Chloride depleted saline responsive (urine chloride <15 mEq/L) Vomiting/nasogastric tube (N GT) suction Saline unresponsive (urine chloride >15 mEq/L) Current diuretics Prior diuretics Post hypercapnia Villous adenoma Laxative abuse /chloride-rich Primary hyperaldosteronism Bartter \200\231s or Gitelman \200\231s syndrome Liddle \200\231 s syndrome Cushing \200\231s syndrome or ectopic diarrhea adrenocorticotropic hormone (ACTH) production Profound K + depletion Exogenous or endogenous miner- alocorticoid production (certain forms of licorice, chewing tobacco, or carbenoxolone) 663 Severe Mg ++ depletion Cystic fibrosis Hypertension (HTN) + Metabolic Alkalosis Differential Renin Low Aldosterone Low Causes Glycyrrhizic acid (certain forms of licorice or chewing tobacco) Carbenoxolone Exoge nous mineralocorticoids Liddle \200\231s syndrome Cushing \200\231s Syndrome Congenital adr enal hyperplasia Deoxycorticosterone (DOC) producing tumor Low High Primary hyperaldosteronism Glucocorticoid remediable aldosteronism (GRA) High High Renovascular HTN Malignant HTN Renin-secreting tumor Secondary Hyperaldosteronism Table 17.9 Respiratory acidosis ACUTE = HCO3 CHRONIC = HCO 3 \206\221CO 2 by 10 mm Hg \206\221 by 1 \206\221 by 3 Compensation respiratory disorders for Respiratory alkalosis ACUTE = HCO 3 CHRONIC = HCO 3 \206\223 by 2 \206\223CO2 by 10 mm Hg \206\223 by 5 664 Urate and the kidney Causes of hyperuricemia Hyperuricemia may result from either \206\221 turnover or \206\223 excretion of urate. Associated conditions may include: Gout and neph rolithiasis . Drugs: Diuretics (both thiazide and loop diuretics), chemotherapy (cisplatin, cyclophosphamide and vincristine), alcohol, cyclosporine, low-dose salicy- lates, ketocona zole, ethambutol, pyrazinamide, theophylline, and levodopa. Increased cell turnover: Lympho ma, leukemia, myeloproliferative disorders, hemolysis, rhabdomyolysis or tumor lysis syndro me (see below). Reduced excretion: Primary hyperuricemia ( gout), chronic kidney disease (CKD), volume depletion, lead nephropathy, pre-eclampsia or toxemia of pregnancy. Miscellan eous: syndrome. Hyperuricemia is normally defined as a serum uric acid >7.0 mg/ dL . In CKD , serum urate increases. Hyperuricemia in CKD has been defined as 3 \212 \212 \212 There is an association between hyperuricemia and CKD. The mechanism may be inflammatory from de position of urate crystals in the interstitium \206\222 progressive tubulointerstitial inj ury. y r t s i m e h c o B i G6PD deficiency, Lesch-Nyhan syndrome, metabolic >9 mg/dL for serum creatinine >10 mg/dL for serum creatinine of 1.5 \200\2232.0 mg/dL >12 m g/dL for serum creatinine of 2.1 \200\2233.0 mg/dL \211 1.5 mg/dL Tumor lysis syndrome (TLS) Constellation of metabolic abnormalities including hyperuricemia , hyperkalemia, hyperphosphatemia, hypocalcemia; frequently associated with acute kidney in jury (AKI; see p. 277, Oncology; see p. 430; Table 17.10) Table 17.10 Pathophysiology and risk factors Rapid cell breakdown post chemotherapy with release of intracel- lular contents. Hyperurice mia can lead to deposition of uric acid crystals within the tissues and renal tubules \206 \222 AKI. Highest risk of development: Burkitt \200\231s lymphoma,lymphoblastic lym- phoma, B-cell ac ute lymphoblastic lymphoma, acute leukemia (especially if WBC count \211 100,000/ L) C airo-Bishop * definition of tumor lysis syndrome Serum values included in the definition of laboratory TLS: \212 \212 \212 \212 \211 7 mg/dL or 25% \206\223 from baseline Crit eria included in the definition of clinical TLS: \212 Uric acid Potassium Phosphorus Calcium \211 8 mg/dL or 25% \206\221 from baseline \211 6 mEq/L or 25% \206\221 from baseline \211 4.5 mg/dL or 25% \206\221 from baseline 665 Serum creatinine of the age-adjusted normal range Cardiac arrhythmia or sudden death Seizur e \211 1.5 mg/dL greater than the value of the upper limit \212 \212 Cairo MS, Bishop M. Tumor lysis syndrome: New therapeutic strategies and clas- sification . Brit J Haematol. 2004;127(1):3 \200\22311. 3 Murray T and Goldberg M. Chronic Interstitial Nephritis: Etiologic Factors. Annals of Int ernal Medicine. 