American Journal of Emergency Medicine
Volume 16 � Number 1 � January 1998
Copyright � 1998 W. B. Saunders Company
Algorithms for Diagnosing Some Electrolyte Disorders
- MILFORD FULOP MD
The differential diagnosis of electrolyte disorders has traditionally been framed in terms of pathophysiology, and analysis of clinical problems has usually proceeded in the same way. However, easier access to rapid-response laboratory analysis has prompted physicians who encounter patients with serious electrolyte abnormalities to try to establish the cause by quickly obtaining further simple tests. In that vein, this article and the algorithms that are presented are intended to assist the preliminary laboratory differential diagnosis of low and high serum levels of sodium, potassium, and calcium.
Received March 27, 1996, returned May 20, 1996;
revision received July 2, 1996,
accepted August 5, 1996.
Address reprint requests to Dr Fulop, 1300 Morris Park Ave, Bronx, NY 10461.
- Serum electrolytes
Reviews of electrolyte disorders have usually been based on our understanding of their pathophysiology.       Experienced clinicians who encounter a patient with hyponatremia will ask themselves early whether there are signs of extracellular fluid volume (ECFV) deficiency, or excess, or neither. Then they consider what the pathophysiological mechanisms may be, and what disease(s) may be responsible. Finally, they ask themselves what tests might confirm their suspicions or expectations, and they may then try to ascertain whether the kidneys are behaving as expected in the respective disorders.
However, this is often no longer how ``electrolyte problems'' are analyzed, especially in emergency departments. Because these disorders commonly accompany or even cause serious illnesses, many patients with electrolyte abnormalities arrive at hospitals acutely ill, where they are examined and stabilized, and have blood and other tests performed. If the test results are abnormal, the physician's response may be to ask, ``What test should be done next?'' Although this way of trying to establish a diagnosis is less elegant than by a process of analyzing the pathophysiology, it works, and has become a fact of life in emergency departments. The frequent success of this approach is of course actually based on our understanding of the pathophysiology of these disorders, as well as on modern laboratory technology. One hopes that, as well as considering what test to do next, the physicians will also ask themselves (and the patient) whether and how the laboratory findings fit with the clinical picture: Are the abnormalities expected or not? Might the abnormalities have caused the symptoms, or vice versa?
Here, emphasizing the use of routine on-line tests, I present several algorithms for the laboratory-based preliminary differential diagnosis of some major electrolyte disorders: hyponatremia and hypernatremia ( Figures 1 and 2 ); hypokalemia and hyperkalemia ( Figures 3 and 4 ); and hypocalcemia and hypercalcemia ( Figures 5 and 6 ). In a few cases (eg, hypercalcemia  ), a similar algorithm has been proposed by others. These algorithms are not intended to bypass concurrent clinical analyses. Questioning and examining patients remain crucial to elucidating diagnosis, guiding therapy, and assessing the significance and sometimes the validity of the laboratory findings. In some cases, the diagnosis is evident from the clinical presentation, and the laboratory abnormalities are not unexpected. Examples of this are the finding of hyperkalemia in a patient with known renal failure who has missed a dialysis treatment session, or of hypocalcemia in a patient with tetany. Here, however, I will deal mainly with abnormal electrolyte findings that are encountered in clinical settings in which the diagnosis may not be obvious, or in which the abnormality is unexpected. The algorithms are intended to help systematize the sequence of obtaining simple tests whose results should be available rapidly and which should help to verify the original abnormal finding and clarify its significance. Additional studies, such as serum hormone assays, may be needed later to elucidate the diagnosis. Although the algorithms treat the various abnormalities as if the causes and findings are discrete, in practice there is often overlap. I have also included tables that list the main diagnostic possibilities for each disorder, arrayed according to their pathophysiological causes. The presentation does not discuss the various disorders at length nor deal with their treatment.
Even before learning that a patient has hyponatremia, experienced physicians will have judged clinically whether the patient may be NaCl-depleted or may have fluid retention, and will then interpret the report of hyponatremia in that light (Figure 1 , Table 1) . Often, however, the finding of hyponatremia is unexpected, especially in patients who do not have clinical signs of either ECFV deficiency or excess. Then one must decide whether the report of hyponatremia
truly signifies the presence of hypo-osmolality. This can be verified by measuring the serum osmolality and comparing the measured and calculated values. Osmolality is calculated as 2 � Na+ + [glucose in mg/dL � 18] + [serum urea nitrogen in mg/dL � 2.8], and the measured and calculated values should match within 10 mosm/L. If the measured osmolality is more than 10 mosm/L below the calculated value, there was probably an error and all the measurements should be repeated in the original and another specimen. If the measured osmolality is more than 10
Figure 1. Hyponatremia. Flow chart of laboratory workup. mSosm , measured serum osmolality; cSosm , calculated serum osmolality (see text); SUN, serum urea N; Uosm , urine osmolality; UNa + , urine Na+ concentration; TB Na+ , total body Na+ content; TB water, total body water.
