leucopenia. It also has a risk of hepatotoxicity. Because of these possibly side effects, a CBC, platelet count, reticulocyte count, serum electrolytes, SGOT, SGPT, LDH, and a pregnancy test (in appropriate patients, since carbamazepine raises the risk a baby will be born with spina bifida) should all be drawn before treatment with carbamazepine is instituted. SGOT, SGPT, and LDP should be drawn every month for the first 2 months, and thereafter, every 3 months.

Sleep deprivation has an antidepressant effect in depressed patients and may trigger a manic episode in bipolar patients.

The use of a long-acting benzodiazepine will allow patients to return to a normal sleep pattern and generally will abort manic episodes.

❌ Antidepressant monotherapy should generally be avoided in patients with bipolar I disorder due to the risk of precipitating mania.

Medications commonly used in the treatment of acute bipolar depression include the second-generation antipsychotics quetiapine and lurasidone and the anticonvulsant lamotrigine. Lithium, valproate, and the COMBINATION of olanzapine and fluoxetine have also demonstrated efficacy. [If necessary, antidepressants should be used in combination with mood stabilizers (eg, lithium, valproate, second-generation antipsychotics) as these appear to decrease the risk of an antidepressant-induced switch from depression to mania.] Other risks of using antidepressants in patients with bipolar depression include the development of rapid cycling (≥4 mood episodes/year) and increased mood cycle frequency.

Question 62

🥛 HypOcalcemia

Question 63

◻ 🎀 ◻ Secondary Hyperparathyroidism

Answer 63

Secondary hyperparathyroidism is characterized by increased secretion of PTH in response to hypocalcemia.

Question 64

Steatorrhea

Answer 64

Prevents usual fat emulsification and disrupts chylomicron-mediated absorption of vitamin D in the intestine, resulting in vitamin D deficiency.

Because vitamin D mediates intestinal calcium and phosphorus absorption, patients develop hypOcalcemia and decreased phosphorus levels.

The hypocalcemia leads to secondary hyperparathyroidism with elevated parathyroid hormone levels.

Vitamin D deficiency can lead to osteomalacia with findings that include bone pain or tenderness, muscle weakness or cramps, gait abnormalities, and increased fracture risk. However, some patients can be asymptomatic.

Question 65

CKD

Answer 65

Secondary hyperparathyroidism is a common finding in chronic kidney disease due to inadequate phosphate excretion and low 1,25-hydroxyvitamin D levels.

Serum phosphorus will be high and calcium will be low or low-normal.

Long-standing secondary hyperparathyroidism can lead to autonomous PTH secretion (tertiary hyperparathyroidism), but this is typically seen in patients with end-stage renal disease

Question 66

◽🎀◽ Hypoparathyroidism

Answer 66

The causes of primary hypoparathyroidism include:

1. Post-surgical (most common cause)
2. Autoimmune
3. Congenital absence or maldevelopment of the parathyroid glands (eg, DiGeorge syndrome)
4. Defective calcium-sensing receptor on the parathyroid glands
5. Non-autoimmune destruction of the parathyroid gland due to infiltrative diseases such as hemochromatosis, Wilson disease, and neck irradiation

Post-surgical hypoparathyroidism can occur during thyroidectomy and sub-total parathyroidectomy (ie, removal of 3½ parathyroid glands for parathyroid hyperplasia).

Autoimmune hypoparathyroidism is the most common nonsurgical syndrome.

Hx:

Hypoparathyroidism causes hypocalcemia (normally 9-10.5 mg/dL) but is NOT associated with vitamin D deficiency or osteoporosis.

Symptoms are primarily neuromuscular, such as paresthesias and muscle cramps.

Tx:

🥛 Oral calcium (carbonate or citrate) supplementation. Intravenous calcium more rapidly increases the serum calcium level and may be indicated in patients with very low (<7.5 mg/dL) calcium levels or more significant clinical findings associated with the hypocalcemia, such as severe musculoskeletal weakness, tetany, or electrocardiographic conduction abnormalities.