1975;82(4):453 \200\223459. Treatment Prevention is the cornerstone, based on recognizing which patient population is a t risk for TLS. Treatment may include: \212Aggressive hydration intravenously, minimum of 2 \200\2233 L/d, maintaining a urine output of 100 \200\223200 mL/h (typically started 48 h before chemotherapy). \212Allopurinol (a competitive inhibitor of xanthine oxidase) admin istered prior to the onset of chemotherapy at a dosage of 300 \200\223800 mg/d (dosage redu ction if CKD or AKI). \212Rasburicase (recombinant urea oxidase that converts uric acid to water-soluble allanto in), IV at a dose of 0.20 mg/kg in a 30-min infusion for up to 5 d. Considered first-line t herapy over allopurinol in patients at significant risk for TLS. Rasburicase typically resu lts in a shorter time to control of uric acid than does allopurinol. \212Urinary alkalinization is controversial as it requires a urine pH of 7.0 to be effecti ve, which may promote calcium-phosphate crystallization and precipitation. \212 Currently If progressive oliguric AKI develops, intermittent hemodialysis or \212 continuous forms o f renal replacement therapy may be required. not recommended in the therapeutic management of TLS. Gout See p. 408. Electrolyte physiology Sodium is pumped out of the cell in exchange for K + by the sodium-p otassium pump, which requires energy from adenosine triphosphate (ATP). Sodium is the major extracellular cation; potassium is the major intracellular cation. \212Osmolarity is the number of osmoles per L of solution. \212Osmolality is the number of osmoles per kg of sol vent ( normal: 280 \200\223300). To calculate plasma osmolality 2(Na + ) + urea/2.8 + gluco se/18. If the measured osmolality >10 mmol/L higher than the calculated osmolality, an osmo lar gap is present. Consider the presence of ketones, ethanol, methanol, or ethylene glycol (see page xxx). Fluid compartments For 70 kg man: Total fluid = 42 L (60% body weight). In tracellular fluid = 28 L (67% body fluid), extracellular fluid = 14 L (33% body fluid). Int ravascular component = 5 L of blood (see Figure 17.1). Figure 17.1 Distribution between intra- and extravascular compartments is determined by osm otic equilibrium and the \200\234oncotic pressure \200\235 exerted by non-diffusible prote ins 666 juxtaglomerular Control of sodium apparatus responds to decreased renal blood flow and cata lyzes conversion of angiotensinogen to angiotensin I . This is then converted by angiotensi n-converting enzyme (ACE), located in the lung and blood vessels, to angiotensin II, which increases efferent renal arteriolar constriction ( \206\221 perfusion pressure), systemic vasoconstriction, and stimulation of the adrenal cortex to produce aldosterone , which acti vates the sodium-potassium pump and other ion channels in the collecting duct, leading to r eabsorption of sodium and water from the urine in exchange for potassium and hydrogen. High renal peritubular blood flow and hemodilution \206\223 sodium reabsorption in the proxima l tubule. Control of water Controlled mainly by sodium concentration. Increased plasma osmo lality stimulates thirst and the release of ADH from the posterior pituitary, which increas es the water reabsorption from the collecting duct by opening water channels to allow water to flow from the hypotonic luminal fluid into the hypertonic renal interstitium. See Table 17.11. Renin produced by the y r t s i m e h c o B i Table 17.11 Natriuretic peptide Brain natriuretic peptide (BNP) is a hormone originally identified from pig brain (hence th e B) and is mostly secreted from ventricular myocardium. Plasma BNP is closely related to l eft ventricular (LV) pres- sure. In MI and LV dysfunction, these hormones can be released i n large quantities. Secretion is also increased by tachycardia, glucocorticoids, and thyroi d hormones. Vasoactive peptides (endothelin-1, angiotensin II) also influence secretion. BN P increases GFR and decreases renal Na + reabsorption; it also decreases preload by relaxin g smooth muscle. BNP as a biomarker of heart failure* Increased BNP distinguishes heart fai lure from other causes of dyspnea more accurately than does LV ejection fraction(sensitivit y, >90%;specificity, 80 \200\22390%). BNP is high- est in decompensated heart failure, inte rmediate in LV dysfunction but not acute heart failure exacerbation, and lowest in those wi thout heart failure or LV dysfunction. What is the BNP threshold for diagnosing heart failu re? If BNP >100 ng/L, this \200\234diagnoses \200\235 heart failure better than history, e xamination, and chest x-ray (CXR). BNP can be used to rule out heart failure if <50 ng/L (n ega- tive predictive value [PV] 96%). In those with heart failure, BNP is higher in systoli c dysfunction than in isolated diastolic dysfunction and is highest in those with systolic and diastolic dysfunction. Threshold (ng/L) Sensitivity (%) Specificity (%) Positive PV Negative PV Accuracy (%) 50 100 150 \212 71 79 83 BNP increases in proportion to right ventricular dysfunction (e.g., in primary pul monary hypertension, cor pulmonale, PE, and congenital heart disease, but rises are less th an in LV disorders). 