Renal and Endocrine Review

In a NORMAL AG Metabolic acidosis, 1 molecule of CHLORIDE is RETAINED for every molecule of BICARBONATE LOST

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K+ is the main CATION in the ICF

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K+ is the main INTRACELLULAR cation (higher concentration in cells than in the serum)

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LH → Leydig Cells → Testosterone

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Na+ is the main EXTRACELLULAR cation (higher concentration in the serum than in cells)

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PROTEINS and ORGANIC PHOSPHATES are the main ANIONS in ICF

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21-Hydroxylase Deficiency ***Most common cause of ambiguous genitalia in 46 XX female ***Consider this Dx in: 1) 46 XX patients with ambiguous genitalia 2) Cryptorchid males 3) Any infant with SHOCK, HYPOGLYCEMIA, HYPERKALEMIA 4) Females/males with precocious puberty (esp. adrenarche)

MOST COMMON FORM OF CAH, leads to DECREASED levels of both GLUCOCORTICOIDS and MINERALOCORTICOIDS with a concomitant RISE in ADRENAL ANDROGENS. ***Clinically patients show HYPOtension, HYPOnatremia, HYPERkalemia, and VIRILIZATION (a) NO ALDOSTERONE - HYPOtension, HYPOnatremia, HYPERkalemia, ACIDOSIS, High RENIN (b) NO CORTISOL - FTT, LETHARGY, HYPOGLYCEMIA (c) HIGH ACTH - PIGMENTATION, HYPERPLASTIC ADRENAL CORTICES ***High 17-OH-Progesterone, Adrenal androgens (DHEA), Renin, K+, ACTH ***Low - Aldosterone, cortisol, Na+

Risk Factors For Type 2 DM

1) Family Hx. of diabetes (i.e., parent or sibling with DM2) 2) Obesity (BMI ≥ 25 kg/m2) 3) Physical inactivity 4) Race/ethnicity (e.g. African American, Latino, Native American, Asian American, Pacific Islander) 5) Previously identified IFG, IGT, or an A1C of 5.7-6.4% 6) Hx. of GDM or delivery of a baby > 4 kg 7) HTN (BP ≥ 140/90 mmHg) 8) HDL cholesterol level < 0.90 mmol/L and/or a TG level > 2.82 mmol/L 9) Polycystic ovary syndrome or acanthosis nigracans (a benign and common condition characterized by velvety, hyperpigmented plaques on the skin - the neck and axillae, are common sites for involvement) 10) History of CVD

Granulomatous Diseases

1-alpha-hydroxylase can become CONSTITUTIVELY ACTIVE resulting in TOO MUCH CALCITRIOL leading to HYPERCALCEMIA and HYPERPHOSPHATEMIA

A woman comes to the office for an OFFENSIVE BODY ODOR and EXCESS SWEATING that she is unable or resolve. Her RING, HAT, and SHOE SIZES have been INCREASING in the last few years. Her voice is THICK and her JAW is PROTRUDING and ENLARGED. She also has JOINT PAIN 1. What is the most likely diagnosis? 2. What is the best initial test? 3. What is the most common cause of death?

1. ACROMEGALY is most often from a PITUITARY TUMOR secreting GH. This leads to ENLARGEMENT of HAT, SHOE, RING, and GLOVE SIZES, beginning in the patient's 30's or 40's. ARTHROPATHY occurs from excessive articular cartilage proliferation. ENTRAPMENT NEUROPATHIES such as CARPEL TUNNEL SYNDROME can also occur. DIABETES occurs in 10-20% of patients. AMENORRHEA can result from excess secretion of prolactin 2. The BEST INITIAL TEST is a level of INSULIN-LIKE GROWTH FACTOR (IGF-1). This is confirmed by finding a FAILURE OF GROWTH HORMONE SUPPRESSION by the INFUSION OF GLUCOSE. 3. The MOST COMMON CAUSE OF DEATH IN ACROMEGALY is from THE EFFECT OF GH ON THE HEART and HTN. There is an INCREASED RISK OF COLONIC POLYPS AND CANCER AS WELL.

On routine screening, a patient is found to have a LOW SODIUM OF 127. He has NO SYMPTOMS of the hyponatremia, and the neurologic examination is normal. The K+ level is ELEVATED and there is a mild METABOLIC ACIDOSIS

1. ADDISON'S DISEASE or HYPOADRENALISM of any cause results in HYPONATREMIA. The LOSS OF ALDOSTERONE results in the URINARY LOSS OF SODIUM and the RETENTION OF BOTH POTASSIUM AND HYDROGEN IONS.

Fine-Needle Aspiration of the Thyroid

A sample of thyroid cells collected by a needle inserted into the thyroid is the INITIAL TEST for ALL SOLITARY NODULES UNLESS the patient is THYROTOXIC ***Look for a case with a PALPABLE nodule and NORMAL thyroid function tests and the question asks for the NEXT step in diagnosis ***This is the WRONG answer in patients with a solitary thyroid nodule who are THYROTOXIC. In such patients a THYROID SCAN should be done first to see if the nodule is HYPERFUNCTIONING (HOT) or HYPOFUNCTIONING (COLD). HYPERFUNCTIONING nodules are almost NEVER MALIGNANT.

What inhibits constriction of the efferent arteriole by AII?

ACE inhibitors

Decreased cortisol levels as in any of the congenital adrenal hyperplasias will have what effect on ACTH?

ACTH levels will be INCREASED contributing to increased skin pigmentation

What does the posterior pituitary secrete?

ADH and oxytocin

Raloxifeneis a selective estrogen receptor modulator (SERM) that has both receptor agonistand antagonistproperties depending on the particular tissue. A. Agonist -mammary tissue; antagonist -bone B. Agonist -uterus; antagonist -CV system C. Agonist -bone; antagonist -CV system D. Agonist -bone; antagonist -mammary tissue

Agonist -bone; antagonist -mammary tissue

Long-term use of GLUCOCORTICOIDS in anti-inflammatory and immunosuppressive therapy is associated with which of the following unwanted side effects? A. INCREASED risk of FRACTURES (osteoporosis) B. SUPPRESSION of responses to INFECTION C. HYPERGLYCEMIA D. MUSCLE WASTING and WEAKNESS E. All of the above

All of the above

Oraldrugs for hyperthyroidism include: A. Radio-iodine (131I) B. Iodine/iodide C. Propythiouracil D. All of the above

All of the above

Acute Tubular Necrosis is an intrinsic renal disease and is the MOST COMMON CAUSE OF ARF. It can be either ISCHEMIC (Decreased Circulating Volume [e.g. hemorrhage, renal losses], Decreased Effective Circulating Volume [e.g. Sepsis, Cirrhosis], Vessel Occlusion) or NEPHROTOXIC (Drugs - NSAIDS, radiocontrast, diuretics...; Diseases - Rhabdomyolysis, gout, multiple myeloma...) in origin.

Associated with ATN: 1. Muddy Brown Casts 2. Rhabdomyolysis 3. Crush Injury

Grave's Disease

Autoimmune hyperthyroidism (Thyroid-Stimulating Immunoglobulin = TSI)

Hashimoto's Thyroiditis

Autoimmune hypothyroidism (antimicrosomal or antithyroglobulin)

Benign Vs. Active Urine

BENIGN URINE SEDIMENT - Lack of inflammation in the glomerular capillary wall - Few RBCs or WBCs - NO cellular casts - Proteinuria and/or lipiduria (nephrotic syndrome) - Few granular casts ACTIVE URINE SEDIMENT - Indicates INFLAMMATION in the glomerular capillary wall - Red blood cells/casts - Granular casts - White cells/casts - Proteinuria

HTN

BP >140/90 on 3 separate occasions two weeks apart

Osteoporosis ***Low bone mass Disrupted bone architecture Normal mineralization Increased fragility and propensity to fracture ***Patient Assessment - Review risk factors - Confirm low bone mass with BMD - RULE OUT SECONDARY CAUSES OF LOW BONE MASS - Determine fracture risk (FRAX) - Consider therapeutic options ***Bone mineral density (BMD) ≥ 2.5 standard deviations below the peak bone mass for young adults (i.e. T-score ≤ -2.5) ***Primary Osteoporosis - Due to post-menopausal decline in estrogen, worsens with age ***Clinical Features - collapsed vertebrae --> height loss, - fractures (commonly occur in hip, vertebrae, humerus, and wrist; fragility fractures) - pain, especially backache, associated with fractures ***Physical Exam: - Wall-Occiput Test for Thoracic Fracture (+) Test; Wall-Occiput Distance > 0cm - Rib-Pelvis Distance Test for Lumbar Fracture (+) Test: Rib-Pelvis Distance ≤ 2 Finger Breadths ***High Risk - START PHARMACOTHERAPY - 10-yr fracture risk > 20%; OR Prior fragility fracture of hip or spine OR More than one fragility fracture ***This BMD-centric labeling is only meant to apply to MENOPAUSAL WOMEN ***The relationship between T score and future fracture risk is AGE and SEX DEPENDENT ***1st Line Therapy -Bisphosphonate (oral or IV) -Raloxifene -Denosumab -HRT (if vasomotor symptoms) 2nd Line Therapy - Calcitonin, etidronate Male Osteoporosis Causes: (1) Delayed puberty (2) Hypogonadism (3) Glucocorticoids (4) Alcoholism (5) Other secondary causes (6) Idiopathic Male Osteoporosis - Who to Screen? (1) Hypogonadal males (2) Prior osteoporotic fracture (3) Glucocorticoid users (4) Age>65 ***Bisphosphonates, denosumab, PTH proven to maintain BMD and reduce vertebral # in males with OP

Bone formation - Genetics - Vitamin D - Sex steroids - Nutrition - Age - Tobacco Bone resorption - Lack of estrogen - Disease states - Lack of testosterone Risks for progressive loss of bone - Age > 60/menopausal/estrogen deficiency - White race - Glucocorticoids (Prednisone) - Hyperthyroidism - Immobilization - Heparin - Tobacco abuse - Low body weight - Family history Investigations - Calcium, Phosphate, ALP - Consider 25-OH vitamin D, protein electrophoresis - Other tests as appropriate to hx ***If abnormal results on any of these biochemical tests, there is likely a secondary bone disease present ***Treatment (1) Lifestyle: Diet: Elemental calcium 1000-1200 mg/d; Vit D 1000 IU/d Exercise: 3x30 min weight-bearing exercises/wk Cessation of smoking, reduce caffeine intake Stop/avoid osteoporosis-inducing medications (2) Drug Therapy a) Anabolic (PTH, Estrogen) b) Anti-Resorptive (Bisphosphonates, SERMs, Calcitonin, Anti-RANKL, Estrogen) ***BISPHOSPHONATES (1st Line) - e.g. Alendronate (oral), zoledronic acid (IV) •Bind to bone surface •Taken up by osteoclasts •Inhibit osteoclast lysosomal enzymes, acid production •Osteoclast apoptosis •Reduce depth of resorption pits NB: Suppression of bone turnover may last up to 5 yrs after cessation Anti-fracture efficacy DISAPPEARS with adherence less than 70% Oral (Alendronate) - Inhibit osteoclastic resorption - Proven to decrease risk of osteoporotic vertebral and hip # by 30-50% over 3-5 years ***Side Effects: GI intolerance/esophageal ulceration, ONJ IV (zoledronic acid) - Once annual infusion (most potent bisphosphonate) ***Side Effects: Post infusion flu-like reaction common SERMS (e.g. Raloxifene) Agonistic effect on bone BUT Antagonistic effect on uterus and breast ***Prevents osteoporotic fractures, improves lipid profile, decreased breast cancer risk ***Side Effects; Increased risk of DVT/PE, stroke mortality, hot flashes, leg cramps CALCITONIN - Inhibits osteoclast activity, is an anti-resorptive agent - Delivery via nasal spray associated with very few side effects - Reduced relative risk of new VERTEBRAL fractures ***Side Effects: Nasal form associated with mild to moderate nasal irritation (rhinitis) ANTI-RANKL ANTIBODY (Denosumab) - Denosumab is an anti-resorptive therapy that inhibits the development and activation of osteoclasts ***Anti-RANKL antibody binds to RANKL --> ↓ osteoclast differentiation and activity - Subcutaneous injection q 6 months - Reduces fracture risk similar to that seen with bisphosphonates ***Side Effects: ONJ, Infections, Hypocalcemia Anobolic Therapy - HRT (combined Estrogen & Progesterone ***Must be taken with progestin if intact uterus) - For most women, risks > benefits Combined estrogen/progestin prevents hip, vertebral, total # ***Side Effects: Increased risks of breast ca, cardiovascular events and DVT/PE PTH (Teriparatide) - Once daily --> Increased osteoblast # and function --> Increased Bone formation/mass/strength - Continuous --> Increased RANKL --> Increased osteoclasts --> Increased bone resorption --> Increased serum calcium ***Structural improvements in both trabecular and cortical bone ***Large increments in BMD over short treatment periods (2 yrs) ***↓ Vertebral Fractures ***Side Effects: Leg cramps

Name the two primary insulin independent organs?

Brain and RBC's take up glucose independent of insulin

Dopamine INHIBITS prolactin synthesis by Lactotrophs

Bromocriptine and Cabergoline are DOPAMINE RECEPTOR AGONISTS useful in the treatment of pituitary adenomas secreting PROLACTIN

How do NSAIDs cause renal failure?

By inhibiting the production of prostaglandins which normally keep the afferent arterioles vasodilated to maintain GFR

Cushing Syndrome

Characterized by a CLASSIC clinical picture: 1) HTN 2) Central Obesity 3) Weight Gain 4) Moon Facies 5) Insulin Resistance 6) Skin Thinning 7) Purple Striae 8) Buffalo Hump 9) Hirsutism 10) Osteoporosis 11) Amenorrhea

PTH is produced by what cell type?

Chief cells of the parathyroid glands

What is the VERY first molecule in the pathway for the synthesis of Aldosterone? Cortisol? Adrenal androgens?

Cholesterol

Waxy casts

Chronic end-stage renal disease

Cotton-wool spots

Chronic hypertension

What does renin do?

Cleave angiotensinogen into angiotensin I

PTH causes increased calcium reabsorption in what part of the kidney?

DCT

A patient is admitted to the ICU because of a SEVERE METABOLIC ACIDOSIS. The SERUM BICARBONATE is LOW at 14. The patient is DISORIENTED and cannot offer an adequate history. No records are available. What is the most likely diagnosis when the following additional features are described? HYPERGLYCEMIA AND HYPERKALEMIA

DIABETIC KETOACIDOSIS (DKA) gives hyperglycemia and hyperkalemia, although the total body level of K+ is depleted The 1st step in the evaluation of any metabolic acidosis is the evaluation of the ANION GAP. An anion gap > 12 is consistent with: Methanol Ueremia Diabetic/alcoholic/starvation ketoacidosis Paraldehyde Isopropyl alcohol/iron Lactic acidosis Ethylene glycol Salicylates "MUDPILES"

Three systemic diseases → NEPHROTIC syndrome.

DM, SLE, and Amyloidosis

What will the levels of Ca2+, phosphate, and alkaline phosphatase be in renal insufficiency?

Decreased Ca2+, increased phosphate, and alkaline phosphates within normal limits

HMG-CoA reductase inhibitors ("statins") reduce plasma cholesterol concentrations by: A. Decreased LDL catabolism B. Decreased LDL production C. Decreased HDL catabolism D. Decreased HDL production

Decreased LDL production

What stimulates angiotensin secretion?

Decreased blood volume

A 21-Beta-hydroxylase deficiency will result in what hormone deficiencies/excesses?

Decreased cortisol and mineralocorticoids (hypotension, hyperkalemia) Increased sex hormones (masculinization)

Cirrhosis, CHF, nephritic syndrome

Differential of HYPERVOLEMIC HYPONATREMIA.

Prostaglandins ***Severe Renal Hypoperfusion → Prostaglandins INHIBT NE Vasoconstriction of Afferent Arteriole

Dilate Afferent Arteriole Increase Renin Block ADH & Na+ Reabsorption

PRO-INSULIN

Distinguish Auto-Immune causes of hypoglycemia from insulinoma ***HIGH LEVELS of PRO-INSULIN = INSULINOMA ***Answer a PRO-INSULIN level when you see a case of RECURRENT FASTING, HYPOGLYCEMIA, SYMPTOMS OF WEAKNESS, and HIGH C-PEPTIDE LEVELS

Cabergoline and Bromocriptine

Dopamine AGONISTS commonly used to treat PROLACTINOMA

The most common cause of uncomplicated (75%) and complicated (48%) urinary tract infections is this strain of bacteria.

E.coli

Conn Syndrome (PRIMARY HYPERaldosteronism)

Excessive aldosterone is produced by adrenocortical adenomas, carcinomas, or hyperplasia of the zona glomerulosa. Patients are generally HYPERtensive, and HYPOkalemic

Diabetes Mellitus: Classification = A group of common metabolic disorders that share the phenotype of HYPERglycemia Criteria for the Diagnosis of Diabetes Mellitus ***The current criteria for the diagnosis of DM emphasize that the A1C or the FPG as the MOST RELIABLE and CONVENIENT tests for identifying DM in asymptomatic individuals.

Factors contributing to hyperglycemia include: 1) Reduced insulin secretion 2) Decreased glucose utilization 3) Increased glucose production DM is the leading cause of ESRD, nontraumatic lower extremity amputation, and adult blindness. It also predisposes to CV disease Type 1 DM is the result of complete or near-total insulin deficiency - Usually < 30 years of age Type 2 DM is a heterogenous group of disorders characterized by variable degrees of INSULIN RESISTANCE, IMPAIRED INSULIN SECRETION, and INCREASED GLUCOSE PRODUCTION. - Preceded by a period of abnormal glucose homeostasis classified as IMPAIRED FASTING GLUCOSE (IFG) or IMPAIRED GLUCOSE TOLERANCE (IGT). - Usually > 40 years of age - More common in African American, Hispanics, Aboriginals, and Asians - Accounts for >90% of all DM ***Both types of diabetes are PRECEDED by a phase of ABNORMAL glucose homeostasis as the pathogenic processes progress. Maturity-onset diabetes of the young (MODY) - AD inheritance - Early onset of hypoglycemia (usually <25 years) - Impairment in insulin secretion DM can result from pancreatic exocrine disease when the majority of pancreatic islets are destroyed Hormones that ANTAGONIZE insulin action can also lead to DM. Thus, DM is often a feature of endocrinopathies such as ACROMEGALY (excess GH in adults) and CUSHING's DISEASE (increased cortisol). Viral infections (congenital rubella, cytomegalovirus, coxsackievirus) have been implicated in pancreatic islet destruction but are an extremely RARE cause of DM. GDM (glucose intolerance developing during pregnancy) - Insulin resistance is related to the metabolic changes of LATE pregnancy, and the increased insulin requirements may lead to impaired glucose tolerance (IGT) or diabetes. - Most women revert to normal glucose tolerance postpartum BUT have a substantial risk of developing DM in the next 10-20 years.

FRACTIONAL EXCRETION OF SODIUM ***SODIUM:CREATININE RATIO IN YOUR URINE COMPARED TO YOUR SODIUM:CREATINE RATIO IN YOUR PLASMA. ***DEHYDRATED --> Urine Na+ is LOW; FeNA is LOW ***ATN (Tubules are damaged) --> Urine Na+ is HIGH; "Waste" Na+ --> FENa is HIGH

FENa = (UNa/UCr)/(PNa/PCr) ***Provides info. to help determine if situations of POOR RENAL FUNCTION and LOW URINE OUTPUT are due to VOLUME AND DEHYDRATION FACTORS (PRE-RENAL) or rather, due to KIDNEY DAMAGE (ATN)

Tendon xanthomas (classically Achilles)

Familial hypercholesterolemia

Treatment of DKA?

Fluids, insulin, and aggressive replacement of electrolytes (e.g., K+)

HEMOPTYSIS and HEMATURIA are features of which types of rapidly progressive Glomerulonephritis (Crescentic RPGN)?

Goodpasture Syndrome/Antiglomerular Basement Membrane Disease (ANCA-negative, linear IgG and C3 deposits along the GBM) And Wegener Granulomatosis (ANCA-positive, NO deposits on the GBM)

Anti-Basement Membrane Antibodies

Goodpasture's Syndrome (***Hematuria/Hemoptysis) ***Autoimmune: ab's to glomerular & alveolar basement membranes; linear immunofluorescence

Throid Stimulating Immunoglobulin results in what disease?

Graves Disease (hyperthroidism)

An auscultatory bruit over a large, smooth, rubbery, non-tender thyroid gland is diagnostic for this condition

Graves' disease

Exophthalmos, pretibial myxedema, and ↓ TSH.

Graves' disease

Palpable purpura on legs and buttocks

Henoch-Schönlein purpura ***IgA Nephropathy associated with extrarenal symptoms is referred to as Henoch-Schonlein Purpura (Skin: Purpural lesions found on the extensor surfaces of the lower extremities, buttocks, and arms. GI: Abdominal pain, intestinal bleeding. MSK: Joint pain)

Alport Syndrome

Hereditary nephritis with nerve deafness, Type 4 collagen defect (basement membranes)

Dyslipidemia ***Dyslipidemia ITSELF usually causes NO symptoms but can lead to symptomatic vascular disease, including coronary artery disease (CAD) and peripheral arterial disease. ***Dyslipidemia is diagnosed by measuring serum lipids. Routine measurements (lipid profile) include total cholesterol (TC), TGs, HDL cholesterol, and calculated LDL cholesterol and VLDL ***The MAJOR risks of hyperlipidemia are PANCREATITIS as a result of HIGH levels of TG from chylomicrons and ATHEROSCLEROSIS as a result of HIGH LEVELS OF CHOLESTEROL (and sometimes TG) from apo-B containing lipoproteins (***Apo B is found in all lipoproteins EXCEPT HDL) ***Cholesterol is removed from the body when it is delivered to the LIVER and excreted as BILE ACIDS

High Levels of TGs can cause ACUTE PANCREATITIS High levels of LDL can cause EYELID XANTHELASMAS; ARCUS CORNEAE; and TENDINOUS XANTHOMAS at the Achilles, elbow, and knee tendons and over metacarpophalangeal joints Patients with severe elevations of TGs can have ERUPTIVE XANTHOMAS over the TRUNK, BACK, ELBOWS, BUTTOCKS, KNEES, HANDS, and FEET. Severe Hypertriglyceridemia can give retinal arteries and veins a creamy white appearance (LIPEMIA RETINALIS) Extremely high lipid levels also give a lactescent (milky) appearance to blood plasma. Symptoms can include paresthesias, dypsnea, and confusion. *** Beta VLDL (IDL) → Palmer Xanthomas (Yellow/Orange creases = beta carotene) - Type 3 Hyperlipoproteinemia ***CHYLOMICRONS or ↑ TG → Eruptive Xanthomas -Circulating chylomicrons are taken up by macrophages in the skin and in the reticuloendothelial system - Small yellowish papules surrounded by a reddish macular area are called "eruptive xanthomas" and are TG-rich skin macrophages - Hepatosplenomegaly can often be seen in severe cases ***"Milky Plasma" ↑ TG → Eruptive Xanthomas & Lipemia Retinalis Tx: Fibrates (***DECREASES TGs; e.g. Gemfibrozil) ↑ lipolysis by ↑ LPL activity → ↓ in VLDL secretion → ↓ beta VLDL remnants & ↑ HDL Minor ↓ in LDL ***LDL → Tendon Xanthomas (***ACHILLES TENDON) - Heterozygous familial hypercholesterolemia (1/500 people) - LDL receptor alteration (absence, #, binding...) - LDL deposits are most obvious on the Achilles tendon and Knuckles - Tx: Statins (***HMGCoA reductase inhibitor) 1. Blocks the action of the rate-limiting enzyme for cholesterol biosynthesis 2. Hepatic response to that is the ↑ synthesis of a series of proteins including HMGCoA reductase and the LDL receptor 3. The ↑ liver LDL receptors reduce plasma LDL levels ***Circulating LDL delivers CHOLESTEROL to cells where it can be used for synthesis of plasma membranes, bile acid production, and stored hormone synthesis (adrenals, ovaries, testes, skin) ***High LDL → Eyelid Xanthelasma (Yellow placques) - risk factor for heart disease and strokes NOTE: Xanthelasma and arcus senilis are NON-SPECIFIC physical findings. They are NOT characteristic of specific lipoprotein disorders. They occur in patients with high cholesterol or in patients without lipid disorders.

Lab findings in Hashimoto's thyroiditis.

High TSH, low T4, antimicrosomal antibodies

Wolff-Chaikoff Effect

INCREASING IODIDE supply INHIBITS iodide organification, thus DECREASING T3 and T4 synthesis ***The Wolf-Chaikoff Effect can be used in the acute treatment of a thyroid storm; when high dose iodine is ingested resulting in decreased production of T4

First-line treatment for moderate HYPERCALCEMIA.

IV hydration and loop diuretics (furosemide)

The most common cause of Cushing's syndrome.

Iatrogenic steroid administration. ***The second most common cause is Cushing's disease

Berger's disease

IgA nephropathy

Which of the following statements about bisphosphonatetherapy (e.g. alendronate) is/are true? A. Good oral absorption B. Incorporated into bone matrix and ingested by osteoclasts C. Stimulates bone resorption D. Stimulates osteoblastsand bone formation

Incorporated into bone matrix and ingested by osteoclasts

What are the Major Regulators of GH?

Increase GH: 1. GHRH 2. REM Sleep 3. Exercise 4. Trauma 5. Acute Illness 6. HYPOglycemia 7. Gonadal hormones (Increase GH action) 8. Insulin-Induced 9. L-dopa Decrease GH: 1. Somatostatin 2. HYPERglycemia 3. HYPOthyroidism 4. Glucocorticoids (Decrease GH action) 5. IGF-1 6. Glucose challenge 7. Dopamine agonists

What are the major regulators of prolactin secretion?

Increase PRL: 1. Pregnancy (estrogen effect) 2. Suckling 3. Nipple stimulation 4. Chest wall trauma 5. Sleep 6. Exercise 7. HYPOthyroidism (HIGH TRH) 8. Pituitary stalk lesions 9. Pituitary tumors 10. Renal failure 11. Liver failure Decrease PRL: - Dopamine antagonist

What will the levels of Ca2+, phosphate, and alkaline phosphatase be in Vit D intoxication?

Increased Ca2+ and phosphate with alkaline phosphatase within normal limits

What will the levels of Ca2+, phosphate, and alkaline phosphatase be in hyperparathyroidism?

Increased Ca2+, decreased phosphate, increased alkaline phosphatase

Decreased phosphate will have what effect on Vit D?

Increased activated Vit D. ***Low phosphate INCREASES 1,25-(OH)2 vitamin D formation

What stimulates ANP secretion?

Increased atrial pressure

What effect does PTH have on bone?

Increases bone resorption of Ca2+ and phosphate

Anti-Basement Membrane Antibodies

Indicative of GOODPASTURE'S SYNDROME ***A patient with HEMATURIA and HTN, accompanied by COUGH, SHORTNESS OF BREATH, and HEMOPTYSIS. RENAL INSUFFICIENCY and RED CELLS OR RED CELL CASTS in URINE are characteristic

17-α-Hydroxylase deficiency

Individuals LACK the enzyme to synthesize CORTISOL or ANDROGENS, resulting in the ACCUMULATION of a shared precursor, PREGNENOLONE. ***Clinically, individuals are HYPERtensive and HYPOkalemic, owing to SHUNTING of pregnenolone into the synthetic pathway of ALDOSTERONE.

What substance is used by the brain for energy during starvation?

Ketone bodies

A man is admitted to the hospital with RENAL FAILURE developing over a few days. His serum BICARBONATE is SLIGHTLY LOW. The URINE SODIUM is LOW and the URINE OSMOLALITY is HIGH. FRACTIONAL EXCRETION of Na+ < 1%. Increased [urea] >> Increased [Cr]. What is the most likely diagnosis when the following additional features are described? SERUM ALBUMIN is 2.2 and the PROTHROMBIN TIME IS ELEVATED. There is SPLENOMEGALY

LOW ONCOTIC PRESSURE for any reason results in PRERENAL AZOTEMIA* because of DECREASED RENAL PERFUSION. In addition, liver disease such as cirrhosis can lead to "HEPATORENAL" SYNDROME, which is renal failure entirely on the basis of liver failure. *Azotemia = asymptomatic increase in serum urea and Cr. Usually cuased by the inability of the kidney to excrete urea, Cr, and other nitrogen-containing compounds in the blood. If azotemia is associated with symptoms of kidney failure then the syndrome of UREMIA is said to be present).

A 55-year-old man presents with irritative and obstructive urinary symptoms. Treatment options?

Likely BPH. Options include no treatment, terazosin, finasteride, or surgical intervention (Trans-Urethral Resection of Prostate = TURP)

What effect does thyroid hormone have on lipolysis?

Lipolysis is stimulated

Apoprotein C2 functions as a coenzyme for this enzyme, which LIBERATES FFAs from circulating CHYLOMICRONS.

Lipoprotein lipase

What is the primary organ that converts Vit D to 25-OH Vit D?

Liver

What is the MOST ACCURATE test for Goodpasture's syndrome?