8] or protein.  When hypertriglyceridemia is responsible for such ``pseudohyponatremia,'' the serum is visibly lipemic. The increasing availability of direct potentiometric analysis of serum Na+ activity will eventually obviate such errors in estimating serum Na+ . Figure 1 does not include the situation in which marked acute hyperglycemia (eg, serum glucose above 500 to 600 mg/dL) may cause hyponatremia, mainly owing to shift of water from cells to ECF.  In this case, the measured and calculated serum osmolarities should be concordant.
Figure 2. Hypernatremia. Flow chart of laboratory workup. *Uosm is less than 150 mosm/L in complete central DI, but may be higher in partial central DI. Except in patients given hypertonic NaCl or NaHCO3 solutions intravenously. DI, diabetes insipidus; for other abbreviations see Figure 1 legend.
True hyponatremia with hypo-osmolality means there is a relative excess of body water compared with Na+ , and laboratory estimates of renal function, including concentrating ability and Na+ excretion, will help evaluate whether the
main problem is Na+ deficiency, water excess, or a surfeit of both water and Na+ with edema. The finding of low-to-normal serum urea nitrogen and urate concentrations in patients with hyponatremia suggest the presence of excess body water, whereas high serum urea nitrogen and urate concentrations suggest Na+ deficiency. Some patients with Na+ deficiency, eg, those overtreated with a loop diuretic drug, with Addison's disease or with salt-wasting nephropathy,  also have a deficit of body water, but because their Na+ deficit exceeds their water deficit they have hyponatremia. Such patients with ongoing urinary Na+ losses may have inappropriately high urinary [Na+ ] until they develop severe renal failure owing to a large ECF deficit. In contrast, patients with hyponatremia owing to gastrointestinal losses of Na+ and water tend to have low urinary [Na+ ], usually below 10 to 15 mmol/L.
Figure 4. Hyperkalemia. Flow chart of laboratory workup. See Figure 3 legend for abbreviations.
Edematous patients with hyponatremia have excess body Na+ , but an even larger excess of water. Like patients with Na+ deficiency, edematous patients may also have mild or moderate elevations of serum urea nitrogen and urate, high urine osmolality, and low urine [Na+ ], so these findings do not differentiate these disorders, but the clinical findings obviously do. On the other hand, patients with hyponatremia owing just to excess total body water, who have normal total body Na+ content, tend to have low-normal serum urea nitrogen and often subnormal serum urate. Among these are compulsive water drinkers who have low urinary osmolality because they are undergoing a water diuresis,  and those with the syndrome of inappropriate ADH secretion (SIADH), whose urinary osmolality is usually higher than that of their serum. 
Hyponatremia is probably encountered most often in patients who have edema, owing to congestive failure, hepatic cirrhosis, or the nephrotic syndrome. These patients' hyponatremia is often aggravated by treatment with diuretic drugs that may impair renal diluting function and cause
natriuresis,  and whose effects may confound interpretation of the urinary findings. On the other hand, patients with NaCl deficiency, and consequent low ECFV, are often hypotensive and have orthostatic pulse and blood pressure changes, hemoconcentration, as well as elevated serum urea nitrogen concentration. The cause of their ECFV deficit is usually evident clinically, for example, severe diarrhea, vomiting, or diuretic therapy.
Figure 5. Hypocalcemia. Flow chart of laboratory work-up. *The normal PTH levels in hypomagnesemic hypocalcemia are inappropriately low in relation to the low serum calcium. Pi , serum inorganic phosphate; PTH, parathormone.