97 90 85 62 76 83 96 89 85 79 83 84 2 667 Prognosis in heart failure: The higher the BNP, the higher the cardiovascular and all-cause mortality (independent of age, New York Heart Association (NYHA) class, previous MI, and L V ejection fraction). Increased BNP in heart failure is also associated with sudden death. Serial testing may be important: Persistently high BNP levels despite vigorous treatment pr edict adverse outcomes. (continued) Table 17.11 (Continued) Prognosis in angina and MI: BNP has some prognostic value here (adverse LV remodeling; LV d ysfunction; death post-MI). Prognosis in COR pulmonale/primary pulmonary hypertension: BNP is useful. Cautions with BNP: A BNP >50 ng/L does not exclude other coexisting diseases suc h as pneumonia. Assays vary, so consult with your lab. Lemos J. B-type natriuretic peptide in cardiovascular disease. Lancet. 2003; 362(9380): 316 \200\223322. Sodium: Hyponatremia How to think about hyponatremia Hyponatremia does not actually imply r educed total body sodium; it is a disorder of excess water relative to total body sodium. I t results from either loss of solute (Na + , K + ) or gain of excess water. ADH mediates wa ter retention by concentrating the urine and is involved in most causes of hyponatremia. Si gns and symptoms depend on severity and rate of change in serum sodium; these include confu sion, seizures, anorexia, nausea, muscle weakness. Diagnosis See tree in diagram, p. 670 . Key information needed is patient \200\231s volume status, serum osmolality, urine osmolali ty, and urinary sodium. Causes of hyponatremia For a full list, see Figure 17.2. \212Hypov olemic hyponatremia: Renal or nonrenal (GI, sweat) volume loss \212Hypervolemic hyponatrem ia : Heart failure, kidney failure, cirrhosis, neph- rotic syndrome \212Euvolemic hyponatremia : Excess water intake, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, cortisol insufficiency \212Pseudohyponatremia : Measurement artifact as plasma water concentration is decreased f rom very high lipids or protein(myeloma), and the mea- sured plasma Na + concentration meas ured plasma Na+ concentration is indirectly measured, but actual Na + concentration and pla sma osmolality is unchanged. \212Dilutional hyponatremia: If plasma glucose 200 mg/dL, make a correction. Add 1.6 mEq/L to plasma Na + concentration for every 100 that glucose is >100 mg/dL to correct for water movement from cells to the extracel- lular space due to excess glucose. Plasma osmolality is increased. Management Don \200\231t base treatment on plasma Na + concentration alone. The presence of symptoms, duration, and volume status influence treatment. If possible, correct the underl ying cause. Treat hyponatremia much more slowly if chronic, as patients can be at risk for osmotic demyelination syndrome, a condition caused by rapid shifts of fluid in the CNS pote ntially causing permanent neurological side effects such as paralysis, cognitive disorders, or death. When treating patients who are asymptomatic from hyponatremia, aim for a rate of rise of serum sodium concentration of <10 \200\22312 mEq/L/24 h. Acute hyponatremia may in itially require more rapid rates of correction, but attempts should be made to keep the ris e to <10 \200\22312 mEq/L/24 h. If patients have severe symptoms or if hypertonic saline is being considered, nephrology consultation is strongly advised. Hypovolemic hyponatremia Re nal or nonrenal losses (urine sodium distinguishes the two). Usually evident from exam. Tre atment is volume resuscitation, but be cautious not to raise sodium too quickly. Attempt to 668 determine whether the condition is likely to be temporary (diarrhea, diuret- ics) or more l ong-lasting (high-output ostomy, salt-wasting nephropathy). Hypervolemic hyponatremia e.g., congestive heart failure (CHF), cir- rhosis, nephrotic syndrome. Treat the underlying diso rder, typically with water restriction and perhaps loop diuretics. Aim to normalize the pat ient \200\231s volume status. SIADH An important but overdiagnosed cause of hyponatremia. T ypically, patients will have a normal plasma volume. Urine osmolality is inappro- priately high; urine sodium will usually be >20 mEq/L and can be very high, and urine osmolality is >100 mOsm/kg which is not maximally dilute. Importantly, if urine osmolality is >300 mOsm/k g, then administration of normal saline will worsen hyponatremia (the urine is more concent rated than 0.9% saline, resulting in net retention of water). Causes: \212Malignancy : E.g ., small cell lung cancer, pancreas cancer, prostate cancer, y r t s i m e h c o B i lymphoma \212CNS disorders: Meningoencephalitis, abscess, stroke, subarachnoid hemor- rhage, subdural hemorrhage, head injury, many others \212Chest disease : TB, pneumonia, abscess, aspergillosis \212Metabolic disease: Porphyri a, trauma \212Drugs: Opiates, chlorpropamide, antipsychotics and antiemetics, selective serotonin reuptake inhibitors (SSRIs), cytotoxics Treatment Treat the cause. Fluid restriction is one mainstay of treatment. Cases with very high urine osmolality usually require either hypertonic saline (3% NaCl) for severe symptom s such as seizures or coma. Vasopressin (V 2 ) receptor antagonists such as tolvaptan may b e useful, but these drugs are very expensive and not recommended for severe symptoms at pre sent. Furosemide may help lower urinary sodium acutely. Demeclocycline should be avoided du e to nephrotoxicity. 