Lung of Kidney BIOPSY

"Wire loop" appearance on Light Microscopy

Lupus Nephropathy

Differential Diagnosis of Cushing's Syndrome

Pituitary Tumor: ↑ ACTH ↑ Cortisol Ectopic ACTH: ↑ ACTH, ↑ Cortisol Adrenal Tumor: ↓ ACTH, ↑ Cortisol Exogenous Cortisol: ↓ ACTH, ↑ Cortisol Exogenous prednisone or dexamethasone: ↓ ACTH, ↓ Cortisol

Nonseminoma

Nonseminoma tumors tend to develop EARLIER in life and grow and spread RAPIDLY. Several different types of nonseminoma tumors exist, including choriocarcinoma, embryonal carcinoma, teratoma and yolk sac tumor. Nonseminomas are sensitive to radiation therapy, but NOT as sensitive as seminomas are. Chemotherapy is often very effective for nonseminomas, even if the cancer has spread.

Sheehan's syndrome

Postpartum pituitary necrosis

"Lumpy-bumpy" appearance of glomeruli on immunofluorescence

Poststreptococcal glomerulonephritis

Subepithelial humps on Electron Microscopy

Poststreptococcal glomerulonephritis

Type of ARF in a patient with FeNa < 1%.

Prerenal

Glomerulonephritis/nephritic syndrome

Presence of red cell casts in urine sediment.

What is the most common pituitary tumor? Treatment?

Prolactinoma. Tx: Dopamine agonists (e.g., bromocriptine)

Thiazide Diuretics

Promote K+ secretion in collecting tubule

The most common cancer in men and the most common cause of death from cancer in men.

Prostate cancer is the most common cancer in men, but lung cancer causes more deaths

Lung cancer associated with SIADH.

Small cell lung cancer (SCLC)

Cholestyramine (Bile acid sequestrant)

Removes cholesterol and bile from the enterohepatic circulation Because less cholesterol is returning to the liver, hepatic LDL receptors are increased, resulting in enhanced removal of LDL from the bloodstream Another response to bile depletion is an increase in hepatic lipoprotein and cholesterol production → vLDL can increase → TG can increase

Hematuria, flank pain, and palpable flank mass.

Renal cell carcinoma (RCC)

Vit D deficiency in kids cause what disease? Adults?

Rickets in kids Osteomalacia in adults

A POSTOPERATIVE patient with significant PAIN presents with HYPONATREMIA and NORMAL volume status

SIADH due to stress

Bilateral hilar adenopathy, uveitis

Sarcoidosis

DYSPNEA, lateral HILAR LYMPHADENOPATHY on CXR, NONCASEATING GRANULOMAS, increased ACE, and HYPERCALCEMIA.

Sarcoidosis

What effect will low serum phosphate have on the kidney?

The kidney will produce more 1-25-OH2 Vit D which will increase phosphate release from bone matrix and increase Ca2+ and phosphate absorption in the GIT

What is the most accurate test for ETHYLENE GLYCOL?

The most accurate test for Ethylene Glycol Intoxication is to DETERMINE THE BLOOD LEVEL. Urine can be examined under a fluorescent WOOD'S LIGHT, however urinary fluorescence lasts only a few hours after ingestion. Because the OXALIC ACID PRECIPITATES WITH CALCIUM, the BLOOD LEVEL OF CALCIUM IS OFTEN LOW. ***ELEVATED ANION GAP & METABOLIC ACIDOSIS ***Question most often describes a DEPRESSED patient with a possible ATTEMPTED SUICIDE. HYPOcalcemia can lead to QT PROLONGATION and CARDIAC ARRHYTHMIAS. OXALATE CRYSTALS DEPOSIT IN THE RENAL TUBULES AND CAUSE ATN

B-hCG (= Pregnancy Test)

Urine and/or serum measurement of B-hCG is the BEST INITIAL TEST for any woman of REPRODUCTIVE AGE COMPLAINING OF A MISSED PERIOD (AMENORRHEA), DELAYED PERIOD, VAGINAL BLEEDING, or ABDOMINAL PAIN. Any UNEXPLAINED ABDO. PAIN in a woman is an ECTOPIC PREGNANCY until you have the B-hCG

24 Hour Urine Cortisol Level

When collected for 24 hours, URINARY CORTISOL EXCRETION is the MOST SENSITIVE INDICATOR OF ENDOGENOUS HYPERCORTISOLISM and is the MOST SENSITIVE TEST for CUSHING'S SYNDROME. ***Cortisol is a GC hormone produced in the ADNRENAL CORTEX ***Look for a case with TRUNCAL OBESITY, "BUFFALO HUMP", STRIAE, and EASY BRUISING "Salt" - GLOMERULOSA - ALDOSTERONE ***Loss leads to hyponatremia, hypovolemia, hyperkalemia "Sugar" - FASCICULATA - CORTISOL ***Loss leads to decreased ability to compensate for physiologic stress, decreased ability to mobilize glucose ***Controlled by ACTH "Sex" - RETICULARIS - Androgens ***Gynecomastia, delayed onset of puberty (in males); not a major androgen contributor ***Controlled by ACTH

Major causes of metabolic acidosis according to mechanism and anion gap

http://www.uptodate.com/contents/image?imageKey=NEPH%2F77464&topicKey=NEPH%2F2348&rank=1~12&source=see_link&search=urine+anion+gap&utdPopup=true

Fanconi's syndrome

impaired proximal tubular reabsorption secondary to lead poisoning or Tetracycline (glycosuria, hyperphosphaturia, aminoaciduria, systemic acidosis)

For drugs subject to renal clearance of the active form, what is the inevitable consequence of ↓ renal clearance due to chronic renal failure?

↑ HALF-LIFE and ↑ DESIRED STEADY-STATE THERAPEUTIC CONCENTRATION (could produce unacceptable toxicities) ***Patients with chronic renal failure can have elevated levels of active (or toxic) metabolites produced by hepatic metabolism.

PSA

↑ PSA can occur in PROSTATITIS, BPH, PROSTATE CANCER, and PROSTATE BIOPSIES. Levels are undetected, after total resection of the prostate. - If the PSA is ↑, a DRE is performed to palpate a lesion. If a lesion is found, it should be biopsied. BIOPSY of the prostate is the MOST ACCURATE DIAGNOSTIC TEST

TSH levels in a hypothroid patient would be? Free T4?

↑ TSH ↓ free T4

What actions does ADH have on the kidney?

↑ water permeability of principle cells in collecting ducts ↑ urea reabsorption in CD ↑ Na/K/2Cl cotransporter expression in the thick ascending limb

Hypocalcemia will have what effect on Vit D metabolism?

↓ Ca2+ will ↑ PTH which will stimulate the kidney to produce more activated Vit D.

What effect does dilation of the afferent arteriole have?

-Increased RPF -Increased GFR - FF remains constant

What does the early distal convoluted tubule actively reabsorb?

-Na ions -Cl ions

Administration of DDAVP ↓ serum osmolality & free water restriction

Treatment of central DI.

What actions does ANP have on the kidney?

(1) ↓ Na reabsorption (2) ↑ GFR

***Thyroid Medications

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Hyperpigmentation of skin

1° adrenal insufficiency (Addison's disease)

What is the most common cause of congenital adrenal hyperplasia?

21-Beta hydroxylase deficiency

A deficiency of 17-alpha hydroxylase will result in an INCREASE in what hormone(s)?

Aldosterone (hypertension, hypokalemia)

Estradiol is converted from what precursor by what enzyme?

Aromatase converts Testosterone to Estradiol

Blood in the urethral meatus or high-riding prostate.

Bladder rupture or urethral injury

Complication of overly rapid correction of HYPONATREMIA.

Central pontine myelinolysis

Chvostek's sign

Hypocalcemia (facial muscle spasm upon tapping)

Cold intolerance

Hypothyroidism

How much of the total body water is part of intracellular fluid?

Two-thirds

Hashitoxicosis

Initial hyperthyroidism in Hashimoto's Thyroiditis that PRECEDES hypothyroidism

Which of the following oral hypoglycemic drugs has as its primary action the inhibition of hepatic glucose production?

Metformin

Long term complications of Diabetes

Microvascular: Nephropathy, Retinopathy, Neuropathy Macrovascular: CAD, CVD, PVD

Podocyte fusion

Minimal change disease

Which healthy population is susceptible to UTIs?

PREGNANT WOMEN. Treat this group aggressively because of potential complications

Phosphate reabsortion in the kidneys is inhibited by what hormone?

PTH

What activates 1 alpha-hydroxylase?

PTH

No lactation postpartum

Sheehan's syndrome (pituitary infarction)

Which of the following drugs produce hypoglycemia as an unwanted side-effect of Type 2 Diabetes therapy? A. Acarbose B. Metformin C. Sulfonylureas D. DPP-4 inhibitors

Sulfonylureas = Insulin Secretagogue

60-40-20 rule of body weigh:

TBW = 60% ICF = 40% ECF = 20%

What does the secretion of prostaglandins from the kidney do?

Vasodilates the afferent arterioles to increase GFR

CHRONIC SINUSITIS, HEMOPTYSIS, and HEMATURIA are features of

WEGENER GRANULOMATOSIS ***Cytoplasmic staining ANCA (c-ANCA)-positive in 80% of patients with renal involvement Tx: Glucocorticoids and Cyclophosphamide ***Think 3 C's 1) C-ANCA 2) Corticosteroids 3) Cyclophosphamide

A 55-year-old man is diagnosed with prostate cancer. Treatment options?

Wait Surgical resection Radiation and/or androgen suppression

Papillary carcinoma

~75% of thyroid cancers are of this variety 98% 10 year survival.

SODIUM is the main CATION in the ECF

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Na+ Deficit ***Correcting HYPOvolemic (non-urgent) HYPOnatremia should be accomplished via normal saline infusion at a rate of 0.5mmol Na+/L/hr

(0.6 x body weight) x (target serum[Na] - current serum[Na])

STRUVITE STONES can resemble coffin lids and normally form in the COLLECTING SYSTEM/TUBULAR LUMEN of the kidney

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TBW = ECF + ICF

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The majority of cases of acute kidney injury in the OUTPATIENT population are due to PRE-RENAL causes, while the majority of cases in the INPATIENT population are due to RENAL causes.

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Key Points For The Pregnant Patient ***The STRONGEST indications for an ORAL GLUCOSE TOLERANCE TEST is in SCREENING for DIABETES DURING PREGNANCY

(1) ALWAYS treat asymptomatic bacteruria (risk of pyelonephritis) ***Stasis of urinary tract --> propensity for asymptomatic bacteria --> pyelonephritis ***DILATED ureters contain ++ Urine (2) Mild proteinuria is NORMAL ***Because of INCREASING GFR, PROTEINURIA INCREASES from 150mg to 300mg/24hr during normal pregnancy (3) Respiratory alkalosis with compensatory metabolic acidosis ***Hyperventilation likely due to progesterone and mechanical causes ***In normal pregnancy serum HCO3- DECREASES (Likely in response to chronic respiratory alkalosis) (4) Blood pressure DECREASES (nadir at 20 weeks gestation) ***BP starts to drop during 1st trimester and is at nadir at 20 weeks GA ***++Vasodilation (Starts in 1st trimester, Increased NO, Decreased Endothelin, RAS stimulated in response to lower BP, vasodilation) (5) Creatinine should DECREASE in pregnancy ***GFR and RPF both INCREASE in pregnancy (peak at 20 weeks) and creatinine production remains the SAME so SERUM CREATININE tends to DECREASE (6) ACE-inhibitors are CONTRAINDICATED in pregnancy - Remember to ask about breastfeeding before re-initiating meds! (7) It is NORMAL to have LOW SODIUM, LOW CALCIUM, and LOW ALBUMIN during PREGNANCY (8) Plasma volume INCREASES by 50%, largest rate of increment midpregnancy (9) INCREASED 1,25 (OH)2 Vitamin D3 [Increased renal and placental production] (10) INCREASED GI ABSORPTION of Ca2+ (11) PTH levels LOWER IN PREGNANCY (12) Serum Mg2+ DECREASE

What actions does Angiotensin 2 have on the kidney?

(1) Constriction of EFFERENT arteriole increasing GFR (2) ↑ Na and HCO3 reabsorption in proximal tubule ***↑ intravascular volume and BP

What stimulates aldosterone secretion?

(1) Decreased Blood Volume (2) Increased plasma K concentration

What are the major causes of hypertonic disorders?

(1) Excess Free H2O Loss - Central DI (defective ADH secretion) - Nephrogenic DI (defective ADH action) - Sweating - Diarrhea - Severe burns (2) Inadequate Free H2O Intake - Impaired thirst - Inadequate access to H2O (3) Solute diuresis - Hyperglycemia - Hypertonic IV infusion

***Dyslipidemia Medications

(1) HMG CoA Reductase Inhibitor (e.g. Atorvastatin) ***MOA: Inhibits cholesterol biosynthesis, ↓ LDL synthesis, ↑ LDL clearance, modest ↑ HDL, limited ↓ VLDL ***CONTRAINDICATIONS: Active liver disease, Persistant ↑ in AST, ALT ***SIDE EFFECTS: GI symptoms, Rash, Pruritus, ↑ Liver Enzymes, Myosnis, Rhabdomyolysis

What stimulates ADH secretion?

(1) Increased plasma osmolarity (2) Greatly decreased blood volume

Cortisol ***Promotes Gluconeogenesis & Suppresses Inflammation (via inhibition of phospholipase A2) under conditions of physiologic stress

(1) Maintains BG - Increases gluconeogenesis - Decreases glucose uptake by cells - Increases Lipolysis - Increases Protein catabolism (2) Anti-Inflammatory Effects ***Inhibits Phospholipase A2 - Inhibits IL-2 production (3) Vasoconstriction - Increases alpha1-receptors

Risk factors for pyelonephritis

(1) Pregnancy (2) Vesicoureteral reflux (3) Anatomic anomalies (4) Indwelling catheters (5) Kidney stones

Eight surgically correctable causes of hypertension.

(1) Renal artery stenosis (2) Coarctation of the aorta (3) Pheochromocytoma (4) Conn's syndrome (5) Cushing's syndrome (6) Unilateral renal parenchymal disease (7) Hyperthyroidism (8) Hyperparathyroidism

Whipple's Triad

(1) Symptoms of hypoglycemia hunger, shakiness, nervousness, sweating dizziness or light-headedness, fatigue, confusion, difficulty speaking, anxiety, weakness (2) Low blood sugar (3) Resolution of symptoms with carbohydrate ingestion

What actions does PTH have on the kideny?

(1) ↑ Ca reabsorption (2) ↓ Phosphate reabsorption (3) ↑ 1,25-(OH)2 Vit D production

What actions does aldosterone have on the kidney?

(1) ↑ Na reabsorption in distal tubule (DT) (2) ↑ K secretion in DT (3) ↑ H ion secretion in DT

In ARPKD, small cysts form in both kidneys, in a specialized part of the kidney tubule called the collecting duct. ***Enlarged Kidneys and Liver ***HTN ***Underdeveloped lungs ***Significant renal failure in utero can lead to Potter's

***The disease also affects the LIVER, causing a condition called CONGENITAL HEPATIC FIBROSIS (CHF). This disease may result in an ENLARGED liver and spleen that can cause life-threatening GI BLEEDING and LOW blood cell counts. ***In utero, kidney function may be impaired, which DECREASES the level of amniotic fluid. Since amniotic fluid is vital for lung development, infants with ARPKD often have UNDERDEVELOPED LUNGS. 30-50% of infants die because of serious breathing difficulties and other lung complications.

HYPOthyroidism - Overview ***Types of hypothyroidism and site of defect (1) Primary hypothyroidism: Thyroid gland (2) Secondary hypothyroidism: Pituitary gland (3) Tertiary hypothyroidism: Hypothalamus (4) Thyroid hormone resistance: Peripheral tissues ***90% of patients: Lethargy, Weakness, Slow Speech, and Dry, Coarse Skin ***Fatigue, Cold Intolerance, and Hoarseness occur frequently ***Delayed absorption of nutrients and drugs ***Slower metabolism of drugs and anesthetics ***Decreased Clearance of Circulating Enzymes (e.g. AST and ALT are often elevated) and Decreased Catabolism of LDL ***Major deposition of glycosaminoglycans and interstitial edema in patients with hypothyroidism is referred to as MYXEDEMA

***Consequences are most SEVERE when hypothyroidism presents in infancy - Untreated neonatal hypothyroidism results in irreversible CRETINISM. - The syndrome includes; Mental retardation, growth failure, puffy hands and face, and often deaf-mutism. ***Hypothyroidism that develops later in childhood is associated with: Slowed mentation, ↓ bone development, ↓ longitudinal growth, and delayed sexual maturation. These are reversible with treatment of the hypothyroidism. ***Delayed relaxation of deep tendon reflexes ***Very severe, UNTREATED hypothyroidism results in WEAKNESS, HYPOTHERMIA, HYPOVENTILATION, WATER RETENTION, HYPONATREMIA, HYPOGLYCEMIA, BRADYCARDIA, PERICARDIAL EFFUSION, SHOCK, DEPRESSION, and SEVERE STUPOR (sometimes called MYXEDEMA COMA = MEDICAL EMERGENCY!) Myxedema Coma: - check ACTH and cortisol for evidence of adrenal insufficiency - Aggressive treatment required a) ABCs - patient should be in ICU setting b) Corticosteroids (due to the possibility of concomitant adrenal insufficiency) c) L-Thyroxine d) Supportive measures: mechanical ventilation, fluids, vasopressor drugs, passive rewarming, IV dextrose e) Monitor for arrhythmia

A patient is admitted to the ICU because of a SEVERE METABOLIC ACIDOSIS. The SERUM BICARBONATE is LOW at 14. The patient is DISORIENTED and cannot offer an adequate history. No records are available. What is the most likely diagnosis when the following additional features are described? FEVER, HYPOTENSION, TACHYCARDIA, and an ELEVATED WHITE-CELL COUNT

***Fever, hypotension, leukocytosis, and tachycardia imply the presence of SEPSIS as a cause of metabolic acidosis. The 1st step in the evaluation of any metabolic acidosis is the evaluation of the ANION GAP. An anion gap > 12 is consistent with: Methanol Ueremia Diabetic/alcoholic/starvation ketoacidosis Paraldehyde Isopropyl alcohol/iron Lactic acidosis Ethylene glycol Salicylates "MUDPILES"

What effect does constriction of the efferent arteriole have?

-Decreased RPF -Increased GFR -FF increases (FF = GFR/RPF; Normal FF = 20%)

What does the anterior pituitary secrete?

-FSH and LH -ACTH -GH -TSH -MSH -Prolactin

What does the thick ascending loop of Henle actively reabsorb?

-Na ions -K ions -Cl ions ***Indirectly induces the PARACELLULAR REABSORPTION of Mg2+ and Ca2+

Urine Anion Gap = Urinary Net Charge = [Na+] + [K+] - [Cl-]

***The three main causes of normal anion gap acidosis are: (1) Loss of HCO3- from Gastrointestinal tract (diarrhea) (2) Loss of HCO3- from the Kidneys (RTAs) (3) Administration of acid In NORMAL subjects, the urine anion gap is usually NEAR 0 or is POSITIVE. In METABOLIC ACIDOSIS, the EXCRETION of the NH4+ (which is excreted with Cl-) should INCREASE markedly if renal acidification is intact. Because of the rise in urinary Cl- , the urine anion gap which is also called the urinary net charge, becomes NEGATIVE, ranging from -20 to more than -50 meq/L. The negative value occurs because the Cl- concentration now exceeds the sum total of Na+ and K+. (High level of unmeasured cations = NH4+) In contrast, if there is an IMPAIRMENT in kidney function resulting in an INABILITY to INCREASE NH4+ EXCRETION (i.e. Renal Tubular Acidosis), then Cl- ions will NOT be increased in the urine and the urine anion gap will not be affected and will be POSITIVE or ZERO. In a patient with a hyperchloremic metabolic acidosis: A NEGATIVE UAG suggests GI LOSS OF BICARBONATE (eg diarrhea), a positive UAG suggests impaired renal acidification (ie renal tubular acidosis). As a memory aid, remember 'neGUTive' - negative UAG in bowel causes. Type 1 RTA (DISTAL): INABILITY to secrete H+ in collecting duct, leading to IMPAIRED excretion of NH4+ into urine. (Basicity of urine --> Kidney stones) Type 2 RTA (PROXIMAL): impaired bicarbonate reabsorption (HIGH bicarbonate in urine) Type 4 RTA: defective ammoniagenesis (NH3) due to HYPOALDOSTERONISM (Low H+ Secretion --> High H+ in serum --> Acidosis; HYPERkalemia; HYPOnatremia)

Gold standard in the diagnosis of kidney stones is intravenous pyelography (IVP), which can detect both anatomic abnormalities and ureteral obstruction as a result of stones.

***Uric Acid = Radiolucent stones ***Kidney stones SMALLER than 4 mm are likely to pass spontaneously, whereas those LARGER than 7 mm have a low likelihood of passing spontaneously. ***Any symptoms such as PAIN, FEVER, or OBSTRUCTION with HYDROURETER should prompt a REFERRAL TO A UROLOGIST for possible stone extraction. Recurrent stone formers should undergo metabolic testing to prevent or reduce the frequency of development of subsequent stones.

Calcitriol

- Active form of Vitamin D - Raises extracellular levels of calcium and phosphate and promotes the mineralization of bones. These metabolic changes are the result of effects on the intestine, kidneys, and bone: (1) Increases intestinal calcium and phosphate absorption (2) Increases bone resorption of calcium and phosphate (3) Increases renal reabsorption of calcium and phosphate

Exogenous Pathway ***Involves metabolism of INGESTED fat

- Dietary TG is partially hydrolyzed in the intestine by pancreatic lipase before being absorbed. - TGs are reformed in intestinal cells and are incorporated into CHYLOMICRONS. ***Chylomicrons are NORMALLY present in the POSTPRANDIAL state but NOT in the fasting state. ***They are the BIGGEST and LIGHTEST LIPOPROTEIN PARTICLES ***Chylomicrons contain 80-90% TG (∴ float to the top of a refrigerated tube of plasma) - Chylomicrons are transported to the circulation via the lymph. - Circulating chylomicrons interact with plasma HDL and with Lipoprotein Lipase (LpL), an enzyme on the endothelial surface of blood vessel walls. - LpL hydrolyzes the TG to release Free fatty acids and produces remnant particles (NB: Liver - Remnant receptor & LDL receptor). - The liberated free fatty acids are bound to albumin and used as fuel by peripheral tissues (MUSCLES, ADIPOSE) and by the LIVER (either oxidized or used for synthesis of TG). - Free fatty acids provide energy for GLUCONEOGENESIS - Surface material liberated during Chylomicron lipolysis contribute to HDL formation. - Chylomicron remnants are taken up by the liver via the apo E receptor and the apo B/E receptor. The ligand for BOTH receptors is apo E

ACE INHIBITORS ***Reduce mortality in DM2 by hindering the development of DIABETIC NEPHROPATHY

- Inhibits RAAS axis - Increases levels of Bradykinin (a potent vasodilator) - Decreases EFFERENT arteriolar resistance improving glomerular blood flow and REDUCING GFR USES: - Mild to moderate HTN - Proven renal protective function in diabetes (DECREASES HYPERFILTRATION and PROTEINURIA and improves renal function in diabetic nephropathy) SIDE EFFECTS: - Dry cough (due to increased levels of bradykinin) - Teratogenic (DO NOT GIVE TO PREGNANT WOMEN) Hypotension - ARF (patients with BILATERAL RENAL ARTERY STENOSIS) - HYPERkalemia - Angioedema (due to increased levels of bradykinin)

A CYSTIC and FUNCTIONING THYROID NODULE is likely to be BENIGN

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A SOLID and NON-FUNCTIONING THYROID NODULE is likely MALIGNANT

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BETA BLOCKERS (***Anti-Hypertensive) → Secondary HYPERlipidemia, increased BG, Weight Gain

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Scrotal Mass/Testis Cancer ***Short duration of symptoms and NEGATIVE urinalysis: HIGH probability of torsion ***Testicular GERM CELL Tumors = More than 90% of testicular tumors, most common malignancy in men age 15-34 ***SEMINOMA - MOST COMMON TESTICULAR TUMOR, MEAN AGE 40 years, Cure rate 95% when confined to testis, WELL DEFINED, UNIFORM, HYPOECHOIC ON U/S, Single or multinodular gray-tan mass, Sheets or lobules of CLEAR CELLS associated with LYMPHOCYTES, VERY SENSITIVE TO RADIATION, hemorrhage or necrosis usually NOT present ***NSGCT - embryonal (MOST COMMON COMPONENT OF NSGCT; 2/3 of patients have advanced disease, vascular invasion common), teratoma, yolk sac tumor (AFP; Presence of YST in advanced stage is associated with poor prognosis, ***Pure form is a childhood tumor (<3 years). Most common testicular tumor of childhood), choriocarcinoma (HCG), MIXED NSGCT = most common (can have seminoma) - 1/3 present with metastatic disease - Cure rate is~90% all stages ***LYMPHOMA- Most common testis tumor in men >50 y.o. ***Testicular Germ Cell Neoplasia Tumor Spread - VIA LYMPHATICS (Retroperitoneal/para-aortic lymphnodes, Mediastinal lymph nodes, Supraclavicular lymph nodes - Hematogeneous spread is later) - Orderly lymphatic spread for all but choriocarcinoma (which is hematogenous)

- Testes START IN ABDOMEN and descend (They go through the INGUINAL CANAL) ***PAINFUL SCROTUM 1. TESTICULAR TORSION (***Rule Out) *Congenital abnormality of the tunica vaginalis *"Bell Clapper" Testicle *Classically young boy or adolescent, SUDDEN ONSET of pain, +/- N&V, High riding, swollen and tender testis, Afebrile, NORMAL URINALYSIS (Good clue to help r/o epididymitis) *Tx: IMMEDIATE Surgical exploration, detorsion and then fixation of BOTH testicles. 2. APPENDIX TESTIS TORSION *Usually present later, i.e. 1-2 days after onset, pain is less severe *Diagnosis confirmed if necrotic appendix is visible through scrotum *No need to explore other side 3. ACUTE EPIDIDYMITIS *Usually in sexually active adults (Chlamydia Tx: Azithromycin or Doxycycline/Gonorrhea - ceftriaxone or cipro) *Relatively gradual onset of testicular pain * Treatment includes bed rest and SCROTAL ELEVATION UNTIL PAIN SUBSIDES. * Potential complications: Scrotal abscesses, infertility, testicular atrophy, chronic epdidymitis 4. TRAUMA *Rule out trauma with U/S *If rupture: Surgical repair *Complications: Loss of testis, decreased fertility, decreased hormone function 5. FOURNIER'S GANGRENE *Severe skin infection, Edema, Swelling, Malodorous, Pain out of proportion to appearance 6. HEMORRHAGE INTO NEOPLASM 7. INCARCERATED HERNIA ***Chronic scrotal pain - Orchalgia (RULE OUT TUMOR W/ EXAM & U/S) - Causes: Granuloma, cystic lesions, hernia - Tx: Reassurance, NSAIDS ***Spermatic Cord Contains 1) Testicular ARTERY (direct branch from aorta) 2) Pampiniform plexus of VEINS 3) LYMPHATICS (drain to Para-Aortic and Interaortocaval nodes) 4) VAS DEFERENS 5) CREMASTERIC MUSCLE FIBERS 6) GENITAL BRANCH OF THE GENITOFEMORAL NERVE ***PAINLESS SCROTAL MASS 1. HYDROCELE *Fluid within tunica vaginalis *Testis not palpable *Transilluminates *Obstruction or Inflammatory *Treated Surgically 2. INDIRECT HERNIA 3. SPERMATOCELE * Mass separate from testicle (Usually on upper pole) * Transilluminates * Treatment is surgical excision if indicated for pain or fertility 4. VARICOCELE * Dilation of the pampiniform venous plexus (aka gonadal vein) * Most commonly LEFT sided ***Obtain U/S or CT of abdo/pelvis if Right sided varicocele found *VERY COMMON - 1/7 MEN *Treatment is ligation of veins at internal ring 5. TESTIS CANCER (***RULE OUT) ***MOST COMMON SOLID ORGAN MALE CANCER 20-35 year old * Risk Factors: WHITES, DES, ESTROGEN, CRYPTORCHIDISM *FIRM or HARD MASS WITHIN THE TESTICLE *Does NOT TRANSILLUMINATE ***ESSENTIAL LABWORK: (1) Alphafetoprotein (Produced by pure embryonal, teratocarcinoma, yolk sac, mixed tumors - Falsely elevated in liver dysfunction, viral hepatitis and ETOH), (2) βHCG (All choriocarcinomas, 40-60% embryonal, 5-10% seminoma - Falsely elevated in hypogonadism and marijuana use) (3) LDH ***IMAGING: U/S SCROTUM (if positive speak to Urologist <24 hours), CXR, CT abdo/pelvis "HYPOECHOIC" = DARK AREA IN A SNOWBALL Tx: RADICAL ORCHIECTOMY - INGUINAL approach (Avoid seeding the scrotum and disrupting lymphatics) - Wait 5 half lives before rechecking markers ***Primary Neoplasm (95% GERM CELL; ***MOST COMMON MALIGNANCY IN MEN AGE 15-34) - Seminoma VS Non-Seminoma GERM CELL - Seminoma (30-60%), Mixed (40%***Majority of non-seminomatous germ cell tumors are mixed types), Teratoma (10%), Embryonal (3-4%), Choriocarcinoma (1%), Yolk Sac (Most common testicular tumor of childhood). NON GERM CELL - LYMPHOMA (5%), Leydig (1-3%) - LYMPHOMA: Most common testis tumor in men >50 y.o., Most common secondary testis tumor, 50% bilateral - LEYDIG CELL TUMOR: 25% in children, early virulization, Gynecomastia in adults PATTERN OF METASTATIC SPREAD - Orderly lymphatic spread for all but choriocarcinoma (which is hematogenous) - Initial "landing zone" is RETROPERITONEAL NODES near renal hilum - Spread is outward from there, usually up to mediastinum and then lung - Visceral metastases occur in advanced disease 6. EPIDIDYMAL CYST 7. SYPHILITIC GUMMA CONSEQUENCES of PATENT PROCESSUS VAGINALIS: - Infants and children - Soft painless scrotal swelling which changes size according to position - Transilluminates - Treated surgically by tying off the patent processus at internal inguinal ring

CHYLOMICRONS * 1/2 life of b/w 5-30 minutes (should only be present fo short periods after meals) * Decreased clearance of chylomicrons → PANCREATITIS, LIPEMIA RETINALIS, ERUPTIVE XANTHOMATA

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Calcium oxalate crystals can resemble envelopes or dumbbells and the majority form in the INTERSTITIUM of the kidney.

