✅ Endocrine Flashcards

Question

Subacute granulomatous thyroiditis

Answer 1

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

Answer 2

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

Answer 3

**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.

Answer 4

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.

Answer 5

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.

Answer 6

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], Lis**_pro_**** 🏌🏽‍♂️**(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)** **🐢 ❕**_L_**on**_g_**: [1 to 2 hours]D[24 hours]** **"Don't Go"** ****_L_**eve**_mir_**🔍 (Dete**_mir_**🔍)[12-16], **_L_**antus (❕_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.

Answer 7

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.

Answer 8

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 t**otal 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.

Answer 9

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.

Answer 10

**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**

Answer 11

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.

Answer 12

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.

Answer 13

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.

Answer 14

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**

Answer 15

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.

Answer 16

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.

Answer 17

**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.

Answer 18

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.

Answer 19

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.

Answer 20

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.

Answer 21

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).

Answer 22

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

Answer 23

**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

Answer 24

(\<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.**

Answer 25

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.

Answer 26

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.

Answer 27

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.

Answer 28

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).

Answer 29

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).**

Answer 30

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.

Answer 31

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.

Answer 32

**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**

Answer 33

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

Answer 34

??? **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. ****_P_**ituitary adenomas** (10%-20%) * Secretion of prolactin, growth hormone, ACTH (or “nonfunctioning” tumors) * Mass effects (eg, headache, visual field defects) ****_P_**arathyroid 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. ****_P_**ancreatic**/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).**

Answer 35

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

Answer 36

**🔘 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. **C**arbamazepine: 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.

Answer 37

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

Answer 38

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.

Answer 39

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

Answer 40

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.

Answer 41

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.

Answer 42

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).

Answer 43

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

Answer 44

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.

Answer 45

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.

Answer 46

**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

Answer 47

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.

Answer 48

**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.

Answer 49

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.

Answer 50

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.

Answer 51

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.

Answer 52

**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. #2 Combination **ACEIs** and **_thiazide_** diuretic therapy reduces **recurrent stroke** rates. #3 Compared with β-blockers, **ARBs** may be specifically beneficial in patients with **left ventricular hypertrophy.** **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.

Answer 53

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.

Answer 54

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**.

Answer 55

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.

Answer 56

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

Answer 57

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.