The formulation in Figure 1 implies that the different types of hyponatremia are discrete and separate but many patients have several contributing factors. For example, a disturbed older patient may have impaired urinary diluting capacity owing either to thiazide use or to low urinary solute excretion because of malnutrition, and may also be taking a neuroleptic drug that can aggravate the diluting defect and cause SIADH. Hyponatremic patients with SIADH do not have edema or signs of ECFV deficiency. Some have taken medications that predispose to water retention, or have a
Figure 6. Hypercalcemia. Flow chart of laboratory work-up. SPEP, serum protein electrophoresis, *PTHrP, PTH-related protein secreting tumors, especially of lung and kidney; for other abbreviations see Figure 5 legend.
|Hyperproteinemia, as with macroglobulinemia or myeloma |
|Shift of water from cells to ECF, as with marked hyperglycemia |
|Increased total body water|
|With normal total body Na+|
|Syndrome of inappropriate ADH secretion (SIADH) |
|Drugs, such as chlorpropamide, haldol|
|Lung diseases, such as pneumonia, TB|
|Ectopic vasopressin secretion, especially with lung tumors|
|CNS diseases, such as meningitis|
|Compulsive water drinking |
|With increased total body Na+ --edematous states|
|Chronic heart failure|
|Chronic liver disease|
|Chronic renal disease, especially nephrotic syndrome|
|Decreased total body Na+|
|Gastrointestinal losses owing to vomiting, diarrhea, drainage|
|Diuretic drugs, especially thiazides |
|Salt-wasting nephropathies |
|Skin losses--sweating, with replacement just by water|
pulmonary or central nervous system disease.  Patients with severe hypothyroidism may also have hyponatremia,  and if this is a consideration serum thyroid function tests should be obtained.
Among hyponatremic patients, compulsive water drinkers are particularly liable to develop acute central nervous system consequences of their hypo-osmolality, such as seizures, clouding of consciousness, and eventually even coma. They may have underlying psychiatric disorders, often are taking neuroleptic drugs, and may have been drinking large amounts of fluids. Similar neurological sequelae may follow excessive intravenous administration of non-electrolyte-containing fluids postoperatively. 
|Increased total body Na+ (rare in adults)|
|Intravenous administration of hyperosmolar NaCl or NaHCO3 solutions|
|Drinking sea water ([Na+ ] nearly 500 mmol/L) |
|Decreased total body water|
|Excess renal losses|
|Osmotic diuresis owing, for example, to severe glucosuria |
|Diabetes insipidus |
|Central--vasopressin deficiency owing to posterior pituitary disease (tumor, granuloma, idiopathic)|
|Congenital--evident from infancy|
|Acquired--Li+ toxicity, K+ depletion, hypercalcemia |
|Decreased intake--deficient thirst owing to impaired osmoreceptor function |
However, adults with this abnormality usually also have NaCl depletion, the increased serum [Na+ ] owing to a disproportionately larger deficit of water.  The finding of normal-to-high serum urea nitrogen and urate concentrations, together with urine [Na+ ] of about 60 to 90 mmol/L in a hypernatremic patient who is diuresing, suggests that the hypernatremia is caused by an osmotic diuresis, such as with heavy glucosuria.  If the NaCl deficit is large, there may be clinical and laboratory signs of ECFV depletion. Hypernatremia evident on entry to the hospital is found especially in elderly patients with curtailed water intake and a renal concentrating defect.  Their decreased water intake may be caused by depressed consciousness accompanying a serious infection, and the renal concentrating defect is usually secondary to diuretic therapy or glucosuria.  Rarely, one may encounter patients with an isolated impairment of thirst sensation, with consequent decreased intake of fluid.  Such patients have high serum urea nitrogen and urate concentrations and high urine osmolality and [Na+ ], but are not polyuric and may even be oliguric. Impaired thirst and decreased water intake may also contribute to the development of hypernatremia and hyperosmolality in elderly or poststroke patients. Far less commonly than from water deficit, hypernatremia may be caused by intravenous administration of hyperosmotic Na+ -containing solutions (such as NaHCO3 ) or, even more rarely, by drinking sea water, which has a [Na+ ] of about 500 mmol/L and osmolality of about 1,000. 
The finding of normal or even low serum urea nitrogen and urate concentrations and low urine [Na+ ] in a hypernatremic patient with polyuria suggests that the hypernatremia is caused by water diuresis rather than by osmotic diuresis. Such adults, notably those with diabetes insipidus (DI), have normal total body NaCl content, and usually do not have signs of ECFV depletion. Those with complete central DI have urinary osmolalities below 150 mosm/L, despite their high serum osmolalities  ; those with partial central DI may have somewhat higher urinary osmolalities, but usually well below 300 mosm/L; and those with nephrogenic varieties of DI  often have less markedly hypo-osmotic urine.