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Cl- and HCO3- are the MAIN ANIONS in the ECF

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FSH → Sertoli Cells → Spermatogenesis

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Flank Pain, Fever and Chills → UPPER UTI

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Osteogenesis Imperfecta *AD *Congenital *Defect in Type 1 collagen production *BLUE SCLERA *Fragile bones (MULTIPLE FRACTURES) *Early hearing loss

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PREGNANCY: Estrogen → Increased synthesis of thyroid binding globulin resulting in a greater amount of total T4 but a normal amount of free T4.

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Prolactin is INHIBITED by DOPAMINE and STIMULATED by ESTROGEN MALES: Prolactin → Decreases Libido (inhibition of GnRH)

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RBCs from a NONglomerular source more closely resemble peripheral blood on microscopy, with ISOMORPHIC RBCs and absence of casts.

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Excess Thyroid Hormone Ingestion (Thyroiditis Factitia) ***Ingestion of exogenous thyroid hormone & Thyroiditis - ↑ FT4, ↓ TSH, and Suppressed RAIU. HOWEVER, thyroiditis usually causes an ↑ of serum thyroglobulin, which is released from the damaged gland. The Thyroglobulin level is NORMAL or LOW after exogenous hormone ingestion b/c TSH and endogenous hormone release are SUPPRESSED

- There is NO GOITER, since TSH is suppressed by exogenous hormone ***HIGH FT4, LOW TSH, SUPPRESSED RAIU. Normal or LOW THYROGLOBULIN

Sick euthyroid syndrome

- This condition can be seen in ill, premature infants. - Reverse-T3 is made instead of the active form of T3 resulting in a HYPOTHYROID state with a NORMAL TSH.

Endogenous pathway ***ALWAYS ACTIVE ***Involves VLDL synthesis in the ER of the LIVER - This synthesis is driven by FATTY ACIDS, which are used for TG synthesis, and apo B-100. - These VLDL particles are secreted by the liver and carry endogenous TG and cholesterol to the circulation

- VLDL contains 50-60% TGs and some cholesterol, apo B-100 (ONE PER MOLECULE), apo C-II, and apo E. - VLDL interacts with HDL and is hydrolyzed by LpL. During hydrolysis, surface material is transferred to HDL, and free fatty acids are transferred to peripheral tissues and the liver. - During hydrolysis, VLDL remnants are formed. - These remnants are further hydrolyzed to produce IDL and LDL or removed by the liver via LDL and remnant receptors. ***LDL is the FINAL PRODUCT of VLDL Lipolysis ***LDL is the MAJOR CARRIER OF CHOLESTEROL IN THE BLOOD ***Apo B-100 is the LIGAND for LIVER LDL RECEPTORS ***Defects in the structure of APO B-100 or the LDL RECEPTOR lead to the ACCUMULATION of LDL in the blood and INCREASED BLOOD CHOLESTEROL LEVELS. - When LDL is taken up by cells through the LDL receptor, it is transferred to the lysosomes where free cholesterol is released and used for membrane synthesis. - The free cholesterol also enters a regulatory pool. As the seize of the regulatory pool INCREASES, further cellular accumulation of free cholesterol is prevented by: (1) INHIBITION of HMG CoA reductase (rate limiting enzyme of cholesterol synthesis) (2) A DECREASE in the # of LDL receptors on the cell membrane, so that less cholesterol can enter the cells (3) ESTERIFICATION of free cholesterol with fatty acid to form cholesterol esters by the enzyme ACAT ***The development of atherosclerosis involves lipoprotein uptake by UNREGULATED PATHWAYS (e.g. unregulated uptake of oxidized LDL by scavenger receptors) ***Remnant particles (both CHYLOMICRON and VLDL) also are potentially atherogenic. They can remain in the circulation for a long time if there are abnormalities in apo E or in the liver receptors. → Remnants become cholesterol enriched by ongoing transfer of cholesterol from HDL in exchange for TGs. → The cholesterol rich remnants can be taken up by cells of the BV wall and can cause atherosclerosis.

Thyroid Cytology - Fine needle aspiration biopsy

- provides a small amount of material for screening thyroid nodules for MALIGNANT CELLS.

A man comes to the ED with WEAKNESS and ORTHOSTATIC HYPOTENSION, He has HYPERPIGMENTED SKIN, HYPONATREMIA, HYPERKALEMIA, and METABOLIC ACIDOSIS. DARK LINES are visible on his GUMS above the teeth. 1. What is the most likely diagnosis? 2. What is the next step in the management of this patient? 3. What is the most accurate diagnostic test?

1. ADDISON's DISEASE and ADDISONIAN CRISIS are the LOSS OF ALDOSTERONE from the adrenal gland resulting in LOSS OF SODIUM AND WATER and the development of HYPOTENSION. = Primary Adrenal Insufficiency 2. The most urgent step is to DRAW A CORTISOL LEVEL and ADMINISTER SALINE and HYDROCORTISONE ***Acute treatment is more important than waiting for the results of specific endocrine diagnostic tests because of the RISK OF DEATH FROM HEMODYNAMIC COMPROMISE 3. ACTH (Cosyntropin) STIMULATION testing is the MOST SPECIFIC test. This is the measurement of cortisol levels BEFORE and AFTER administering artificial ACTH. In a NORMAL patient the cortisol level will RISE with ACTH.

What hormones act on the kidney?

1. ADH 2. Aldosterone 3. Angiotensin II 4. Atrial Natriuretic Peptide 5. PTH

Diabetic Medications*** ***Sensitizers (Promote uptake of glucose by peripheral tissues; Are useful during the FASTING state) - Biguanide - TZDs (the glitazones) - Incretins: DPP-4 (the gliptins) - Glucagon-Like Peptide (GLP)-1 Analogue ***Secretagogues (promote increased insulin secretion, are useful during the POST PRANDIAL stage, short acting offer better control, can cause HYPOGLYCEMIA due to over-secretion of insulin) - Sulfonylureas - Meglitinides (the glinides) ***Absorption reducers - Glucosidase inh.

1. Biguanide (METFORMIN = 1st LINE) ***MOA: Sensitizes peripheral tissues to insulin → Increases glucose uptake; ↓ hepatic glucose production; ↓ HbA1c 1-1.5% ***Useful in OBESE TYPE 2 DM ***IMPROVES both FASTING and POSTPRANDIAL HYPERGLYCEMIA; DECREASES TG ***CONTRAINDICATIONS: Moderate to severe LIVER, RENAL, and CARDIAC DYSFUNCTION ***SE: GI UPSET (abdo. discomfort, bloating, diarrhea), LACTIC ACIDOSIS, ANOREXIA 2. Insulin Secretagogue (SULFONYLUREAS - e.g. glyburide) ***MOA: Stimulate INSULIN RELEASE from β cells by causing K+ CHANNEL CLOSURE → DEPOLARIZATION → Ca2+ MEDIATED INSULIN RELEASE ***Used in NON-OBESE DM2 ***↓ HbA1c 1-1.5% ***CONTRAINDICATIONS: Moderate to severe liver dysfunction; AVOID GLYBURIDE in patients with severe kidney dysfunction and the elderly; DO NOT COMBINE with a non-sulfonylurea or preprandial insulin ***SE: HYPOGLYCEMIA and Weight Gain 3. Insulin Sensitizers (Thiazolidinedione) ***MOA: Sensitizes peripheral tissues to insulin → INCREASES glucose uptake. Decreases FFA release from adipose. Binds to Nuclear receptor PPAR-y. ***CONTRAINDICATIONS - Severe liver dysfunction; NYHA > class II CHF; DO NOT COMBINE WITH INSULIN ***SE: EDEMA (peripheral & pulmonary), CHF, Anemia, Weight gain, fractures 4. Alpha Glucosidase Inhibitor (Acarbose) - DECREASE POSTPRANDIAL HYPERGLYCEMIA ***MOA: Decrease carbohydrate GI absorption by INHIBITING brush border alpha-glucosidase ***CONTRAINDICATIONS: Inflammatory bowel disease, severe liver dysfunction ***SE: Flatulence, abdominal cramps, diarrhea 5. Incretins: Dipeptidyl Peptidase-4 Inhibitor ("gliptans" - e.g. Sitagliptan) ***MOA: Inhibits degradation of endogenous anti-hyperglycemic incretin hormones - Incretin hormones STIMULATE INSULIN SECRETION, INHIBIT GLUCAGON RELEASE, and DELAY GASTRIC EMPTYING ***CONTRAINDICATIONS (Sitagliptan): DM1, DKA, Kidney disease ***SE: Nasopharyngitis, URTI, Headache, Pancreatitis 6. Glucagon-like Peptide (GLP)-1 Analogue (e.g. Exenatide) ***MOA: Binds to GLP-1 receptor to PROMOTE INSULIN RELEASE; Slows gastric emptying, SUPPRESS inappropriately ELEVATED GLUCAGON LEVELS; Causes Beta-cell regeneration and differentiation in vitro. ***CONTRAINDICATIONS:

A man comes in with a long history of EPISODIC FLUSHING OF HIS HEAD AND NECK. The flushing is associated with STRONG EMOTIONS and the use of ALCOHOL. He is HYPOTENSIVE and TACHYCARDIC with the episodes. He has ABDOMINAL CRAMPING and DIARRHEA. On physical examination, there are TELANGIECTASIA and the MURMURS OF TRICUSPID INSUFFICIENCY and PULMONIC STENOSIS. 1, What is the most likely diagnosis? 2. What is the best initial diagnostic test?

1. CARCINOID SYNDROME most often presents with episodes of CUTANEOUS FLUSHING in association with DIARRHEA and ADBOMINAL CRAMPING. HYPOTENSION and TACHYCARDIA occur with the episodes. The recurrent episodes of flushing lead to VASCULAR TELANGIECTASIA. Longstanding disease is associated with RIGHT-SIDED CARDIAC LESIONS (e.g. TR, PS) from the chronic exposure to serotonin. Some patients have wheezing 2. The best initial test is a urinary hydroxyindoleacetic acid (5-HIAA) level. The tumors are localized in the GI tract with abdominal CT and pentetreotide imaging.

What are the 4 endocrine functions of the kidney?

1. EPO release 2. Vitamin D conversion (1alpha-hydroxylase) 3. Renin release 4. Prostaglandins release

What 3 layers form the glomerular filtration barrier?

1. Fenestrated capillary endothelium 2. Fused basement membrane with heparan sulfate (negative charge barrier - ***repel anionic proteins such as albumin) 3. Epithelial layer consisting of podocyte foot processes ***Proteinuria (>3.5g/day = NEPHROTIC) (1) Problem with the glomerular capillary wall - CLINICALLY SIGNIFICANT - Mainly ALBUMIN - DETECTED on Urinalysis Dipstick - Is the urine sediment active or benign? BENIGN - Lack of inflammation in the glomerular capillary wall - Immune process or damage to the EPITHELIAL side of the glomerular capillary wall - No access to circulating leukocytes - Lots of proteinuria - Few RBC or WBC - No cellular casts - Proteinuria and/or Lipiduria - Few granular casts ***Nephrotic Syndrome - Nephrotic range proteinuria (>3.5 grams/d) - Low albumin - High cholesterol - Lipiduria - Edema - Benign urine sediment - Always persistent - Reflects significant GLOMERULAR DISEASE - Primary = Confined to kidney; Secondary = Systemic Illness ***Proteinuria (>150mg/d) → Glomerular → Benign urine sediment →Persistent (1) Minimal change disease (2) Focal segmental glomerulosclerosis (3) Membranous nephropathy (4) Diabetic nephropathy (5) Protein deposition disease (eg. Amyloidosis) ACTIVE - Indicates INFLAMMATION in the glomerular capillary wall - immune process on the ENDOTHELIAL side of the glomerular capillary wall or mesangium - Access to complement and circulating leukocytes - Proteinuria (generally LESS than when injury is on epithelial side) - RBCs/casts - Granular casts - WBCs/casts - Proteinuria (2) Problem with tubules (a) Defect in proximal tubule function (Hereditary or secondary to tubulointerstitial disease) - NOT detected by urinalysis dipstick - RARELY clinically significant (b) Overflow proteinuria - MULTIPLE MYELOMA ***Non-nephrotic proteinuria (1) Transient (e.g. fever, exercise, urinary tract infection) (2) Orthostatic (***seen in healthy adolescents) (3) Persistent (usually reflects glomerular disease)

A woman comes to the office because of INFREQUENT PERIODS. Her menstrual abnormalities have been going on for several months. On PE, she has GALACTORRHEA. Her urine HCG is NORMAL. 1. What is the most likely diagnosis? 2. What is the most accurate diagnostic test?

1. GALACTORRHEA is the abnormally increased flow of milk from the breasts. It is caused by HYPERPROLACTINEMIA. Medications such as ALPHA-METHYLDOPA TRICYCLIC ANTIDEPRESSANTS or PHENOTHIAZINES and BETA-BLOCKERS can cause it. it can occur NORMALLY from PREGNANCY and the FIRST STEP IS ALWAYS A PREGNANCY TEST. Head trauma can RUPTURE THE PITUITARY STALK and REMOVE the normally INHIBITORY DOPAMINE that comes down from the hypothalamus. If these have been excluded, MRI of the brain may show a PITUITARY TUMOR. ***Prolactin INHIBITS the release of of LH and INHIBITS menstruation 2. MEASURE THE PROLACTIN LEVEL. If it is markedly ELEVATED in the ABSENCE of pregnancy, than an MRI IS THE MOST ACCURATE TEST TO DETECT A PITUITARY LESION.

A patient comes in with ANXIETY, unexplained WEIGHT LOSS, DIARRHEA, TACHYCARDIA, and PALPITATIONS. PE shows TREMOR, THIN HAIR, and MOIST SKIN. The Thyroxine (T4) level is ELEVATED. 1. EXOPHTHALMOS, skin abnormalities above the knee, and PROPTOSIS. 2. An ELEVATED TSH level 3. A TENDER gland 4. Normal-appearing gland, LOW TSH, LOW RADIOACTIVE IODINE UPTAKE

1. GRAVES DISEASE is characterized by OCULAR and SKIN FINDINGS. The radioactive iodine scan reveals a HYPERFUNCTIONING GLAND. The TSH is LOW. ***Treatment is with METHIMAZOLE or PROPYLTHIOURACIL (PTU), followed by radioactive ablation and hormone replacement, if hypothyroid. 2. TSH-PRODUCING TUMORS are the only form of HYPERthyroidism associated with an ELEVATED LEVEL OF TSH. Perform an MRI OF THE BRAIN to confirm the diagnosis. 3. SUBACUTE THYROIDITIS is associated with a TENDER GLAND. The TSH level will be SUPPRESSED and the RADIOACTIVE IODINE UPTAKE (RAIU) WILL BE DIMINISHED 4. SILENT THYROIDITIS is associated with a NORMAL-APPEARING GLAND, LOW TSH LEVEL, and LOW RAIU, The gland is NONTENDER.

***What are the factors that govern tissue swelling?

1. HIGH hydrostatic pressure (***CV PROBLEMS) ***Increased venous pressure generates edema (e.g. severe heart failure, tricuspid valve disease) 2. LOW oncotic pressure ***Low protein (albumin) levels - Low production or high losses 3. LEAKY cappillaries ***Widespread severe inflammation (SEPSIS) ***Determine the INTRAVASCULAR VOLUME STATUS vs. THE EXTRAVASCULAR VOLUME STATUS INTRAVASCULAR VOLUME STATUS (vol. inside the blood vessels) - JVP - Signs the vascular tree is UNDERFILLED *low blood pressure *orthostatic hypotension *evidence of organ hypoperfusion (kidney - ↑ Cr) EXTRAVASCULAR VOLUME STATUS - Tissue edema (feet, legs, genitals, hands, arms, face, eyes) - 3rd space fluid (3rd space = not in vessels, not in tissues) *Ascites *Pleural effusions NB: The EXTRA-vascular status can be HIGH and The INTRA-vascular status can be HIGH, NORMAL or LOW DIURETICS (1) LOOP DIURETICS (FUROSEMIDE) - INHIBIT the Na/K/2 Cl co-transporter channel - MORE Na arrives at distal tubule (Na+ reabsorbed in exchange for K+ and H+ excreted) - Lose: H2O, Na+, K+, H+, Mg2+, Ca2+ ***Toxicity can occur through complications of excessive loss of these items LOOP DIURETIC TOXICITY * Too much H2O Loss * Hemodynamic problems (HIGH HR, LOW BP) * Renal Hypoperfusion - higher creatinine, even by 10-20% indicates diuretic should be stopped or reduced * Low K+ can increase probability of ARRHYTHMIAS such as A. Fib * Low H = High Bicarbonate = Metabolic alkalosis. Look for a rising bicarb to indicate "too much" diuretic * OTOTOXICITY (usually reversible, more probable with other ototoxic agents - gentamicin) * There is a risk of ALLERGIC REACTION in patients with a true "sulpha" allergy (common to sulfa antibiotics) HCTZ - most commonly used as 1st line anti-HTN K+ SPARING -

What are the major actions of PTH

1. Increases RELEASE of calcium and phosphorous from bone 2. Increases renal tubular REABSORPTION of calcium 3. Increases renal phosphate EXCRETION 4. Increases renal conversion of 25(OH)D to ACTIVE 1,25(OH)D ***NET RESULT: INCREASED PLASMA CALCIUM and DECREASED PLASMA PHOSPHOROUS

A young man is being evaluated for HTN. He has episodes of HEADACHE, PALPITATIONS, TACHYCARDIA, and SWEATING along with the HTN 1. What is the most likely diagnosis 2. What is the most accurate diagnostic test?

1. PHEOCHROMOCYTOMA presents with episodes of HTN, PALPITATIONS, TACHYCARDIA, and HEADACHE. The clue to the diagnosis is the EPISODIC nature of the HTN. The other symptoms are nonspecific. 2. The best INITIAL TEST is the BLOOD LEVEL OF FREE METANEPHRINES. This is MORE SENSITIVE than levels of epinephrine and norepinephrine because the CATECHOLAMINES are secreted in an EPISODIC FASHION and have a SHORT 1/2 LIFE. ***A 24-HOUR URINE FOR CATECHOLAMINES & METANEPHRINES IS HIGHLY SENSITIVE AND SPECIFIC as well. USE CT or MRI scanning of the adrenal glands if the catecholamine levels are ELEVATED in order to localize the tumor.

A patient comes in with MUSCULAR WEAKNESS, POLYURIA, and POLYDIPSIA. There is a METABOLIC ALKALOSIS and the K+ level is profoundly LOW. What is the most likely diagnosis when the following additional features are described? 1. HTN, LOW RENIN ACTIVITY WITHOUT EDEMA 2. HIGH RENIN and HIGH ALDOSTERONE activity with an ELEVATED LEVEL OF URINARY SODIUM until the body is depleted of sodium. URINARY CALCIUM IS HIGH. Normal BP 3. Patient has a BOX OF LICORICE in his hand. The RENIN LEVEL IS LOW. BP is HIGH

1. PRIMARY HYPERALDOSTERONISM, or CONN's SYNDROME, presents with HTN, HYPOkalemia, and METABOLIC ALKALOSIS. The PLASMA RENIN activity is SUPPRESSED because of HTN. HIGH ALDOSTERONE levels with LOW RENIN LEVELS is the HALLMARK of PRIMARY HYPERALDOSTERONISM. ***The patient's MUSCLE WEAKNESS is from LOW K+ ***The polyuria is NEPHROGENIC DIABETES INSIPIDUS from LOW K+ 2. BARTER's SYNDROME is from a GENETIC defect in the LoH. Patients LOSE Na+, Cl-, and Ca2+, resulting in vol. depletion and secondary ELEVATIONS in RENIN and ALDOSTERONE LEVELS. BP is NORMAL or LOW 3. Licorice contains a substance that is similar in function to ALDOSTERONE. Licorice ingestion will present in an IDENTICAL fashion to PRIMARY HYPERALDOSTERONISM. ***Anything that gives LOW K+ → Muscular weakness (Nonspecific finding of hypokalemia). BP is HIGH

What increases 1,25-(OH)2 vitamin D formation

1. PTH 2. Low calcium 3. Low Phosphate

Cause of Chronic Renal Failure

1. Prerenal - Renal artery stenosis - Embolism (both kidneys) 2. Renal - DM - SLE - HTN - Amyloidosis - Chronic glomerulonephritis - Chronic tubulointerstitial nephritis - Adult polycystic kidney disease - Renal cancer 3. Postrenal - Chronic urinary tract obstruction

Secondary Dyslipidemia/Hypertriglyceridemia ***4D's

4 D's 1. Drugs (Glucocorticoids, OCP, Thiazides, B-Blockers, Accutane, EtOH) 2. Diet (Obesity, Sedentary lifestyle, smoking) 3. Disorders of Metabolism: (Diabetes, Hypothyroidism, Pregnancy, Cushing's..etc) 4. Diseases: Nephrotic Syndrome, CLD, CRF...

TSH, Thyroxine (T4), Thyroglobulin 1. For which clinical scenario(s) are these tests used? 2. What are these substances? 3. When do you answer TSH and Thyroxine (T4)? 4. When do you answer Thyroglobulin?

1. Serum levels of TSH and T4 are measured to assess THYROID FUNCTION (both HYPOfunction and HYPERfunction). THYROGLOBULIN is used to MONITOR RECURRENCE in patients who have been treated for papillary or follicular cancer of the thyroid 2. TSH is produced by the pituitary to stimulate the thyroid. T4 is one of the principal metabolism-inducing hormones produced by the thyroid gland, and THYROGLOBULIN is an iodine-containing glycoprotein synthesized by the thyroid gland from which T4 is derived. THYROID-BINDING globulin is the transport protein. 3. TSH and T4 are ALWAYS the BEST INITIAL TEST for THYROID DISEASE 4. THYROGLOBULIN is to follow the response to the TREATMENT OF THYROID CANCER

A young woman comes to see you because of the FAILURE TO UNDERGO MENARCHE. She has normal breast development but a PAUCITY OF PUBIC HAIR. The vagina is short and the CERVIX IS ABSENT. 1. What is the most likely diagnosis? 2. What is the treatment?

1. TESTICULAR FEMINIZATION or COMPLETE ANDRONGEN INSENSITIVITY often comes to light when there is a failure to achieve menses at the appropriate time. The patient appears female, with NORMAL BREAST DEVELOPMENT,but there is marked DIMINISHMENT IN THE AMOUNT OF PUBIC AND AXILLARY HAIR. The VAGINA IS SHORT, and the CERVIX, UTERUS, and OVARIES ARE ABSENT. Testicles can be found in the abdomen or labia. 2. SURGICAL REMOVAL OF THE GONAD with ESTROGEN REPLACEMENT and DILATION OF THE VAGINA is the management. These patients are emotionally and socially functional as females.

RAIU (Radioiodine Uptake) 1. For which disease(s) is this test the right answer? 2. When do you expect uptake to be high? 3. When do you expect uptake to be low?

1. The measurement of orally ingested radioactive iodine (I121) that accumulates in the thyroid gland is used to DIFFERENTIATE GRAVES'/TOXIC MULTINODULAR GOITER from THYROIDITIS/FACTITIOUS 2. RAIU is INCREASED in GRAVES' DISEASE and with HOT NODULES (Toxic multinodular goiter, toxic solitary nodule). 3. RAIU is DECREASED when THYROIDITIS induces a THYROTOXIC STATE or when a person is ABUSING THYROID HORMONE (thyroiditis factitia) ***Answer RAIU scan when the question shows a case of HYPERTHYROIDISM. The question will include a HIGH T4 level, for instance, and will ask you the next best step to determine the etiology.

A patient is in your office for evaluation of BLOOD IN HIS URINE for the last few days. What is the most likely diagnosis in each of these cases? 1. He has BURNING ON URINATION and must urinate frequently 2. He also has PAIN GOING FROM HIS SIDES INTO HIS GROIN. The pain is extremely severe 3. RED-CELL CASTS AND PROTEIN are found in the urine as well. URINE SODIUM IS LOW. 4. He has recently undergone CHEMOTHERAPY.

1. UTI of any kind, such as cystitis or pyelonephritis, can lead to HEMATURIA. Definitive diagnosis rests on the location of the pain described in the question. Urinalysis and urine culture should still be obtained. 2. NEPHROLITHIASIS, or kidney stones, present with severe flank pain radiating to the groin, also known as RENAL COLIC. 3. GLMERULONEPHRITIS of any kind can present with HEMATURIA. When RED-CELL CASTS, red cells, and MILD PROTEINURIA are present the MOST LIKELY DIAGNOSIS is GLOMERULONEPHRITIS. THE URINE SODIUM IS LOW because of VASOCONSTRICTION of the AFFERENT ARTERIOLE, which is present in ALL forms of glomerulonephritis. 4. CYCLOPHOSPHAMIDE leads to HEMORRHAGIC CYSTITIS.

Consequences of Renal Failure

1. Uremic syndrome - occurs as BUN rises; lethargy, seizures, myoclonus, asterixis, pericardial friction rub 2. Hyperkalemia ***Look for peaked T waves on ECG, which can lead to ventricular fibrillation 3. Metabolic Acidosis - Impaired renal production of HCO3- so H+ cannot be excreted 4. Na+ and H2O Retention - Early CKD --> Decreased urine concentration --> dehydration and Na+ wasting - Late CKD --> Volume overload --> pulmonary edema 5. Renal osteodystrophy - Decreased vitamin D activation and increased bone turnover 6. Anemia - Failure of EPO production 7. HTN 8. Fanconi Syndrome - Damage to proximal tubules compromises reabsorption of glucose, amino acids, phosphate, and bicarbonate

What are the 4 actions of angiotensin II?

1. Vasoconstriction 2. Release of aldosterone from adrenal cortex 3.Release of ADH from posterior pituitary 4.Stimulates hypothalamus to increase thirst

Niacin

1. ↓ fat cell lipolysis → ↓ liver production of apo B - containing lipoproteins (vLDL and LDL) 2. ↑ LPL activity → breaks down TG 3. BOTH TG and LDL levels ↓ 4. AND due to stimulation of the lipolysis pathway, HDL ↑

What are the criteria for the diagnosis of SIADH?

1. ↓ plasma osmolality 2. Inappropriately ↑ urine osmolality for plasma osmolality 3. HYPOnatremia 4. Normal plasma volume 5. Normal renal and adrenal function

What enzyme deficiency will produce BOTH hypertension and masculinization of females?

11-Beta hydroxylase deficiency 11-deoxycorticosterone will act as a mineralocorticoid

A female child is brought to you because of ABNORMAL HAIR GROWTH. She has NOT DEVELOPED MENSTRUATION and she has ACNE, HIRSUTISM of her face, and ABNORMAL BALDING - HTN - HYPOKALEMIA - METABOLIC ALKALOSIS - LEVELS of 11-deoxycorticosterone are elevated

11-Hydroxylase deficiency presents with HTN and HYPOkalemia because of INCREASED levels of 11-deoxycortisone (11DOC). 11DOC has MINERALOCORTICOID activity, which accounts for the HTN and METABOLIC ALKALOSIS. Adrenal hormones end up shunted into the production of adrenal ANDROGENS such as DHEA. ***Conn's syndrome would present similar, but with ELEVATED levels of ALDOSTERONE and DECREASED RENIN.

