normal anion gap

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    C li nic al B io ch em is tr y, F li nd er s Medica l Centre, Bedford Park,S ou th A us tr alia 5 04 2.R ec ei ve d A u gu st 10 ,1 9 84 ; a cc ep te d N ovem ber 5, 1984.

    CLINICALCHEMISTRY,Vol . 31, No. 2, 1985 309

    C LIN . C HE M, 31/2, 309-313 1985

    Norm al A nio n Gap H yp erch lo remic) A cido sisR . N . W alm sle y an d G . H . W h ite

    I

    H y pe rc hlo re m ic m e ta bo lic a cid os is in w h ic h t he a nio n g ap isw ith in n orm al lim its is a c om mo n co nd itio n in th e h os pita lpopu la tio n , and o ft en p resen ts a d if fic u lt d i agnos ti c p rob lem .W e d es cr ib e n in e t yp ic al c as es o f t h is d is or de r a nd s ug ge st alogical approach to i ts evalu a ti on .A lo w plasm a bicarbonate concentration represents, byde fin it io n , a metabolic a cid os is , w h ic h m a y be prim ary or

    can be secondary to a resp irato ry alkalosis. F urth er divisionof metabolic acidoses in to those with a high or a normalanion gap facilitates the etiological diagnosis of th is disor-der. An increased gap is associated with renal failure,ketoacido sis, lac tic a cido sis, an d ingestion of v ariou s to xins able 1).

    T ab le 1 . C au se s o f M e ta bo lic A cid os isH ig h -a nI on -g ap m e ta bo lI c a cl do sl sRenal fa i lure:acute ,chronicKetoacidosisLactic acidosis:L-lactate,D-lactateDrugs/toxins:salicylatemethanolethanolethyleneglycolparaldehydeNormal -an ion -gap hyperch lorem lc me tabo lI c ac idos isHyperkalemicEarly uremic acidosis

    O b st ru c ti ve u ro p at hyRenal t ubu la r ac idosis type 4:mineralocorticoid deficiencyp rimar y, s e conda ryt ubu le unrespons ivepo tass ium-spar ing d iure ti csinterstitialneph ntisl upus e rythema tosussicklecel lanemiarena l t ransp lantamyloidosispseudohypoaldosteronismIngest ions / in fusion: HCI , NH4CI , lys ine - , a rg in ine-HCID ia b et ic k et oa ci do s is : p o st -t he ra p yHypokalemicRenaltubularacidosis:type 1, type 2Carbonic anhydrase inhibi tion:acetazolamideAcutediarrheaUrinediversions:ureterosigmoidostomyvesico-colic f istulaobst ruc ted i lea l b ladderPost -h ypo capn ic a c id o sis

    Unlike an increased-anion-gap metabolic acidosis, thecause of which can usually be easily identified by inspectionof th e routine chemical resu lts for plasma and the clinicalpicture, th e e tio lo gic al diagnosis o f th e n orm al- an io n- ga ptype may in some cases require further la bo ra to ry in ve st ig a-tions. Patients w ith the latter type of metabolic acidosis alow bicarbonate concentration and a normal anion gap inplasma) may have either a primary re sp ir ato ry a lk alo sis ith a secondary m etabolic acidosis) or a p rim ary m etabo licacidosis, and the latter can be due to a variety of causes able 1).Here, w e describe nine cases of norm al anion gap acidosisrecently encountered in our hospital . Some of the casespresented a diagnostic problem , and we suggest a simpleinvestigative scheme that has proved helpful to us inevaluation of this b io ch em ic al a bn orm alit y.

    Note: A normal-anion-gap acidosis is often referred to ashyperchloremic metabolic acidosis, because so many pa -tients w ith the disorder have hyperchloremia. H ow ever, thelatter disturbance only occurs if the plasma sodium concen-tration is normal. If there is an a sso ciate d h yp on atre mia ,th e c hlo ri de concentration m ay be norm al or even low ; thus,we prefer the term norm al-anion-gap acidosis.The plasma anion gap AG) in the following cases hasbeen calculated from the concentrations of sodium , potassi-um , chloride, and bicarbonate in plasm a by the w idely usedformula 1 :AG, mmol/L = [Na] mmolJL + [K I mmolIL)

    - HC03] mmol/L + [C l] m mol/L)Case Presentat ionCase 1A 45-year-old woman presented w ith a long history of

    malaise , nausea, and loss of energy. She also complained ofheadaches and rheumatism, for which she had beentak ing various analgesic preparations. Her plasm a electro-lyte values on adm ission are shown in Table 2.