A report of low serum K+ concentration (Figure 3 , Table 3) should prompt obtaining an electrocardiogram to look for sagging ST segments, prolongation of the QT interval and appearance of U waves,  although these ECG findings are usually just confirmatory because they are not very sensitive.
Hypokalemic patients who have low serum CO2 and high Cl- values may have either metabolic acidosis or respiratory alkalosis or both, and these can be differentiated by measuring the blood pH.  Hypokalemia associated with metabolic acidosis is often secondary to diarrhea, which should be evident from the history, and less commonly to a renal tubular acidification defect, which is characterized by an inappropriately high urine pH (usually above 6.5). Patients with renal tubular acidosis may also have osteomalacia, and kidney stones or nephrocalcinosis.  Patients with hypokalemia whose low serum CO2 and high Cl- values are caused by respiratory alkalosis, or by concurrent primary respiratory
|Inadequate K+ intake--often a contributing factor but seldom a sufficient cause in the absence of increased K+ losses|
|K+ shift from ECF to cells |
|Alkalemia, especially caused by acute respiratory alkalosis|
|Hypokalemic (familial) periodic paralysis |
|Gastrointestinal--from diarrhea, drainage, vomiting (in the last, usually mainly from kaliuresis)|
|Diuretic drugs--thiazides and loop diuretics |
|Hyperaldosteronism caused by adrenal adenoma |
|Mg++ deficiency  |
|Type 1 renal tubular acidosis |
alkalosis and metabolic acidosis, usually have either hepatic cirrhosis  or sepsis.  Patients with cirrhosis usually have typical clinical signs, and those with sepsis usually have fever, leukocytosis, perhaps hypotension, and focal signs of infection. Salicylate intoxication can also cause a mixed respiratory alkalosis and metabolic acidosis.  These patients are likely to have serum salicylate concentrations well above 30 mg/dL, often extremely low serum bicarbonate and P co2 and blood pH that is near-normal, and may have disturbed consciousness.
Hypokalemic patients with normal serum CO2 and Cl- levels usually have a normal blood pH, and this pattern may occur with hypokalemic periodic paralysis.  However, even before the laboratory reports their hypokalemia, these patients will usually have described abrupt muscle weakness or paralysis, and there is often also a family history of the disorder,  although some have Graves disease. 
Hypokalemic patients who have high serum CO2 and low Cl- concentrations are most likely to have a metabolic alkalosis, which can be confirmed by finding a blood pH above 7.45. The common causes of metabolic alkalosis are diuretic therapy or vomiting, which should be evident from the history. Patients with hyperaldosteronism will have come to attention because of hypertension,  and those with hypomagnesemia are usually chronic alcohol abusers.  Hypokalemia owing to diuretic-induced K+ depletion  sometimes occurs in patients with cor pulmonale whose underlying pulmonary insufficiency may be associated with high serum CO2 and normal or even low blood pH. In addition to their features of pulmonary insufficiency, and perhaps cardiac failure, another key laboratory finding in these patients is usually severe hypoxia.
A report of hyperkalemia (Figure 4 , Table 4) should also prompt obtaining an electrocardiogram (ECG) to look for peaked T waves and, in extreme cases, atrioventricular conduction block and/or widening of the QRS interval,  although, as with hypokalemia, the ECG is not very sensitive to the presence of moderate hyperkalemia. Serum total CO2 and Cl- concentrations are customarily reported together with the serum K+ and a report of hyperkalemia is an indication to also measure the arterial blood pH. 
A low serum bicarbonate, with either a normal or high serum Cl- , in a patient with hyperkalemia usually means that the patient has a metabolic acidosis, and the blood pH will indicate whether acidemia is present. (A low serum CO2 sometimes signifies respiratory alkalosis rather than metabolic acidosis, but alkalosis is usually associated with hypokalemia, not hyperkalemia.) Patients with hyperkalemia caused by renal failure have elevations of serum urea nitrogen and creatinine. Patients with hyperkalemia caused by Addisonian adrenal insufficiency usually have hyponatremia, hypotension, and hyperpigmentation as well, and further laboratory studies should disclose low serum concentrations of cortisol and aldosterone, and an elevated concentration of renin. Patients with hypoaldosteronism that is instead caused by hyporeninemia usually have moderate renal failure, sometimes associated with diabetic nephropathy   or with the use of nonsteroidal anti-inflammatory  or other drugs,  and these patients have normal serum cortisol concentrations. Hyperkalemia can also be a feature of the tumor lysis syndrome,  with lactic acidosis, hyperuricemia, hyperphosphatemia and hypocalcemia, and severe rhabdomyolysis. 