669 6 7 0 Figure 17.2 Diagnostic approach to hyponatremia Hyponatremia Hyperlipidemia Hyperproteinemia Hyperglycemia Glycine Mannitol Maltose Exclude pseudohyponatremia, isotonic/hypertonic causes Hypovolemia \206\223 Total body water \206\223 \206\223 Na Euvolemia \206\223 Total body water Normal Na Hypervolemia \206\223 \206\223 Total body water \206\221 Na UNa \206\221 UNa \206\221 UNa \206\221 UNa \206\223 UNa \206\223 UNa \206\223 Heart failure Cirrhosis Nephrotic syndrome Pregnancy Iatrogenic (high volume of hypotonic f luids) AKI CKD Water intake > solute ADH-mediated Extrarenal loss Renal loss Psychogenic polydipsia Beer potomania Tea-and-toast SIADH Hypothyroidism Adrenal insufficiency Nausea Pain Drugs Vomiting Diarrhea Third spacing Diuretics Mineralo- corticoids \206\223 Renal or cerebral salt-wasting Bicarbonaturia (RTA , metabolic alkalosis) Sodium: Hypernatremia How to think about hypernatremia Unlike hyponatremia, most causes of hypernatremia are due to dehydration with water loss in excess of sodium loss; typically im plies impaired access to water. Signs and symptoms Look for thirst, confusion, coma, and se izures with signs of dehydration: Dry skin, reduced skin turgor, postural hypotension, and oliguria if water deficient. Laboratory features: Hematocrit (HCT) \206\221 , \206\221 al bumin, \206\221 urea. Causes Mostly related to dehydration: \212Fluid loss without water replacement (e.g., diarrhea, vomiting, burns) \212DI : Caused by inability of the kidney t o concentrate urine. Suspect if large urine volume. Can be central (deficiency of ADH [may follow head injury, or CNS surgery, especially pituitary]) or nephrogenic (resistance to AD H [lithium, NSAIDs, genetic diseases]). y r t s i m e h c o B i \212Osmotic diuresis (e.g., mannitol, very high-protein diet). \212Incorrect iv fluid rep lacement (excess hypertonic fluid); patients are hypervolemic. \212Primary aldosteronism : Patients not dehydrated, results from excess sodium retention. Plasma Na + concentration is usually only mildly ele- vated. Suspect if BP \206\221 , K + \206\223 , alkalosis (HCO 3 \200\223 \206\221 ). Licorice and Cushing \200\231s syndrom e can cause a similar picture. Management Give water orally if possible; if not, dextrose 5% IV guided by urine output and plasma Na + concentration. Giving 0.9% saline can be help- ful if the patient is hypovolem ic as this causes less marked fluid shifts and is hypotonic in a hypernatremic patient. Aim for a rate of sodium correction of 10 mEq/L/24 h to avoid cerebral edema from rapid overco rrection. DI is treated differently, depending on whether it is central or nephrogenic, but free access to water is crucial to avoid dehydration (see page 325; Endocrine). Central DI can be treated with long-term arginine vasopressin (DDAVP, which is the same compound as A DH). Nephrogenic diabetes insipidus (DI) can be treated with thiazide diuretics. Potassium General Points 98% of potassium (K + ) is intracellular ( 3,500 meq total with th e majority found in skeletal muscle), thus the serum potassium is a poor reflection of tota l body potassium. The main factors that control the internal distribution of K + are insuli n and 2 stimulation, which drive K + into cells by stimulation of the Na + K + ATPase pu mp. Mineralocorticoid activity (aldosterone) and the delivery of sodium to the cortical col lecting duct (CCD) are the main regulators of K + secretion. Addison \200\231 s disease ma y cause hyperkalemia due to loss of mineralocorti- coid activity. 671 Hyperkalemia The urgency of treatment depends on several factors: The cause of hyper- kalem ia (hemolysis or muscle/tissue breakdown), preexisting chronic hyper- kalemia, the presence of oliguric/anuric renal failure, and the rate of rise (Figure 17.3). Aggressive treatment may be required even in modest degrees of hyperkalemia or associated ECG manifestations. P ersistent hyperkalemia requires an associated impairment in urine potassium excretion. Although there are no standard definitions, a K + \211 6.5 \200\2237.0 mEq /L requires ur gent evaluation and treatment. Signs and Symptoms Muscle weakness/paralysis, cardiac conduc tion abnor- malities, and decreased ammonium excretion (NH 4 + ) leading to metabolic acido sis. Tall, peaked T waves and shortened QT interval are the earliest changes. Clinical pear l : The ECG is insensitive for the diagnosis of hyperkalemia, espe- cially if of rapid onse t. The presence of hypocalcemia or metabolic acidosis may precipitate symptoms or ECG abnor malities at a lower serum K + . Causes Pseudohyperkalemia : Mechanical trauma (hemolysis du e to tourniquet com- pression), marked leukocytosis (white blood cells [WBC] >100,000/ L ) or thrombocytosis (platelet count >700,000/ L). To diagnose, draw a plasma K + in a he parinized tube to determine the actual K + level. Excessive K + intake : Typically seen in disorders with reduced renal func- tion. Always consider nutritional products (noni or coco nut juice) or salt substitutes. Cell shifts : Rhabdomyolysis, TLS, drugs (digoxin, RAAS blo ckers, trimethop- rim), diabetic ketoacidosis (DKA)/hyperosmolar states, inorganic or min- eral acidosis due to buffering of excess H + ions with movement of K + out of cells. Figure 17.3 Hyperkalemia Tall, peaked T wave Decreased R wave amplitude Wide, Flat P wave Depressed ST segment Prolonged PR interval Widened QRS 672 Impaired renal excretion: Most common cause of sustained hyperkalemia. Typically not seen u ntil the eGFR is <15 mL /min/1.73 m 2 unless other factors. Treatment of severe hyperkalemi a Three guiding principles: 1. Antagonize metabolic effects of \206\221 K + with calcium g luconate 1 g IV given over 5 \200\22310 min, especially if loss of P waves or QRS widening. May be repeated if ECG manifestations continue. y r t s i m e h c o B i 2. Drive K + into cells. Insulin (given as bolus or continuous infusion, not sub- cutaneous ly) D 50 W IV ( not used if significantly hyperglycemic already, i.e., \211 250 mg/ dL ). Inhaled albuterol (double to quadruple strength, 5 \200\22310 mg) may be syner- gistic with insulin therapy. The role of sodium bicarbonate is controversial and may only be helpf ul in associated states of metabolic acidosis. 3. Remove K + from the body. Diuretics (loop diuretics) may be best for patients with mild or moderate degree of kidney failure. Cationic exchange resins (sodium polystyrene sulfonate [SPS]) may take 4 \200\2236 h to be effective; not helpful if post colectomy. May be dangerous with ileus (potential for intest inal ischemia and ulcerations). Typical dose is 15 \200\22360 g. Dialysis: Indicated if the above measures are not successful, progressive oliguria ensues, or there is significant K + release from tissue. Hemodialysis is preferred over continuous renal replacement therapy or peritoneal dialysis. Eliminate reversible causes of impairment in renal function (drugs, hypov- olemia, or urinary obstruction). Hypokalemia Typically, there are no symptoms until the serum K + is <3.0 mEq/L, but a serum K + <2.5 mEq/L (especially if accompanied by symptoms) requires urgent treatment (Figure 1 7.4). Symptoms may depend on the speed of development. It may be potentiated by use of digo xin or underlying car- diovascular disease. Signs and symptoms Muscle weakness, cramps, par alysis, rhabdomyolysis, respiratory failure from respiratory muscle weakness, ileus, impair ed urinary concentration (polyuria), and cardiac arrhythmias and ECG abnormalities. Figure 17.4 Hypokalemia Slightly prolonged PR interval ST depression 673 Slightly peaked P wave Prominent U wave Shallow T wave Causes \212Shift or redistributive process (typically transient): Insulin or hypokalemic periodic paralysis \212Decreased intake : Unusual cause by itself \212Gastrointestinal losses : Diarrhea, vi llous adenoma or chronic laxative abuse \212Renal losses \212Miscellaneous : Hypothermia can lead to a decrease in K + . Metaboli c and respiratory alkalosis facilitates entry of K + into cells (trivial effect). Diagnosis Urine K + /Cr ratio <15 mmol/g of creatinine is seen with poor dietary intake, tr anscellular K + shifts, GI loss, or prior diuretic usage. Treatment Depends on urgency and symptoms. If mild (>2.5 mEq /L and no symptoms), given oral K + supplements, 20 \200\22340 mEq at a time. If severe (<2.5 mEq/L and musculoskeletal or cardiac symptoms), give IV pota ssium cautiously (10 mEq/h via a peripheral IV, 20 mEq/h via a central line). Never give IV K + as a bolus; typically give over 1 h; be cautious if patient is oliguric or anuric. Alw ays evaluate for magnesium deficiency and replete. It will be difficult to normalize low po tassium levels unless hypomagnesemia is normalized. Calcium: Physiology General points About 40% of plasma calcium is bound to albumin. Usually , it is total plasma calcium that is measured although it is the unbound, ionized portion t hat is important. Therefore, adjust total calcium level for albumin as follows: Add 0.8 mg/ dL to the measured calcium for every 1 g/dL that albumin is below 4.0 g/dL (perform the rev erse if albumin is elevated). However, many factors affect binding (e.g., other proteins in myeloma, cirrhosis, acid \200\223base status, individual variation) so be cautious in your interpretation. If in doubt over an abnormal calcium, check the ionized calcium. The control of calcium metabolism \212Parathyroid hormone (PTH): A rise in PTH causes a ri se in plasma Ca 2+ 3- reabsorption and a \206\223 in plasma PO4 from bone; and \206\221 C a 2+ but \206\223 PO4 3- reabsorption from the kidney. PTH secretion enhances active vitam in D formation. PTH secretion is itself controlled by ionized plasma calcium levels. 