    T ab le 2. P lasm a A nalyte Valu es In C ase 1PlasmaNaHC03UreaCreatinineAnion ga pBlood gasespHPco2

    Units Reference In terva ls141 mmol/L 132-144)5.7 m mol/L 3.2-4.8115 mmol/L 98-108)17 mmol/L 23-33)21 m mol/L 3.0-8.00.21 mmol /L 0.06-0.12)15 mmol /L 7-17)

    7.29 - 7.35-7.4537 mmHg 35-45In the tablesthat f o ll ow , the un it s and referenceintervalsare as above.

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    Tab le 3. Plasm a A nalyte V alu es in C ase 2+1AdmIssion day

    PlasmaNaKCIHCO3UreaCreatinineA nio n g apBlood gasespHPco2

    137 1425.4 5.0111 11419 1820.7 15.50.61 0.2912 157.3336

    T ab le 4 . P la sm a a nd U rin ary A naly te V alu es inCase3days Plasma

    Na 12713 5 K 744.8 C l 100103 HC03 1924 Urea 18.7

    9.0 Creatinine 0.220.15 Anion gap 1513 Blood gasespH 7.36- PCO2-. U rinary pH 4.7

    31 0 C LIN IC AL C HE MIS TR Y, Vo l. 31, No. 2, 1985

    The urinary pH o n a dm is sio n was 4.5 , her creatin ineclearance 26 m L/m in refe ren ce interval 90-130 m L/m in).

    F in al d iag nosis: Chronic renal insufficiency ow ing toan alg esic n ep hro path y,

    Comnient: A characteris tic b iochem ica l feature of ad-vanced renal fa ilure is a high-anion-gap m etabolic acidosisconsequent to tubular dysfunction retention of H f an ddecreased glom erular filtration rate retention of acid an-ions). However, H is not retained by the kidneys inuncomplicated renal insufficiency until late in the diseaseprocess, and usually not before the glomerular filtrationrate GFR) declines to less than about 20 mL/m in 2 or theplasm a creatinine concentration increases above about 0 .35m mol/L --4.0 m g/dL ).In diseases that predom inantly affect the renal medullasuch as in terstitial nephritis, pyelonephritis, cystic disease,and analgesic nephropathy, distal nephron function is com -prom ised early in the disease process. In these cases Hexcretion m ay be sufficien tly decreased as to resu lt in ametabolic acidosis long before the dim inishing glomerularfunction is decreased enough to produce a plasma creatin ineconcent ra ti on > 0 .3 5 mmolIL . Indeed, there is o ften suffi-cient g lomeru la r func t ion to clear the plasm a of endogenous-ly produced ac id an ions phosphate, sulfate, etc.) norm allyan d thus resu lt in a norm al-anion-gap m etabolic acidosis.Potassium homeostasis in progressive renal failure fol-low s a sim ilar pattern to that of H , i.e., K retention tendsnot to occur until the GFR falls below about 20 mL/m in, and

    so hyperkalem ia is rare in renal fa ilure patients w ith aplasma creatinine concentration 0.35 mmol/L), indicating a severe drop inthe G FR , they often have a normal plasma anion gap, whichsuggests adequate clearance of plasma acid anions. Insevere prolonged obstruction, however, the plasma aniongap is usually increased and m ay be associated with anormal-or occasionally a high-chloride concentration inplasma. This p lasma electro lyte disorder has been termed amixed hyperchloremic high-anion-gap metabolic acidosis 5 .As shown in the above case the abnorm al plasma bio-chem istry of obstructive uropathy usually starts to resolve

    when the obstruction is relieved, but may take severalw eek s to no rm alize.

    Case 3A 67-year-old man was adm itted to hospital fo r i nves ti ga -

    tion of general malaise and hyperkalem ia plasma [K J of7 ,0 mmol IL ), which w as noted on a biochem ical screen.The values at adm ission for plasma are shown in Table 4. Aplasm a cortiso l value before adrenocortical stim ulation was229 nmol/L reference interval 170-690); 30 mm afterstim ulation w ith Synacthen it was 224 nmolJL norma lresponse is a rise exceeding 200 nmoltL over basal level).