A recombinant form of parathyroid hormone (teriparatide) is available, although its primary use is in the treatment of advanced osteoporosis in selected patients. Although teriparatide holds promise as a potential therapy for chronic hypoparathyroidism, its safety and long-term effectiveness for this indication have not been established, and it does not have Food and Drug Administration approval for treatment of acute hypoparathyroidism.

Question 67

DiGeorge Syndrome

Answer 67

DiGeorge syndrome (DGS), or velocardiofacial syndrome, is a disorder caused by a chromosome 22q11.2 microdeletion resulting in abnormal development of the pharyngeal pouch system and subsequent abnormalities of the face, neck, and mediastinum.

The clinical presentation varies but includes the triad of conotruncal anomalies, hypocalcemia, and thymic hypoplasia. Cleft palate and facial dysmorphisms (eg, low-set ears) may also be present, as in this patient.

Once DGS is suspected, echocardiography and serum calcium levels should be obtained. Truncus arteriosus is one of the conotruncal anomalies strongly associated with DGS and typically presents with cyanosis and hypoxemia refractory to oxygen administration; other common conditions include tetralogy of Fallot and interrupted aortic arch.

Hypocalcemia results from hypoplasia of the parathyroid glands and is likely present in this neonate with tremulousness. Neonates are at high risk for life-threatening hypocalcemic tetany, seizures, and arrhythmias.

Depending on the degree of thymic hypoplasia, patients can have T-cell lymphopenia and increased risk of viral and fungal infections.

Humoral immunodeficiency can also result from defective T-cell help in B-cell activation for antibody production, increasing susceptibility to sinopulmonary bacterial infections as well.

Question 68

♨♨♨ SECONDARY HYPERTENSION

Answer 68

Patients initially diagnosed with hypertension should have a detailed history and physical examination. In addition, the following basic testing should be performed:

Urinalysis for occult hematuria and urine protein/creatinine ratio

Chemistry panel

Lipid profile (risk stratification for coronary artery disease)

Baseline electrocardiogram (to evaluate for coronary artery disease or left ventricular hypertrophy).

Question 69

Drug-induced hypertension

Answer 69

Possible causes include NSAIDs, amphetamines, cocaine, sympathomimetic agents (eg, decongestants, dietary supplements), oral contraceptives, antidepressants, bromocriptine, erythropoietin, and glucocorticoids.

Question 70

Chronic kidney disease

Answer 70

Late manifestations of kidney failure include elevated BUN, creatinine, potassium, and phosphate levels; low calcium level; and anemia. Most patients present at an earlier stage, with minimal signs and symptoms.

Question 71

Renovascular disease (atherosclerotic and fibromuscular [FMD])[Renal artery stenosis]

Answer 71

FMD most commonly affects women age 15-50. It is a noninflammatory and nonatherosclerotic condition caused by abnormal cell development in the arterial wall that can lead to vessel stenosis, aneurysm, or dissection. FMD can involve any artery but most commonly involves the renal, carotid, and vertebral arteries.

Patients with renal artery involvement usually develop hypertension. Involvement of cerebrovascular arteries (eg, carotid, vertebral) can lead to nonspecific symptoms (eg, headache, pulsatile tinnitus, dizziness) or symptoms of brain ischemia (eg, transient ischemic attack, stroke, amaurosis fugax). FMD can also involve the iliac, subclavian, and visceral arteries.

Dx: Diagnosis is usually confirmed with noninvasive imaging (computed tomography (digital subtraction) angiography of the abdomen or duplex ultrasound). Patients with inconclusive noninvasive tests require catheter-based digital subtraction arteriography for diagnosis. FMD decreases perfusion to the kidneys, which increases both renin and aldosterone levels (secondary hyperaldosteronism). The aldosterone concentration to renin activity ratio is ~10 (<20).

Digital subtraction angiography (gold standard)[“string of beads”]

ACE inhibitor renal scan

Renal magnetic resonance angiography

Tx: Renal revascularization is indicated for most patients with fibromuscular dysplasia, but benefit is less clear with atherosclerotic stenosis.