3-. This is due to \206\221 Ca 2+ and \206\221 PO4 \212Parathyroid hormone-related peptide (PTHrP): A substance mostly secreted by tumors, it acts similarly to PTH. If elevated, a cause of hypercalcemia in malignancy. \212Vitamin D: Cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) are biolog ically identical in their actions. Serum vitamin D is converted in the liver to 25-hydroxy vitamin D (25[OH] vitamin D). In the kidney, a second hydroxyl group is added to form the b iologically active 1,25-dihydroxy vitamin D (1,25[OH] 2 vitamin D), also called calcitriol. Calcitriol produc- tion is stimulated by \206\223 Ca 2+ , \206\223 PO4 3- , and PTH. Its actions include \206\221 Ca 2+ and \206\221 PO 4 absorption from the gut; \206\221 Ca 2 + and \206\221 PO4 3- reabsorption in the kidney; enhanced bone turnover; and inhibition o f PTH release. 674 \212Calcitonin: Made in C-cells of the thyroid, this causes a decrease in plasma calcium a nd phosphate, but its physiological role is unclear. It is a marker to detect recurrence or metastasis in medullary carcinoma of the thyroid. \212Thyroxine: May increase plasma Ca 2+ , although this is rare. \212Magnesium: \206 \223 Mg 2+ prevents PTH release, and may cause hypocalcemia. Hypercalcemia Signs and symptoms \200\234Bones, stones, groans, and psychic moans \200\235 : Abdominal pain, vomiting, constipation, polyuria, polydipsia, depression, anorexia, weigh t loss, tiredness, weakness, BP \206\221 , confusion, fever, renal stones, acute kidney in jury, corneal calcification, cardiac arrest. ECG: Q T interval \206\223 . Causes and diagn osis See Figure 17.5. Most commonly, malignancy (myeloma, bone metastases, PTHrP \206\221 ) and primary hyperparathyroidism. Others include sarcoidosis or lymphoma (granulomas activ ate vitamin D to the 1,25-hydroxylated form), vitamin D intoxication, and familial benign h ypocalciuric hypercalcemia (rare; defect in calcium-sensing receptor). Pointers to malignan cy are \206\223 albumin, \206\223 Cl \200\223 , \206\223 K + , alkalosis, \206\223 PO4 3- , \206\221 alk phos. Other investigations (e.g., isotope bone scan, CXR, ESR) may also be of diagnostic value. Treat the underlying cause. If Ca 2+ >13 mg/dL, and severe abdomin al pain, vomiting, fever, or confusion, aim to reduce calcium as follows: \212Blood tests: Measure urine and electrolytes, Mg 2+ , creatinine, Ca 2+ , PO4 y r t s i m e h c o B i 3- , alk phos. \212Fluids: Rehydrate with IVF 0.9% saline (e.g., 4 \200\2236 L in 24 h as needed). Correc t hypokalemia/hypomagnesemia (mild metabolic acidosis needs no treatment). This will reduce symptoms, and increase renal Ca 2+ loss. Monitor urine and electrolytes. \212Diuretics : Controversial, but can increase renal calcium loss. Use loop diuret- ics , avoid thiazides, and be careful not to volume deplete. \212Bisphosphonates: IV pamidronate will lower Ca 2+ over 2 \200\2233 d. Maximum effect is at 1 wk. These drugs inhibit osteoclast activity and so bone resorption. \212Steroids: Useful in granulomatous disease (e.g., prednisone 40 \200\22360 mg/d for sarcoidosis). \212Salmon calcitonin: Used for temporization of symptomatic hypercalcemia. Less effective than bisphosphonates, but quicker onset. Inhibits osteo- clasts. Tachyphylaxis occurs afte r several doses, reducing its effectiveness. \212Other: Chemotherapy may deplete Ca 2+ in malignant disease (e.g., myeloma). Hypocalcemia Apparent hypocalcemia may be an artifact of hypoalbuminemia (above). Signs and symptoms Tetany; depression; perioral paresthesias; carpope- dal spasm (wrist flexion and fingers drawn together), especially if brachial artery is occluded with BP cuff ( Trousseau \200\231s sign ); neuromuscular excitability (e.g., tapping over parotid [facial nerve] ca uses facial muscles to twitch [ Chvostek \200\231s sign ]). Cataract if chronic Ca 2+ \206 \223 . ECG : QT interval \206\221 . Causes Most commonly, hypoparathyroidism (may be a con sequence of thyroid or parathyroid surgery). Check PTH and phosphate levels. If phos- phate raised, then either chronic kidney disease (high phosphate causes \206\221 PTH, which \206\221 urinary Ca 2+ excretion), hypoparathyroidism, pseudohy- poparathyroidism, or acute rhabdomyolysis. If phosphorus normal or decreased \206\223 , then either osteomalacia (hi gh alkaline phosphatase), over- hydration, or pancreatitis. In respiratory alkalosis, the t otal Ca 2+ may be normal, but ionized Ca 2+ \206\223 due to increased binding to albumin, and the patient may have symptoms because of this. Prolonged IV fluid administra- tion (e.g ., long hospital stay) can also cause hypocalcemia. Treatment If symptoms are mild, replete calcium orally (e.g., 5 mmol/6 h). Check daily plasma and periodic ionized calcium levels. If hypoparathyroidism 675 6 7 