Patients with hyperkalemia whose serum CO2 and Cl- levels are normal usually also have a normal blood pH. Hyperkalemia without an acid-base abnormality may occur in patients with insulin deficiency and severe hyperglycemia  without ketosis, which should be evident from the history and laboratory studies. Hyperkalemia with normal acid-base status is sometimes secondary to the use of potassium supplements  (given to prevent diuretic-induced hypokalemia) or rarely to massive overdosage with digitalis  ; the latter should be evident from the history and characteristic electrocardiographic findings. Patients with
|Measurement artifact owing to in vitro leakage of K+ from leukocytes (with marked leukocytosis)  or platelets (with marked thrombocytosis) |
|K+ shift from cells to ECF |
|Hyperosmolarity, as with severe hyperglycemia |
|Severe tissue damage, as with tumor lysis  or rhabdomyolysis |
|Excess K+ intake--an uncommon cause except when associated with decreased renal excretion |
|Decreased renal excretion|
|Renal failure, especially acute, and particularly if associated with major tissue damage (eg, tumor lysis  or rhabdomyolysis  )|
|Antikaliuretic drugs |
|Diuretics--spironolactone, triamterene, amiloride|
|Angiotensin receptor blocking drugs|
|Hyporeninemic (ie, type 4 renal tubular acidosis)  |
|Adrenocortical insufficiency (Addison disease)|
|A bbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; ACE, angiotensin converting enzyme.|
striking leucocytosis (above 100,000/cmm)  or thrombocytosis (above 1,000,000/cmm)  may have in vitro elevation of serum K+ owing to ``leakage'' of K+ from leucocytes or platelets into the serum during and after clotting. Patients with unusually high leucocyte or platelet counts should therefore have their ECF K+ concentration measured in plasma, obtained from rapidly centrifuged heparinized blood.
In addition to the diagnoses indicated in the Figure 5 , hypocalcemia may occur in desperately ill patients such as those in intensive care units.  The cause of the hypocalcemia in such patients is not well understood and probably is multifactorial (Table 5) , but has been attributed in part to hypoalbuminemia owing to overhydration, to binding of serum calcium by elevated plasma fatty acids, and in some patients to magnesium depletion.   The hypocalcemia that may occur in patients with acute pancreatitis  is contributed to by hypoalbuminemia and precipitation of calcium with fatty acids from mesenteric fat necrosis and lipolysis. Some hypocalcemic patients have tetany, although not those in whom it is merely secondary to hypoalbuminemia, whose serum ionized calcium concentration is normal, nor usually in those with untreated renal failure.
The main early laboratory aid for elucidating the cause of hypocalcemia is the serum inorganic P concentration (Pi ). A high Pi suggests either renal failure, which will be associated with at least moderate serum urea nitrogen elevation, or some type of hypoparathyroidism, in which the serum urea nitrogen level is ordinarily normal. Patients with hypoparathyroidism secondary to surgery have a neck scar from their previous thyroid or parathyroid operation, and those with idiopathic hypoparathyroidism may have various skeletal abnormalities and calcified basal ganglia. Hyperphosphatemia may be the cause of hypocalcemia in patients with the tumor lysis syndrome,  or with acute rhabdomyolysis,  in both of which large amounts of phosphate leak from damaged and necrotic cells.
|Low serum protein-bound calcium owing to hypoproteinemia (especially hypoalbuminemia)|
|Gastrointestinal malabsorption or protein leak|
|Low serum ionized Ca++|
|Major tissue damage--tumor lysis,  rhabdomyolysis |
|Hypomagnesemia, especially in malnourished ethanol abusers  |
|Vitamin D deficiency--seldom a cause of severe hypocalcemia in adults except when associated with hypoalbuminemia|
|``Hungry bone syndrome''--bone repair after parathyroid adenomectomy |
|In acutely severely ill patients (ICU hypocalcemia) |
If the serum Pi concentration is low or normal in a hypocalcemic patient, the serum albumin concentration provides the next laboratory diagnostic clue. A low serum albumin may be caused by impaired liver function, severe malnutrition, and/or gastrointestinal or renal loss of albumin. Which of these is responsible usually should be evident from the history, physical findings, and simple laboratory studies. Patients with hypocalcemia associated with chronic diarrhea, especially those with steatorrhea, have decreases in both the albumin-bound fraction of serum calcium, and also of ionized calcium, the latter secondary to vitamin D deficiency.