Percutaneous transluminal kidney angioplasty is indicated for patients with renovascular hypertension secondary to fibromuscular dysplasia, a nonatherosclerotic, noninflammatory renovascular disease.

Question 72

Primary hyperaldosteronism

Answer 72

Hx: Difficult-to-control or worsening hypertension despite multiple antihypertensive agents; hypertension at a young age. Characterized by muscle cramping, nocturia, thirst, hypokalemia, and hypernatremia.

Dx: Spontaneous hypokalemia, severe hypokalemia after institution of low-dose diuretic therapy. Elevated aldosterone and suppressed renin level, a midmorning ambulatory plasma aldosterone concentration (PAC)/PRA ratio > 20 to 30. A high ratio of greater than 30 strongly suggests aldosterone oversecretion.

Despite the increase in sodium absorption, hypernatremia and pedal edema are rarely observed in due to the phenomenon of aldosterone escape. After a few days (usually when patients gain ~3 kg in weight), the hypernatremia and hypervolemia are largely corrected during aldosterone escape. The high aldosterone levels lead to increased intravascular volume (hypervolemia) and therefore cause increased renal blood flow (with resulting pressure natriuresis)[ANP] and augmented release of atrial natriuretic peptide. This ultimately results in increased sodium excretion by the renal tubules, which limits net sodium retention and prevents the development of overt volume overload and significant hypernatremia. Clinical manifestations can include episodic weakness, paresthesias, and transient paralysis due to hypokalemia.

Asses for serum aldosterone suppression after dietary or intravenous sodium loading.

Adrenal CT scan: Bilateral adrenal hyperplasia (also termed idiopathic primary hyperaldosteronism) is the most common cause of primary hyperaldosteronism, followed by unilateral aldosteronoma (Conn syndrome), and more rarely, unilateral hyperplasia or adrenal carcinoma.

Tx: Adrenalectomy is the treatment of choice for aldosteronoma.

Rx: Spironolactone is the treatment of choice for idiopathic hyperaldosteronism, bilateral adrenal hyperplasia, and nonsurgical candidates with aldosteronoma

Question 73

Pheochromocytoma

Answer 73

Pheochromocytomas are paraganglioma tumors that arise in the chromaffin cells of the adrenal medulla that accounts for a small number of cases of secondary hypertension (0.1%-0.6%). Ten percent of pheochromocytomas are extra-adrenal, 10% are malignant, 10% recur, and 10% are asymptomatic. The tumors can produce, store, and secrete catecholamines (norepinephrine, epinephrine, and/or dopamine); most produce norepinephrine.

Hx: Hyperadrenergic cyclic spells of hypertension, diaphoresis, palpitations, or headache, familial predisposing syndrome (neurofibromatosis type 1, MEN2, succinate dehydrogenase subunit B mutation), previous vasopressor response to anesthesia or angiography, incidentally discovered adrenal mass, hypertension at a young age (<20 years), drug-resistant hypertension. Other symptoms include anxiety, tremor, and pallor. Chronic complications of excess catecholamine release include cardiac arrhythmias, both dilated and hypertrophic cardiomyopathy, and accelerated atherosclerosis related to hypertension.

Characterized by sweating, heart racing, pounding headache, pallor, tachycardia.

Hypertension is present in more than 90% of patients with pheochromocytoma: more than 50% of these patients have sustained elevations in blood pressure; 30% to 40% have episodic elevations; and up to 10% have no hypertension. Lability of blood pressure is due to episodic catecholamine release, volume depletion, and adrenergic receptor desensitization caused by chronic stimulation.

Dx: Measurement of 24-hour urine catecholamine and metanephrine excretion is used to screen when pretest probability is low. Plasma free metanephrine levels are more sensitive and best used when pretest probability is high (if positive, the diagnosis should be confirmed with 24-hour urine studies). Testing should be avoided in the setting of acute illness, as catecholamine production is increased. Patients under marked psychological stress, or with anxiety or panic disorder, may have increased catecholamine production, but measured levels should be less than 2 to 4 times the upper limit of normal.