17-HYDROXYPROGESTERONE LEVEL

17-Hydroxyprogesterone level is the BEST INITIAL TEST to diagnose 21-Hydroxylase deficiency or CAH ***Answer 17-Hydroxyprogesterone in a patient presenting with one of the following syndromes: (1) Female infant with ambiguous genitalia (simple virilizing) (2) Infant with HYPONATREMIA, HYPERKALEMIA, and HYPOTENSION (salt-wasting syndrome) (3) Young woman with HIRSUTISM, ACNE, IRREGULAR MENSES (4) Child with PRECOCIOUS PUBERTY

Hypoglycemic Unawareness *** Prerequisite: Frequent hypoglycemia - Loss of body's perception of what is a "normal" sugar. - Adrenergic symptoms are lost due to: (1) Frequent Lows (2) Autonomic dysfunction (Less recognition of lows, less epinephrine release) - Neuroglycopenic symptoms occur without the preceding warning adrenergic symptoms (coma, seizure...etc)

1st Defense against Hypoglycemia: Decrease in Insulin release 2nd Defense: Increase in Glucagon release 3rd Defense: Increase in Epinephrine release 4th Defense: GH and Cortisol (only if hypoglycemia persists for 30+ minutes) ***Adrenergic "Warning" systems as sugars drop in the 3's (sweating, pale, cool and clammy skin, tachycardia, anxiety and shakiness, weakness and hunger) ***Neuroglycopenic symptoms (confusion, headache, dizziness, seizure, coma) due to insufficient glucose in the brain (as sugars approach the low 3's and 2's)

A patient presents with WEAKNESS, NAUSEA, VOMITING, WEIGHT LOSS, and NEW SKIN PIGMENTATION. Labs show HYPONATREMIA and HYPERKALEMIA. Treatment?

1° adrenal insufficiency (Addison's disease). Treat with replacement glucocorticoids, mineralocorticoids, and IV fluids

A patient complains of HEADACHE, WEAKNESS, and POLYURIA; exam reveals HTN and TETANY. Labs reveals HYPERNATREMIA, HYPOKALEMIA, and METABOLIC ALKALOSIS

1° hyperaldosteronism (due to Conn's syndrome or bilateral adrenal hyperplasia)

A female child is brought to you because of ABNORMAL HAIR GROWTH. She has NOT DEVELOPED MENSTRUATION and she has ACNE, HIRSUTISM of her face, and ABNORMAL BALDING - HYPOTENSION - HYPERKALEMIA - HYPONATREMIA - ELEVATED LEVELS OF 17-HYDROXYPROGESTERONE with DIMINISHED 11-deoxycorticosterone What is the most likely diagnosis?

21-HYDROXYLASE DEFICIENCY presents with HYPOTENSION, HYPERKALEMIA, and METABOLIC ACIDOSIS because of the LOSS of SUFFICIENT MINERALOCORTICOID activity. BOTH aldosterone and 11-deoxycorticosterone levels are decreased. Adrenal hormones are shunted into the EXCESS production of DHEA, which accounts for AMBIGUOUS GENITALIA in FEMALES, such as CLITOROMEGALY. In addition, there is ACNE and HIRSUTISM. ***All forms of CONGENITAL ADRENAL HYPERPLASIA have ELEVATED LEVELS OF ACTH and LOW LEVELS OF CORTISOL. 17-Hydroxyprogesterone levels are INCREASED because that is the precursor that should be converted by 21-hydroxylase.

24-Hour Urine for Metanephrine, Vanillymandelic acid (VMA), and catecholamines

24 hour urine collection for metanephrines, VMA, and catecholamines is the BEST INITIAL TEST for PHEOCHROMOCYTOMA = Adrenal tumor secreting catecholamines. Manifests with TRIAD of HYPERTENSION, DIAPHORESIS, and TACHYCARDIA = Pheochromocytoma is associated with MEN 2 and MEN 3 ***Formed from chromaffin cells in the adrenal medulla (90%) or extra-adrenal sites (10%). ***Most common tumor of the adrenal medulla in adults ***Presentation: HTN, PALPITATIONS, ANXIETY, WEIGHT LOSS, and HEADACHES -all occurring in an EPISODIC fashion ***Tx: Surgical removal of the pheochromocytoma (NB: Alpha blockade (phenoxybenzamine, phentolamine) should be achieved prior to surgery) ***Rule of 10s: 10% familial 10% bilateral 10% malignant 10% in children 10% extra-adrenal ***If the question says the VMA or catecholamines are HIGH, then answer CT or MRI of the ADRENAL GLANDS as the NEXT BEST TEST to find the PHEOCHROMOCYTOMA

5-HIAA

A 24-hour urine level of 5-HIAA is the BEST INITIAL DIAGNOSTIC TEST for CARCINOID SYNDROME. 5-HIAA is the end-product of serotonin metabolism ***Look for a patient with EPISODIC DIARRHEA and/or HYPOTENSION associated with UNEXPLAINED FLUSHING and WHEEZING. ***The MOST ACCURATE TEST for CARCINOID SYNDROME is a BIOPSY.

You are called to evaluate a patient with WORSENING RENAL FUNCTION over the last few days. The Creatinine is 2.5 mg/dL and the BUN is 28 units. The urine sodium is 45 mEq/L and the urine osmolality is 290 mosm/kg. His serum bicarbonate is low. What is the most likely diagnosis when the following additional features are described? The patient has been on GENTAMICIN for the last 8 days.

AMINOGLYCOSIDE-INDUCED RENAL INSUFFICIENCY generally occurs AFTER 5-10 days of exposure to the medication. As with all forms of ATN, the BUN and Creatinine will rise in about a 10:1 ratio. The urine Na+ will be high (>40) and the urine osmolality will be low (<350) because of the INABILITY OF THE DAMAGED KIDNEY TUBULES TO CONCENTRATE URINE. Amphotericin and any other renal toxic medication will result in the same numbers. ***ATN (Lab Investigations) Serum BUN:Creatinine Ratio: 10-15:1 Urine [Na+] > 40 mEq/L FeNa > 1% Urine Osmolality <350 mosm/kg Urinalysis: RBC, Pigmented Granular Casts

What may act as a 'check' on the renin-angiotensin system in heart failure?

ANP

ACE inhibitors

ANTIHYPERTENSIVE for a DIABETIC patient with PROTEINURIA

Dysmorphic red cells and RBC casts → Glomerular source of bleeding (These findings + Proteinuria = Evaluation for glomerular disease)

Abnormal RBC morphology (e.g., dysmorphic RBCs) and the presence of RBC casts are almost PATHOGNOMONIC for PARENCHYMAL DISEASE Primary renal diseases such as membranoproliferative glomerulonephritis (MPGN), acute glomerulonephritis such as poststreptococcal glomerulonephritis (PSGN), and rapidly progressive glomerulonephritis (RPGN) may all have RBC casts in the urine. Any evidence of renal parenchymal disease should prompt a referral to a nephrologist for consideration of a kidney BIOPSY and treatment.

Paget's Disease

Abnormal bone architecture (thickened, numerous fractures, pain) , woven and lamellar bone mosaic

A 55-year-old obese patient presents with dirty, velvety patches on the back of the neck.

Acanthosis nigricans. Check fasting blood sugar to rule out diabetes

Why does the nephron secrete ammonia?

Acts As a buffer for secreted H ions

WBCs in urine

Acute cystitis

RBC casts in urine

Acute glomerulonephritis

Side effects of corticosteroids.

Acute mania, immunosuppression, thin skin, osteoporosis, easy bruising, myopathies

WBC casts in urine

Acute pyelonephritis

H2O Deprivation Test

Allows us to distinguish b/w the causes of DI and to objectively assess patients with HYPERNATREMIA and HIGH URINE OUTPUT - Restrict water intake for 12-24 hours with observation for the VOLUME of urine, urine osmolality, and change in body weight to evaluate whether the kidneys are conserving or excreting water properly. - If the URINE VOL. STAYS ELEVATED after the SERUM OSMOLALITY goes UP, then it is DI. - If there is a DECREASE in VOLUME in response to GIVING VASOPRESSIN/ADH, then it is CENTRAL DI. If there is NO RESPONSE, it is NEPHROGENIC DI ***When you see a case of HYPERNATREMIA and HIGH URINE OUTPUT, answer H2O DEPRIVATION TEST as the BEST INITIAL TEST

Nephritis + cataracts + hearing loss

Alport's syndrome

You are called to evaluate a patient with WORSENING RENAL FUNCTION over the last few days. The Creatinine is 2.5 mg/dL and the BUN is 28 units. The urine sodium is 45 mEq/L and the urine osmolality is 290 mosm/kg. His serum bicarbonate is low. What is the most likely diagnosis when the following additional features are described? There is an EMPTY BOTTLE of ANTIFREEZE at his bedside

Anitfreeze contains ETHYLENE GLYCOL, which leads to ACUTE RENAL FAILURE from OXALIC ACID ACCUMULATION in the kidney tubule. Look for "envelope-shaped oxalate crystals" in the urine. Formic acid accumulates with methanol ingestion and causes blindness.

Drowsiness, asterixis, nausea, and a pericardial friction rub.

Uremic syndrome seen in patients with renal failure

Why is inulin used to measure GFR?

Because it is FREELY FILTERED and is NEITHER ABSORBED or SECRETED

A man is admitted to the hospital with RENAL FAILURE developing over a few days. His serum BICARBONATE is SLIGHTLY LOW. The URINE SODIUM is LOW and the URINE OSMOLALITY is HIGH. FRACTIONAL EXCRETION of Na+ < 1%. Increased [urea] >> Increased [Cr]. What is the most likely diagnosis when the following additional features are described? He has an EJECTION FRACTION OF 24% with EDEMA. A DIURETIC WAS RECENTLY STARTED

CHF from any cause leads to PRERENAL AZOTEMIA. It can become SUDDENLY WORSE with the volume depletion of a DIURETIC. Prerenal azotemia leads to a LOW URINE [Na+] and HIGH URINE OSMOLALITY

LIPOPROTEIN STRUCTURE ***Lipoproteins transport lipids within the body ***Functions of Apolipoproteins: 1) Solubilize Lipid in Plasma 2) Acts as ligands for lipoprotein receptors (apo B and apo E) ****CHYLOMICRONS, VLDLs, REMNANTS, and IDLs contain apo E and apo B. ***apo E has a GREATER AFFINITY for LDL receptors than apo B, so apo E mediates the cellular UPTAKE of these lipoproteins ***LDL contains ONLY apo B, so apo B is the LDL ligand for the LDL receptor. 3) Act as cofactors for enzymes (apo C-II and apo A-I) ***Apolipoprotein C-II is a cofactor for the enzyme LIPOPROTEIN LIPASE (LpL) ***HDL is considered antiatherogenic - does NOT contain apo B

CHOLESTEROL - A component of CELL MEMBRANE structure and a PRECURSOR of BILE ACID and STEROID SYNTHESIS TG - Production and storage of ENERGY LIPOPROTEINS - Since lipids are INSOLUBLE in H2O, they are carried in the plasma as lipid-protein structures called LIPOPROTEINS - The protein portion of a lipoprotein is called an apolipoprotein and is designated by a capital letter (e.g. apolipoprotein A = apo A). - Lipoproteins contain a CORE OF NONPOLAR (totally insoluble) TG and CHOLESTEROL ESTERS. Their SURFACE contains FREE CHOLESTEROL and the detergent-like PHOSPHOLIPIDS and APOLIPOPROTEINS, which enable them to be SOLUBLE in plasma. CHYLOMICRONS and VERY LOW-DENSITY LIPOPROTEINS (VLDLs) - CORES are rich in TGs SMALL, DENSER LIPOPROTEINS such as LDLs and HDLs which contain MORE PROTEIN, have CORES that contain MOSLTY CHOLESTEROL ESTERS. CHYLOMICRON REMNANTS and VLDL REMNANTS, including IDLs, are DENSER than Chylomicrons and VLDLs but LIGHTER than LDLs and HDLs. - Remnants contain approximately equal proportions of cholesterol and TG. ***The MAJOR Lipoprotein receptor that recognizes circulating lipoproteins and allows them to be REMOVED from the circulation is the LDL RECEPTOR (aka B/E receptor because it recognizes apo B and apo E). - The hepatic LDL receptor is involved in LIPOPROTEIN CLEARANCE. ***CHYLOMICRONS, VLDLs, REMNANTS, and IDLs contain apo E and apo B. Apo E has a GREATER AFFINITY for LDL receptors than apo B, so apo E mediates the cellular UPTAKE of these lipoproteins ***LDL contains ONLY apo B, so apo B is the LDL ligand for the LDL receptor. ***Ligand-binding by the LIVER receptors CLEARS the lipoproteins from the circulation, BUT ligand-binding to cells in the BV wall can result in FOAM CELL FORMATION, which initiates ATHEROSCLEROSIS. ***Apo B-containing lipoproteins can be ATHEROGENIC. There is ONLY 1 apo B per lipoprotein particle; therefore, the blood concentration of apo B reflects the # of potentially atherogenic particles in the circulation. ***Apo B is found in all lipoproteins EXCEPT HDL. HDL, which contains large amounts of apo A-I, is considered ANTIATHEROGENIC (prevents atherosclerosis)

Chylomicrons & Chylomicron Remnants

CHYLOMICRONS deliver dietary fat to tissues for fuel - contain small amounts of dietary cholesterol, phospholipid, apo B-48 (ONE PER PARTICLE), apo E, apo C-II, apo A-I, and apo A-IV. ***Chylomicrons are NORMALLY present in the postprandial state but NOT in the fasting state. ***They are the BIGGEST and LIGHTEST LIPOPROTEIN PARTICLES CHYLOMICRON REMNANTS deliver dietary cholesterol to the liver

A 40 year old man with a history of HEPATITIS C comes in with HEMATURIA, JOINT PAINS, and PURPURIC SKIN LESIONS. Urinalysis reveals RED-CELLS, RED-CELL CASTS, and MILD PROTEINURIA What is the most likely diagnosis?

CRYOGLOBULINEMIA is MOST OFTEN ASSOCIATED WITH CHRONIC HEPATITIS C. Cryoglobulinemia leads to RENAL DYSFUNCTION, SKIN LESIONS, and JOINT PAINS. NEUROPATHY is COMMON. ***MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) can occur idiopathically or more commonly, secondary to monoclonal immunoglobulin deposition diseases, autoimmune diseases such as SLE, chronic thrombotic microangiopathies, or chronic infections. There are 2 distinct types: 1) Type 1 (2/3 of cases): Due to deposition of immune complexes. Associated with HEPATITIS B, HEPATITIS C, and CRYOGLOBULINEMIA. Some cases have a NEPHRITIC presentation -70-85% of patients have NO chronic decline in GFR 2) Type 2 (1/3 of cases): Often associated with the C3 nephritic factor (C3NeF). It is also called DENSE DEPOSIT DISEASE, due to the deposition of an electron-dense material b/w the lamina densa and subendothelial space of the GBM. - A majority of patients progress to ESRD after 5-10 years Presentation: Patients with Type 1 disease tend to present with NEPHROTIC syndrome, whereas those with Type 2 can present with either nephortic or nephritic syndrome, or a mix of the two. *Tram-track appearance on electron microscopy and subendothelial humps (TYPE1) or intramembranous deposits (TYPE 2) Tx: Plasma exchange with albumin has been shown to slow disease progression

What is reabsorbed in the early distal tubule under the control of PTH?

Ca ions

The most common type of nephrolithiasis.

Calcium oxalate

Laboratory Studies in Cases of Polyuria: DI Vs. Psychogenic Polydipsia

Central DI Plasma Osmolality: ↑ or Normal Urine Osmolality: ↓ Urine Osmolality during H2O deprivation: No change Urine Osmolality after dDAVP: ↑ Plasma ADH: ↓ ***Patients with Central DI have inappropriately ↓ plasma ADH levels after H2O deprivation BUT are able to ↑ urine osmolality in response to ADH injection. `Nephrogenic DI Plasma Osmolality: ↑ or Normal Urine Osmolality: ↓ Urine Osmolality during H2O deprivation: No change Urine Osmolality after dDAVP: No change Plasma ADH: Normal to High Psychogenic H2O Drinking Plasma Osmolality: ↓ Urine Osmolality: ↓ Urine Osmolality during H2O deprivation: ↑ Urine Osmolality after dDAVP: ↑ Plasma ADH: ↓

A 20-year-old man presents with a PALPABLE FLANK MASS and HEMATURIA. Ultrasound shows BILATERAL ENLARGED KIDNEYS with CYSTS. Associated brain anomaly?

Cerebral berry aneurysms (ADPCKD)

Diuretics

Carbonic Anhydrase Inhibitors (e.g, Acetazolamide) Mechanism: BLOCKS carbonic anhydrase, primarily in the PCT, PREVENTING reabsorption of sodium bicarbonate and leading to diuresis. Uses: Glaucoma, Acute Mountain Sickness (stimulates ventilation via metabolic acidosis), Elimination of acidic toxins (alkalinizes urine, leading to INCREASED excretion of weak acids), and corrects alkalosis. Side Effects: Renal stones (Increases urine concentration of Ca2+ and Phosphates), HYPOkalemia (↑ HCO3- in tubules attracts K+), Hyperchloremic metabolic acidosis (↑ Cl-, ↑H+) Loop Diuretics (e.g. Furosemide) Mechanism: INHIBITS Na+-K+-2Cl- transporter in THICK ascending limb. Decreases (+) luminal potential, leading to INCREASED EXCRETION of CALCIUM and MAGNESIUM Uses: Treatment of acute pulmonary or other edema, hypercalcemia, hyperkalemia, HTN, and ARF. Side Effects: Hypokalemic metabolic acidosis (↓ K+, ↓H+), Ototoxicity, Hyperuricemia (↑ urea), Hypomagnesemia (↓ Mg2+), Allergic reactions (all loop diuretics are sulfonamide derivatives EXCEPT Ethacrynic Acid) Thiazide Diuretics (e.g HCTZ) Mechanism: Inhibits Na+-Cl- cotransporter in DCT Uses: 1st LINE AGENT FOR TREATMENT OF HTN, CHF, HYPERCALCIURIA, and NEPHROGENIC DI Side Effects: Dehydration, Hypokalemia, HYPERCALCEMIA, HYPERGLYCEMIA, HYPERLIPIDEMIA, hyperuricemia, HYPONATREMIA, Allergic reactions (sulfonamide derivatives) K+ Sparing Diuretics Mechansim: Spironolactone and Epleronone DIRECTLY ANTAGONIZE the MINERALOCORTICOID RECEPTOR (target of aldosterone), thereby REDUCING Na+ reuptake in the late DCT and collecting duct. Both drugs PREVENT the aldosterone-mediated INCREASE in apical membrane permeability to K+ (ROMK channels) and therefore are considered "K+ sparing" Amiloride and Triamterene directly INHIBIT ENaCs in the late DCT and collecting duct, which also REDUCES Na+ reabsorption. This renders the charge in the lumen more (+), which is unfavorable for K+ secretion. Hence, these ENaC ANTAGONISTS are also considered "K+ sparing" Uses: Spironolactone (Binds and blocks androgen receptor --> Gynecomastia) and Eplerenone (NO anti-androgen side effects): PRIMARY HYPERaldosteronism (CONN SYNDROME) and EDEMETOUS states caused by SECONDARY HYPERaldosteronism (CIRRHOSIS, NEPHROTIC SYNDROME, and CARDIAC FAILURE) ***ANTI-ANDROGEN ACTIVITY can be useful for treatment of PCOS and HIRSUTISM Amiloride and Triamterene: Counteract K+loss caused by other diuretics, ADJUNCT therapy to other diuretics to TREAT EDEMA or HTN. Side Effects: HYPERkalemia, metabolic acidosis, gynecomastia (spironolactone), impotence (males), abnormal menses (females)

Clues for Pre-Renal Etiology *Hypovolemia or Effective Volume Depletion *Hemorrhage, Dehydration, Atherosclerotic disease of the renal artery, CHF, Cirrhosis, Sepsis *The 2 MOST COMMON causes of AKI in HOSPITALIZED patients are PRE-RENAL AZOTEMIA and ATN (NB: Pre-renal failure can lead to ATN).

Clinical: Decreased BP, Increased HR, and orthostatic HR and BP changes Increased [urea] >> Increased [Cr] Urine [Na+] < 10-20 mmol/L Urine osmolality >500 mosm/kg FeNa+ < 1% Serum BUN:Creatinine Ratio ≥ 20 ***Tachycardia and Hypotension suggest hypovolemia or any form of shock Drugs implicated in Pre-Renal Azotemia: 1. Anti-hypertensives 2. Diuretics 3. NSAIDs 4. ACEi/ARBs

A congenital heart disease that causes 2° hypertension.

Coarctation of the aorta

Hypertension + Hypokalemia

Conn's syndrome (1° aldosteronism)

Thyrotoxicosis = Results from the actions of EXCESS thyroid hormone from ANY CAUSE on peripheral tissues ***HYPERTHYROIDISM refers specifically to OVERPRODUCTION of thyroid hormone by the THYROID GLAND ***Typical presentation of Thyrotoxicosis YOUNG PATIENTS: Nervousness, Tachycardia, Sweating, Lid Lag, Stare and Tremor (This combination = catecholamine excess) NB: Plasma epinephrine levels are NORMAL, but their EFFECTS are ↑ because the # of catecholamine receptors is ↑. Tx: β -blockers (suppress symptoms) ELDERLY PATIENTS - manifestations of thyrotoxicosis are often very subtle. These patients may present with WEIGHT LOSS, FATIGUE, LETHARGY, and DEPRESSION, rather than with signs of catecholamine excess. This presentation = APATHETIC HYPERTHYROIDISM ***This diagnosis should be considered in ELDERLY patients who develop a NEW MOOD DISORDER ***Treatment options for Thyrotoxicosis (1) Antithyroid drugs (thionamides, PTU, or MMI for Graves' disease) (2) Radioactive iodine (3) Partial thyroidectomy NB: If too little thyroid tissue is removed, patients remain hypothyroid. If too much tissue is removed, patients develop hypothyroidism.

Common symptoms of thyrotoxicosis include: (1) Hyperactivity (2) Nervousness (3) Generalized fatigue (4) Palpitations (5) Excessive sweating (6) Increased apetite & Hyperdefecation (7) Heat intolerance (8) Decreased menstrual flow Signs of thyrotoxicosis include: (1) Weight loss DESPITE a good appetite (2) Lid lag and stare due to spasm of the upper eyelid (3) Sinus Tachycardia (4) Atrial Fibrillation, High CO (5) Warm and moist skin (6) Fine tremor of the outstretched hands (7) Muscle weakness and muscle wasting (8) Increased Bone Turnover and Bone Loss (9) Rapid relaxation of deep tendon reflexes (10) CHILDHOOD - Rapid growth, accelerated bone maturation Causes of Thyrotoxicosis: (1) Graves' disease - RAIU = ↑; Iodine Scan = Diffuse uptake (2) Toxic mutlinodular goiter - RAIU = ↑; Iodine Scan = Patchy Uptake (3) Toxic adenoma - RAIU = ↑; Iodine Scan = HOT Nodule (4) Thyroiditis (e.g. Hashimoto's, subacute granulomatous, acute bacterial, radiation-induced) RAIU = ↓ ; Iodine Scan = Little Uptake (5) Exogenous Thyroid Hormone - RAIU = ↓; Iodine Scan = Little Uptake (6) Rare causes of thyrotoxicosis a) TSH-secreting pituitary adenoma - RAIU = ↑; Iodine Scan = Diffuse Uptake b) Metastatic Thyroid Cancer - RAIU = ↑; Iodine Scan = Uptake in Metastases c) Ectopic Thyroid Tissue (struma ovarii) - RAIU = ↑; Iodine Scan = Uptake in PELVIS ONLY Treatments (1) Antithyroid Drugs - must be continued for many years - incidence of permanent remission is LOW - Major side effects: rash, hepatitis-like reaction and agranulocytosis (a failure of the bone marrow to make enough white blood cells) (2) Radioactive Iodine - 50% of patients successfully treated with radioactive iodine EVENTUALLY will require THYROID HORMONE SUPPLEMENTATION. - Contraindicated in pregnancy (3) Surgery - Performed after patients have been made euthyroid with antithyroid drugs - Major complications include: DAMAGE TO THE RECURRENT LARYNGEAL NERVE with VOCAL CORD PARALYSIS and HOARSENESS and DAMAGE TO THE PARATHYROID GLANDS resulting in HYPOPARATHYROIDISM.

What value is used clinically to represent GFR?

Creatinine clearance

Failure of brain maturation due to lack of thyroid hormone is known as?

Cretinism

A major purpose of drug metabolism is that drug metabolites have increased water solubility; renal elimination of metabolites is increased because of: A. Increased glomerular filtration B. Increased secretion at proximal tubules C. Decreased passive reabsorption from distal tubules D. All of the above

Decreased passive reabsorption from distal tubules ***drug metabolites with ↑ WATER SOLUBILITY will be EXCRETED MORE RAPIDLY than the parent (lipid-soluble) drug because tubular reabsorption will be ↓. Thus, the major purpose of metabolism is to facilitate kidney elimination by producing water-soluble metabolites. ***Pharmocokinetics - Kidney Elimination Processes: filtration, secretion and reabsorption - Some drugs are excreted in their non-metabolized (ACTIVE) forms; thus kidney elimination will determine the DURATION of the pharmacological response.

What stimulates PTH secretion?

Decreased plasma calcium concentration ***Inhibitors: High plasma ionized calcium Very low plasma magnesium

What stimulates renin release?

Decreased renal arterial pressure

A deficiency of 17-alpha hydroxylase will result in an DECREASE in what hormone(s)?

Decreased sex hormones and cortisol

Hypertension is a common feature in diabetics. What are the potential consequences of using propranololas an anti-hypertensive treatment in someone with insulin-dependent type 1 diabetes?

Delay recovery from insulin-induced hypoglycemia

Kimmelstiel-Wilson Nodules are a pathognomic feature of?

Diabetic Nephropathy

Kussmaul hyperpnea

Diabetic ketoacidosis

Kimmelstiel-Wilson Nodules

Diabetic nephropathy

Complications of DM in Pregnancy ***Preconception - pre-plan and refer to high-risk clinic, optimize glycemic control, counsel patient re: potential risks and complications, evaluate for diabetic retinopathy, neuropathy, coronary artery disease. ***Pregnancy - if already on medication, generally switch to INSULIN therapy - Tight glycemic control (diet management first line therapy) - post-prandial blood glucose values seem to be the most effective at determining the likelihood of MACROSOMIA or other adverse pregnancy outcomes - frequent measurements of blood glucose during pregnancy are advised for women with Type 1 or 2 diabetes to help prevent or treat both hypoglycemia and hyperglycemia, and also improves neonatal outcome - Monitor as for normal pregnancy plus initial 24 h URINE PROTEIN and CREATININE CLEARANCE, RETINAL EXAM, HbA1c - Increased fetal surveillance

EARLY COMPLICATIONS (DM1 and DM2) (1) Congenital Defects - Neural Tube - Cardiac - Renal (2) Pregnancy Loss LATE COMPLICATIONS (DM1, DM2, GDM) (1) Macrosomia - Delivery trauma - Instrumentation - C/Section (2) Placental insufficiency --> Fetal Demise (3) Neonatal effects - Hypoglycemia (due to pancreatic hyperplasia and excess insulin secretion in the neonate) - Hyperbilirubinemia and jaundice (due to prematurity and polycythemia) - Hypocalcemia - Polycythemia (hyperglycemia stimulates fetal erythropoietin production) (4) Maternal Effects - Preecclempsia - Ecclempsia

A patient is admitted to the ICU because of a SEVERE METABOLIC ACIDOSIS. The SERUM BICARBONATE is LOW at 14. The patient is DISORIENTED and cannot offer an adequate history. No records are available. What is the most likely diagnosis when the following additional features are described? OXALATE CRYSTALS in the urine with a LOW SERUM CALCIUM

ETHYLENE GLYCOL overdose results in OXALATE CRYSTALS in the urine. The formation of calcium oxalate crystals LOWERS THE CALCIUM LEVEL. ***Look for the term "envelope-shaped" crystals The 1st step in the evaluation of any metabolic acidosis is the evaluation of the ANION GAP. An anion gap > 12 is consistent with: Methanol Ueremia Diabetic/alcoholic/starvation ketoacidosis Paraldehyde Isopropyl alcohol/iron Lactic acidosis Ethylene glycol Salicylates "MUDPILES"

Nephron Physiology

Early Proximal Tubule - Contains Brush Border - Reabsorbs all of the glucose and amino acids and most of the bicarbonate, sodium, chloride, and water. - ISOTONIC absorption - Generates and secretes AMMONIA, which acts as a buffer for secreted H+ PTH - INHIBITS Na+/Phosphate cotransport --> PHOSPHATE EXCRETION Angiotensin 2 - STIMULATES Na+/H+ echange --> INCREASES Na+ and H20 REABSORPTION 65-80% Na+ Reabsorbed THIN Descending Loop of Henle - Passively reabsorbs water via medullary HYPERtonicity (impermeable to Na+). - CONCENTRATING SEGMENT - Makes urine HYPERtonic THICK Ascending Loop of Henle - ACTIVELY reabsorbs Na+, K+, and Cl- and indirectly induces the paracellular reabsorption of Mg2+ and Ca2+. - IMPERMEABLE to H2O. - Makes urine LESS concentrated as it ascends. - 10-20% Na reabsorbed Early distal convoluted tubule - ACTIVELY reabsorbs Na+ and Cl- - DILUTING segment - Makes urine HYPOtonic PTH - Increases Ca2+/Na+ exchange --> Ca2+ reabsorption 5-10% Na+ reabsorbed Collecting Tubules - Reabsorb Na+ in exchange for secreting K+ and H+ (regulated by aldosterone). Aldosterone - leads to INSERTION of Na+ channel on luminal side ADH - acts on V2 receptors of principle cells in the late DCT/collecting ducts. It causes an INCREASE in the # of functioning water channels (aquaporins), thereby INCREASING the permeability of the collecting ducts to water. 3-5% Na+ reabsorbed

What part of the nephron secretes ammonia?

