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Acromegaly
- Clinical Features:
- coarse facial features, arthralgias, uncontrolled hypertension, enlargement of the digits·, carpal tunnel syndrome.
- This condition is caused by excessive secretion of growth hormone (GH), usually due to a pituitary somatotroph adenoma.
- Other common features include malocclusion of the jaw, hyperhidrosis, heart failure, macroglossia, and local mass-effect symptoms (eg, headache, visual field defects).
- GH stimulates hepatic insulin-like growth factor 1 (IGF-1) secretion, which is responsible for most of the clinical manifestations of acromegaly. IGF-1 levels in acromegaly are consistently elevated throughout the day.
- In contrast, GH levels can fluctuate widely and cannot be used alone to diagnose acromegaly.
- As a result, IGF-1 is the preferred initial test.
- Patients with elevated IGF-1 should undergo confirmatory testing with an oral glucose suppression test
- Once acromegaly is confirmed with a glucose suppression test, patients should have an MRI of the brain to identify a pituitary mass.
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Clinical Features Of Acromegaly
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Effect Of Excess growth Hormone on Heart
- Acromegaly causes concentric myocardial hypertrophy leading to diastolic dysfunction, along with left ventricular dilation and global hypokinesis.
- This cardiomyopathy is worsened by concurrent hypertension, obstructive sleep apnea , and valvular heart disease, which are common in acromegaly.
- Complications include heart failure (eg, dyspnea, crackles at bases) and arrhythmias.
- Cardiovascular disease is the leading cause of death in patients with acromegaly, but normalization of growth hormone levels following successful treatment markedly reduces cardiovascular mortality.
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Hypertrophic cardiomyopathy
- a congenital cardiomyopathy that should be distinguished from myocardial hypertrophy due to other cardiovascular diseases (eg, hypertensive, valvular, ischemic) - is characterized by asymmetric thickening of the interventricular septum, leading to left ventricular outflow tract obstruction, diastolic dysfunction, and mitral regurgitation.
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Acute adrenal insufficiency (adrenal crisis)
- Etiology:
- • Adrenal hemormage or infarction
- • Triggered by Acute illness/injury/surgery in patient with chronic adrenal insufficiency or suppression of the hypothalamus-pituitary-adrenal (HPA) axis due to chronic glucocorticoid use
- Clinical features:
- • Hypotension/shock
- • Nausea, vomiting, abdominal pain
- • Weakness
- • Fever, hyponatremia and hyperkalemia due to concurrent mineralocorticoid insufficiency
- Treatment:
- • Hydrocortisone or dexamethasone
- • High-flow intravenous fluids should be started emperically without waiting for lab results.
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HPA Axis Suppression after long term Glucocorticoid Therapy
- Patients on long-term glucocorticoid therapy who have Cushingoid features (eg, central obesity, moon facies) are at very high risk of adrenal crisis.
- However, HPA suppression can be seen in as little as 3 weeks in patients taking prednisone more than 20 mg/day or equivalent.
- These patients may not respond appropriately to acute stressors and should be given higher doses ("stress doses") of glucocorticoids during the acute condition.
- Low-dose glucocorticoids (less than 5 mg/day) have minimal risk and usually do not require stress dosing. Intermediate doses (5-20 mg/day) can cause HPA suppression and require preoperative evaluation with an early-morning cortisol level to determine risk.
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Primary vs Central Adrenal Insufficiency
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Primary AI
- Have loss of glucocorticoid, mineralocorticoid, and adrenal androgen secretion.
- Patients may develop significant hypotension, hyperkalemia, and hyperchloremic acidosis.
- Primary AI is also frequently associated with hyperpigmentation due to increased pituitary secretion of ACTH and melanocyte-stimulating hormone.
- Autoimmune adrenalitis ( more than 90% ) is the most common etiology and it is due to autoantibodies against adrenal enzymes that are responsible for corticosteroid synthesis and involves both humoral and cell-mediated immune destruction of the adrenal cortex.
- Autoimmune adrenalitis can occur as an isolated disorder or in association with other autoimmune syndromes (eg, hypothyroidism, Pernicious Anemia, vitiligo).
- Eosinophilia and hyperplasia of lymphoid tissue (eg, tonsils) are common but nonspecific findings
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Secondary AI
- They have only glucocorticoid and adrenal androgen deficiency with preservation of mineralocorticoid production (regulated primarily by the renin-angiotensin system, not the pituitary).
- Therefore, hyperkalemia, significant hypotension, and hyperchloremic acidosis are not seen.
- Lymphocytic hypophysitis (lymphocytic infiltration of the pituitary gland) and Sheehan syndrome (pituitary infarction due to hemorrhage/hypotension during labor) are common causes of postpartum secondary AI.
