The causes of magnesium depletion and hypomagnesemia are decreased gastrointestinal (GI) absorption and increased renal loss. Decreased GI absorption is frequently due to diarrhea, malabsorption, and inadequate dietary intake. Common causes of excessive urinary loss are diuresis due to alcohol, glycosuria, and loop diuretics. Medical conditions putting persons at high risk for hypomagnesemia are alcoholism, congestiveheart failure, diabetes, chronic diarrhea, hypokalemia, hypocalcemia, and malnutrition (strength of recommendation: C, based on expert opinion, physiology, and case series). Evidence suggests that magnesium deficiency is both more common and more clinically significant than generally appreciated

Latessa, Robyn A.

Mouw, David R.

Sullo, Elaine J.

University of Missouri: MOspace

C L I N I C A L  I N Q U I R I E S174 FEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practicecare by medical staff and compliance bypatients. Additionally, monitoring has sec-ondary benefits; it reinforces the risks asso-ciated with warfarin, and it provides furtheropportunities to educate the patient.Rick Guthmann, MD, Advocate Illinois MasonicMedical CenterWhat are the causes of hypomagnesemia? ■ EVIDENCE-BASED ANSWERThe causes of magnesium depletion and hypo-magnesemia are decreased gastrointestinal(GI) absorption and increased renal loss.Decreased GI absorption is frequently due to diarrhea, malabsorption, and inadequatedietary intake. Common causes of excessiveurinary loss are diuresis due to alcohol, glyco-suria, and loop diuretics. Medical conditions putting persons at highrisk for hypomagnesemia are alcoholism, con-gestive heart failure, diabetes, chronic diarrhea,hypokalemia, hypocalcemia, and malnutrition(strength of recommendation: C, based onexpert opinion, physiology, and case series).Evidence suggests that magnesium deficiencyis both more common and more clinically significant than generally appreciated. ■ EVIDENCE SUMMARY Prevalence and incidence. In general, studiesare limited by variations in analytic techniquesand differences in defining the lower limit fornormal serum magnesium.1 Estimates of theprevalence of hypomagnesemia in the generalpopulation range from 2.5% to 15%. A study of11,000 white urban Americans aged 45 to 64years (probability sampling) found 2.5% withmagnesium <0.7 mmol/L and 5% with magne-sium <0.75 mmol/L; rates for 4000 AfricanAmericans were twice as high.2Some authors have proposed a higher rangefor normal serum magnesium, asserting thatdietary magnesium deficiency is endemic indeveloped countries where acid rain reduces themagnesium content of crops and food processingcauses further large reductions in the magne-sium content of the diet.1 Moreover, common dis-eases are associated with hypomagnesemia andlikely contaminate studies of “normal” popula-tions. Thus, a study of 16,000 German subjects(including blood donors, outpatients, and chil-dren) found a 14.5% prevalence of hypomagne-semia using a lower limit of 0.76 mmol/L1; how-ever, applying the more commonly cited lowerlimit of 0.70 mmol/L (1.7 mg/dL) to the samedata yielded a prevalence of 2%.Numerous studies agree that the prevalenceof hypomagnesemia is much higher (10%–65%)in subpopulations defined by severity of illness(hospitalization, in intensive care unit [ICU] orpediatric ICU), increasing age (elderly/in nurs-ing home), or specific diseases. For example, of94 consecutive patients admitted to the ICU,65% had hypomagnesemia.3 Likewise, for 127consecutive patients admitted with a diagnosisof alcoholism, the prevalence was 30%.4Because of limitations noted above, as wellas the lack of control groups, the relativeprevalence in these groups (compared with thegeneral population) is uncertain, but the stud-ies do identify high-risk populations. A singlestudy, which included a control group, demon-strated an 11% prevalence of hypomagnesemiaamong 621 randomly selected hospitalizedpatients compared with 2.5% among 341 hospi-tal employees.5 Other diseases associated