Early proximal convoluted tubule

↓ Ca2+ , ↑ K+ , ↑ phosphate, ↑ uric acid

Electrolyte changes in tumor lysis syndrome.

Treatment of DI ***Treatment depends on its cause

Free access to water is essential for ALL patients Central DI - Vasopressin or one of its pharmacologic analogs (e.g. dDAVP) to ↓ urine output and alleviate the need for chronic H2O drinking Nephrogenic DI - Maintaining adequate free water intake is the principal therapy - HCTZ - Indomethacin (NSAID) - Amiloride (K+ sparing diuretic)

This exam should take place in any patient with a HYPERTENSIVE EMERGENCY (***EVOLVING TARGET ORGAN DAMAGE, BP MAY EXCEED 210/140), as it is the only way to directly visualize arteries on physical exam.

Fundoscopy (for the presence of evolving retinopathy)

Thyroid hormones acts synergistically with what hormone with respect to bone growth?

GH

"Go Look For The Adenoma Please" ***This is a mnemonic to remember the order of hormone loss in pituitary HYPOfunction

GH LH FSH TSH ACTH Prolactin

Alport's Syndrome

Glomerulonephritis with deafness.

Wegener's granulomatosis and Goodpasture's syndrome

Glomerulonephritis with hemoptysis.

GH-Producing Pituitary Adenomas ***GH HYPERsecretion is often associated with hypersecretion of other pituitary hormones, particularly PRL ***The disorder of excessive GH secretion presents as GIGANTISM in children (epiphyses have not yet closed), or as ACROMEGALY in adults. ***GH levels may fluctuate wildly in an individual patient. This is NOT true of IGF-1 level, which makes IGF-1 a more useful diagnostic measurement. ***Cardiac Failure is the MOST COMMON cause of death in acromegalic patients. They also suffer an INCREASED risk of colon cancer and pituitary insufficiency.

GH-producing tumors --> ACROMEGALY (2nd most common disorder of pituitary overproduction) ***Acromegaly derives its name from the ACRAL SEGMENTS, which include the HANDS, FEET, NOSE, CHIN, and FOREHEAD. Stimulation of growth of these bony and soft tissue segments is the HALLMARK of this disorder. Advamced acromegaly is characterized by: 1) Spade-like hands 2) Large feet 3) Prognathism (prominent lower jaw) 4) Large and fleshy nose 5) Frontal bossing 6) Enlarged liver and heart (cardiomyopathy) 7) Peripheral neuropathies (e.g. CARPEL TUNNEL SYNDROME) secondary to nerve compression. 8) Headache & Bitemporal hemianopsia - superior growth of tumor leading to compression of optic chiasm 9) Thickened synovium, resulting in PAINFUL JOINTS 10) Large tongue and thickened tracheal cartilage, resulting in SLEEP APNEA 11) Thickened vocal cords, resulting in DEEP VOICE 12) Increased glucose production and INCREASED INSULIN RESISTANCE, resulting in IMPAIRED GLUCOSE TOLERANCE - Progressive dental malocclusion occurs because of MANDIBULAR ENLARGEMENT, and SPACES FORM B/W THE TEETH. ***Often a history of INCREASING HAT, COLLAR, SHIRT, GLOVE, RING, and SHOE-SIZE suggests the diagnosis - These changes occur insidiously over MANY YEARS, so patients and family members often do NOT note them. ***In children, GH-producing tumors cause ACCELERATED LINEAR GROWTH, resulting in GIGANTISM. In adults, the epiphyseal plates have already closed, and further longitudinal growth is NOT possible. ***Differential - Precocious puberty, normal genetics, and hyperthyroidism should be RULED OUT. ***Diagnosis - Elevated serum IGF-1 (sensitive screening test) - Glucose suppression of GH is the best test for diagnosing acromegaly. Plasma GH is measured before and one hour after administration of oral glucose (75-100g). In NORMAL persons, but NOT in people with acromegaly, GH is SUPPRESSED to less than 2 ng/mL after this glucose load. ***Treatment - Transsphenoidal surgery is the treatment of choice. Can be accompanied by radiotherapy - Octreotide is a long acting SOMATOSTATIN ANALOG that can LOWER GH levels to normal - Bromocriptine, a DOPAMINE AGONIST, can work synergistically with octreotide therapy - Pegvisomant (GH-receptor antagonist)

A child comes in with ABDOMINAL PAIN, HEMATURIA, JOINT PAINS, and PURPURIC SKIN LESIONS. Urinalysis reveals RED-CELLS, RED-CELL CASTS, and MILD PROTEINURIA. What is the most likely diagnosis?

HENOCH-SCHONLEIN PURPURA is the most likely diagnosis when the patient is an ADOLESCENT or CHILD presenting with GI symptoms in combination with RENAL, JOINT, and SKIN FINDINGS. PALPABLE PURPURA OF THE LOWER EXTREMITIES IS THE KEY. The MOST ACCURATE TEST is a SKIN BIOPSY with IgA deposited in the skin, but routine biopsy is not necessary.

RAIU ***Order if patient is HYPERthyroid

HIGH - Graves' disease or toxic nodular goiter LOW - Subacute thyroiditis, active phase of Hashimoto's thyroiditis, and excess iodine intake (e.g. amiodarone)

Horseshoe kidney

HIGHER risk of RCC

CAH

HTN (↑ Aldosterone) --> 17-α-hydroxylase deficiency ↑ Sex Hormones --> 21-hydroxylase deficiency ↑ Sex Hormones & HTN --> 11β-hydroxylase deficiency ***ACTH and ANG 2 stimulate the conversion of cholesterol to pregnenolone. ***3-β-Hydroxysteroid dehydrogenase and 21-hydroxylase are required for the synthesis of precursors in the pathways to BOTH ALDOSTERONE and CORTISOL. ***11-β-Hydroxylase is required for SYNTHESIS OF CORTISOL ***17-α-Hydroxylase is required to convert pregnenolone and progesterone into ANDROSTENEDIONE and DHEA, respectively, both PRECURSORS OF ADRENAL ANDROGENS

Anemia, thrombocytopenia, and acute renal failure

HUS triad

DM Related Symptoms

HYPERGLYCEMIA 1. Polyphagia 2. Polydipsia, 3. Polyuria 4. Weight change 5. Blurry vision 6. Yeast infections DIABETIC KETOACIDOSIS (DKA) ***Can be triggered by infection, ischemia, infarction, intoxication, medication, non-compliance 1. Fruity Breath (Acetone) 2. Anorexia 3. N/V 4. Fatigue 5. Abdominal Pain 6. Kussmaul breathing (rapid, deep breathing) 7. Dehydration, Orthostatic Hypotension 8. Altered consciousness/coma ***DKA is a complication of DM-1 ***Lack of insulin causes lipolysis and releases FFAs from adipose tissue. ***Decreased insulin --> Increased Lipolysis --> Increased glycerol and FFAs --> β oxidation of FFAs --> Increased Ketones HYPOGLYCEMIA 1. Hunger 2. Anxiety 3. Tremors 4. Palpitations 5. Sweating 6. Headache 7. Fatigue 8. Confusion 9. Seizures 10. Coma

You are called to evaluate a patient with WORSENING RENAL FUNCTION over the last few days. The Creatinine is 2.5 mg/dL and the BUN is 28 units. The urine sodium is 45 mEq/L and the urine osmolality is 290 mosm/kg. His serum bicarbonate is low. What is the most likely diagnosis when the following additional features are described? CHEMOTHERAPY for lymphoma was started two days ago.

HYPERURICEMIA* from TUMOR LYSIS SYNDROME will lead to acute renal failure.

Trousseau's sign ***Trousseau's sign involves inflation of a BP cuff above systolic pressure for 2 minutes to watch for characteristic muscle contractions in the hand; it is a physical exam technique that can reveal this electrolyte abnormality.

HYPOcalcemia (carpal spasm)

The most common cause of hypothyroidism.

Hashimoto's thyroiditis

Niacin (water-soluble B vitamin)

Hypercholesterolemia treatment (increases HDL) - Side Effects: Flushing and Pruritus

Peaked T waves and widened QRS.

Hyperkalemia

"Doughy skin."

Hypernatremia

Barter's Syndrome

Hyperreninemia

Rare Causes of Thyrotoxicosis

Hyperthyroidism caused by a TSH-producing tumor is distinguished by a HIGH TSH LEVEL ***In ALL other forms of thyrotoxicosis, TSH IS SUPPRESSED Metastatic thyroid carcinoma occasionally is able to produce sufficient thyroid hormone to cause thyrotoxicosis Women with struma ovarii have mild thyrotoxicosis due to oversecretion of thyroid hormones by thyroid tissue within an ovarian teratoma. ***Ovarian thyroid tissue takes up iodine, but since TSH is suppressed, thyroid tissue does NOT.

Chvostek's and Trousseau's signs.

Hypocalcemia

T-wave flattening and U waves.

Hypokalemia

A patient presents with signs of hypocalcemia, high phosphorus, and low PTH.

Hypoparathyroidism

Myxedema

Hypothyroidism

Signs and Symptoms of HYPOthyroidism ***Mnemonic: "HIS FIRM CAP"

Hypoventilation Intolerance to cold Slow HR Fatigue Impotence Renal impairment Menorrhagia/amenorrhea Constipation Anemia Paresthesia

Shock

Hypovolemic: patients have COOL extremities due to peripheral VASOCONSTRICTION. Ex: hemorrhage, dehydration, vomiting, diarrhea, interstitial fluid redistribution Cardiogenic: patients usually have signs of LEFT-SIDED HEART FAILURE Ex: myopathic (myocardial ischemia ± infarction), mechanical, arrhythmic, pharmacologic Obstructive: varied presentation. Ex: massive PE (saddle embolus), pericardia! tamponade, constrictive pericarditis, increased intrathoracic pressure (e.g. tension pneumothorax) Distributive: patients have WARM extremities due to peripheral VASODILATION. Ex: sepsis, anaphylactic reaction, neurogenic, endocrinologic, toxic Treatments: - Treat underlying cause - Treatment goal is to return critical organ perfusion to normal (e.g. normalize BP) Common treatment modalities include: 1. Fluid resuscitation 2. Inotropes (e.g. dobutamine), vasopressors (e.g. norepinephrine), vasopressin 3. Revascularization or thrombolytics for ischemic events

What stimulates EPO release?

Hypoxia

CAUSES OF HYPONATREMIA: 1) Hypervolemic Hyponatremia - Cirrhosis, Heart Failure, Nephrotic Syndrome 2) Hypovolemic Hyponatremia - Renal loss, Extrarenal loss 3) Euvolemic Hyponatremia - SIADH, Polydipsia, Adrenal Insufficiency, Hypothyroidism 4) Pseudohyponatremia - Increased glucose, lipids, proteins, urea

In Heart failure, due to decreased forward flow by the failing heart, the kidneys sense decreased perfusion and try to increase what it perceives as diminished intravascular volume (decreased effective circulating volume) via the RAAS. Additionally, perceived low volume activates ADH secretion further increasing water retention. Cirrhosis of the liver can lead to effective volume depletion secondary to pooling of blood in the mesenteric veins. This also decreases the amount of blood seen by the kidneys, resulting in subsequent reasbsorption in an effort to increase what is perceived as a low intravascular volume. Thus urine sodium concentration DECREASES in these situations, because the kidneys are attempting to retain Na+ along with water. The amount of water retention EXCEEDS that of Na+ retention, resulting in the HYPERVOLEMIC HYPONATREMIA.

Multicystic dysplastic kidney (MCDK)

In this congenital condition, the URETER IS ABSENT or just a fibrotic structure, with the net result potentially being a dysfunctional kidney that resembles a "bag of grapes".

Brief Overview of Renal Acid Excretion

Ingestion of a typical western diet generates approximately 50 to 100 meq of hydrogen ions per day. To maintain balance, these hydrogen ions must be excreted in the urine in a process that includes the following: 1. Reabsorption of filtered bicarbonate, since bicarbonate loss is equivalent to the generation of hydrogen ions. 2. Excretion of the daily acid load cannot be achieved as free hydrogen ions since at a urine pH of 4.5 the free hydrogen ion concentration is less than 0.04 meq/L. Thus, free hydrogen ions are either bound to buffers (such as phosphate or, in ketoacidosis, ketoacid anions), or to ammonia (NH3) to form ammonium (NH4). 3. The main adaptive renal response to metabolic acidosis is to increase hydrogen ion excretion as NH4. In patients with metabolic acidosis and normal renal function, NH4 excretion can increase from the normal value of 30 to 40 meq/day to as much as 200 to 300 meq/day in severe metabolic acidosis

What secretes renin?

JG cells

K+ Shifts

K+ shift OUT of cell (causing HYPERkalemia) 1. Insulin Deficiency (↓ Na+/K+ ATPase) 2. B-adrenergic ANTAGONISTS (↓ Na+/K+ ATPase) 3. Acidosis, severe exercise (↑ K+/H+ exchanger) 4. Hyperosmolarity 5. Digitalis (Blocks Na+/K+ ATPase) 6. Cell lysis Shift INTO cell (causing HYPOkalemia) 1. Insulin (↑ Na+/K+ ATPase) 2. B-adrenergic AGONISTS (↑ Na+/K+ ATPase) 3. Alkalosis (↑ K+/H+ exchanger) 4. Hypo-osmolarity

Intracellular Fluid ***2/3 of total body water

K+, Mg, and PO4 are the PRIMARY ICF Electrolytes

ORAL GLUCOSE TOLERANCE TESTING

Measurement of serum glucose levels at baseline and 2 hours after the ingestion of an oral load of 75g of glucose (+) test: 2 hr plasma glucose ≥ 11.1 mmol/L during an oral glucose tolerance test - One of the methods of DIAGNOSING DIABETES - The ordinary method is to find 2 FASTING GLUCOSE LEVELS to be ≥ 7.0 mmol/L - The strongest indication for an oral glucose tolerance test is in SCREENING FOR DIABETES DURING PREGNANCY

Medullary cystic kidney ***Small Kidney ***Kidney stones ***Inability to concentrate urine

Medullary cysts sometimes lead to fibrosis and progressive renal insufficiency with INABILITY to concentrate urine. U/S shows SMALL KIDNEY 70% develop kidney stones. Poor prognosis.

"Tram-track" appearance on Light Microscopy

Membranoproliferative glomerulonephritis

Spike and dome on Electron Microscopy

Membranous glomerulonephritis

An antidiabetic agent associated with lactic acidosis.

Metformin ***Two classes of oral hypoglycemic drugs directly improve insulin action: biguanides (only metformin is currently available) and thiazolidinediones. In the absence of contraindications, metformin is considered the FIRST CHOICE for oral treatment of type 2 diabetes ***Metformin is effective only in the presence of insulin, and its major effect is to DECREASE HEPATIC GLUCOSE OUTPUT. In addition, metformin increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis Side Effects ***The most common side effects of metformin are GASTROINTESTINAL, including a metallic taste in the mouth, mild anorexia, nausea, abdominal discomfort, and soft bowel movements or diarrhea ***Metformin-induced lactic acidosis can occur in patients with normal renal and hepatic function.

Urine Microalbumin

Microscopic urine albumin is a sensitive screening test for DIABETIC NEUROPATHY ***Screening for diabetic neuropathy is done YEARLY in diabetic patients ***If the test is (+) → ACE INHIBITORS or ARBs to prevent progression of the disease ***Renal biopsy is the ONLY test of the effect of diabetes on the kidney that is MORE SENSITIVE than microalbuminuria

What are the features of Multiple Myeloma?

Mnemonic: "CARLl" Calcium (elevated) Anemia Renal Failure Lytic Bone Lesions Infections -malignant proliferation of plasma cells in the bone marrow with the production of immunoglobulins - patients may present with severe bone disease and renal failure - light chains are filtered at the glomerulus and appear as Bence-Jones proteins in the urine (monoclonal light chains) -Kidney damage can occur by several mechanisms: • hypercalcemia • light chain cast nephropathy (LCCN) or "myeloma kidney" • hyperuricemia • infection • secondary amyloidosis • monoclonal Ig deposition disease (MIDD) • diffuse tubular obstruction Lab features: increased BUN, increased Cr, urine protein immunoelectrophoresis positive for Bence-Jones protein (not detected on urine dipstick)

A 60-year-old African-American male presents with bone pain. Workup for multiple myeloma might reveal?

Monoclonal gammopathy, Bence Jones proteinuria, "punched-out" lesions on x-ray of the skull and long bones

Lytic bone lesions on x-ray

Multiple myeloma

What is the most common 1° malignant tumor of bone

Multiple myeloma

Monoclonal antibody spike

Multiple myeloma (called the M protein; usually IgG or IgA)

Bence Jones Proteins

Multiple myeloma (kappa or lambda Ig light chains in urine)

Male Reproductive Endocrinology - Hypogonadism and Infertility ***Deficiency in gametogenesis & testosterone production ***2 distinct features of PRIMARY HYPOGONADISM (1) The DECREASE IN SPERM COUNT is affected to a GREATER extent then the decrease in serum testosterone level (2) Likely to be associated with GYNECOMASTIA* *Causes of gynecomastia 1. Drugs (Spironolactone, estrogens and estrogen agonists, digoxin, chemo., etc), 2. Congenital (Klinefelter's syndrome, androgen insensitivity) 3. Tumor (pituitary, adrenal, testicular, breast) 4. Endocrine (primary or secondary hypogonadism, hyperthyroidism, adrenal disease) 5. Chronic Disease (liver, renal, malnutrition (with refeeding)) 6. Other *3 peaks (1) Infancy [maternal hormone] (2) Puberty (3) Age 50-80 PRIMARY HYPOGONADISM IS MORE COMMON THAN SECONDARY ***2 Features of SECONDARY HYPOGONADISM (1) Associated with an EQUIVALENT decrease in sperm count and serum testosterone (2) Less likely to be associated with gynecomastia ***Testicular defects result in ↓ Testosterone with ↑ gonadotropin levels (LH and FSH) because the pituitary is no longer suppressed by (-) feedback. ***Most men with testicular failure are treated with testosterone. Testosterone replacement can RESTORE LIBIDO and SEXUAL FUNCTION, INCREASE MUSCLE MASS, REDUCE FATIGUE, and MAINTAIN BONE MASS. NB: Boys who develop gonadal failure BEFORE puberty usually are NOT treated with testosterone until they are around 13 y.o., to AVOID PREMATURE EPIPHYSEAL CLOSURE RESULTING IN SHORT STATURE ***Androgen therapy is CONTRAINDICATED in some men with prostate hyperplasia and in men with prostate cancer. Androgen replacement therapy does NOT cause prostate cancer but STIMULATES growth of hormone-sensitive cancers already present. ***Causes of male infertility (1) Primary hypogonadism (2) Secondary hypogonadism (3) Other causes - autoimmune disorders - anatomy - sexual dysfunction - obstruction

NB: Androgens are critical for the maintenance of fertility - TESTOSTERONE (from the Leydig cell) primarily involved in (-) feedback on LH, whereas INHIBIN (from the Sertoli cell) suppresses FSH secretion - Testosterone → 5α Reductase → DHT (Targets: External genitalia, male pattern body hair, temporal baldness, and prostate) ***DHT has greater receptor affinity and more androgen effect - Testosterone → Fat → Aromatase → Estradiol - Testosterone Targets: Wolffian duct, brain, muscle, body hair, spermatogenesis, and libido HYPERgonadotropic Hypogonadism (Primary Hypogonadism) = Primary Testicular Failure = ↑ LH and FSH, ↑ FSH:LH Ratio = ↓ Testosterone and sperm count ETIOLOGY (1) Congenital ***Klinefelter's (47 XXY) - Men with Klinefelter's syndrome develop normally until puberty, when the testes fail - ↑ LH and FSH - Testes remain small and become fibrotic - A Karyotype is required to confirm the diagnosis ***Gynecomastia, impotence, and infertility are common complaints. - Men who go untreated develop osteopenia because they produce too little testosterone to maintain bone mass. - Cryptorchidism - Mutation of FSH or LH receptor gene - Varicocele - Disorders of androgen synthesis (2) Germ Cell Defects (3) Infection/Inflammation - Orchitis: TB, lymphoma. mumps, leprosy - Genital tract infection (4) Physical Factors - Trauma, heat, irradiation, testicular torsion (5) Drugs - Chemotherapy, alcohol, glucocorticoid (6) Autoimmune (7) Chronic Systemic Diseases (AIDS) (8) Idiopathic Dx: Sperm count, LH, FSH, Testosterone, hCG stimulation, Testicular size and consistency (SOFT/FIRM), Karyotype HYPOgonadotrophic Hypogonadism (Secondary Hypogonadism) = HPA axis failure = ↓ LH and FSH = ↓ Testosterone and sperm count (1) Congenital (2) Infection - TB, Meningitis (3) Endocrine - Adrenal androgen excess - Cushing's syndrome - HYPO or HYPERthyroidism - Hypothalamic-pituitary disease (4) Drugs - Alcohol, SPIRONOLACTONE, GnRH agonists, androgen/estrogen/progestin use (5) Chronic Illness - Cirrhosis, chronic renal failure, AIDS, Sarcoidosis, hemochromatosis (6) Critical illness - Surgery, MI, head trauma (7) Idiopathic Dx: Sperm count, LH, FSH, Testosterone, Prolactin levels, MRI of hypothalamic-pituitary region ***Treatment (1) Testosterone Replacement (improves libido, muscle mass, strength, hair growth) - SE: acne, fluid retention, erythrocytosis (2) GnRH agonist to restore fertility

What do the collecting ducts reabsorb in exchange for K or H?

Na ions

Hematuria, hypertension, and oliguria.

Nephritic syndrome

A patient with a history of LITHIUM USE presents with COPIOUS AMOUNTS of DILUTE URINE.

Nephrogenic diabetes insipidus (DI)

A 49-year-old male presents with acute-onset flank pain and hematuria.

Nephrolithiasis

Nephrotic vs. Nephritic Syndrome

Nephrotic Syndrome ***The excess fluid in the body may manifest as: (1) Puffiness around the eyes, characteristically in the morning (2) Pitting edema over the legs (3) Pleural effusion (4) Ascites - Acronym = PLACE PROTEINURIA LIPIDURIA ↓ ALBUMIN ↑ CHOLESTEROL EDEMA PRIMARY CAUSES: (1) MINIMAL CHANGE DISEASE ***Most common cause of CHILDHOOD nephrotic syndrome. Responds well to STEROIDS (2) FOCAL SEGMENTAL GLOMERULOSCLEROSIS ***Most common glomerular disease in HIV patients and manifests more severely in those patients. ***This disease accounts for 50% of cases of nephrotic syndrome in African Americans ***Nonselective proteinuria, HTN, Hematuria ***HIV and Heroin use (3) MEMBRANOUS GLOMERULONEPHROPATHY ****Leading cause of nephrotic syndrome in ADULTS. ***Peak incidence is from 30-50, and it is seen predominantly in MEN ***Occurs in association with SYSTEMIC DISEASES such as SLE, and RA, INFECTIONS such as Hep B and Hep C, Syphilis, Schistosomiasis, as well as DRUGS (Gold and penicillamine) ***Diffuse GBM thickening ***Subepethelial deposits in a "spike" and "dome" pattern (4) HEREDITARY NEPHROPATHIES SECONDARY CAUSES (1) DIABETIC NEPHROPATHY ***Leading cause of ESRD in Western society, secondary to GLOMERULAR HTN and HYPERFILTRATION ***1st SIGN OF INJURY TO THE GLOMERULUS = MICROALBUMINURIA, which occurs about 5-10 years before other symptoms develop (→Gross proteinuria) ***Nephropathy is generally MORE COMMON in DM-1 ***Cardinal symptoms include: HTN and EDEMA (as a result of fluid retention; NB: CRF aggravated by glomerulosclerosis → Fluid filtration abnormalities and a full spectrum of other disorders of kidney function). Other complications may include ARTERIOSCLEROSIS of the RENAL ARTERY and the EFFERENT ARTERIOLES. If left UNTREATED, NEPHROTIC-RANGE PROTEINURIA ULTIMATELY DEVELOPS. ***Late stage diabetic nephropathy manifests as full-blown CKD ***Should be suspected in patients with either DM-1 or DM-2 who have already developed evidence of end-organ damage from DM, such as RETINOPATHY and NEUROPATHY, and have DIPSTICK-POSITIVE PROTEINURIA ***Thickening of the GBM and Expansion of the Mesangium. Classic Kimmelstiel-Wilson lesions, areas of nodular glomerulosclerosis, may be found. ***Treatment should be started for patients long before their symptoms have progressed to overt nephrotic syndrome. ***ACE inhibitors (counteract hyperfiltation --> delay nephropathy); GLUCOSE CONTROL (2) LUPUS NEPRHROPOATHY ***As the disease progresses → patients present with nephrotic or nephritic syndrome, or both, ultimately leading to ESRD. Presentation: Glomerular pathology → Weigh gain, high BP, darker foamy urine, and swelling around the eyes, legs, ankles, or fingers. ***Gold standard to confirm renal involvement = renal biopsy (3) AMYLOIDOSIS ***Multisystem disorder of protein folding and can be acquired or hereditary ***Dx: Renal, abdominal fat pad, or rectal biopsy ***Presentation: Nephrotic-range proteinuria, severe edema, and renal insufficiency ***Congo red stain → Apple-green birefringence = Amyloidosis ***Mesangial expansion (w/ amyloid), thickening of GBM ***Tx: Melphalan & Prednisone (4) VIRAL INFECTIONS (Hep B, Hep C, HIV) NEPHRITIC SYNDROME - Acronym = PHAROH PROTEINURIA HEMATURIA AZOTEMIA (aka UREMIA) RENAL FAILURE OLIGURIA HYPERTENSION - Causes a) Immune response that is triggered by infection/other disease IN CHILDREN (1) IgA NEPHROPATHY (2) HENOCH-SCHONLEIN PURPURA (3) HEMOLYTIC UREMIC SYNDROME (4) POST-STREPTOCOCCAL GLOMERULONEPHRITIS IN ADULTS (1) ABDOMINAL ABSCESSES (2) INFECTIVE ENDOCARDITIS (3) KLEBSIELLA PNEUMONIA (4) GOODPASTURE'S SYNDROME (5) HEPATITIS (6) MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (7) RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (8) STIS (9) TYPHOID FEVER (10) PAUCI-IMMUNE GLOMERULONEPHRITIS

Proteinuria, hypoalbuminemia, hyperlipidemia, hyperlipiduria, edema.

Nephrotic syndrome

Waxy casts in urine sediment and Maltese crosses (seen with lipiduria).

Nephrotic syndrome

If clearance of substance X is less than GFR, what occurs?

Net tubular reabsorption of X

If clearance of substance X is greater than GFR, what occurs?

Net tubular secretion of X

A patient presents with TACHYCARDIA, WILD SWINGS IN BP, HEADACHE, DIAPHORESIS, ALTERED MENTAL STATUS, and a sense of PANIC.

Pheochromocytoma

A patient is admitted to the ICU because of a SEVERE METABOLIC ACIDOSIS. The SERUM BICARBONATE is LOW at 14. The patient is DISORIENTED and cannot offer an adequate history. No records are available. What is the most likely diagnosis when the following additional features are described? Normal Anion Gap, elevated chloride level, and hypokalemia

Normal anion gap implies either *RENAL TUBULAR ACIDOSIS (RTA) or *DIARRHEA. *Most common In RTA, the URNIE ANION GAP IS POSITIVE (suggests problem is lack of NH4+ in urine - e.g. distal RTA). With DIARRHEA, the URINE ANION GAP is STRONGLY NEGATIVE (suggests adequate NH4+ in urine) The LOWER the URINE ANION GAP NUMBER, the GREATER the KIDNEY'S ABILITY TO EXCRETE ACID. ***The urine anion gap is calculated from the difference between the major measured urinary cations (Na and K) and urinary anions (Cl). UAG (in meq/L or mmol/L) = Urine (Na + K - Cl) - Calculation establishes the presence or absence of unmeasured positive ions (e.g. NH4+) in urine. Diarrhea - HCO3- loss from GI tract Type 1 RTA (distal): inability to secrete H+ in collecting duct, leading to impaired excretion of ammonium into urine Type 2 RTA (proximal): impaired HCO3- reabsorption Type 4 RTA: defective ammoniagenesis (NH3) due to decreased aldosterone, hyporesponsiveness or hyperkalemia ***A negative UAG suggests GI loss of bicarbonate (eg diarrhea), a positive UAG suggests impaired renal acidification (ie renal tubular acidosis).

How much of the ECF is plasma?

One-fourth

How much of the total body water is part of the extracellular fluid?