Hypomagnesemia is an inadequately appreciated cause of hypocalcemia, and occurs particularly in very malnourished people,  especially those who are chronic ethanol abusers.  A laboratory clue to the presence of hypomagnesemia is often the concomitant presence of mild to moderate hypokalemia.  Hypophosphatemia may also accompany hypocalcemia in patients with acute new bone formation such as those with the hungry bone syndrome after parathyroid adenomectomy  or with osteoblastic metastases.
In adults, the hypocalcemia that may occur with vitamin D deficiency is usually mild, except in those with end-stage renal disease. In most other westernized adults with vitamin D deficiency, for example owing to gastrointestinal malabsorption, the mild hypocalcemia seems to cause compensatory hyperparathyroidism that offsets the development of serious hypocalcemia. These patients usually have low serum Pi concentrations owing to the parathormone (PTH)-evoked phosphaturia, and only mild or borderline hypocalcemia.
The causes of hypocalcemia are multifactorial in some patients, such as in those with inflammatory gastrointestinal malabsorptive disorders, who may have losses of magnesium, albumin, and deficient absorption of vitamin D, as well as excess enteric loss of calcium. Measurements of serum 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D concentrations may sometimes be needed to elucidate the cause of hypocalcemia, but the results of these assays usually are not quickly available.
Increased serum ionized calcium of any origin (Figure 6 , Table 6) may cause gastrointestinal, urinary, central nervous system, and cardiac abnormalities. Among these are anorexia, nausea, and vomiting; polyuria and polydipsia; mental confusion; and a shortened QT interval on electrocardiograms. 
Early laboratory aids to diagnosis are the serum total protein and partition measurements, and the serum Pi . Severe dehydration may result in an increased concentration of serum albumin and hence of protein-bound calcium, as well as elevated hematocrit and serum urea nitrogen. If the total serum protein is high but albumin is normal or low, this suggests there is a dysproteinemia, in which case elevation of serum calcium usually reflects an increase of the ionized fraction. The specific type of dysproteinemia can be differentiated by electrophoretic analysis, and patients with multiple myeloma may have proteinuria, bone disease, anemia, and
|High serum albumin owing to hyperproteinemia--seldom causes serum calcium much above about 11 mg/dL|
|Thiazide diuretic therapy |
|Multiple myeloma (a very uncommon cause of the hypercalcemia in this disorder, see below).|
|High serum ionized Ca-+|
|Increased bone dissolution|
|Tumors, especially of lung or kidney, with increased PTHrP secretion  |
|Bone metastases, especially from breast or prostate cancer|
|Multiple myeloma, and perhaps other tumors, with increased OAF secretion|
|Increased gastrointestinal absorption of calcium|
|Increased vitamin D|
|Granulomatous diseases--sarcoid,  TB (with increased 1,25-dihydroxy-D)|
|Lymphoma   (increased 1,25-dihydroxy-D)|
|Milk-alkali syndrome (excess intake of CaCO3 ) |
|Decreased renal excretion--familial hypocalciuric hypercalcemia (FHH) |
|Decreased bone formation despite continuing dissolution, as in bedfast patients with extensive Paget disease|
|A abbreviations: PTHrP, parathormone-related protein; OAF, osteoclast activating factors.|
elevated ESR. The next clue to the differential diagnosis of hypercalcemia is provided by the serum Pi . If low, this suggests either primary hyperparathyroidism, with excess secretion of PTH, or a nonparathyroid malignant tumor, especially of lung or kidney, with excess secretion of PTH-related-protein (PTHrP).  If the serum Pi is normal or elevated, this suggests one of the other causes indicated in Figure 6 .
Patients with primary hyperparathyroidism tend to have mildly depressed serum total CO2 and reciprocally elevated serum Cl- concentrations owing to a mild defect of urinary acidification secondary to the action of PTH.  This pattern also occurs in patients with hypercalcemia secondary to secretion of PTHrP by various nonparathyroid tumors (pseudohyperparathyroidism).  In contrast, patients with hypercalcemia caused by causes other than excess secretion of PTH or PTHrP, such as those with metastatic bone disease, tend to have the opposite pattern. They may have mild elevations of serum CO2 and reciprocal depression of serum Cl- concentrations, secondary to inhibited parathyroid secretion of PTH and consequent increased renal excretion of H+ . Patients with the milk-alkali syndrome tend to have more marked elevations of serum CO2 with metabolic alkalosis owing to ingestion of absorbable alkali, these days often as calcium carbonate. 