    F in al d ia gn osis : Primary adrenal failure Addisons dis-ease).Comment : The m ineralocorticoid aldosterone not onlyincreases reabsorption of Na + and secretion of K by thedistal renal tubule, it is a ls o as so ciate d w ith W secretion inthis portion of the nephron 6). A ldosterone increases Hsecretion and excretion) by the fol lowing mechanisms: aincreases conductance of protons by the dista l nephronm ainly collecting-duct) cell proton pum p; b increases thenegative potential in the tubular lumen, necessary forefficient secretion of H an d K, by increasing Na reab-sorption; and c) increases ammonia synthesis directly , andalso indirectly by increasing K excretion hypokalem ia is apotent stimulus fo r a mm on ia sy nthesis . Hypoaldosteronismis therefore associated with renal re tention of both H andK and c an re su lt in hyperkalem ic m etabolic acidosis.

    The GFR i n hypoaldos te ron ism may be decreased to som eextent, ow ing to d eh yd ra tio n s ec on da ry t o s o d iu m d ep le ti on ,but it is usually suffic ien t to clear the plasma of theendogenous acid anions; thus the metabolic acidosis ofprimary a dre na l fa ilu re is usual ly o f t he n orma l- an io n- ga pvariety.

    A lt ho ug h t he se p at ie nt s ha ve a d ef ec ti n t he r en al e xc re -tion of IF , they still have an intact proton-secreting m echa-nism and are thus able to secrete sufficient H so as todecrease th e urinary pH to

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    1305. 311 0

    1294. 9114

    15 12. 8

    92527. 50.14107.56

    Case 4

    CLINICALCHEMISTRY,Vol . 31, N o. 2, 1985 31 1

    A man, 38 years of age, was having continuous gastricsuction because of a small-bowel obstruction related to acutepancreatitis. The loss of gastric ju ice resulted in a severepersistent h yp oka le mic m etab olic alkalosis first set of val-ues, Table 5), which was difficult to control. To relieve thisalkalosis he was given an in fu sio n o f HC1 se t 2, Table 5) ,which unfortunately was made 1.0 mol/L rather than 0.1mol/L.

    Comment : Infusion or ingestion) of HC1 or compoundsthat ar e m etabolized to HC1 e.g ., N H4 C1 , arginine HC 1, a ndlysine HC1), if given in sufficient quantities w ill result in ahyperchlorem ic m etabolic acidosis, i.e., consumption ofextracellular HCO by H and its replacement by C.Acidem ia affects potassium m etabolism in tw o ways: a) itreleases intracellular po tassium i ons , wh ich a re e xc ha ng ed

    fo r extracellular hydrogen io ns, a nd th is can result inhyperkalem ia; and b) it increases renal po tassium excr e-tion, which can result in potassium depletion.The acidemia-induced re le as e o f c ellu la r p ota ss iu m de-pends on the nature of the acid anions. If the anion is C1e.g., hyperchloremic acidosis) H is exchanged across thecell membrane for K because C1 is not easily taken up bycells. On the other hand, if the acid anions are organic innature e .g ., l actate or acetate th e hydrogen ions are takenup by the cell in a ss oc ia tio n with t he ir co rr espond inga nio ns , w hic h r ead il y c ro ssce ll m em b ranes , an d th ere is n oex tr ace ll ula r m ovem en t of potassium ions 3 . T hus hy per-kalem ia can be associated w ith HC1- in du ce d acidemia, bu tis unusual w ith organic acid-induced acidemia.In th e e ar ly s ta ge s o f a cid em ia m e ta bo lic o r re sp i ra to ry )th ere is decreased renal K excretion, possibly because of a

    decreased cell concentration of this io n exchange withextracellular H) in the renal tubular cell. However, inp ro lo ng ed a cid em ia th ere is increased renal potassium ex -cretion, ow ing to increased distal renal tubular flow rate.Th is in cr ea sed flow rate results from decreased reabsorptionof Na in th e proximal r en al t ub ule 8 .Case 5The clinical chem ical results for plasma shown in Table 6

    are those of a 36-year-old female diabetic. The first set ofresu lts are the adm ission values; the second set a re th os eafter 8 h o f i nt ra ve no u s therapy, which included saline,insulin 2 mt. u nits p er h ou r , a nd potassium supplements.