6 Figure 17 .5 Diagnostic approach: Hypercalcemia Confirm with elevated ionized calcium, albumin Check PTH High or normal Low Check 25-hydroxy and 1,25-hydroxy vitamin D, PTHrP Check urinary calcium excretion 1,25-hydroxy D \206\221 25-hydroxy D \206\223 25-hydroxy D \206\221 Normal vit D, PTHrP Low PTHrP \206\221 High Primary hyperparathyroidism Excess vitamin D intake Malignancy Metastases Multiple myeloma Hyperthyroidism Others Granulomas (sarcoid, TB, lymphoma) Familial hypocalciuric hypercalcemia is the cause, calcitriol is often necessary to maintain a normal calcium. If symptoms are s evere , give 10 mL of 10% calcium gluconate (2.25 mmol) IV over 30 min (bolus injections ar e only needed very rarely). Repeat as neces- sary. If due to alkalosis, correct the alkalos is and recheck values. y r t s i m e h c o B Magnesium Magnesium is distributed 65% in bone and 35% in cells; plasma concentra- tion ten ds to follow that of Ca 2+ and K + . Magnesium excess is usually caused by renal failure, b ut rarely requires treatment in its own right. Hypomagnesemia causes paresthesias, seizures , tetany, and arrhythmias. Digitalis toxicity may be exacerbated. Causes: Severe diarrhea; ketoacido- sis; alcoholism or poor diet; diuretics or other medications (e.g., tacroli- mus , proton pump inhibitors), total parenteral nutrition (monitor weekly); accompanying hypoca lcemia. May accompany hypokalemia (especially with diuretics) and hypophosphatemia. Treatme nt: Give magnesium salts. IV is more effective than PO. Hypermagnesemia is usually iatrogen ic or from excessive intake (e.g., antacids). Features: Neuromuscular depression, \206\223 BP, CNS depression, coma. i Trace elements A number of trace elements are of biological importance and can cause clinic al disease in deficiency or excess. Disorders of most trace elements are rare without a ver y unusual diet or long-standing malabsorptive process (e.g., short gut syndrome). Zinc is i mportant in many enzymatic processes and plays multiple roles in insulin metabolism. Zinc d eficiency may occur in parenteral nutrition or, rarely, from a poor diet (too few cereals a nd dairy products, anorexia ner- vosa, alcoholism). Rarely, it is due to a genetic defect. Signs and symptoms: Look for red, crusted skin lesions, especially around nostrils and corn ers of mouth. Diagnosis: Therapeutic trial of zinc (plasma levels are unreliable as they ma y be low, e.g., in infection or trauma, without deficiency). Zinc excess is rare, usually r elated to excess intake. Its major clinical effect is copper deficiency (through inhibiting copper absorption). Copper An essential element for synthesis of heme and oxidation of met - als. Copper deficiency can result from parenteral nutrition, zinc excess, malabsorption ( e.g., short bowel). Deficiency can cause anemia and neutro- penia. Diagnosis of copper defi ciency: Check serum copper levels. Copper excess is rare outside of Wilson \200\231s diseas e and is caused by excess intake, often from contaminated water. Copper toxicity causes cir rhosis, kidney disease, and various neurological diseases. Treatment can involve chelation with penicillamine; consult an expert. Selenium An essential element present in cereals, nu ts, and meat. It is required for the antioxidant glutathione peroxidase (which protects aga inst harmful free radicals). It is also antithrombogenic and is required for sperm motility proteins. Deficiency may increase the frequency of neoplasia and atheromata and may lead t o a cardiomyopathy (Keshan \200\231s disease). There is interest that selenium may modulate the oxidative stress response in sepsis. Serum levels are a poor guide. Toxic symptoms may also be found with excessive supplementation or contaminated food products. 677 Plasma proteins Serum protein electrophoresis (SPEP) distinguishes a number of bands (see F igure 17.6, p. 680 ). Albumin is synthesized in the liver; t \211\210 20 d. It binds bi lirubin , free fatty acids , calcium , and some drugs (penicillin and acetylsalicylic acid) . It typically requires a fall in albumin of 30% before it shows up on a electrophoresis. Low albumin may result in edema from low oncotic pressure. Causes: Liver disease, nephrotic syndrome, burns, protein-losing enteropathy, malabsorp- tion, malnutrition, late pregnancy , artifact (e.g., from arm with IVF), posture (5 g/L higher if upright), genetic variations , malignancy. Causes of high albu- min: Acute dehydration; artifact (e.g., stasis). 1 Zo ne 1 -Antitrypsin, thyroid-binding globulin, 1 glycoprotein (oroso- mucoid), and high -density lipoprotein (HDL). A decreased band may be seen: Cirrhosis and nephrotic syndrome. 