witha high prevalence of hypomagnesemia includecardiovascular disease (hypertension, conges-tive heart failure, coronary artery disease), diabetes, diarrhea, diuretics use, hypokalemia,hypocalcemia, and malabsorption.6–9Common causes. We found no high-qualitystudies to establish the relative probabilities ofvarious causes in the general population or anysubpopulation.10 The most common causes ofsignificant hypomagnesemia in developed coun-C L I N I C A L  I N Q U I R I E SFEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practice 175C O N T I N U E Dtries are said to be diabetes, alcoholism, andthe use of diuretics. In a group of 5100 consec-utive patients (predominantly outpatient, middle-aged, and female) presenting to a diag-nostic lab, the most common diagnoses associ-ated with hypomagnesemia were diabetes (20%of cases) and diuretic use (14% of cases); however, other potential causes, including alcoholism, were not identified.11 A completelist of causes is in the Table.Serious causes. A critical serum magnesiumlevel is less than 0.5 mmol/L and is associatedwith seizures and life-threatening arrhythmias.6Very low magnesium levels typically resultwhen an acute problem is superimposed onchronic depletion. For example, critical levelscan occur among patients with diabetes duringcorrection of ketoacidosis or alcoholics whodevelop vomiting, diarrhea, or pancreatitis. Magnesium in the 0.5 to 0.7 mmol/L rangemay be life-threatening in certain disease contexts, such as acute myocardial infarction or congestive heart failure, where there isalready a risk of fatal arrhythmia.8Impact. The impact of hypomagnesemia is underestimated largely because clinicians fail to measure magnesium.12 Since magnesiumis a cofactor for more than 300 enzymes and is involved in numerous transport mechanisms,it is not surprising that hypomagnesemia isassociated with significant morbidity. For example, in a study of 381 consecutiveadmissions at an inner-city hospital,13 approxi-mately half the admissions went to ICUs andhalf to regular wards. Despite similar AcutePhysiology and Chronic Health Evaluator(APACHE) scores at admission, hospital mor-tality was twice as high for hypomagnesemicpatients in both care settings.■ RECOMMENDATIONS FROMOTHERSSeveral review articles include a compre-hensive differential diagnosis for causes ofCauses of hypomagnesemiaGastrointestinalDiarrhea, dietary deficiency (including protein-calorie malnutrition, parenteral and enteral feeding with inadequate magnesium, alcoholism, and pregnancy), familial magnesium malabsorption, gastrointestinal fistulas, inflammatory bowel disease, laxative abuse, malabsorption (sprue, steatorrhea, chronic pancreatitis), nasogastric suction, surgical resection, vomitingRenalAlcoholism, diabetes, diuretics (thiazide, loop, and osmotic/hyperglycemia), other medications, hormones (hypoparathyroidism, hyperthyroidism, hyperaldosteronism, SIADH (syndrome of inappropriate antidiuretic hormone secretion), excessive vitamin D, ketoacidosis, renal disease (acute tubular necrosis, interstitial nephritis, glomerulonephritis, post-obstructive diuresis, post-renaltransplantation), hypercalcemia/hypophosphatemia, tubular defects (primary magnesium wasting,Welt’s syndrome, Gitelman’s syndrome, renal tubular acidosis)Shifts from extracellular to intracellular fluidAcidosis (correction of), blood transfusions (massive), epinephrine, hungry bone syndrome, insulin/glucose/refeeding syndrome, pancreatitis (acute)Transdermal lossesExcessive sweating, massive burnsTA B L EC L I N I C A L  I N Q U I R I E S176 FEBRUARY 2005 / VOL 54, NO 2 · The Journal of Family Practicemagnesium deficiency based on physiologicprinciples as listed in the Table, but none provide data on the relative frequency of thevarious causes in the general population or specific subgroups.6–9David R. Mouw, MD, PhD, Robyn A. Latessa, MD,University of North Carolina, MAHEC Family PracticeResidency, Asheville, NC; Elaine J. Sullo, MLS, East Carolina University, Laupus