    Comment: D ia be tic k et oa cid os is usually presents w ith ahigh-anion-gap m etabolic acidosis, the increased gap beingascribable to the anions acetoacetate and hydroxybutyrateketone bodies). O ccasionally th is disorder may presentw ith a norm al-anion-gap hyperchlorem ic) metabolic acido-s is, a nd this typ e o f ac idos is m ay also occur during therapywith fluids and insulin. T he m echanism of the hyperchlore-m ia is related to t he pa tien ts h ydr at io n s ta tu s , i n pa rt icu la rto the reabsorption of sodium in the proximal renal tubule.

    T ab le 5. Plasm a A nalyte V alues in C ase 4PlasmaNaC1HCOUreaCreatinineAn ion gapBlood gasespH

    Sefl

    Pco, 59

    T ab le 6. P lasm a A nalyte Valu es In C ase 5Seti Set2

    PlasmaNaCLHC03UreaCreatinineAnion gapGlucoseBlood gasespHPco2

    Re f. i nt er val 3 .0 - 5. 5 mmol /L .

    4 66.0 3.70.18 0.1621 1419.2 13.Oa7.03 7.1015 20

    If the patient is severely dehydrated there is avid proxi-mal r ena l t ubu la r r eabso rp ti on of sodium ions. T his encour-ages-in t he in te re s t of electroneutral i ty-reabsorption ofk eto -anio ns and thus ma intenance of the high anion gap inplasma. D u rin g t he ra py w ith saline and insulin there isrete ntio n o f N aC l s o t ha t th e e xp an din g e xtra ce llu la r v ol-u m e d ec re as es th e p ro xim a l tu bu le re ab so rp tio n o f sodiumand keto-anions, which are then lost in the urine. Insummary, Na a nd k eto -a nio ns a re lo st from the body andreplaced with Na and Cl, resulting in hyperchloremia.

    Recove ry f rom thi s type o f a c id os is i s s lo w er t ha n f ro m t heh igh -an ion -gap vari ety , because in the l a tt e r s ituat ion th eretained keto-anions are taken up by the cells along w ithH , under the influence of i nsu li n, r esu lt ing in the genera-tio n o f extracellularb ica rbona te . In t he f orm er case , b ecauseth e keto-anions are lost in th e u rin e, b ic arb on ate can begenerated only by the kidney. This can take considerabletim e, a nd th e p atien t will o ft en r eq uir e in tr av en ou s b ic ar -bonate supplementation in order to normalize his acid-bases ta tu s 9 .Case 6

    Th e first se t of values show n in Table 7 w ere those for a70-year-old man w ith a vesico-col ic fistu la secondary to ana de no ca rc in om a o f t he c olo n.Comment : W hen urine is diverted into th e large gut ureterosigmoidostomy, vesico-col ic f istula , a nd re ma in s in

    p ro longed con tac t with th e m uc osae, th ere is r eabso rp ti on o fw a te r a nd c hlo rid e a nd s ec re tio n o f bicarbonate and po tassi-um 1 0 . The result is a hypokal em ic norma l-anion -gapmetabol ic ac idos is . The urete ros igmo idos tomy procedure israrely performed these days; rather, the ureters, if theyrequire diversion, are im p la nt ed in to an exteriorized ileallo op . O b st ru ct io n o f t his ileal bladder will also result inb io ch em ic al a bn orm alitie s s im ila r to th os e in c as e 6 .Case 7A woman, 66 years old, was treated w ith oral acetazola-

    m ide 250 mg twice daily) and epinephrine eye drops fora cu te g la uc om a. Blood sampled three days later Table 7)showed a h yp ok alem ic no rm al-an io n-gap m etab olic acid osis.