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Chronic Primary Adrenal Insufficiency
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Evaluation of Adrenal Insufficiency
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Evaluation of adrenal Insufficiency
- The initial evaluation should include an 8 AM serum cortisol and plasma ACTH.
- A low cortisol level (less than 5 ) with high ACTH confirms PAl, a low cortisol level with low ACTH suggests central (pituitary or hypothalamic) adrenal insufficiency, and a high or high-normal cortisol level (more than 15 microgram /dL) rules out PAl.
- However, the ACTH assay can take several days, so an ACTH stimulation test (cosyntropin test) is usually performed concurrently to rapidly confirm the diagnosis.
- Cosyntropin is a synthetic ACTH analog. Infusion of a 250 microgram bolus of cosyntropin normally triggers a rapid increase in serum cortisol, but patients with PAl will not have a significant rise.
- In addition, most patients with central adrenal insufficiency haye a blunted response due to adrenal atrophy from chronically low ACTH.
- The ACTH stimulation test can clarify the diagnosis in patients with suspected PAl who have low-normal cortisol levels (5-15 microg/dl).
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Adrenoleukodystrophy
- Is the common cause of congenital problems which lead to adrenal insufficiency.
- It is typically seen in young males, and its pathophysiology involves the accumulation of very long chain fatty acids within the adrenal glands.
- Females can serve as carriers; they do not show any clinical manifestations of adrenoleukodystrophy.
- Adrenal insufficiency soon after birth is also seen in congenital adrenal hyperplasia due to classic 21 hydroxylase deficiency
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Carcinoids
- Carcinoids are slow-growing tumors found most commonly in the distal small intestine, proximal colon, and lung.
- These tumors can secrete several products, including histamine, serotonin, and vasoactive intestinal peptide, that are metabolized in the liver.
- Gastrointestinal carcinoid tumors often metastasize to the liver. In such cases, the liver is unable to metabolize these hormones before they are released into the systemic circulation, leading to the carcinoid syndrome.
- Other clinical features include cutaneous telangiectasias and tricuspid regurgitation.
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Secondary Hyperparathyroidism
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Calcium Metabolism in CKD
- Circulating parathyroid hormone (PTH) levels increase with declining glomerular filtration rate (GFR), and the magnitude of PTH elevation usually correlates with severity of renal failure.
- Secondary hyperparathyroidism is the body's response to normalize serum calcium, phosphorus, and calcitriol in renal failure.
- Phosphate retention begins early with decreasing GFR and decreased renal phosphate excretion. Phosphate binds to circulating calcium and also interferes with renal production of 1,25 dihydroxyvitamin D (calcitriol).
- Decreased calcitriol leads to decreased intestinal calcium absorption. Both of these mechanisms cause hypocalcemia, which also stimulates PTH release from the parathyroid glands.
- Hyperphosphatemia directly stimulates the parathyroid glands to synthesize and release PTH.
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Hypocalcemia due to hypomagnesemia
- Hypomagnesemia causes hypocalcemia by inducing PTH resistance and decreasing PTH secretion.
- As a result, hypomagnesemia could have variable PTH levels.
- Despite PTH resistance in hypomagnesemia, serum phosphate levels are typically normal or low in contrast to hyperphosphatemia in renal failure
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Secondary Causes Of Hypertension
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Cushing Syndrome
- Clinical Features:
- Hypertension, neuropsychiatric disturbances, hyperglycemia, weight gain, Proximal muscle weakness, Central obesity (eg, fat accumulation in the cheeks and dorsocervical and supraclavicular fat pads), Skin atrophy, wide purplish abdominal stria, facial rounding, and ecchymosis, Glucose intolerance, Skin hyperpigmentation (due to ACTH excess)
- Causes:
- Exogenous glucocorticoid intake
- ectopic ACTH production (eg, small cell lung cancer),
- ACTH-producing pituitary adenomas (Cushing disease).
- Primary adrenal hypercortisolism (eg, adrenal adenoma) is less common.
- Associated hypokalemia suggests severe hypercortisolism and is most often seen with ectopic ACTH-producing tumors.
- Diagnosis:
- • 24-hour urinary cortisol excretion
- • Late-night salivary cortisol assay
- • Low-dose dexamethasone suppression test
- Two of these first-line tests should be abnormal to establish the diagnosis.
- If hypercortisolism is confirmed, ACTH levels are measured to differentiate ACTH-dependent (ie, Cushing disease, ectopic ACTH) from ACTH-independent (eg, adrenal adenoma) causes
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Evaluation of Hypercortisolism
- Initial testing for suspected hypercortisolism can include a 24-hour assay for urine free cortisol, a late-night salivary cortisol measurement, or a low-dose dexamethasone suppression test.