The hypercalcemia that occurs in patients with familial hypocalciuric hypercalcemia  (with familial stone disease) and in some patients receiving thiazide diuretics  or lithium therapy  is usually mild. Some less common causes of hypercalcemia, for which clues are also usually present in the history and on examination, are Boeck's sarcoid,  lymphomas,   and hyperthyroidism. 
The ready availability of rapid and accurate blood chemical studies in recent years has facilitated the differential diagnosis of electrolyte disorders. Diagnosis and treatment must still be guided by clinical findings, but discriminating use of selected laboratory data, especially those obtained from pretreatment specimens, may simplify the preliminary differential diagnosis.
1. Arieff A, DeFronzo RA (eds): Fluid Electrolyte and Acid-Base Disorders. New York, Churchill Livingstone, 1985
2. Kokko JP, Tannen RC (eds): Fluids and Electrolytes. Philadelphia, Saunders, 1986
3. Brenner BM, Rector FC Jr (eds): The Kidney, 4th ed. Philadelphia, Saunders, 1991
4. Schrier RW (ed): Renal and Electrolyte Disorders, 4th ed. Boston, Little, Brown, 1992
5. Narins RG (ed): Maxwell & Kleeman's Disorders of Fluid and Electrolyte Metabolism, 5th ed. New York, McGraw-Hill, 1994
6. Rose BD: Clinical Physiology of Acid-Base and Electrolyte Disorders, 3rd ed. New York, McGraw-Hill, 1994
7. Benabe JE, Martinez-Maldonado M: Disorders of Calcium Metabolism. In Narins RG (ed): Maxwell & Kleeman's Disorders of Fluid and Electrolyte Disorders. New York, McGraw-Hill, 1984, pp 1009-1044
8. Albrink MJ, Hald PM, Man EB, et al: The displacement of serum water by the lipids of hyperlipemic serum. J Clin Invest 1955;34:1481-1488
9. Tarail R, Buchwald KW, Holland JF, et al: Misleading reductions of serum sodium and chloride: Association with hyperproteinemia in patients with multiple myeloma. Proc Soc Exp Biol Med 1962;110:145-148
10. Popli S, Leehey DJ, Daugirdas JT, et al: Asymptomatic, nonketotic, severe hyperglycemia with hyponatremia. Arch Intern Med 1990;150:1962-1964
11. Uribarri J, Oh MS, Carroll HJ: Salt-losing nephropathy. Am J Nephrol 1983;3:193-198
12. Hariprasad MK, Eisinger RP, Nadler IM, et al: Hyponatremia in psychogenic polydipsia. Arch Intern Med 1980;140:1639-1642
13. Cooke CR, Turin MD, Walker WG: The syndrome of inappropriate antidiuretic hormone secretion (SIADH): Pathophysiologic mechanisms in solute and volume regulation. Medicine 1979;58:240-251
14. Fichman MP, Vorherr H, Kleeman CR, et al: Diuretic-induced hyponatremia. Ann Intern Med 1971;75:853-863
15. Macaron C, Famuyiwa O: Hyponatremia of hypothyroidism: Appropriate suppression of antidiuretic hormone levels. Arch Intern Med 1978;138:820-822
16. Arieff AI: Hyponatremia, convulsions, respiratory arrest and permanent brain damage after elective surgery in healthy women. N Engl J Med 1986;314:1529-1535
17. Palevsky PM, Bhagrath R, Greenberg A: Hypernatremia in hospitalized patients. Ann Intern Med 1996;124:197-203
18. Arieff AI, Carroll HJ: Nonketotic hyperosmolar coma with hyperglycemia. Clinical features, pathophysiology, renal function, acid-base balance, plasma cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine 1972;51:73-94
19. Halter JB, Goldberg AP, Robertson GL, et al: Selective osmoreceptor dysfunction in the syndrome of chronic hypernatremia. J Clin Endocrinol Metab 1977;44:609-616
20. Davson H: A Textbook of General Physiology (ed 2). Boston, Little, Brown, 1959
21. Blevins LS Jr, Wand GS: Diabetes insipidus. Crit Care Med 1992;20:69-93
22. Singer I, Forrest JN: Drug-induced states of nephrogenic diabetes insipidus. Kidney Int 1976;10:82-95
23. Schlant RC, Alexander RW (eds): The Heart (ed 8). New York, McGraw-Hill, 1994
24. Sterns RH, Cox M, Feig RU, et al: Internal potassium balance and the control of the plasma potassium concentration. Medicine 1981;60:339-354
25. Caruana RJ, Buckalew VM Jr: The syndrome of distal (type 1) renal tubular acidosis. Medicine 1988;67:84-99