Non-contrast Adrenal CT or MRI for tumor localization. If no adrenal abnormality is seen, CT scans of the chest, abdomen, and pelvis should be obtained to look for paragangliomas along the sympathetic chain.

Tx: Surgical resection; full α-adrenergic blockade (Phenoxybenzamine, terazosin, prazosin, or doxazosin) prior to surgery to avoid a hypertensive emergency during the procedure.

Question 74

Cushing syndrome

Answer 74

Hx: Weight gain, history of recurrent or chronic infections (especially candidal), worsening diabetic control, change in menses, or fractures; feminization, virilization, an abdominal mass (adrenal tumor), or visual field losses (pituitary tumor).

Px: Abnormal fat distribution (not just the presence of adipose tissue), particularly in the supraclavicular and temporal areas, proximal muscle weakness, or wide (>1 cm) purple striae.

Dx: 24-hour urine free cortisol measurement (>3 times normal), overnight 1-mg dexamethasone suppression test (failure to suppress cortisol), or nighttime salivary cortisol level. Typically, 2 to 3 of these tests are performed to confirm the diagnosis; metabollic alkalosis.

Basal ACTH levels <6 pg/mL are found in adrenal forms of Cushing syndrome, while levels >6 pg/mL occur in ACTH-dependent disease. An adrenal computed tomography (CT) or MRI scan should be obtained to localize lesions in patients with suppressed ACTH values. In patients with nonsuppressed ACTH levels, a pituitary MRI scan should be obtained.

Tx: Surgical resection of an identified tumor (adrenal, pituitary, or ectopic) is the optimal therapy for Cushing syndrome. Pituitary radiation (“gamma knife”) therapy can be used for patients with persistent or recurrent Cushing disease after transsphenoidal surgery or for those in whom pituitary surgery is contraindicated.

Rx: Drugs are used adjuvantly in patients undergoing surgery and as sole therapy for those with occult ectopic ACTH secretion or metastatic adrenal cancer to reduce cortisol production. Ketoconazole, mitotane, metyrapone, and aminoglutethimide reduce endogenous cortisol production and reverse most signs and symptoms of Cushing syndrome.

Question 75

Thyroid disease

Answer 75

Either hyper- or hypothyroidism may increase blood pressure. Hyperthyroidism is characterized by sweating, tachycardia, weight loss, tremor, and hyperreflexia. Hypothyroidism is characterized by cold intolerance, weight gain, goiter, and slowed reflexes.

Question 76

Obstructive sleep apnea

Answer 76

Characterized by daytime sleepiness, snoring, nonrestorative sleep, gasping or choking at night, witnessed apnea, morning headaches, obesity, large neck circumference, and crowded oropharyngeal airway.

Dx: Diagnosis is established with polysomnography.

Tx: Treatment with positive airway pressure may decrease blood pressure modestly in some patients.

Question 77

Coarctation of the Aorta

Answer 77

Fairly common cause in children.

Hx: Headache, cold feet, leg pain, reduced or absent femoral pulse, delay in femoral compared with radial pulse, murmur (continuous systolic and diastolic) heard between the scapulae, and three sign on chest radiography. More than 50% of people with coarctation also have bicuspid aortic valve.

Dx:

ECG will likely show left ventricular hypertrophy

CRX will show rib notching.

Tx: Correction of the defect should be considered if the gradient is greater than 20 mm Hg, not based on level of blood pressure. Oftentimes, even after surgical correction, patients continue to be hypertensive for years, based on permanent changes in the rennin-angiotensin system.

Question 78

*Hypertension (primary)

Answer 78

2 Combination ACEIs and thiazide diuretic therapy reduces recurrent stroke rates.

Malignant hypertension is usually seen in patients with long-standing and uncontrolled hypertension. It is associated with retinal hemorrhages, exudates, and/or papilledema.

Hypertensive emergency is defined as markedly elevated BP (≥180/120 mm Hg) combined with symptoms or signs of end-organ damage, such as encephalopathy, papilledema, retinal hemorrhages or exudates, stroke, myocardial ischemia or infarction, aortic dissection, pulmonary edema, or acute kidney injury.