One-third

PROGESTERONE CHALLENGE

Oral dosing of progesterone of 10 mg daily for 5 days is used in AMENORRHEIC WOMEN AFTER PREGNANCY IS EXCLUDED to determine if the cause of amenorrhea is due to OUTFLOW TRACT OBSTRUCTION or SECONDARY TO THE HYPOTHALAMUS and PITUITARY. ***Look for a woman who has NO PERIODS and a NEGATIVE B-hCG ***If BLEEDING occurs following the challenge, it indicates that there is ADEQUATE ESTROGEN and that the OUTFLOW TRACT EXISTS. ***The NEXT BEST TEST is to check FSH, LH, PROLACTIN, and TSH to RULE OUT a HYPOTHALAMIC or PITUITARY ETIOLOGY. ***If there is NO BLEEDING, the next best test is to EVALUATE for an OUTFLOW TRACT OBSTRUCTION with U/S, and with MRI if U/S is not definitive.

Which of the following statements about drugs for hyperthyroidism is/are true? A. Oral radio-iodine (131I) damages thyroid follicle cells and eventually tends to produce hypothyroidism B. Oral iodine/iodide inhibits deiodinationof T4 to T3 in peripheral tissues C. Oral propylthiouracilinhibits secretion of thyroid hormones

Oral radio-iodine (131I) damages thyroid follicle cells and eventually tends to produce hypothyroidism

Blue sclera

Osteogenesis imperfecta

Hypothyroidism - Classification ***↓ FT4 and a low or low-normal FT3. ***HIGH TSH ***Treatment (PRIMARY Hypothyroidism): Administration of L-Thyroxine (T4 analog). After initiating L-Thyroxine, TSH needs to be evaluated in 6 weeks; dose adjusted until TSH returns to normal reference range. Once maintenance dose achieved, follow-up with patient annually. ***Treatment (SECONDARY/TERTIARY Hypothyroidism); Need to RULE OUT and/or treat ADRENAL INSUFFICIENCY FIRST. - Monitor via measurement of TSH and T4

PRIMARY HYPOTHYROIDISM (1) Chronic Lymphocytic Thyroiditis (Hashimoto's Thyroiditis) ***Most common cause of HYPOthyroidism in NA ***Presence of thyroid peroxidase and thyroglobulin antibodies in serum ***Risk factors: FEMALE gender, increased frequency in patients with Down's syndrome, Turner's syndrome, certain HLA alleles, Family Hx or personal Hx of other autoimmune diseases, Cigarette Smoking, High Iodine Intake, Stress and Infection. - Autoimmune destruction of the thyroid gland - Associated with the production of specific antibodies directed against thyroglobulin and thyroid peroxidase (NB: these antibodies are the result of thyroid damage) ***useful markers of Hashimoto's thyroiditis - Destruction of the thyroid gland occurs SLOWLY over many years. ***The constellation of a LOW T4 level, an ELEVATED TSH level, and a NORMAL T3 level is known as the "failing gland" syndrome - Patients are clinically euthyroid during this phase, BUT the ↑ in TSH and the lymphocytic infiltration of the thyroid gland can produce very firm goiters that can become quite large. Tx: If hypothyroid, replace with L-thyroxine (analog of T4) (2) Antibodies to the TSH Receptor ***These autoantibodies are INHIBITORY (NOT stimulatory like the antibodies to the receptor associated with GRAVES' DISEASE) (3) Thyroid Ablation - Secondary to surgery, radioactive iodine therapy, external radiation to the neck - Radioactive iodine damages thyroid cell DNA. - Hypothyroidism may develop over several weeks, or it may take as long as 30 years to develop. (4) Subacute Thyroiditis (Resolving Phase) - Patients in the resolving phase of subacute thyroiditis may develop hypothyroidism. This usually is TEMPORARY, but some patients fail to recover fully and remain hypothyroid. (5) Dietary Goitrogens (e.g. cabbage, sweet potatoes) and Drugs (Lithium - inhibits thyroid hormone synthesis, amiodarone - contains excess iodine, PTU and MMI - interfere with thyroid hormone synthesis) (6) Iodine Deficiency - B/c there is no underlying destruction of the thyroid gland, the associated rise in TSH leads to the development of a GOITER. (7) Congenital Defects - Intrathyroid defects: Iodide transporter defects, Thyroid peroxidase defects, Thyroglobulin defects - Intrathyroid and peripheral tissue defects: Deiodinase deficiency SECONDARY HYPOTHYROIDISM Pituitary Hypothyroidism - Insufficiency of pituitary TSH - Usually associated with other pituitary hormone deficiencies - Serum TSH is DECREASED or NOT appropriately elevated. In these patients, the diagnosis is based on symptoms and signs of hypothyroidism, a LOW FT4, and evidence (clinical, laboratory, x-ray) of other defects in pituitary function. Tx: Replacement T4 (L-Thyroxine). In these patients the serum TSH level CANNOT be used to titrate the replacement dose of hormone. Rather the physician must rely on changes in signs and symptoms while monitoring the serum FT4. Most patients' TSH levels will be appropriately replaced at a time when the FT4 is near the upper limit of normal. TERTIARY HYPOTHYROIDISM Hypothalamic hypothyroidism - Decreased TRH from hypothalamus (rare)

What overall effects does PTH have on body electolytes?

PTH increases serum Ca 2+, decreases serum phosphates, increases urine phosphates

Thyroiditis **Caused by release of STORED thyroid hormone from a damaged gland

Painful, Subacute Thyroiditis (aka De Quervain's or granulomatous thyroiditis) - Inflammatory disorder often associated with a VIRAL INFECTION. ***Painful, tender thyroid gland, fever, muscle aches, ↑ ESR ***FT4 and FT3 are ↑ and TSH is SUPPRESSED ***Radioactive iodine uptake is very low (thyroid gland is damaged) ***As the gland becomes DEPLETED of stored hormone, circulating levels of T3 and T4 drop, and the suppressed TSH level begins to ↑. Patients may then pass through a hypothyroid phase until the gland recovers and the patients return to euthyroidism. (Rise in RAIU reflects gland recovery) Tx: ***NO treatment is needed for the HYPERthyroidism, which is SELF-LIMITED, but β-adrenergic blockers can alleviate some of the symptoms. - High dose anti-inflammatories (NSAIDS) --> relief of fever and muscle aches - Prednisone --> severe pain Chronic Lymphocytic Thyroiditis (Hashimoto's Thyroiditis) - Autoimmune disease that is usually associated with HYPOthyroidism but also can be associated in it's early phase with transient HYPERthyroidism ***Autoimmune destruction of the thyroid gland leads to release of preformed hormone and transient hyperthyroidism. During the hyperthyroid phase, TSH and RAIU are suppressed. Many of these patients have ongoing destruction of the thyroid gland --> HYPOthyroidism Acute Bacterial Thyroiditis and Radiation Thyroiditis (RARE) - Release of PREFORMED hormone from a damaged gland --> HYPERTHYROIDISM

Role of Lipases in Lipid Metabolism

Pancreatic Lipase - Hydrolyzes dietary TG in intestine Lipoprotein Lipase (LpL) - Hydrolyzes TG in CHYLOMICRONS and VLDL in BV walls ***Niacin, Insulin, Exercise, Heparin, ↓ Fat intake, ↓ Alcohol intake → ↑ LpL activity (↑ TG breakdown) Adipose Tissue Lipase - Hydrolyzes TG in adipose tissue to release stored fat; it is INHIBITED by insulin and STIMULATED by epinephrine

"Orphan Annie" nuclei

Papillary carcinoma of the thyroid

NSAIDs

Papillary necrosis can result from the use of this class of drugs, which cause constriction of the afferent arteriole leading to reduced blood flow to the vasa recta.

11-β-Hydroxylase deficiency

Patients with 11-β-Hydroxylase deficiency LACK an enzyme in the ADRENAL STEROID SYNTHETIC PATHWAY. ***They CANNOT produce normal levels of CORTISOL and ALDOSTERONE. ***The steroid precursors are shunted into the production of EXCESSIVE quantities of SEX HORMONES. Consequently, patients with 11-β-Hydroxylase deficiency are HYPERTENSIVE, and females are virilized. NB: 11-Deoxycorticosterone has MINERALOCORTICOID ACTIVITY --> HTN

Elevated erythropoietin level, elevated hematocrit, and normal O2 saturation suggest?

RCC or other erythropoietin-producing tumor; evaluate with CT scan

A man is admitted to the hospital with RENAL FAILURE developing over a few days. His serum BICARBONATE is SLIGHTLY LOW. The URINE SODIUM is LOW and the URINE OSMOLALITY is HIGH. FRACTIONAL EXCRETION of Na+ < 1%. Increased [urea] >> Increased [Cr]. What is the most likely diagnosis when the following additional features are described? A BRUIT is present at the FLANKS and he has just started an ACE INHIBITOR

RENAL ARTERY STENOSIS is associated with DECREASED RENAL PERFUSION. ACE inhibitors can precipitate acute renal failure. Think about FIBROMUSCULAR DYSPLASIA in a YOUNG WOMAN

A patient is admitted to the ICU because of a SEVERE METABOLIC ACIDOSIS. The SERUM BICARBONATE is LOW at 14. The patient is DISORIENTED and cannot offer an adequate history. No records are available. What is the most likely diagnosis when the following additional features are described? ELEVATED CREATININE

RENAL FAILURE causes metabolic acidosis because of the kidney's INABILITY to EXCRETE ACID. The 1st step in the evaluation of any metabolic acidosis is the evaluation of the ANION GAP. An anion gap > 12 is consistent with: Methanol Ueremia Diabetic/alcoholic/starvation ketoacidosis Paraldehyde Isopropyl alcohol/iron Lactic acidosis Ethylene glycol Salicylates "MUDPILES"

Toxic Adenoma (Toxic Nodule) ***A single nodule accounts for the HYPERthyroidism ***The incidence of HYPOthyroidism following radioactive iodine treatment for a toxic nodule is much LOWER than the incidence of HYPOthyroidism after similar treatment for Graves' disease

Radioactive Iodine scan reveals a SINGLE "HOT" TOXIC NODULE - these patients may be ideal candidates for RADIOACTIVE IODINE TREATMENT (most of the gland is suppressed and will NOT take up the radioactive iodine, ∴ ONLY the nodule is destroyed) - After destruction of the nodule, TSH is NO LONGER SUPPRESSED, and the rest of the gland can resume normal function.

What is the function of the early proximal convoluted tubule?

Reabsorbs all of the glucose and amino acids and most of the bicarbonate, sodium, and water

GDM (A disease of LATE PREGNANCY) ***Usually around 24-28 wks GA, anti-insulin factors produced by PLACENTA and high MATERNAL CORTISOL levels create increased peripheral insulin resistance --> higher fasting glucose --> leading to GDM and/or exacerbating pre-existing DM ***Sugars are NORMAL at conception ***Pregnancies complicated by GDM do NOT manifest an increased risk of congenital anomalies because GDM develops after the critical period of organogenesis (in Tl) ***In women with GDM all of the following are associated with POOR GLYCEMIC CONTROL: (1) Increased risk of C/Section (2) Increased neonatal respiratory distress syndrome (hyperglycemia interferes with surfactant synthesis) (3) Increased birth weight (Macrosomia - maternal hyperglycemia leads to fetal hyperinsulinism resulting in accelerated anabolism) - Birth trauma due to macrosomia, can lead to difficult vaginal delivery and shoulder dystocia

Screening and Diagnosis - @ 24-28 weeks GA - Pregnant females age >25 or age <25 yrs with >1 risk factor (e.g. Obesity, Ethnicity (Aboriginal, Asian, African), FHX of DM, Previous history of GDM, Previous child with birthweight > 4.0 kg, PCOS, etc) Management - Treat both GDM and Impaired Glucose Tolerance - Tight glycemic control optimal as in Type 1 and Type 2 DM - Stop insulin and diabetic diet postpartum - Follow-up with 2 h, 75 g OGTT 6 wks-6 mo postpartum Long Term Maternal Complications - Type 1 and Type 2 DM: risk of progressive retinopathy and nephropathy - GDM: 50% risk of developing Type 2 DM in next 20 yrs ***Increased incidence of spontaneous abortion (in DMl and DM2, NOT in GDM): related to pre-conception glycemic control ***Congenital Anomalies (e.g. VSD, Cystic Kidneys) occur in DM1 and DM2, NOT in GDM ***Maternal End Organ Involvement or Deterioration (e.g. Retinopathy, Nephropathy) occur in DM1 and DM2, NOT in GDM

The Pathway Sperm Take To Exit The Body ("SEVEn UP")

Seminiferous Tubules (site of spermatogenesis) Epididymis Vas Deferens Ejaculatory Ducts Urethra Penis

C-PEPTIDE

Serum measurement of C-Peptide is the BEST TEST TO DISTINGUISH ENDOGENOUS FROM EXOGENOUS HYPERINSULIN in patients with HYPOGLYCEMIA ***LOW values of C-PEPTIDE in patients with HYPOGLYCEMIA --> Patient is ABUSING INSULIN ***HIGH values of C-PEPTIDE represent endogenous insulin production, such as that induced by SULFONYLUREAS (stimulates the beta cells to produce more insulin) or from an INSULINOMA ***Look for a patient with unexplained HYPOGLYCEMIA , HIGH INSULIN LEVEL, and MULTIPLE HOSPITAL VISITS. Answer C-PEPTIDE as the next best step to determine the etiology

IGF-1 (Insulin-like Growth Factor-1)

Serum measurement of IGF-1 is the BEST INITIAL TEST for ACROMEGALY IGF-1 is a somatomedin secreted by the LIVER. GH when COMBINED with THYROID HORMONE STIMULATES LINEAR SKELETAL GROWTH in children through IGF-1. It stimulates PROTEIN SYNTHESIS in muscle (anabolic effect) in CHILDREN and the release of FFAs from adipose tissue (catabolic effect) in ADULTS. ***GH secretion is PULSATILE, has a SHORT 1/2 LIFE, and REACHES MAXIMAL LIFE IN THE MIDDLE OF THE NIGHT. A SINGLE TEST of the GH level is NOT accurate. IGF-1 levels are MORE STABLE and RELIABLE. The BEST CONFIRMATORY TEST for ACROMEGALY is the ORAL GLUCOSE TOLERANCE TEST. Glucose normally SUPPRESSES GH. In ACROMEGALY glucose does NOT suppress GH. ***The most common wrong answer is GH

A patient FAILS to lactate after an emergency C-section with marked BLOOD LOSS.

Sheehan's syndrome (postpartum pituitary necrosis)

Angiotensin II has what effect on the adrenal cortex?

Stimulates aldosterone production by enhancing the activity of aldosterone synthase

A dopaminergic antagonist would be expected to have what effect on prolactin secretion?

Stimulates prolactin secretion

Oxytocin ***stimulates uterine contractions at the time of labor and delivery in response to distension of the reproductive tract ***stimulates smooth muscle contraction in the breast during suckling, which results in milk let down. ***Oxytocin has a MINOR role in the regulation of H2O homeostasis

Suckling and Distension of the reproductive tract stimulate Oxytocin release through neural pathways Oxytocin release is stimulated by ↑ plasma tonicity. In pharmacologic amounts, oxytocin potentiates H2O retention ***Severe water intoxication can occur in women who receive HIGH doses of oxytocin to promote uterine contractions during labor

Hypothalamic-Pituitary Hormone Regulation ***Anteirior Pituitary Cell Types 1) Acidophils: Somatotropes (GH), Lactotropes (Prolactin) 2) Basophils: Gonadotropes (FSH, LH), Corticotropes (ACTH), Thyrotropes (TSH) "B-FLAT" 3) Chromophobes: "Empty" cells (lack cytoplasmic granules); former acidophils or basophils after release of hormone-containing granules

TRH --> TSH, Prolactin Dopamine --Inhibits-- Prolactin CRH --> ACTH GHRH --> GH Somatostatin --Inhibits-- GH, TSH GnRH --> FSH, LH Prolactin --Inhibits-- GnRH

PRINCIPAL CELL K+ EXCRETION CAN BE QUANTIFIED BY THE TRANS-TUBULAR [K+] GRADIENT (TTKG): ***Compares luminal [K+] to capillary [K+]; reflects how much K+ has been excreted into the lumen by the principal cell. ***Normally, TTKG should be between 4-7

TTKG = CCD [K+]/Serum [K+] = Urine [K+] x SerumOsm/Serum [K+] x UrineOsm TTKG>7 = HIGH Principal cell activity, appropriate when the ECF is HYPERkalemic (to excrete more K+) TTKG<4 = LOW Principal cell activity, appropriate when ECF is HYPOkalemic (to preserve more K+) If the TTKG is ever inappropriate given the ECF [K+] status, it's a PRINCIPAL CELL DEFECT!

Diabetes Risk Factors

TYPE 1 DM: - Personal or family history of AUTOIMMUNE DISEASE TYPE 2 DM: - First degree relative with DM - Age ≥ 40 - Obesity (especially abdominal), HTN, Hyperlipidemia, CAD, vascular disease - Prior GDM, macrosomic baby (>4 kg) - PCOS - history of impaired glucose tolerance or impaired fasting glucose - presence of complications associated with diabetes ***BOTH - Member of a high risk population (e.g. Aboriginal, Hispanic, Asian or African descent)

Which of the following osteoporosis drugs are anabolic = compounds that stimulate bone formation? A. Teriparatide: parathyroid hormone (PTH) analog B. Denosumab: anti-RANKL antibody (osteoclast differentiating factor) C. Calcitonin

Teriparatide - stimulates NEW bone formation by preferential stimulation of OSTEOBLASTIC ACTIVITY over OSTEOCLASTIC ACTIVITY (SE: Orthostatic hypotension, HYPERcalcemia, Dizziness, Leg cramps) Denosumab inhibits osteoclastic-mediated bone resorption by binding to osteoBLAST-produced RANKL. By ↓ RANKL binding to the osteoCLAST receptor RANK, BONE RESORPTION and TURNOVER ↓ SE: Fatigue/headache, Dermatitis, HYPOphosphatemia, HYPOcalcemia, HYPERcholesterolemia, GI discomfort Calcitonin - Inhibits OSTEOCLAST mediated bone resorption (SE: Rhinitis, epistaxis, sinusitis, nasal dryness) Raloxifene (SERM) - DECREASES RESORPTION of bone through binding to estrogen receptors SE: Hot flashes, leg cramps, INCREASED RISK OF FATAL STROKE, VENOUS THROMBOEMBOLISM Bisphosphonates (alendronate; Zoledronate [IV]) - Inhibits OSTEOCLAST mediated bone resorption (SE: GI, MSK PAIN, HEADACHE, ONJ)

Retrograde cystourethrogram

Test to rule out urethral injury.

Choriocarcinoma

Testicular cancer associated with β-hCG, AFP.

ACTH STIMULATION TEST

The ACTH stimulation test evaluates adrenal function and is the best test for ADRENAL INSUFFICIENCY. Baseline cortisol levels are taken, then ACTH is administered and follow up cortisol levels monitored. If CORTISOL is ↓, think PRIMARY AI. If cortisol levels are ↑, the adrenal gland is functioning. ***Look for a FATIGUED patient with SKIN HYPERPIGMENTATION, HYPERKALEMIA, slight METABOLIC ACIDOSIS and a TASTE FOR PICKLE JUICE (HIGH SALT CONTENT). ***Also look for an ICU PATIENT with untreated hypotension

Envelope-Shaped Oxalate Crystals

They precipitate in the RENAL TUBULES when a toxic dose of ETHYLENE GLYCOL, a component of antifreeze, is ingested

Hyperparathyroidism and Malignancy

The MOST COMMON causes of HYPERCALCEMIA.

In what organ is Vitamin D3 produced?

The skin. Vit D requires sun exposure (UV light and heat)

increased urine output

The first sign that a patient is recovering from kidney failure due to acute tubular necrosis

Membranous glomerulonephritis ***Glomerular basement membrane thickening with little or no cellular proliferation or infiltration ***Subepithelial spikes

The most common form of nephrotic syndrome. ***MN is more common in white males over the age of 40 years. ***MN in young women should raise the suspicion of lupus. *** Most cases of MN in adults are idiopathic (approximately 75 percent). ***Systemic lupus erythematosus (WHO Class V), Penicillamine, Gold salts, NSAIDs, Hepatitis B virus, Malignancy

chronic abacterial prostatitis

The most common form of prostatitis, which most often occurs without any history of UTI

Transitional cell carcinoma

The most common histology of bladder cancer.

Seminoma—a type of germ cell tumor

The most common type of testicular cancer. ***Seminoma tumors occur in all age groups, but if an older man develops testicular cancer, it is more likely to be seminoma. Seminomas, in general, aren't as aggressive as nonseminomas and are PARTICULARLY SENSITIVE TO RADIATION THERAPY

If clearance of substance X is equal to GFR, what occurs?

There is no net secretion or reabsorption

Why are β-blockers contraindicated in diabetics?

They can MASK symptoms of hypoglycemia

Thirst ***Regulation of thirst depends on many of the same factors as ADH release

Thirst is stimulated by a 2-3% INCREASE in plasma tonicity. The osmotic regulation of thirst occurs through osmoreceptors in the hypothalamus. Volume depletion detected by baroreceptors in the cardiac atria also regulates the water drinking response. Satiation of thirst occurs in response to many stimuli including normalization of osmolality and esophageal stretch

5-alpha reductase inhibitors (e.g. Avodart, Proscar) ***DOUBLE THE PSA VALUE ***DECREASES DHT ***SE: impotence, decreased libido, decreased ejaculate volume, depression.

This class of drugs, which is capable of shrinking the prostate, may actually confer some protection against prostate cancer.

Posterior urethral valves

This is the MOST COMMON form of LOWER URINARY TRACT OBSTRUCTION in MALE babies, with nearly 1/3 of patients eventually progressing to end stage renal disease.

Prolactin

This is the most common hormone to be overproduced in pituitary hyperfunction

Dopamine

This molecule tonically INHIBITS prolactin secretion

Oral Glucose Challenge

This test is administered to try and suppress GH levels

How much of the ECF is interstitial fluid?

Three-fourths

What signal from the body decreases TRH secretion?

Thyroid hormones, T3

Tests of Thyroid Autoimmunity ***TSI ↑ in GRAVES' disease ***Antithyroid-Peroxidase and Antithyroglobulin Antibodies ↑ in Hashimoto's disease

Thyroid-Stimulating Immunoglobulin (TSI) - Useful in the Dx. of GRAVES' disease, a form of HYPERthyroidism caused by endogenously generated AUTOANTIBODIES to the TSH RECEPTOR. Antithyroid-Peroxidase and Antithyroglobulin Antibodies - ↑ in patients with CHRONIC LYMPHOCYTIC THYROIDITIS (Hashimoto's disease) and reflect the autoimmune basis of this disorder - Markers of thyroid damage - Patients with ↑ titers of these antibodies need periodic evaluation for HYPOthyroidism

cryotherapy

Treatment for prostate cancer, normally reserved for older, non-surgical candidates, 100% of patients experience erectile dysfunction as a side effect.

Signs and Symptoms of HYPERthyroidism ***Mnemonic: "THYROIDISM"

Tremor Heart rate up Yawning (fatigued) Restlessness Oligomenorrhea/amenorrhea Intolerance to heat Diarrhea Irritability Sweating Muscle wasting/weight loss

T/F - PTH stimulates both osteoclasts and osteoblasts?

True

Renal tubular acidosis (RTA) associated with ABNORMAL H+ SECRETION and NEPHROLITHIASIS.

Type I (distal) RTA

RTA associated with ABNORMAL HCO3 − and RICKETS.

Type II (proximal) RTA

RTA associated with aldosterone defect.

Type IV (distal) RTA

What is the thick ascending loop of Henle impermeable to?

Water

What is passively reabsorbed in the thin descending loop of Henle?

Water via medullary hypertonicity (impermeable to sodium)

Necrotizing vasculitis (lungs) and necrotizing glomerulonephritis

Wegener's and Goodpasture's (hemoptysis and glomerular disease)

c-ANCA

Wegener's granulomatosis

What is the oncotic pressure of Bowman's space?

Zero

A patient with SEVERE HYPERNATREMIA is admitted to the ICU for CONFUSION. There is POLYURIA despite the increase in serum sodium. The patient is DEHYDRATED. What is the most likely diagnosis in each of these cases? 1. The URINE VOLUME MARKEDLY DECREASES in response to the administration of ADH 2. There is NO RESPONSE TO THE ADMINISTRATION OF ADH. The urine volume remains HIGH and the urine osmolality remains LOW.

1. CENTRAL DIABETES INSIPIDUS IS AN INSUFFICIENCY OF ADH due to damage to either the hypothalamus or posterior pituitary. There is MARKED RESPONSE IN URINE VOLUME TO THE ADMINISTRATION OF ADH 2. With NEPHROGENIC DIABETES INSIPIDUS (NDI), there is NO response to the administration of ADH. NDI is often from HYPOKALEMIA or HYPERCALCEMIA. There may also be a history of LITHIUM ADMINISTRATION.

Prostaglandins ***NSAIDS inhibit prostaglandin synthesis by inhibiting COX and interfere with the renal protective effects of prostaglandins (GFR and RBF are ↓) ***Patients with decreased renal perfusion (chronic or acute) are at increased risk of NSAID-induced AKI ***NSAIDS ↓ K+ excretion ***NSAIDs and CHF, Cirrhosis, Nephrotic Syndrome DON'T mix and contribute to diuretic resistance ***NSAIDs may cause resistant hypertension and cause antihypertensive medications to be ineffective

1. Dilation of Afferent Arteriole 2. ↑ Renin 3. ↓ ADH response 4. Inhibit Tubular Na+ reabsorption ***Prostaglandins have a larger role in RBF regulation in patients with underlying renal disease and ↓ EABV (i.e. heart failure)

SIADH ***The most common HYPOTONIC disorder

1. Excessive H2O retention 2. HYPOnatremia 3. Urine osmolality > Serum osmolality Body responds with ↓ aldosterone (HYPOnatremia) to maintain near normal volume status. Very ↓ serum Na+ levels can lead to SEIZURES (***CORRECT SLOWLY). Tx: H2O restriction Causes include: 1. Ectopic ADH (SCC) 2. CNS disorders/head trauma 3. Pulmonary disease 4. Drugs (e.g. cyclophosphamide, narcotic analgesics, beta agonists, barbiturates)

What are the major causes of Cushing's Syndrome?

1. Exogenous glucocorticoids (cortisol, prednisone, dexamethasone) 2. ACTH-producing pituitary tumors 3. Cortisol-secreting adrenal adenoma or adrenal carcinoma 4. Ectopic ACTH production by non-pituitary tumors (e.g. (e.g. SCC of the lung, bronchial carcinoid tumors) 5. Ectopic CRH production by non-hypothalamic tumors

Signs and symptoms of pressure from a pituitary tumor may include:

1. HEADACHE 2. Vision loss, PARTICULARLY LOSS OF PERIPHERAL VISION 3. Nausea and vomiting 4. Symptoms of pituitary hormone deficiency 5. Fatigue 6. Weakness 7. Cold intolerance 8. Constipation 9. Low blood pressure 10. Body hair loss 11. Sexual dysfunction 12, Unintended weight loss or gain

What are the hallmarks of NEPHRITIC SYNDROME?

1. Hematuria 2. Oliguria (urine output <500 mL/24 hours) 3. Azotemia (elevated BUN and serum Cr levels) 4. HTN

What are the Major Causes of Hypotonic Disorders?

(1) Decreased H2O excretion - Euvolemic states - ADH excess due to SIADH - Pain and physical stress - CNS infection, tumor, and trauma - Ectopic tumors producing ADH - Lung disease (Tumor, TB, Pneumonia) - Drug induced ADH release (Opiates, analgesics) (2) Decreased H2O excretion - Hypovolemic states (Decreased distal solute delivery) - CHF - Cirrhosis - Nephrotic syndrome*** - Adrenal insufficiency - Starvation (3) Excess water ingestion - Psychogenic polydipsia ***Nephrotic syndrome presents with MASSIVE PROTEINURIA (>3,5g/day, frothy urine), HYPERLIPIDEMIA, FATTY CASTS, EDEMA. Associated with thromboembolism (hypercoagulable state due to Angiotensin 2 loss in urine) and ↑ risk of infection (loss of immunoglobulin)

What are the Causes of NONTOXIC GOITER?