26. Mulhausen R, Eichenholz A, Blumentals A: Acid-base disturbances in patients with cirrhosis of the liver. Medicine 1967;46:185-189
27. Blair E: Acid-base balance in bacteremic shock. Arch Intern Med 1971;127:731-739
28. Gabow PA, Anderson RJ, Potts DE, et al: Acid-base disturbances in the salicylate-intoxicated adult. Arch Intern Med 1978;138:1481-1484
29. Links TP, Smit AJ, Molenaar WM, et al: Familial hypokalemic periodic paralysis. J Neurol Sci 1994;122:33-43
30. Ober KP: Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine 1992;71:109-120
31. George JM, Wright L, Bell NH, et al: The syndrome of primary aldosteronism. Am J Med 1970;48:343-356
32. Estep H, Shaw WA, Watlington C, et al: Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab 1969;29:842-848
33. Tannen RL: Diuretic-induced hypokalemia. Kidney Int 1985;28:988-1000
34. Villoria JG, Nunez JFM, Miralles JM, et al: Hyporeninemic hypoaldosteronism in diabetic patients with chronic renal failure. Am J Nephrol 1988;8:127-137
35. Tan SY, Burton M: Hyporeninemic hypoaldosteronism: An overlooked cause of hyperkalemia. Arch Intern Med 1981;141:30-33
36. Tan SY, Shapiro R, Franco R, et al: Indomethacin-induced prostaglandin inhibition with hyperkalemia. A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 1979;90:783-785
37. Ponce SP, Jennings AE, Madias NE, et al: Drug-induced hyperkalemia. Medicine 1985;64:357-370
38. Cohen LF, Balow JE, Magrath IT, et al: Acute tumor lysis syndrome. A review of 37 patients with Burkitt's lymphoma. Am J Med 1980;68:486-491
39. Gabow PA, Kaehny WD, Kelleher SP: The spectrum of rhabdomyolysis. Medicine 1982;61:141-152
40. Goldfarb S, Cox M, Singer I, et al: Acute hyperkalemia induced by hyperglycemia: hormonal mechanisms. Ann Intern Med 1976;84:426-432
41. Wenger TL, Butler VP Jr, Haber E, et al: Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. J Am Coll Cardiol 1985;5:118A-123A
42. Bronson WR, DeVita VT, Carbone PP, et al: Pseudohyperkalemia due to release of potassium from white blood cells during clotting. N Engl J Med 1966;274:369-375
43. Graber M, Subramani K, Copish D, et al: Thrombocytosis elevates serum potassium. Am J Kidney Dis 1988;12:116-120
44. Zalago GP, Chernow B: Hypocalcemia in critical illness. JAMA 1986;256:1924-1929
45. Shils ME: Experimental human magnesium depletion. Medicine 1969;48:61-85
46. Ranson JHC: Etiological and prognostic factors in human acute pancreatitis. A review. Am J Gastroenterol 1982;77:633-638
47. Albright F, Reifenstein EC Jr: The Parathyroid Glands and Metabolic Bone Disease. Baltimore, Williams and Wilkins, 1948
48. Budayr AA, Nissenson RA, Klein RF, et al: Increased serum levels of parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med 1989;111:807-812
49. Muldowney FP, Carroll DV, Donohoe JF, et al: Correction of renal bicarbonate wastage by parathyroidectomy. Q J Med 1971;40:487-498
50. Lafferty FW: Pseudohyperparathyroidism. Medicine 1966;45:247-260
51. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. Medicine 1995;74:89-96
52. Law WM Jr, Heath H III: Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med 1985;102:511-519
53. Christensson T, Hellstrom K, Wengle B: Hypercalcemia and hyperparathyroidism: prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med 1977;137:1138-1142
54. Mallette LE, Eichhorn E: Effects of lithium carbonate on human calcium metabolism. Arch Intern Med 1986;146:770-776
55. Barbour GL, Coburn JW, Slatopolsky E, et al: Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981;305:440-443
56. Breslau NA, McGuire JL, Zerwekli JE, et al: Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann Intern Med 1984;100:1-7
57. Seymour JF, Gagel RF, Hagemeister FB, et al: Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 1994;121:633-640
58. Burman KD, Monchick JM, Earll JM, et al: Ionized and total serum calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976;84:668-671