2 Zone 2 -Macroglobulin, ceruloplasmin, and haptoglobin (predominant component). The 2 zone is typically decreased in hemolytic anemia. Zone Transferrin (major band), low -density lipoprotein (LDL), fibrino- gen, and C3 complement (C4 may be visible if increased or high-normal). Reduced in active glomerulonephritis and systemic lupus erythematosus (SL E). Zone Immunoglobulins and C-reactive protein (CRP). Diffusely raised in chronic infec tions, liver cirrhosis, sarcoidosis, SLE, rheumatoid arthritis (RA), Crohn \200\231s diseas e, TB, bronchiectasis, primary biliary cirrhosis (PBC), hepatitis, and parasitemia. It is l ow in nephrotic syndrome, malabsorption, malnutrition, immune deficiency (severe illness, d iabetes mellitus, renal fail- ure, malignancy, or congenital). Paraproteinemia See p. 635. Acute-phase response The body responds to a variety of insults with, among other things, th e synthesis by the liver of a number of proteins (normally present in serum in small quanti ties) \200\224e.g., 1 -antitrypsin, fibrino- gen, complement, haptoglobin, and CRP. An in creased density of the 1 - and 2 -fractions, often with a reduced albumin level, is c haracteristic of conditions such as infection, malignancy (especially if the 2 -fraction is elevated), trauma, surgery, and inflammatory disease. CRP Levels help monitor inflammati on/infection. Normal <0.5 mg/ d L, but can be elevated age, race, BMI, and smoking . Like t he ESR, it is raised in many inflammatory conditions, but changes more rapidly; increases i n hours and falls within 2 \200\2233 d of recovery. Therefore, it can be used to follow the response to therapy (e.g., antibiotics in osteomyelitis) or disease activ- ity (e.g., Croh n \200\231s disease). CRP values in mild inflammation are 10 \200\22350 mg/L; active bacter ial infection, 50 \200\223200 mg/L; severe infection or trauma >200 mg/L; see Table 17.12. Elevated CRP levels may suggest an increased risk in patients with cardiovascular disease i f measured using a highly sensitive assay. Low risk <1 mg/dL; moderate risk 1 \200\2233; an d high risk >3 mg/L. Urinary proteins If urinary protein loss is >0.15 g/24 h (24 h urine), then this is considered pathological. Albuminuria Caused by kidney disease. Microalbuminur ia (albumin excretion between 30 \200\223300 mg/d) is an important screening test for diabe tic nephropathy. >300 mg/d of albuminuria is considered macroalbuminuria or clinical protei nuria. Microalbuminuria by spot urinary albumin to creatinine ratio is 30 \200\223300 mg/g creatinine. Bence Jones proteinuria consists of light chains excreted in excess by some pat ients with myeloma. They are not detected by dipsticks and may 678 occur with normal serum electrophoresis. Typically diagnosed with urinary electrophoresis ( UPEP). Serum free light chains Recently, a highly sensitive assay has been developed to mea sure and light chains (Freelite \204 ) as an indicator of monoclonality. Serum free light chains have a greater sensitivity than SPEP, UPEP, and immunofixation electrophoresi s (IFE) alone in the detection of myeloma, light chain myeloma, and nonsecretory myeloma an d are impor- tant in both treatment response and prognosis. y r t s i m e h c o B i Plasma enzymes Reference intervals vary between laboratories. Raised levels of specific enz ymes can be a useful indicator of a disease. However, remember that most can be raised for other reasons, too. The major causes of raised enzymes are given below. Alkaline phosphatase \212 \212 Liver disease (suggests cholestasis) Bone disease (isoenzyme distinguishable, reflects oste oblast activity) espe- cially Paget \200\231s, growing children, healing fractures, osteoma lacia, metasta- ses, primary hyperparathyroidism, and renal failure Pregnancy (placenta mak es its own isoenzyme) \212 Alanine-amino transferase (ALT; serum glutamic-pyruvic transaminase [ SGPT ]) \212 Liver disease (suggests hepatocyte damage); also raised in shock Amylase \212 \212 Acute pancreatitis (not chronic pancreatitis as little tissue remaining) Severe uremia, dia betic ketoacidosis serum glutamic-oxaloacetic Aspartate-amino transferase (AST; transaminase [ SGOT ]) \212 \212 \212 CK \212 Liver disease (suggesting hepatocyte damage) MI Skeletal muscle damage and hemolysis MI (isoenzyme \200\234CK-MB. \200\235 MI diagnosed if CK-MB >6% total CK, or CK-MB mass >9 9 percentile of normal) Table 17.12 CRP Marked elevation Bacterial infection Normal to slight elevation Viral infection 679 Abscess Crohn \200\231s disease Connective tissue diseases ( SLE) Steroids/estrogens Ulcerative colitis Atherosclerosis Neoplasia Trauma Necrosis (e.g., MI) Figure 17.6 LDL \212 Muscle damage (rhabdomyolysis, prolonged running, hematoma, seizures, IM injection, defibri llation, bowel ischemia, myxedema, dermatomyositis) and drugs (e.g., statins). A raised CK does not necessarily mean an MI. GGT \212 Liver disease (particularly alcohol-induced damage, cholestasis, drugs) LDH \212 \212 \212 MI(nonspecific) Liver disease (suggests hepatocyte damage) Hemolysis, pulmonary embolism, a nd tumor necrosis