- Once hypercortisolism is established, an ACTH level can determine whether it is ACTH-dependent (Cushing disease or ectopic ACTH production) or ACTH-independent (adrenal disease or exogenous glucocorticoid intake).
- Patients with an elevated ACTH should have a high dose dexamethasone suppression test to determine whether ACTH production is pituitary (dexamethasone suppresses cortisol production) or ectopic (dexamethasone does not suppress cortisol).
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Metabolic Abnormality in Cushing Syndrome
- 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:
- Hyperpigmentation (in ACTH-dependent Cushing syndrome)
- 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.
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Differential Diagnosis of Myopathy
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Myopathy in Cushing syndrome
- is 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 tyrosine kinase activity.
- Interference of insulin-like growth factor 1 signaling may also contribute.
- Furthermore, glucocorticoids may decrease muscle cell differentiation and protein synthesis.
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Diabetes Insipidus
- Dl can be central (decreased antidiuretic hormone [ADH] secretion from the pituitary) or nephrogenic (normal ADH levels with renal ADH resistance).
- Central Dl patients usually do not have an intact thirst mechanism and can have serum sodium more than 150 mEq/L.
- Nephrogenic Dl patients usually have an intact thirst mechanism and adequate water intake: they usually compensate for renal water loss and may have a normal sodium level( 145 mEq/L).
- However, some cases may not be clinically obvious.
- A water deprivation test can distinguish between central and nephrogenic Dl and also definitively exclude primary polydipsia.
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Evaluation of Diabetes Insipidus
- The patient must first abstain from water for at least 2-3 hours. The serum and urine osmolality are measured periodically.
- Urine osmolality more than 600 mOsm/kg suggests primary polydipsia due to intact ADH and ability to concentrate urine in the absence of water intake.
- Patients with continued dilute urine likely have Dl. These patients then receive desmopressin to distinguish between central and nephrogenic Dl.
- Central Dl typically has more than 50% (sometimes up to 200%-400%) increase in urine osmolality with desmopressin.
- Nephrogenic Dl has minimal change in urine osmolality with desmopressin.
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Tolvaptan
- is a V2 vasopressin receptor antagonist that causes a selective water loss in the kidney without affecting sodium or potassium excretion.
- Due to its cost and side effects (eg, increased liver enzymes), it is usually reserved for significant hypervolemic (due to heart failure) or euvolemic (due to SIADH) hyponatremia that does not improve with standard therapy ( eg, fluid restriction).
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ADH related causes of Polyuria and Polydipsia
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Screening for Diabetes Mellitus
- • The US Preventive Services Task Force (USPSTF) recommends screening in patients with sustained blood pressure (treated or untreated) more than 135/80 mm Hg. However, there is insufficient evidence to establish the benefits of screening
- patients with blood pressure less than 135/80 mm Hg.
- • The American Diabetes Association recommends screening in all patients age more than 45 years, as well as those at any age with additional risk factors for diabetes.
- Recommended screening tests include fasting plasma glucose (FPG), 2-hour oral glucose tolerance test (OGTT) or hemoglobin A1C.
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Diabetes risk factors in adults with BMI more than 25 kg/m2
- • Physical inactivity
- • First-degree relative with diabetes
- • High-risk race/ethnicity (eg, African American, Latino, Native American, Asian, Pacific Islander)
- • Women whose children's birth weight more than 9 lb
- • History of gestational diabetes mellitus
- • Hypertension or prior cardiovascular disease
- • Dyslipidemia (low HDL & high triglyceride level)
- • History of polycystic ovarian syndrome
- • History of glucose intolerance
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MOA of antidiabetic Drugs
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Management Of Diabetic Nephropathy
- Diabetic nephropathy begins with hyperfiltration (increased glomerular filtration rate - GFR) and microalbuminuria (incipient nephropathy).
- If not treated adequately, microalbuminuria may progress to macroproteinuria, defined as urine protein excretion >300 mg/24 hr.
- Intensive blood pressure (BP) control is the primary intervention proven to slow the decline in GFR once azotemia develops.
- Most patients with diabetes mellitus should be treated toward a target BP of 140/90 mm Hg
- Most guidelines now recommend a target BP of 130/80 mm Hg for patients who are diabetic with signs of nephropathy.
- Angiotensin-converting enzyme (ACE) inhibitors, and perhaps angiotensin receptor blockers (ARBs), are the preferred antihypertensive drugs for patients with diabetes mellitus.
- These drugs may have actions in addition to BP control, such as reducing intraglomerular pressure, which may be renoprotective.
- However, ACE inhibitors or ARBs in patients with diabetic nephropathy must pe initiated carefully as they may induce an acute decline in GFR and hyperkalemia.