Hypertensive urgency is a severe elevation in BP without acute end-organ damage.

Hypertensive encephalopathy is associated with cerebral edema due to breakthrough vasodilation from failure of autoregulation. Patients usually develop insidious onset of headache, nausea, and vomiting followed by non-localizing neurologic symptoms (eg, restlessness, confusion, seizures/coma if untreated). Patients also can develop subarachnoid or intracerebral hemorrhage.

Dx: Obtain the following studies in all patients: hematocrit, glucose, creatinine, electrolytes, urinalysis, fasting lipid profile, and electrocardiography. Blood or protein in the urine may indicate kidney damage or suggest secondary hypertension.

An electrocardiogram showing left ventricular hypertrophy and/or signs of previous infarction (Q waves) is evidence of cardiovascular damage. Although echocardiography is more sensitive in diagnosing ventricular hypertrophy, it is not routinely recommended in all patients with a new diagnosis of hypertension.

Tx: Weight reduction is most beneficial, and systolic blood pressure can fall from up to 20 mm Hg for each 10 lb of weight lost.

Dietary recommendations to lower BP consist of consuming a diet that emphasizes the intake of fruits, vegetables, and whole grains; includes poultry, fish, legumes, nuts, nontropical vegetable oils, and low-fat dairy products; and restricts the consumption of red meat, sweets, and sugar-sweetened beverages.

DASH (Dietary Approaches to Stop Hypertension) diet can help to achieve these goals.

Dietary sodium reduction: Sodium should be restricted to <2400 mg/day (<1500 mg/day results in greater reductions) or by at least 1000 mg/day. [can lower blood pressure between 8 and 14 mm Hg]

Three to four sessions averaging 40 minutes in duration per week of moderate to vigorous aerobic physical activity may also lower BP. [Less than 10 mmHg]

Rx: In the general adult population <60 years of age, pharmacologic treatment is recommended when the systolic BP is ≥140 mm Hg or the diastolic BP is ≥90 mm Hg. In patients ≥60 years of age, therapy is recommended if the systolic BP is ≥150 mm Hg or the diastolic BP is ≥90 mm Hg. Typically, a single agent decreases systolic BP by 12 to 15 mm Hg and diastolic BP by 8 to 10 mm Hg.

In the general non-African American population, thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) may all be considered for initial treatment of hypertension, and all reduce the complications of hypertension.

For African Americans, initial therapy should be a thiazide diuretic or CCB, including those with diabetes.

For all patients (regardless of race or the presence or absence of diabetes) >18 years of age with chronic kidney disease (including those with and those without proteinuria), initial therapy should be an ACEI or ARB because these agents are renoprotective and improve renal outcomes.

In blacks with chronic kidney disease but without proteinuria, the initial agent can be a CCB, thiazide diuretic, ACEI, or ARB. Diuretics may equalize the response of black patients to ACEIs and ARBs. Loop diuretics are preferred for patients with chronic kidney disease and a serum creatinine level >1.5 mg/dL (132.6 µmol/L) or a glomerular filtration rate <30-50 mL/min/1.73 m². Thiazide diuretics are much more likely than loop diuretics to cause significant hyponatremia, particularly in elderly women.

In patients with hypertension and coronary artery disease, β-blockers are the drugs of choice because they decrease cardiovascular mortality.

The presence of asthma or chronic bronchitis may limit the use of β-blockers.

#1 ACEIs are preferred for use in patients with asymptomatic ventricular dysfunction and symptomatic heart failure because they decrease cardiovascular mortality.

ACEIs and ARBs reduce albuminuria and the progression of chronic kidney disease, including diabetic nephropathy.

ACEIs produce greater reductions in cardiac morbidity and mortality compared with calcium channel blockers. An increase of up to 33% in serum creatinine is acceptable and not a reason to discontinue ACEI therapy; however, hyperkalemia may limit the use of ACEIs.