(1) Iodine deficiency (2) Genetic defects in thyroid hormone synthesis (3) Drugs or chemicals impairing thyroid hormone synthesis (4) Goitrogens (interfere with function of the thyroid gland) in the diet (e.g. Soybean and soy products, broccoli, cauliflower, Brussels sprouts, cabbage, mustard, etc)

Functions ↑ by T3

(1) O2 Consumption (2) Heat Produciton (3) Metabolic Rate (4) Lipid Synthesis (5) Lipid Oxidation (6) Cholesterol synthesis and degradation (7) Protein Synthesis (8) Protein Degradation (9) Drug metabolism (10) Catecholamine receptors (IMPORTANT ONLY IN HYPERthyroidism) (11) Glucose absorption (IMPORTANT ONLY IN HYPERthyroidism) (12) Gluconeogenesis (IMPORTANT ONLY IN HYPERthyroidism)

Cushing Syndrome = Signs and symptoms of excess cortisol and is most commonly caused by exogenous glucocorticoid therapy. ***The INITIAL SCREEN is the overnight dexamethasone (a cortisol analog) suppression test. In NORMAL individuals, dexamethasone suppresses ACTH release from the pituitary and results in DECREASED cortisol release. In Cushing syndrome, cortisol levels FAIL to be suppressed. A 24-hr urinary free cortisol level is the GOLD STANDARD diagnostic test. Once the diagnosis is confirmed, an ACTH level is assessed. If the ACTH level is HIGH, then the excess cortisol is ACTH-dependent and a HIGH dose dexamethasone suppression test is performed. Cortisol is suppressed in Cushing disease, but NOT with ectopic ACTH-producing tumors (e.g. SCC of the lung, bronchial carcinoid tumors)

***CUSHING'S DISEASE = ACTH-Producing Pituitary Tumors ↑ ACTH from the pituitary → Bilateral Adrenal Hyperplasia - Excess ACTH production by a pituitary tumor causes the adrenal gland to secrete EXCESS GLUCOCORTICOIDS and ANDROGENS. The resulting syndrome is called CUSHING'S DISEASE ***Clinical manifestations of Cushing's Disease reflect the biologic effects of adrenal corticosteroids. These include: (1) Central Obesity, Moon Facies, Buffalo hump (2) HTN (3) Glucose intolerance (decreased peripheral glucose utilzation, ↑ hepatic gluconeogenesis) (4) Purple abdominal striae (5) Proximal muscle wasting and weakness, back pain (7) Osteoporosis (8) Depression and mania (9) Hirsutism (10) Easy bruising (11) Acne (12) Superficial fungal infections (13) Menstrual disorders ***Cushing's disease occurs MORE FREQUENTLY in WOMEN (female-to-male ratio 8:1) Tx: Transsphenoidal Surgery

Differential Diagnosis of DI

***DI should be suspected whenever patients present with UNEXPLAINED THIRST, HIGH FLUID INTAKE, LARGE URINE VOLUMES, and DILUTE URINE (Urine osmolality<plasma osmolality) The initial problem in differential diagnosis usually is distinguishing DI from PSYCHOGENIC POLYDIPSIA (compulsive water drinking) or an ABNORMAL THIRST MECHANISM. - Psychogenic H2O drinkers ingest LARGE volumes of H2O, which DILUTES PLASMA, SUPPRESSES ADH, and results in LARGE VOLUMES of DILUTE URINE. ***Psychogenic H2O drinkers should have DECREASED PLASMA OSMOLALITY, and patients with DI should have INCREASED OSMOLALITY or NORMAL OSMOLALITY if water intake is adequate. ***H2O DEPRIVATION TEST --> Urine osmolality will NOT increase in patients with either form of DI but should INCREASE in patients with psychogenic polydipsia.

Central DI (↓ ADH secretion) Vs. Nephrogenic DI (↓ ADH action)

***H2O CONSERVATION in the DISTAL COLLECTING TUBULES CANNOT OCCUR because ADH either is not present or is inactive. Dilute urine created in the proximal nephron is NOT concentrated as it passes through the renal parenchyma, and EXCESS FREE H2O losses occur Major causes of Central DI: - Trauma to pituitary stalk - Hypothalamic or pituitary surgery - Tumors (infiltration) - Granulomatous disease (TB, Sarcoid) - Ischemia (Postpartum hemorrhage) - Infection (Viral encephalitis, meningitis) - Inflammation (AI hypophysitis) - Familial (AD) Major causes of Nephrogenic DI (***Usually due to chronic renal disease, which destroys the medullary concentrating gradient or to drugs that inhibit ADH action): - Toxins or drugs (***LITHIUM - inhibit ADH action) - Vascular (Sickle cell disease) - Infection (Pyelonephritis) - Inflammation (Amyloid) - Familial (X-Linked) ***The clinical picture of POLYURIA and THIRST is the SAME regardless of the cause of DI.

The regulation of Prolactin (PRL) secretion is UNIQUE among pituitary hormones because DOPAMINE from the hypothalamus is required to keep PRL secretion SUPPRESSED.

*Disruption of the hypothalamus or the pituitary stalk can cause PRL levels to INCREASE *Dopamine antagonists (e.g. antipsychotics, antidepressants, antihypertensives, H2-blockers) --> INCREASE PRL levels *High levels of TRH (e.g. patients with primary HYPOthyroidism) --> INCREASE PRL levels *Suckling stimulates PRL synthesis via a neural reflex arc ***Prolactinoma is the MOST common pituitary adenoma (prolactin-secreting tumours may be induced by estrogens and grow during pregnancy) ***The primary physiologic actions of PRL are PREPARATION OF THE BREASTS FOR LACTATION and STIMULATION OF MILK PRODUCTION POSTPARTUM. - PRL levels rise throughout the course of pregnancy, but their effects on lactation are INHIBITED by placental progesterone until birth.

Thyroid Hormones - The FOLLICLE (basic functional unit of the thyroid gland; ***T4 synthesis) consists of a single layer of epithelial cells surrounding a sphere of COLLOID, which contains the protein thyroglobulin ***Na/I Symporter in thyroid cells ***Steps in Thyroid Hormone Synthesis involves: (1) Iodide trapping (2) Oxidation of Iodide to iodine by the enzyme thyroid peroxidase (3) Iodination of Thyroglobulin (4) Release of T3 and T4 ***The recommended intake of iodine to maintain thyroid hormone synthesis is 150 ug/d. ***TSH stimulates nearly all reactions required for thyroid hormone synthesis. - Secretion of TSH is regulated primarily by the pituitary T3 level (An ↑ in pituitary T3 INHIBITS synthesis and secretion of TSH) ***Glucocorticoids and Dopamine SUPPRESS TSH - TRH regulates pituitary sensitivity to TSH - TRH stimulates acute TSH release - TRH regulates glycosylation of TSH which is required for TSH bioactivity ***When plasma T3 levels are ↑, hypothalamic TRH content is ↓ ***~99.9% of T4 and T3 are BOUND in plasma - Thyroxine-binding globulin (TBG) & Albumin ***Thyroid hormone exerts major effects on GROWTH and DEVELOPMENT. ***Thyroid hormone ↑ O2 consumption and heat production ***T3 is more biologically active, BUT T4 has a longer 1/2 life.

- 2 major thyroid hormones: Thyroxine (T4) and Triiodothyronine (T3) ***The major secretory product of the thyroid is T4 - T4 is made within the basic functional unit of the thyroid gland, the thyroid follicle. - T4 is synthesized and is covalently linked to THYROGLOBULIN (stores iodinine-containing thyroid hormone - important given the decreased availability of iodine in certain geographic regions of the world) ***Thyroid hormone MUST BE RELEASED from thyroglobulin to be released into the circulation - T3 is the PHYSIOLOGICALLY ACTIVE HORMONE (85% produced in peripheral tissues by the deiodination of T4) Causes of congenital Thyroid Hormone Deficiency: (1) Intrathyroid defects - Iodide transporter defects - Thyroid peroxidase defects - Thyroglobulin defects (2) Intrathyroid and Peripheral Tissue Defects - Deiodinase deficiency - The secreted hormones are deiodinated in peripheral tissues to release FREE Iodide. - Kidney can excrete free iodide - Thyroid hormone action at the cellular level is initiated by the binding of thyroid hormones to a specific nuclear receptor. ***The receptors preferentially bind T3, which is why T3 is more active than T4. - Thyroid hormone DEFICIENCY in the first few months of life leads to IRREVERSIBLE abnormalities in brain development. ***Prolonged and severe thyroid hormone deficiency in early infancy ---> Cretinism (characterized by marked mental retardation and short stature). - If HYPOthyroidism develops later in childhood, growth is delayed, BUT normal growth can be restored by thyroid hormone replacement therapy. Effects of Thyroid Hormone on Organ Systems: Hormone Excess: Heart - ↑ HR, ↓ Contractility Vascular - Vasodilation Skin - Warm, smooth and moist GI - ↑ motility and absorption Skeletal - ↑ bone turnover Neuromuscular - Hyperactivity, ↑ muscle contraction Hormone Deficiency: Heart - ↓ HR, ↓ CO Vascular - HTN Skin - Rough and dry GI - ↓ motility Skeletal - ↓ bone turnover Neuromuscular - Lethargy, slow muscle relaxation

Thyroid Imaging ***U/S - measure size of gland, solid vs. cystic nodule ***Thyroid scan (Technetium-99) - differentiates b/w HOT (functioning) and COLD (non-functioning) nodules. - Distinguish b/w 3 major types of ↑-uptake HYPERthyroidism (1) Graves' disease (diffuse uptake) (2) Toxic multinodular goitre (multiple discrete areas) (3) Solid toxic adenoma (single intense area of uptake) - Test of structure - order if there is a THYROID NODULE + patient is HYPERthyroid.

- A radioactive iodine or technetium scan provides info. about the SIZE and FUNCTIONING areas of the thyroid gland ***Functioning thyroid nodules that TAKEUP the isotopes are called "HOT" nodules; nonfunctioning or poorly functioning areas of the thyroid that take up little isotope are called "COLD" areas - Thyroid U/S is used primarily to FOLLOW CHANGES in SIZE of thyroid nodules and for DIFFERENTIATING CYSTIC from SOLID nodules. - CT and MRI --> Follow THYROID MALIGNANCIES in the neck

Extracellular Fluid ***1/3 of total body water

- Consists of BOTH interstitial fluid and intravascular fluid - Na+, Cl-, and HCO3- are the PRIMARY ECF electrolytes ***Na+ is the MAJOR determinant of ECF volume - Interstitial Fluid (Surrounds the cells, but does NOT circulate) = 3/4 of ECF - Intravascular Fluid = 1/4 of ECF (Na+, Cl+, HCO3-) ***Hyponatremia and Hypernatremia are disorders of H2O Balance - Hyponatremia → TOO MUCH H2O in the ECF relative to Na+ - Hypernatremia → TOO LITTLE H2O in the ECF relative to Na+

Goiter = Enlargements of the thyroid gland which arise b/c of ↑ stimulation of the thyroid gland by TSH or by Thyroid-Stimulating Immunoglobulins.

- Diffuse, simple or nontoxic goiters may develop in response to INADEQUATE synthesis of thyroid hormone. TSH secretion then ↑ and induces diffuse thyroid HYPERPLASIA - Some follicles become AUTONOMOUS; there growth is NO longer dependent on TSH. - Diffuse goiter --> Multinodular goiter - Patients may complain of neck pressure or difficulty swallowing Tx: T4 to suppress TSH into the normal range may cause these goiters to regress, BUT Autonomous areas and necrotic, hemorrhagic, or fibrotic areas do NOT respond. ***Patients with these goiters are EUTHYROID IF THYROID HYPERPLASIA COMPENSATES FOR THE DEFECT IN THYROID HORMONE SYNTHESIS, AND THEIR FT4 AND TSH LEVELS ARE NORMAL ***If the ↑ follicle growth is NOT enough to compensate for the defect in hormone synthesis, patient are HYPOTHYROID ***These goiters can be associated with HYPERthyroidism, if autonomous follicle growth is accompanied by EXCESSIVE THYROID HORMONE SECRETION. In these cases, the nontoxic goiters have been transformed into TOXIC MULTINODULAR GOITERS

What are the symptoms and signs of DI

- Free H2O loss & Increased osmolality --> Excessive Thirst - High fluid intake - High urine output - Plasma osmolality HIGH or NORMAL - Urine osmolality is LOW

Insulin * INsulin moves glucose INto cells * BRICK L (don't need insulin for glucose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver * GLUT-1: RBCs, brain - Brain depends on glucose under normal circumstances and uses ketone bodies in starvation. - RBC's ALWAYS depend on glucose because they have NO mitochondria for aerobic respiration * GLUT-2 (bidirectional): Beta islet cells, liver, kidney, small intestine * GLUT-4 (insulin responsive): Adipose tissue, Skeletal Muscle *Insulin does NOT cross the placenta *Inhibits glucagon release by alpha cells of pancreas *Regulation - HYPERglycemia, GH, and Cortisol ↑ insulin; HYPOglycemia and somatostatin ↓ insulin; Beta agonists STIMULATE insulin release; Alpha agonists INHIBIT insulin release *Anabolic effects of insulin: 1) Skeletal muscle and adipose tissue depend on insulin for ↑ glucose update (GLUT-4) 2) ↑ Glycogen synthesis and storage 3) ↑ TG synthesis and storage 4) ↑ Na+ retention (kidneys) 5) ↑ Protein synthesis (muscles) 6) ↑ Cellular uptake of K+ and amino acids * The SUR receptor is the binding site for some drugs that act as insulin secretagogues (e.g. sulfonylureas) *Serum C-peptide is NOT present with exogenous insulin intake *A decrease in Insulin is the FIRST DEFENSE against HYPOglycemia

- Insulin is produced in the beta cells of the pancreatic islets - Preproinsulin --> Proinsulin --> Insulin + C-peptide - The mature insulin molecule and C-peptide are stored together and co-secreted from secretory granules in the beta cells. ***Because C-peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia. -Glucose is the KEY regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. 1) Increased levels of glucose in the circulation lead to increased glucose uptake into pancreatic beta cells through GLUT2, a glucose transporter. *Glucose phosphorylation by glucokinase is the RATE-LIMITING STEP that controls glucose-regulated insulin secretion. 2) Increased intracellular glucose then leads to increased production of ATP, and an increase in the ATP/ADP ratio 3) The increased ATP/ADP ratio leads to CLOSING of an ATP-sensitive K+ channel* and DEPOLARIZATION of the cell *This channel consists of 2 separate proteins: one is the binding site for certain oral hypoglycemics (e.g., sulfonylureas); the other is an inward rectifying K+ channel protein (Kir6.2) 4) Cell depolarization opens a calcium channel which leads to insulin secretion *Incretins are released from neuroendocrine cells of the GIT following food ingestion and AMPLIFY glucose-stimulated insulin secretion and SUPPRESS glucagon secretion. - Glucagon-like peptide 1 (GLP-1), the MOST POTENT incretin, is released from the small intestine and stimulates insulin secretion ONLY when the blood glucose is above the fasting level. Incretin analaogues, are used to ENHANCE endogenous insulin secretion. Once insulin is secreted into the portal venous system, ~50% is removed and degraded by the liver. Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. INSULIN is the MOST IMPORTANT REGUlATOR of this metabolic equilibrium, but neural input, metabolic signals, and other hormones (e.g. glucagon) result in integrated control of glucose supply and utilization. - Fasting state: ↓ insulin --> ↑ glucose production by promoting hepatic gluconeogenesis and glycogenolysis and ↓ glucose uptake in insulin-sensitive tissues (skeletal muscle and fat), thereby promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). Glucagon (secreted when BG is ↓) stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla. Insulin, an ANABOLIC hormone, promotes the storage of carbohydrate and fat and protein synthesis. The MAJOR portion of postprandial glucose is utilized by SKELETAL muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most notably the BRAIN, utilize glucose in an INSULIN-INDEPENDENT fashion.

Leptin *Produced in fat cells *DECREASES FOOD INTAKE *Signals the brain about the quantity of stored fat

- Leptin is produced primarily in fat cells, and also in the gut and placenta. It signals the brain about the quantity of stored fat - Humans with congenital leptin DEFICIENCY are profoundly hyperphagic and obese, and their food intake decreases dramatically when treated with exogenous leptin. - Several mechanisms appear to be involved in the reduction in food intake with leptin therapy, including a decrease in hunger ratings in the fasted state, enhanced perception of satiety after a meal, and a diminished perception of food reward

Toxic Multinodular Goiter (aka Plummer's disease) ***50+ y.o. ***In some cases, the HYPERthyroidism is precipitated by the ingestion of large quantities of iodide, especially iodide-containing drugs like AMIODARONE or CONTRAST DYE

- Long history of BENIGN GOITER and NORMAL THYROID TESTS - HYPERthyroidism develops gradually and is usually is LESS severe then Graves' disease ***FT4, FT3 and radioactive iodine uptake are HIGH ***TSH level is SUPPRESSED ***Radioactive iodine scan reveals DIFFUSE PATCHY UPTAKE, with more active areas taking up iodine more intensely Tx options are the same as those for Graves' disease: (1) Antithyroid drugs (2) Radioactive iodine (3) Surgery

Disorders of Pituitary Failure ***Pathophysiology of Hypopituitarism (1) Primary pituitary disorder - loss of hormone secreting cells (2) Hypothalamic disorder - Loss of releasing hormones (3) Extrinsic destruction of the hypothalamus, stalk, or pituitary gland. ***If hypopituitarism is due to damage to the hypothalamus, ALL pituitary hormones may be deficient EXCEPT PRL, which normally is INHIBITED by DOPAMINE from the hypothalamus. ***The most LIFE-THREATENING pituitary deficiency is ACTH, followed by TSH, then FSH/LH, and lastly GH ***Hypopituitarism is treated by REPLACING TARGET HORMONES, not pituitary hormones. Pituitary hormones must be given in a pulsatile fashion. They have very short half-lives, and they CANNOT be given orally because they are destroyed in the GIT. ***Lab. evaluation includes measurement of pituitary and target organ hormones (BOTH SHOULD BE LOW). Further evaluation (e.g. MRI) depends on the suspected cause of pituitary failure.

- Pituitary tumors are the MOST common cause of hypopituitarism in ADULTS - Postpartum pituitary necrosis, known as SHEEHAN'S SYNDROME, occurs in women who experience MASSIVE BLOOD LOSS, HYPOVOLEMIC SHOCK or BOTH during delivery. The pituitary gland enlarges during pregnancy, and hypotension or hemorrhage creates vasospasm in the hypophyseal vessels and ischemia. - A hemorrhage that occurs in a preexisting pituitary adenoma is called PITUITARY APOPLEXY. ***Rapid expansion of the hemorrhage presents as SEVERE HEADACHE, VISUAL FIELD DEFECTS, and ACUTE HYPOPITUITARISM. This situation requires IMMEDIATE SURGERY for decompression of the pituitary fossa. Patients with pituitary failure usually are PALE with FINE SKIN and FINE FACIAL WRINKLES. Symptoms and Signs are due to the failure of the target organs to produce their hormones. ***A precipitous ↓ in ACTH causes a ↓ in glucocorticoids, which can lead to HYPOTENSION and CARDIOVASCULAR COLLAPSE. B/c this is life-threatening, GLUCOCORTICOIDS are administered if this diagnosis is suspected, even before diagnostic testing is complete. - Usually ACTH deficiency occurs gradually, causing chronic symptoms of glucocorticoid deficiency: WEAKNESS, LETHARGY, FATIGUE, NAUSEA, ARTHRALGIAS, MYALGIAS, and VOMITING. Chronic or partial ACTH deficiency may be exacerbated by an ACUTE ILLNESS ***Resembles primary adrenal insufficiency but WITHOUT skin hyperpigmentation from MSH (melanocyte-stimulating hormone) or volume depletion, hypokalemia, and salt craving due to INTACT RAAS. ***Hypopituitarism can also include TSH deficiency, which results in symptoms of hypothyroidism. These include FATIGUE, COLD INTOLERANCE, CONSTIPATION, DRY SKIN, SLOW HR, and DELAYED DRUG METABOLISM. There is NO GOITER in the absence of TSH stimulation of the thyroid gland ***Deficiency of LH and FSH produces symptoms with HYPOGONADISM. - Women develop amenorrhea and infertility. - Men develop impotence and infertility. - Both men and women develop experience LOSS of secondary sex characteristics and LOSS of libido.

Radioactive Iodine Uptake (RAIU) ***HIGH - Grave's disease, Multinodular goiter (Thyroid hormone synthesis is ↑), Toxic Nodule, TSH producing tumors ***LOW - Thyroiditis, after ingestion of thyroid hormone, After ingestion of iodide-containing medications, After administration of iodide containing contrast material, Ectopic thyroid tissue

- RAIU measures the TURNOVER of iodine by the thyroid gland in vivo. - The normal range for RAIU depends on dietary iodine intake. - The RAIU is ↑ in areas where usual dietary iodine intake is LOW. - RAIU is ↑ in HYPERthyroid states (e.g. Graves' disease) - RAIU is LOW in patients with Thyroiditis who are HYPOthyroid due to RELEASE OF STORED HORMONE from damaged cells. The injured or inflamed gland CANNOT take up iodine.

Screening for diabetes mellitus

- SYMPTOMS of diabetes PLUS random blood glucose concentration ≥ 11.1 mmol/L or - Fasting plasma glucose (FPG) ≥ 7.0 mmol/L or - A1C > 6.5% - 2 hour plasma glucose ≥ 11.1 mmol/L during an oral glucose tolerance test (OGTT) ***Fasting is defined as NO caloric intake for at least 8 hours ***Pre-diabetes = Impaired fasting glucose (6.1-6.9 mmol/L) or impaired glucose tolerance (7.8-11.0 mmol/L) - 1-5% per year go on to develop DM Widespread use of the FPG or the A1C as a screening test for type 2 DM is recommended because (1) A large # of individuals who meet the current criteria for DM are asymptomatic and unaware that they have the disorder (2) Type 2 DM may be present for up to a DECADE before diagnosis (3) Some individuals with type 2 DM have one or more diabetes-specific complications at the time of of their diagnosis (4) Treatment of type 2 DM may favorably alter the natural history of DM ***The ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight (BMI > 25 kg/m2) and have one additional risk factor (e,g, family history of diabetes, HTN, history of CVD) ***A long asymptomatic period of hyperglycemia is RARE prior to the diagnosis of type 1 DM.

Pituitary Tumors ***The problems they cause are related to: (1) Their space occupying effects (2) Excessive hormone production - PRL (Galactorrhea) - GH (Acromegaly in adults, gigantism in children) - ACTH (Cushing's disease = Cushing's syndrome caused by a pituitary tumor) (3) Loss of function of the remaining gland ***The most common pituitary tumor is a NONFUNCTIONING, NONSECRETORY ADENOMA

- Seldom Malignant and seldom metastasize - Pituitary tumors that grow beyond the small, confined area of the sella turcica can impinge on or expand into surrounding structures and produce significant signs and symptoms. ***A tumor that ERODES THE FLOOR of the sella or extends into the SPHENOID SINUS may allow CSF to leak into the sphenoid sinus and into the nose, causing CSF RHINORRHEA. ***Tumors extending LATERALLY into either cavernous sinus can surround the carotid artery and produce unilateral defects in CRANIAL NERVES 3,4,5 and 6. ***The OPTIC CHIASM is located superiorly to the sella; in 80% of people, it is directly over the gland, separated from the pituitary only by the thin fold of dura called the diaphragm sella. The hallmark of chiasmal compression by a tumor EXPANDING UPWARD is the visual field defect called BITEMPORAL HEMIANOPSIA (LOSS OF PERIPHERAL VISION), The eyes may not be affected equally, and other visual field defects, LOSS OF VISUAL ACUITY and DIPLOPIA also are possible. ***MRI and CT ***~90% of pituitary tumors secrete one or more of the anterior pituitary hormones - Prolactin: 60% - GH: 20% - ACTH: 10%

Prolactinomas ***Average age of onset is 20-40 yrs ***Most common FUNCTIONING pituitary tumor and is characterized by HYPERsecretion of PRL ***Excess PRL can arise from drugs that deplete or inhibit the synthesis/action of dopamine (e.g. antipsychotics). ***In HYPOthyroidism, ELEVATED TRH stimulates the anterior pituitary to UPREGULATE PRL production.

- The CLASSIC SIGNS of a prolactinoma in a premenopausal woman are: (1) Galactorrhea (leakage of milk from the breasts) (2) Amenorrhea or infertility - Hyperprolactinemia SUPPRESSES pulsatile LH secretion and GnRH pulses. When the gonadotropin leves are suppressed, estrogen production is lower, and OVULATION DOES NOT OCCUR. ***The consequences are INFERTILITY and DECREASED LIBIDO and SEXUAL FUNCTION - Over 90% of MEN with prolactinomas have macroadenomas. Further evaluation often reveals IMPOTENCE, LOSS OF LIBIDO, and INFERTILITY ***Presentation: Amenorrhea, infertility, galactorrhea; decreased libido and osteopenia due to ↓ estrogen in women Impotence and gynecomastia in men Bitemporal hemianopsia (loss of peripheral vision) due to SUPERIOR GROWTH of tumor, leading to compression of optic chiasm. ***Diagnosis Serum chemistry: ELEVATED PRL (RULE OUT SECONDARY CAUSES by screening for hypothyroidism, pregnancy, confounding antiemetic/antipsychotic medications, renal failure, cirrhosis and marked psychological stress) - once secondary causes have been ruled out, MRI (or CT scan) to identify mass lesions. ***Treatment - 1st line = Dopamine AGONISTS (e.g. bromocriptine) - Transsphenoidal surgery is performed when dopamine agonists are ineffective in decreasing serum PRL concentration or the size of the adenoma or if the patient is pregnant and is suffering mass effect from the tumor. - Asymptomatic patients WITHOUT hypogonadism can be followed with SERIAL PRL levels.

Ghrelin *Plays a central role in the neurohormonal regulation of food intake and energy homeostasis *Stimulates secretion of growth hormone * Over 90 percent of the body's ghrelin is in the stomach and duodenum STIMULATES APPETITE and induces a positive energy balance that can lead to weight gain. Ghrelin is implicated in regulating mealtime hunger and meal initiation

- The STOMACH is the richest source of ghrelin. - Grehlin is the natural ligand for the growth hormone secretagogue (GHS) receptor. - Ghrelin concentrations in the blood INCREASE during FASTING and surges occur shortly BEFORE meals. Ghrelin levels DECREASE after eating. The suppressive effects of food on plasma ghrelin appear to be nutrient specific, with CARBOHYDRATES having the greatest effect followed by protein and lipids. - Ghrelin STIMULATES appetite and induces a positive energy balance that can lead to weight gain. Ghrelin is implicated in regulating mealtime hunger and meal initiation. Accumulating evidence indicates that ghrelin plays a central role in the neurohormonal regulation of food intake and energy homeostasis. - Gastric bypass patients LACK the premeal increase in plasma ghrelin that is seen in normal individuals and cumulative ghrelin secretion is much LOWER. This lack of ghrelin response may be one of the mechanisms contributing to the overall effectiveness and negative energy balance seen after gastric bypass surgery. - Reduced Ghrelin secretion following gastric bypass surgery may IMPROVE glucose tolerance. Under normal conditions, ghrelin stimulates secretion of insulin counterregulatory hormones, suppresses adiponectin secretion, and INHIBITS insulin secretion. These negative actions on insulin secretion are diminished when ghrelin release is impaired

Thyroid-Pituitary Axis Hormones in Blood ***The sensitive TSH assay has become the single most useful clinical test of thyroid function HYPERTHYROIDISM - Primary: TSH is ↓ b/c of (-) feedback from ↑ levels of circulating T3 and T4 - Secondary: ↑TSH --> ↑ T3 and T4 HYPOTHYROIDISM - Primary: ↑ TSH (most sensitive test) b/c of less (-) feedback from T3 and T4 - Secondary: TSH is low with variable response to TRH depending on the site of the lesion (pituitary or hypothalamic) ***The level of circulating thyroid hormone is ↓ in patients with SEVERE ILLNESS. ***Serum thyroglobulin is used to monitor residual thyroid activity POST-THYROIDECTOMY, e.g. for THYROID CANCER RECURRENCE (NB: Normal or ↑ levels may suggest persistent, recurrent, or METASTATIC disease, especially on stimulation)

- The level of T4 does NOT always reflect the actual thyroid status of the patient. The total T4 is a MIXTURE of FREE T4 (FT4) [active form] and T4 attached to binding proteins (e.g. Thyroxine-Binding Globulin [TBG]) Increased Binding: - Pregnancy - ↑ TBG synthesis, ↓ TBG clearance - Estrogen treatment (e.g. OCP) - ↑ TBG synthesis, ↓ TBG clearance - Acute hepatitis (damaged cells release TBG) - Hereditary ↑ in TBG - Hypothyroidism ( ↓ catabolism of TBG) Decreased Binding: - Nonthyroid illness (e.g. malnutrition, nephrotic syndrome) - Testosterone treatment ( ↓ TBG synthesis, ↑ TBG clearance) - NSAIDS - ASA - Hereditary ↓ in TBG - Hyperthyroidism (↑ catabolism of TBG) ***The major indication for determination of serum T3 levels is suspected Hyperthyroidism. - In patients with early GRAVES' disease or a TOXIC ADENOMA, secretion of T3 is ↑ even more than the secretion of T4 ***Dx. early thyroid failure --> Serum TSH levels together with serum T4 levels or the FT4 or FT4 index ***TSH assay is particularly helpful for following the results of treatment of hypthyroidism and hyperthyroidism. - The TSH level is ↓ or ↓-normal if hypothalamic or pituitary disease is present. - A Dx. of pituitary hypothyroidism can be made by finding a ↓ FT4 level in addition to deficits of other pituitary hormones. Serum THYROGLOBULIN is ↑ in various forms of THYROIDITIS, patients with HYPERthyroidism, patients with large GOITERS, and in patients with METASTATIC THYROID CARCINOMAS.