Library, Greenville, NC■ CLINICAL COMMENTARYWe need to know when magnesiumreplacement improves patient outcomesTreating the underlying cause of hypomagne-semia makes sense. However, even though cli-nicians often treat “the numbers,” it is not clearthat magnesium replacement therapy is benefi-cial in the absence of symptoms caused by thehypomagnesemia. For example, hypomagne-semia is common for patients with acutemyocardial infarction, but magnesium replace-ment therapy has not been shown to improveoutcomes in 2 large randomized trials, theFourth International Study of Infarct Survival(ISIS 4)14 and Magnesium in Coronaries(MAGIC).15 We need better-designed random-ized trials to know for what clinical conditionsmagnesium replacement leads to improvedpatient-oriented outcomes. John Hickner, MD, MSc, Department of FamilyMedicine, The University of Chicago Pritzker School of Medicine, Chicago, IllREFERENCES1. Schimatschek HF, Rempis R. Prevalence of hypomagne-semia in an unselected German population of 16,000 indi-viduals. Magnes Res 2001; 14:283–290.2. Ma J, Folsom AR, Melnick SL, et al. Associations of serumand dietary magnesium with cardiovascular disease,hypertension, diabetes, insulin, and carotid arterial wallthickness: the ARIC study. Atherosclerosis Risk inCommunities Study. J Clin Epidemiol 1995; 48:927–940.3. Ryzen E, Wagers PW, Singer FR, Rude RK. Magnesiumdeficiency in a medical ICU population. Crit Care Med1985; 13:19–21. 4. Elisaf M, Merkouropoulos M, Tsianos EV, SiamopoulosKC. Pathogenic mechanisms of hypomagnesemia in alco-holic patients. J Trace Elem Med Biol 1995; 9:210–214. 5. Wong ET, Rude RK, Singer FR, Shaw ST Jr. A high preva-lence of hypomagnesemia and hypermagnesemia in hospi-talized patients. Am J Clin Pathol 1983; 79:348–353. 6. Topf JM, Murray PT. Hypomagnesemia and hypermagne-semia. Rev Endocr Metab Disord 2003; 4:195–206.7. Whang R, Hampton EM, Whang DD. Magnesium home-ostasis and clinical disorders of magnesium deficiency.Ann Pharmacother 1994; 28:220–226.8. Kelepouris E, Agus ZS. Hypomagnesemia: renal magne-sium handling. Semin Nephrol 1998; 18:58–73. 9. Dacey MJ. Hypomagnesemic disorders. Crit Care Clin2001; 17:155–173.10. Richardson WS, Wilson MC, Guyatt GH, Cook DJ,Nishikawa J. Users’ Guides to the Medical Literature: XV.How to use an article about disease probability for differ-ential diagnosis. Evidence-Based Medicine WorkingGroup. JAMA 1999; 281:1214–1219. 11. Jackson CE, Meier DW. Routine serum magnesium analy-sis. Correlation with clinical state in 5,100 patients. AnnIntern Med 1968; 69:743–748.12. Whang R, Ryder KW. Frequency of hypomagnesemia andhypermagnesemia. Requested vs routine. JAMA 1990;263:3063–3064.13. Rubeiz GJ, Thill-Baharozian M, Hardie D, Carlson RW.Association of hypomagnesemia and mortality in acutelyill medical patients. Crit Care Med 1993; 21:203–209.14. ISIS-4 (Fourth International Study of Infarct Survival)Collaborative Group. ISIS-4: a randomised factorial trialassessing early oral captopril, oral mononitrate, and intra-venous magnesium sulphate in 58,050 patients with sus-pected acute myocardial infarction. Lancet 1995;345:669–685. 15. Magnesium in Coronaries (MAGIC) Trial Investigators.Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in theMagnesium in Coronaries (MAGIC) Trial: a randomisedcontrolled trial. Lancet 2002; 360:1189–1196. What are effective therapiesfor Clostridium difficile–associated diarrhea?■ EVIDENCE-BASED ANSWEROral metronidazole and oral vancomycin areequally effective treatments for Clostridium dif-ficile–associated diarrhea (CDAD) (strength ofrecommendation [SOR]: A, based on random-ized trials). Oral vancomycin is considerablymore expensive and may select for colonizationwith vancomycin-resistant enterococci, leadingthe American College of Gastroenterology torecommend oral metronidazole as preferredtherapy (SOR: C, expert opinion). They recom-mend therapy with vancomycin for those whoare pregnant, breast feeding, less than 10

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