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JNC Recommendation for treatment of HTN
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ACE Inhibitor in Diabetic Nephropathy
- The use of ACE inhibitors reduces urinary albumin excretion and the decline in creatinine clearance.
- Its use is recommended in patients with microalbuminuria even if their blood pressure is normal, since microalbuminuria is a sensitive marker of renal microvascular damage.
- The beneficial effect of ACE inhibitors is due to the reduction in blood pressure as well as the direct effect on reducing intraglomerular pressure.
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Drugs for Neuropathic Pain
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Sensorimotor polyneuropathy due to diabetes mellitus:
- Clinical features of diabetic neuropathy depend on the type of nerve fibers involved; small fiber neuropathy predominantly causes pain, anodynia, and paresthesias, whereas large fiber involvement causes more numpness, loss of proprioception, diminished vibration sense, and loss of ankle reflexes.
- As diabetic neuropathy progresses, the pain may diminish but the sensory deficits persist.
- Initial treatment options for painful diabetic neuropathy include tricyclic antidepressants (eg, amitriptyline), dual serotonin norepinephrine reuptake inhibitors (eg, duloxetine), and anticonvulsants (eg, pregabalin, gabapentin).
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Pregabalin
- is a structural analogue of gamma-aminobutyric acid and decreases pain by inhibiting the release of excitatory neurotransmitters by binding to voltage-gated calcium modulators on nerve terminals.
- Common side effects are drowsiness, weight gain, and fluid retention.
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Neuropathic Ulcers
- Diabetic neuropathy is the most common underlying cause and is found in more than 80% of patients with diabetic foot ulcers.
- Neuropathy decreases pain sensation and pressure perception, it causes muscle imbalance leading to foot deformities, and impairs the microcirculation and integrity of the skin.
- Neuropathic ulcers most commonly occur in the feet under bony prominences, such as the metatarsal heads.
- They typically have a punched-out or undermined border.
- Peripheral sensory neuropathy can be documented by testing for pressure sensation with a 10-g monofilament (placed on the plantar surface at a right angle with increasing pressure until filament buckles).
- Patients with neuropathy have a higher pressure threshold and loss of monofilament sensation, which are associated with an increased risk of foot ulcerations.
- Other sensory deficits may include decreased vibratory sensation (tested with a tuning fork), decreased pinprick pain, or decreased temperature sensation
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Ankle Brachial Index Interpretation
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Neuronal injury in diabetes
- is due to a number of factors, including microvascular injury, demyelination, oxidative stress, and deposition of glycosylation end products.
- 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, and 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).
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Effect of intensive glycemic control in type 2 DM
- Optimization of glycemic control in diabetes mellitus is associated with a reduced risk of microvascular complications (eg, nephropathy, retinopathy). However, the benefits in preventing macrovascular complications (eg, myocardial infarction, stroke, peripheral arterial disease) have not been firmly established
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Diabetic Ketoacidosis
- In patients with type 1 diabetes mellitus, infection can precipitate DKA due to systemic release of insulin counterregulatory hormones such as catecholamines and cortisol.
- The resultant excess of glucagon causes hyperglycemia, ketonemia, and an osmotic diuresis.
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Paradoxical Hyperkalemia in DKA
- Metabolic acidosis during DKA is typically accompanied by hyperkalemia.
- This hyperkalemia is sometimes called paradoxical, because the body potassium reserves are actually depleted due to increased gastrointestinal losses and osmotic diuresis.
- Causes of this paradoxical hyperkalemia are:
- 1) extracellular shift of potassium in exchange to hydrogen ion, with resultant intracellular potassium deficit, and
- 2) impaired insulin-dependent cell entry of the potassium ion.
- Early potassium supplementation is very important in the treatment of patients with DKA.
- Treatment with insulin and intravenous fluids lead to a rapid decrease in serum potassium levels even if they are initially elevated.
- All hyperkalemic patients should start receiving potassium once the serum potassium level goes below 4.5 mEq/L. In patients with normal or low potassium levels, potassium replacement should be started with initiation of intravenous fluid therapy.
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Management of DKA and HHs
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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.
- 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 pe 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.
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Guidelines for lipid lowering Therapy
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Lipid Lowering In Diabetes
- Because diabetes is a strong predictor for the risk of cardiac events, current guidelines recommend statins for all diabetics age 40-75.
- Statins lower low-density lipoprotein and reduce CHD risk for any baseline lipid level.
- High-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) is suggested for patients with diabetes who have a calculated 10-year risk of cardiac events more than 7.5% .
- Moderate-intensity statin therapy (eg, atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg daily) is recommended for patients with a calculated 10- year risk of cardiac events less than 7.5%.
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