Graves' Disease = Autoimmune disorder due to a defect in T-suppressor cells ***MOST COMMON CAUSE OF HYPERTHYROIDISM - Peak in 3rd and 4th decade - More common in WOMEN - May be associated with other inherited autoimmune disorders (e.g. pernicious anemia, Hashimoto's disease) ***Immune response can be triggered by pregnancy (especially postpartum), iodine excess, lithium therapy, viral or bacterial infections, and glucocorticoid withdrawal. ***Hallmarks: Labs - HIGH FT3 and FT4, Suppressed TSH, HIGH RAIU, (+) TSI PE - SMOOTH DIFFUSE GOITER +/- THYROID BRUIT secondary to increased blood flow through the gland), PRETIBIAL MYXEDEMA (pink nodules over shins), EXOPHTHALMUS (PROPTOSIS), PERIORBITAL EDEMA, THYROID ACROPACHY (clubbing and thickening of the skin on dorsa of fingers and toes), ONYCHOLYSIS (separation of fingernails from their beds) LID LAG, LID RETRACTION (Sclera visibile above iris), DIPLOPIA, CONJUNCTIVAL INJECTION

- This autoimmune disease often runs in familes, with a very HIGH concordance among MZ twins. - The prevalence of Graves' disease is HIGHER in Caucasians who carry the human leucocyte antigen (HLA), HLA-B8, and DR3. - B lymphocytes produce a Thyroid-Stimulating Immunoglobulin (TSI) that binds the TSH receptor and stimulates the thyroid gland. ***The auto-antibody causes EXCESS production of T4 and T3 independent of TSH. TSH is SUPPRESSED by the HIGH levels of T3 and T4 since the normal feedback regulation of the pituitary remains intact. - The stimulatory action of the Graves' immunoglobulin G (IgG) causes the thyroid gland to TAKE UP A LARGE FRACTION OF RADIOACTIVE IODINE in spite of the suppressed TSH. A radioactive iodine scan shows that the iodine is taken up DIFFUSELY throughout the ENLARGED GLAND. ***IgG readily crosses the placenta --> stimulate the fetal or neonatal thyroid gland --> neonatal hyperthyroidism ***Antibodies against extraocular muscle antigens (fibroblasts implicated) with lymphocytic infiltration. Treatment of Graves' disease is directed toward REDUCING SECRETION OF THYROID HORMONE. - If symptoms of thyrotoxicosis are severe, β-adrenergic blockade can be used until an antithyroid drug (e.g, thionamides - PTU or MMI), radioactive iodine, or surgery has treated the underlying disease. ***Patients with ophthalmopathy should be treated by an ophthalmologist. Ophtalmopathy Tx: Prevent drying, High dose prednisone in severe cases, orbital radiation, surgical decompression. ***lifetime follow-up needed

Serum Electrolytes Na+: 135-145 mmol/L K+: 3.5-5 mmol/L Cl-: 95-105 mmol/L HCO3: 18-23 mmol/L

-Screen for/monitor medical conditions (esp. in critical care, cardiology, and nephrology) - Monitor fluid balance - Monitor effects of medications - Patients with ACUTE, SYMPTOMATIC ONSET of an electrolyte imbalance especially with potentially life-threatening clinical presentations such as EKG changes***, should be treated promptly - HYPOkalemia and HYPERkalemia require IMMEDIATE treatment * HYPOkalemia - Etiology (1) ↓ Intake (2) ↑ Losses (GI - NG drainage, vomiting, diarrhea; Skin losses; Renal losses - Hypomagnesemia, diuretics, mineralocorticoid & glucocorticoid effects) (3) Shifts INTO cells - Metabolic ALKALOSIS (K+/H+ exchange acros cell membrane), Insulin (stimulates Na/K ATPase), β2-agonists (stimulates Na/K ATPase) * HYPOkalemia - Signs & Symptoms - CNS: Diminished reflexes, muscle weakness, muscle cramping, myalgias, weakness, fatigue - CVS: Arrhythmias, HTN - Resp: Respiratory failure - GI: Constipation * HYPERkalemia - Etiology (1) ↑ K+ Intake (***Especially a problem in patients with renal insufficiency) (2) ↓ K+ Excretion (Acute or Chronic Renal Failure, Adrenal Insufficiency, Drugs: ACE, ARB, K-Sparing Diuretics, NSAIDS (↓ GFR)) (3) Redistribution of K+ Into Extracellular Space (e.g. metabolic ACIDOSIS, Digoxin overdose (blocks Na/K ATPase), β-blockers (Inhibits Na/K ATPase)) (4) Tubular unresponsiveness to aldosterone (***If normal GFR, calculate TTKG (Uk/Pk)/(Uosm/Posm)) TTKG< 7 = ↓ effective aldosterone function (5) Pseudohyperkalemia - Intracellular release (e.g. phlebotomy, fist clenching) - Hemolyzed blood sample falsely ELEVATES K+ * HYPERkalemia - Signs and Symptoms - CNS: Muscle weakness, parasthesias - GI: Paralytic ileus ***ECG Changes (HYPOkalemia) - Note: More predictive of clinical picture than serum [K] - U waves MOST Important (low amplitude wave following a T wave) - Flattened or inverted T waves - Depressed ST segment - Prolongation of Q-T interval - With severe hypokalemia: P-R Prolongation, wide QRS, arrhythmias; increases risk of digitalis toxicity. HYPOkalemia Treatment: ***Treat underlying cause ***Risk of HYPERKALEMIA with K+ replacement especially high in elderly, diabetics, and patients with decreased renal function. - Oral sources: food, tablets, KCl liquid solution - IV: KCl in saline solution - K+ sparing diuretics (e.g. amiloride, spironolactone) - Restore Mg2+ if necessary NB: P Wave = represents Atrial Depolarization QRS Complex = represents Ventricular Depolarization T Wave = represents Ventricular Repolarization Q Wave = The first downward wave of the QRS complex (the Q wave is often absent) R Wave = The initial positive deflection S Wave = The negative deflection following the R wave ***ECG Changes (HYPERkalemia) - Peaked and narrow T waves - Decreased amplitude and eventual loss of P waves - Prolonged PR interval - Widening of QRS and eventual merging with T wave (Sine-wave pattern) - AV block - Ventricular fibrillation, asystole HYPERkalemia treatment: ***Protect the heart - Calcium Gluconate ***Shift K+ Into Cells - Insulin, Sodium Bicarbonate (drives K+ into cells in exchange for H+), β2-agonist (ventolin; stimulates Na/K ATPase) ***Enhanced K+ Removal from the body - Diuretics (e.g. Furosemide - may need IV NS to avoid hypovolemia), Kayexalate enemas with tap water, Dialysis (renal failure, life threatening hyperkalemia unresponsive to therapy)

A man comes to see you because of PERSISTENT HEMATURIA. The urinalysis shows RED-CELL CASTS AND 1+ PROTEINURIA. THE URINE SODIUM IS LOW What is the most likely diagnosis in each of the these cases? 1. The patient is ASIAN with a RECENT VIRAL ILLNESS. There are NO systemic manifestations 2. He has had LIFELONG EYE PROBLEMS AND EAR PROBLEMS WITH DEAFNESS 3. He had a PHARYNGITIS a week ago and has PERIORBITAL EDEMA

1. IgA NEPHROPATHY, or BERGER's DISEASE, presents as ISOLATED HEMATURIA at the same time as a VIRAL ILLNESS. It is MORE COMMON in ASIANS, and is the MOST COMMON CAUSE OF ACUTE GLOMERULONEPHRITIS ***Painless hematuria following infection suggests Berger disease ***IgA Nephropathy associated with extrarenal symptoms is referred to as Henoch-Schonlein Purpura (Skin: Purpural lesions found on the extensor surfaces of the lower extremities, buttocks, and arms. GI: Abdominal pain, intestinal bleeding. MSK: Joint pain) 2. ALPORT'S SYNDROME presents with glomerulonephritis in association with EYE and EAR PROBLEMS such as early development of cataracts and deafness. All forms of glomerulonephritis give red-cell casts and mild proteinuria. ***A hereditary form of glomerular injury that is typically X-LINKED RECESSIVE (defect in α5 chain of type IV collagen) - Male patients exhibit the full spectrum of this disease: deafness, cataracts and renal failure. Female patients are carriers, symptoms are limited to mild hematuria ***Patients are typically between 5 and 20 years old. 3. POSTSTREPTOCOCCAL GLOMERULONEPHRITIS leads to "TEA-" or "COLA-" COLOURED URINE which is proteinuria and hematuria. PERIORBITAL EDEMA IS CHARACTERISTIC. The blood will show anti-streptolysin O antibodies as a sign of streptococcal infection.

If the HEMATURIA is associated with an ACTIVE urine sediment and/or the nephritic syndrome then there are three major pathologic patterns with this presentation:***

1. Immune complex glomerulonephritis 2. Antibody-mediated glomerulonephritis (Anti-GBM disease;Goodpasture's) 3, Pauci-immune glomerulonephritis (ANCA-positive)

The presentation of BOTH nephrotic range proteinuria and hematuria with an active urine is associated with three major pathologic patterns:***

1. Membranoproliferative glomerulonephritis (MPGN) 2. Lupus glomerulonephritis 3. Post-infectious or post-streptococcal glomerulonephritis

Patients that present with persistent proteinuria (nephrotic or non-nephrotic range) have a disorder of the glomerular basement membrane or the epithelial cell (podocyte). There are 5 patterns of glomerular injury that will give this presentation:

1. Minimal Change Disease (MCD) - MOST COMMON cause of CHILDHOOD NEPHROTIC SYNDROME (>80% of cases seen in those aged 2-3 years) - Often PRECEDED by RESPIRATORY INFECTION or ROUTINE IMMUNIZATION - Proximal tubules are often heavily laden with LIPIDS secondary to increased tubular reabsorption of lipoproteins that passed through the injured glomerulus, hence, another name for this disease is "lipoid nephrosis" - Presentation: Children b/w the ages of 2 and 3, insidious onset of nephrotic syndrome w/o any other obvious clinical disease, primarily albumin (LMW) is lost ("selective proteinuria"), renal function is normally maintained. - Electron Microscopy: EFFACEMENT of visceral epithelial foot processes and increased lipoproteins in the PCTs. - Responds well to STEROIDS (For this reason, many children with a typical presentation of MCD will be given a trial of empiric steroids WITHOUT a renal biopsy). FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) - MOST COMMON GLOMERULAR DISEASE IN HIV PATIENTS and manifests more SEVERELY in those patients. - The pathologic lesion is sclerosis of <50% of glomeruli (hence the name FOCAL), with the sclerosis involving only distinct portions of the affected glomeruli (hence the name SEGMENTAL). - Presentation: Nonselective proteinuria as well as HTN, mild hematuria, and possibly decreased renal function. This disorder is associated with HIV and heroin use. - Definitive diagnosis is based on renal biopsy - Light microscopy: (1) Focal accumulation of hyaline material (2) Segmental sclerosis. - Tx: If there is no remission of proteinuria with steroids, cyclophosphamide and cyclosporine can be used. - Generally poor prognosis, with ~50% of patients with this disorder developing ESRD within 10 years. DIFFUSE MEMBRANOUS GLOMERULONEPHROPATHY - LEADING CAUSE OF NEPHROTIC SYNDROME IN ADULTS (Peak incidence is from ages 30-50, and it is seen predominantly in men (2:1 ratio)). -Presentation: Insidious onset of NEPHROTIC SYNDROME with NONSELECTIVE PROTEINURIA in otherwise healthy patients. Membranous Glomerulopathy occurs in association with SYSTEMIC DISEASES such as SLE, RA, Hep. B and C, syphilis, schistosomiasis, malaria, and leprosy, as well as drugs such as gold and penicillamine. - Diagnosis: Based on renal biopsy. Light Microscopy - Diffuse GBM thickening due to subepithelial deposits nestled against the GBM Electron Microscopy - Subepithelial deposits in a "SPIKE" (extensions of GBM around deposits) and "DOME" (deposits in GBM) pattern. - Tx: Given the HIGH rate of spontaneous remission, ONLY patients with SEVERE disease should be treated with immunosuppressive therapy. Cyclophosphamide and cylosporine when combined with glucocorticoids REDUCE PROTEINURIA and SLOW THE DECLINE OF GFR. Transplantation has been shown to be effective for patients that progress to ESRD. DIABETIC NEPHROPATHY - LEADING CAUSE OF ESRD in Western Society, secondary to GLOMERULAR HTN and HYPERFILTRATION. The 1st sign of injury to the glomerulus is MICROALBUMINURIA, which occurs about 5-10 years before other symptoms develop. If untreated, microalbuminuria slowly progresses to nephrotic-range proteinuria. - Nephropathy is generally MORE COMMON in DM-1 than DM-2 - Presentation: Typically, CRF aggravated by glomerulosclerosis leads to fluid filtration abnormalities and a full spectrum of other disorders of kidney function. Cardinal symptoms include HTN, and EDEMA. Other complications may include ARTERIOSCLEROSIS of the RENAL ARTERY and the EFFERENT ARTERIOLES. If left untreated, NEPHROTIC-RANGE PROTEINURIA ultimately develops. ***HYALINE ARTERIOSCLEROSIS is a HALLMARK of DM; Efferent arterioles are affected BEFORE afferent arterioles. Dx: Should be suspected in patients with EITHER DM-1 or DM-2 who have already developed evidence of END-ORGAN DAMAGE from DM, such as retinopathy and neuropathy, and have dipstick-positive proteinuria. Light microscopy - THICKENING of GBM and EXPANSION of MESANGIUM. Classic KIMMELSTIEL-WILSON LESIONS, areas of nodular glomerulosclerosis, may be found. Tx: Patients who develop microalbuminuria should be started on ACEi*** (to counteract hyperfiltration) - delay the progression of nephropathy. Good glucose control with diet, exercise, and hypoglycemic agents has also been shown to delay the development and progression of symptoms. ***ACEi can cause hyperkalemia. Therefore, be sure to watch serum K+ RENAL AMYLOIDOSIS (Associated with CHRONIC conditions) - It is a MULTISYSTEM DISORDER OF PROTEIN FOLDING and can be acquired or hereditary - Nodular deposits of amyloid in mesangium, usually related to amyloid light chain (AL) - Presentation: Nephrotic-range proteinuria, severe edema and progressive renal insufficiency. If amyloidosis is caused by a secondary disease (e.g., Multiple Myeloma, TB, RA, etc.), the patient will also show signs and symptoms of the primary disease. - Dx: Definitive diagnosis is based on RENAL, ABDOMINAL FAT PAD, or RECTAL BIOPSY Light microscope - Tissue stained with CONGO RED has deposits of AMYLOID that show APPLE-GREEN BIREFRINGENCE under polarized light. In addition, MESANGIAL EXPANSION is present with amorphous hyaline material (amyloid) and THICKENING of the GBM. Tx: Some improvement has been shown with a combination of melphalan (chemotherapy) and prednisone. Transplantation is an option, although extrarenal organ involvement may be a contraindication.

A woman is in your clinic because of EDEMA developing over months. She has a normal echocardiogram. Her URINALYSIS shows 4+ PROTEIN and the spot protein/creatinine ratio is 7:1. Triglycerides are ELEVATED. What is the most likely diagnosis in each of these cases? 1. There is a history of DIABETES and HYPERTENSION. The eyes show background RETINOPATHY 2. She has been an INJECTION DRUG USER of heroin in the past. 3. She was recently diagnosed with LYMPHOMA

1. NEPHROTIC SYNDROME is the combination of EDEMA, a 24-hr URINE PROTEIN GREATER THAN 3.5g and HYPERLIPIDEMIA. A SPOT PROTEIN/CREATININE RATIO GRETER THAN 3.5 is the same as a 24-hr urine protein. DIABETES and HYPERTENSION are the MOST COMMON causes of nephrotic syndrome. The ratio of protein to creatinine is equal to the amount found on a 24-hr urine. ***Nephrotic syndrome is associated with thromboembolism and increased risk of infection (loss of immunoglobulin) 2. INJECTION DRUG USE and HEROIN both cause FOCAL SEGMENTAL GLOMERULONEPHRITIS. ***MOST COMMON GLOMERULAR DISEASE in HIV patients. ***Segmental sclerosis and hyalinosis 3. The MOST COMMON CAUSE OF ADULT NEPHROTIC SYNDROME is MEMBRANOUS GLOMERULONEPHRITIS. Caused by DRUGS, INFECTIONS, SLE, and SOLID TUMORS ***Subepithelial spikes, diffuse capillary and GBM thickening

A patient comes in with the SUDDEN ONSET of FLANK PAIN and HEMATURIA What is the most likely diagnosis when the following additional features are described? 1. There is a history of SICKLE-CELL DISEASE. The patient has taken extra doses of multiple pain medications, including NSAIDS. There is some necrotic material in the urine 2. The pain RADIATES TO THE GROIN in an otherwise healthy person

1. PAPILLARY NECROSIS occurs in patients who have underlying kidney disease such as SICKLE-CELL DISEASE or CHRONIC PYELONEPHRITIS. The presentation is SIMILAR to NEPHROLITHIASIS in that there is SUDDEN FLANK PAIN and HEMATURIA. However, it often OCCURS FROM THE USE OF EXTRA NSAID MEDICATIONS and is associated with NECROTIC MATERIAL IN THE URINE. The most accurate test is a CT SCAN. There is no specific therapy 2. NEPHROLITHIASIS presents with SUDDEN FLANK PAIN RADIATING TO THE GROIN. The most accurate test is a SPRIAL CT SCAN. Kidney stones do NOT need contrast to be visible. X-rays of the abdomen have POOR sensitivity.

A 27-year-old woman comes in because of HEMATURIA and FLANK PAIN as well as LEFT LOWER QUADRANT ABDOMINAL PAIN with DIVERTICULI found on colonoscopy. Auscultation shows a MID-SYSTOLIC CLICK. There are CYSTS found on the ovary and in the liver as well. 1. What is the most likely diagnosis? 2. What is the most common cause of death?

1. POLYCYSTIC KIDNEY DISEASE presents with HEMATURIA and can present with KIDNEY STONES that occur with increased frequency. In addition to kidney disease, there are also CYSTS of the LIVER and OVARY with DIVERTICULOSIS, MITRAL VALVE PROLAPSE, and ANEURYSMAL DISEASE in the circle of Willis. 2. The MOST COMMON CAUSE OF DEATH from POLYCYSTIC KIDNEY DISEASE is RENAL FAILURE. Renal failure occurs from CHRONIC and REPEATED INFECTIONS such as pyelonephritis. In addition, there are RECURRENT KIDNEY STONES secondary to the significant anatomic abnormalities. Aneurysm rupture is NOT the most common cause of death from polycystic kidney disease

What are the hallmarks of NEPHROTIC syndrome?

1. Proteinuria (>3.5g/24h) - frothy urine 2. Hypoalbuminemia 3. Edema 4. Hyperlipidemia 5. Urinary fatty casts 6. Hypercoagulation ***Patients with nephrotic syndrome are at INCREASED RISK OF INFECTION with ENCAPSULATED BACTERIA such as STAPHYLOCOCCI and PNEUMOCOCCI due to the LOSS OF GAMMA-GLOBULINS in the URINE.

In NEPHROTIC SYNDROME, the excess fluid in the body may manifest as:

1. Puffiness around the eyes, characteristically in the morning. 2. Pitting edema over the legs 3. Pleural effusion 4. Ascites

A man comes to the office and is found to have CASTS in his urinalysis. What diagnosis is suggested with each of the following casts? 1. White-cell casts 2. Red-cell casts 3. Eosinophil casts 4. Hyaline 5. Muddy-Brown or granular casts

1. Pyelonephritis is associated with WHITE-CELL CASTS. If they are there, they are specific for the disease. Generally, casts add little to help the diagnosis, which is usually obvious from the presence of FEVER, DYSURIA, and FLANK PAIN and TENDERNESS 2. Red-cell casts are specific for GLOMERULONEPHRITIS 3. Eosinophil casts are specific to ALLERGIC INTERSTITIAL NEPHRITIS 4. Hyaline casts are found with DEHYDRATION or any other form of pre-renal azotemia. They are the accumulation of normal protein which sludges because of decreased renal flow 5. Granular or Muddy-brown casts are found in ATN. The "granules" are sloughed-off, necrotic epithelial cells from the kidney tubules.

A man comes to the ER after sustaining a PROLONGED SEIZURE. He has DARK URINE WHICH IS STRONGLY POSITIVE ON THE DIPSTICK FOR BLOOD BUT IN WHICH NO RED CELLS are seen on microscopic examination. His SERUM BICARBONATE LEVEL IS LOW 1. What is the most likely diagnosis? 2. What is the most SPECIFIC diagnostic test?

1. RHABDOMYOLYSIS presents after a CRUSH INJURY or SEVERE EXERTION of any kind with DARK URINE IN THE ABSENCE OF VISIBLE RED CELLS. This is indicative of URINE MYOGLOBIN. Rhabdomyolysis leads to METABOLIC ACIDOSIS, HYPERKALEMIA, and eventually RENAL FAILURE. 2. URINE MYOGLOBIN is the MOST SPECIFIC DIAGNOSTIC TEST for rhabdomyolysis. The K+ and EKG are probably the most URGENT diagnostic steps because they determine who is most likely to die. The CPK levels will be significantly ELEVATED. Administration of IV fluids and alkalinazation of the urine are important. An elevated CPK is NOT specific for indicating the cause of the renal failure. ***Red Urine/Hematuria - (+) Disptick, NO RBCs = Myoglobin (rhabdomyolysis)

Morphology of Renal Casts

1. Red Blood Cell Casts - Glomerulonephritis: IgA Nephropathy, Post infectious GN (e.g. poststreptococcal GN following either pharyngeal or skin infections), and Goodpasture syndrome* - Malignant HTN - Vasculitis - Renal Ischmia ***Clumps of DYSMORPHIC RBCs with blebs and buds indicate RBCs are of GLOMERULAR ORIGIN versus bladder origin (e.g. bladder cancer) 2. White Blood Cell Casts (indicate inflammation in renal interstitium, tubules, and/or glomeruli) - Pyelonephritis - Interstitial nephritis - Lupus nephritis ***WBCs in URINE indicate LOWER UTI ***WBC casts in the urine are PATHOGNOMONIC for ACUTE PYELONEPHRITIS 3. Hyaline Casts - They can be seen in NORMAL individuals and in VOLUME-DEPLETED STATES. 4. Granular Casts - ATN (Muddy brown granular casts), ***CHRONIC RENAL FAILURE, Nephrotic Syndrome - Derived from the breakdown of cellular casts, especially epithelial cell casts 5. Fatty Casts - Nephrotic Syndrome - Fat droplets in hyaline matrix ***MALTESE-CROSS CONFIGURATION due to presence of CHOLESTEROL (when viewed under polarized light)

You are evaluating a patient because of confusion. His Na+ is LOW at 122 mEq/L. He has NO edema, clear lungs, and no jugulovenous distension. There is no orthostasis. What is the most likely diagnosis in each of these cases? 1. The patient has LUNG CANCER with metastases to the brain. URINE Na+ IS 70 (HIGH) AND URINE OSMOLARITY IS 450 (HIGH). 2. The patient is BIPOLAR, with frequent urination all day that is LESS AT NIGHT. Urine Na+ is 10 (LOW) and Urine Osmolarity is 75 (LOW). 3. The patient has DIABETES with a GLUCOSE LEVEL OF 850 (Normal: 80-110)

1. SIADH is caused by ANY ABNORMALITY OF THE BRAIN OR LUNGS. The can be a cancer, infarction, or infection. SIADH is associated with an inappropriately HIGH URINE Na+ and OSMOLARITY. The NORMAL response to a LOW serum Na+ should be a LOW urine Na+ and LOW urine osmolarity. SIADH is a case of EUVOLEMIC HYPONATREMIA. FREE WATER RESTRICTION IS THE TREATMENT. 2. PSYCHOGENIC POLYDIPSIA is associated with bipolar disorder. There is a NORMAL urinary response to hyponatremia. The normal response is a LOW urine sodium and osmolarity. A DECREASE IN SYMPTOMS AT NIGHT is the key to the diagnosis. When he goes to sleep he stops drinking, so he stops urinating. 3. PSEUDOHYPONATREMIA is from an ELEVATED GLUCOSE for any reason. For every INCREASE IN GLUCOSE OF 100 ABOVE NORMAL THERE IS A 1.6-POINT DECREASE IN THE SODIUM.

If the HEMATURIA is ISOLATED (i.e. not associated with an active urine or the nephritic syndrome) then there are three major pathologic patterns with this presentation:***

1. Thin basement membrane disease 2. Hereditary nephritis (Alport's) 3. IgA nephropathy (Berger Disease)

60-40-20 Rule

60% of body weight is water 40% of body weight is intracellular fluids 20% of body weight is extracellular fluids

Empty Sella Syndrome (ESS) ***Common in OBESE women

In primary ESS, ↑ pressure in the sella turcica flattens the pituitary along the walls of the cavity. (Obese, multiparous, middle-aged women who are often hypertensive) Secondary ESS is the REGRESSION of the pituitary secondary to injury or radiation. Both give the impression of an empty sella on imaging. This syndrome occasionally results in endocrine dysfunction.

ADH or Arginine Vasopressin (AVP) ***Plays a central role in osmoregulation ***Stimulation of hypothalamic osmoreceptors and atrial and carotid baroreceptors ↑ ADH ***A ↓ in BV stimulates ADH release even if plasma osmolality is normal (or low). In DEHYDRATED patients, ↓ intravascular volume is a more potent stimulus for H2O conservation than osmotic pressure. ***Negative feedback (via thirst receptors and ANP) to inhibit further ADH release and ANG 2 production ***Water balance is primarily regulated by water ingestion (under the control of thirst) and water retention (under the control of ADH) ***The NORMAL THRESHOLD for ADH release and for stimulation of THIRST is plasma osmolality GREATER than 285 mOsm/L - Individuals with CENTRAL DI FAIL TO INCREASE ADH in response to plasma osmolality ABOVE 285 mOsml/L

Increase ADH Secretion: ↑ Plasma Osmolality ↓ Plasma Volume (***ADH secretion is affected by LARGE changes in plasma volume) ↓ BP ADH regulates water conservation at the level of the kidney by INCREASING the PERMEABILITY of the RENAL COLLECTING DUCT TO H2O. In the ABSENCE of ADH, the renal collecting duct remains IMPERMEABLE to H2O, and the DILUTE URINE created in the distal nephron is excreted, resulting in FREE H2O LOSS. In the PRESENCE of ADH, water channels (AQUAPORIN 2) are translocated to the LUMINAL CELL MEMBRANE. This allows H2O to pass freely down its concentration gradient from the tubular lumen into the HYPERTONIC renal interstitium. The URINE becomes CONCENTRATED. ***The concentrating effect of ADH is critically dependent on the solute gradient across tubular cells, which is established in the renal medulla. ***ADH is also a potent PRESSOR agent (hence the alternate name AVP) - There is little evidence that ADH plays a significant role in maintaining normal blood pressure or causes HTN in humans

What are the Effects of Growth Hormone (GH)? ***Synthesized, stored and secreted by the somatotroph cells in the pituitary ***GH secretion is pulsatile and is controlled by the action of 2 hypothalamic hormones (GHRH - stimulates GH release; Somatostatin - inhibits GH release; An increase in GH levels inhibits the action of GHRH and stimulates somatostatin). ***GH acts directly on tissues; its growth-promoting effect is primarily mediated by IGF-1, formerly known as somatomedin. ***IGF-1 is regulated by the action of GH on GH receptors ***IGF-1 is secreted by the liver, exerts (-) feedback on GH release, and stimulates somatostatin release. ***After adolescence, overall production of GH DECREASES and continues at a lower rate during adult life

Increased: 1. Linear growth 2. Bone thickness 3. Soft tissue growth 4. Nitrogen retention, amino acid uptake, and protein synthesis 5. Insulin resistance and blood glucose 6. Fatty acid release from adipose tissue Decreased: Muscle glucose uptake ***Both GH and IGF-1 interact with different cell types to promote growth Direct effects of GH 1. ↓ glucose uptake (counterregulatory effects) 2. Mobilizes fatty acids 3. Stimulates protein synthesis in muscle 4. Increases lean body mass Indirect effects of GH (Through IGF-1) 1. Stimulates protein synthesis at the organ level 2. Increases protein synthesis in chondrocytes (promotes linear growth) 3. Stimulates protein synthesis in muscle 4. Increases lean body mass

Physiologic Responses to Decreasing Plasma Glucose Concentrations * ↓ Insulin - ↑ hepatic glycogenolysis and hepatic (and renal) gluconeogenesis; reduces glucose utilization in peripheral tissues, inducing lipolysis and proteolysis, thereby releasing gluconeogenic precursors. Glucagon - stimulates hepatic glycogenolysis Epinephrine - stimulates hepatic glycogenolysis and gluconeogenesis (and renal gluconeogenesis)

↓ Insulin - Primary glucose regulatory factor/first defense against hypoglycemia ↑ Glucagon - Primary glucose counterregulatory factor/second defense against hypoglycemia ↑ Epinephrine - Third defense against hypoglycemia, critical when glucagon is deficient ↑ Cortisol and GH - Involved in defense against prolonged hypoglycemia, not critical Symptoms (Recognition of hypoglycemia) - Prompt behavioural defense against hypoglycemia (food ingestion) ↓ Cognition - Compromises behavioural defense against hypoglycemia