Parenteral drugs are usually not necessary in hypertensive urgency, unless symptoms or progressive end-organ damage is present. Initial treatment is with one or more rapid-onset oral anti-hypertensive drugs (such as clonidine or a short-acting ACEI such as captopril) followed by a longer-acting formulation once BP is <180/110 mm Hg. Clonidine may be given hourly until the desired BP is achieved, although care must be taken to not excessively lower the BP. BP should be rechecked within 48 hours. Avoid short-acting calcium channel blockers in patients with ischemic heart disease (such as nifedipine), because reflex adrenergic stimulation and tachycardia may lead to myocardial ischemia.

Resistant hypertension is BP that is not at target level despite maximal doses of three antihypertensive agents, one being a diuretic. Important causes include medication nonadherence, inadequate therapy, excessive alcohol consumption, and other drugs (eg, NSAIDs, sympathomimetic agents).

A patient with resistant hypertension and systolic heart failure should begin taking a newer-generation dihydropyridine calcium channel blocker, such as amlodipine, to improve control of blood pressure (amlodipine and felodipine to have little or no negative inotropic effect (nodal) and a neutral effect on morbidity and mortality rates). However, because they do not decrease morbidity or mortality rates, calcium channel blockers are not first-line treatment for systolic heart failure. Use of calcium channel blockers in systolic heart failure is generally reserved for treatment of conditions such as hypertension or angina that are not optimally managed with maximal doses of evidence-based medications such as ACE inhibitors and β-blockers. Many calcium channel blockers are relatively contraindicated in patients with systolic heart failure because of an associated increased risk of exacerbation of heart failure. Older-generation calcium channel blockers, such as diltiazem, nifedipine, and verapamil, may precipitate exacerbation of heart failure because of their negative inotropic effects.

Question 79

White coat HTN

Answer 79

Ambulatory blood pressure monitoring is indicated for patients with suspected white coat hypertension, to monitor patients with difficult-to-control blood pressure or those with significant symptoms such as hypotension on therapy, or if autonomic dysfunction is suspected.

Question 80

Pre HTN

Answer 80

Although this is not considered a mild form of hypertension, it is a category used to define persons considered at increased risk for the development of true hypertension. Increasing age and family history are also associated with an increased risk of eventually developing hypertension requiring treatment. The patient should be advised to make appropriate lifestyle changes if indicated, such as weight loss (if overweight), increase his exercise level, and control his dietary intake of cholesterol and saturated fats. His blood pressure should then be rechecked in 1 year.

Question 81

MODY

Answer 81

Maturity-onset diabetes of young is the opposite of LADA, that is, that is, a condition resembling type 2 diabetes (ie, often associated with obesity and a positive family history) yet occurring before the age of 20. T his patient’s autoantibodies, thin body habitus, and unresponsiveness to oral hypoglycemic would not go with MODY.

Question 82

Kleinfelters Syndrome

Answer 82

XXY; Pituitary function in Klinefelter syndrome is normal, so gonadotropin levels are elevated in response to underproduction of testosterone.

Question 83

Telogen effluvium

Answer 83

Clinical findings

• Acute, diffuse, noninflammatory hair loss
• Scalp & hair fibers appear normal
• Hair shafts easily pulled out (hair pull test)

Triggers

• Severe illness, fever, surgery
• Pregnancy, childbirth
• Emotional distress
• Endocrine & nutritional disorders

Management

• Address underlying cause
• Reassurance (self-limited disorder)

Telogen effluvium(TE), one of the most common causes of hair loss in adults. Hair follicles pass through 3 phases: growth phase (anagen; 90% of follicles), transformative phase (catagen; <1%), and rest/shedding phase (telogen; 10%). In TE, follicles undergo a widespread shift into the rest/shedding phase, with cessation of growth and subsequent shedding. It is often triggered by a stressful event, such as weight loss, pregnancy, major illness or surgery, or psychiatric trauma.

Patients with TE have widespread thinning of hair but the scalp and hair shafts appear normal. In the hair pull test, small tracts of hair (50-60 fibers) are pulled firmly; extraction of >10%-15% of fibers is abnormal and suggests TE. It is a self-limited disorder but may take up to a year to resolve completely.

Question 84

Lithium