    2 Comment : A ceta zola mide in hibits carbon ate d ehy drataseEC 4.2.1.1) activ ity both w ithin the proxim al renal tubular15 2 celland at itsbrush border. T his h as th e effect o f suppress -6.0 ing H se cre tion . T hus r eabso rp ti on o f HCO is inhibited13 4 and it is lost in th e urine as NaHCO3 1 0 . The consequent12 hypovo lem ia sodium d ep le tio n) c au se s increased renal tu -

    12.9 bular reabsorp tion of Na and C l and this resu lts in a0.18 hyperchlorem ic me tab ol ic a ci do si s- i. e. , Na and HCO are12 lost in the urine a nd rep lac ed in th e extracellular flu id by7.18 NaCl dietaryN aC l a nd th at re ab so rb ed by the kidney).This acidosis, which is sim ilar in nature to prim ary

    proxim al re nal tubular acidosis, is self-lim iting: w hen th e

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    14 52.912 6

    1313.60.099

    13 92. 8

    11 2196. 50.1111

    13 71. 7120118. 40.1887.2127

    312 C LIN IC AL C HEM ISTR Y, Vol. 31, No. 2, 1985

    plasma bicarbonate declines to a certain concentration-14-15 mmol lL) the tubules can then reabsorb all that ispresented by the glom eruli. D istal tubular function rem ainsin ta ct in th es e c as es , an d if th e p atie nt i s cha ll enged by ana cid lo ad e.g., NH4C 1) h e i s ab le t o a ci di fy h i s u r ine to belowpH 5.3 c f. Case 9).The hypokal em ia seen in th es e p atie nts is a ttrib uta ble toin c reased r ena l po tassium lossconsequen t t o th e increaseddistal re na l tu bu la r u rin e flo w ra te in du ce d b y th e h ig h lo adof NaHCO3 in th e tu bu le s.Case 8

    A 4 4-y ea r-o ld m an presented with a two-day h is to ry o fa cu te s ev ere d ia rrh ea . H e w as m od era te ly dehydrated andhad a hypokalem ic norm al-anion-gap m etaboli c ac idosisTable 7) .

    Comment : D uring acute diarrhea th ere is lo ss o f w ater,sodium, b ica rbona te , and potass ium in the fecalf lu id . T hisresultsin a dehydration and contraction of the extracellu-la r f lu id around the rem aining sodium and chloride produc-in g hyperchloremia, b hypobicarbonatem ia m etabolic aci-d os is ), a nd c potassium depletion. The dehydration hypo-volemia also results in increased renal reabsorption ofNaC I and re tention of an y N aCl ingested the sodium l ost asNaHCO3 in the diarrhea flu id is replaced by NaC1 and thisfurther accentuates the hyperchloremia) and in secondaryhyperaldosteronism, whic h in cr ea se s K excretion by thekidney and thus worsens th e p ota ss iu m d ep le tio n.Patients w ith HC03 depletion du e to diarrhea are able

    to replete it in their p lasma only by renal generation of newbicarbonate . This may take several days, and thus suchpatients will usually require intravenous th era py w ithbicarbonate if their acidosis is severe.Case 9A 60-year-old man was adm itted to hospital with a four-

    w ee k h is to ry o f i ncreasing mu sc le w ea kn es s and lethargy.His plasm a and urinary biochem istry values Table 7)suggested a distal renal tubular acidosis, which was laterconfirmed by f ur th e r i nve st ig a ti on s .

    Comment : In classical d istal renal tubular acidosis thereis an inability of the dista l nephron mainly the collectingducts) to secrete H ; thus regeneration of the HC03consumed during the normal buffering of endogenouslyp ro du ce d a cid s d oe s n ot o cc ur a nd h yp ob ic arb on ate miaresults 7 . T he d ec re as ed re na l tu bu la r H secretion alsoin du ce s in cr ea se d r en al sodium loss decreased Na-Hexchange), which will re su lt in w ate r lo ss an d hypovolemia.The hypovo lem ia causes increased NaCl reabsorption in theproxim al nephron as w ell as retention of any ingested

    T ab le 7. P la sm a A na ly te V alu es in Cases 6- 9Case 6 7 8 9

    PlasmaNa 13 4K* 2.9CL 11 3HC03 16Urea 12.3Creatinine 0.30Anion gap 8Blood gasespH 7.31 7.31 7.31Pc oUrMe 26 38 33Na - - - 42 mmoIfLK - - - 24 mmol/LpH - 5.7 4.4 7.0

    NaCl . Thus h yp er ch io re mi a d ev el op s i n a ss oc ia ti on w it ht he a bn or ma l p la sm a b ic ar bo na te c on ce nt ra ti on .Patients with this type o f r en al t ub ula r a cid os is , u nlik ethose with the proxim al-tubular variety, are unable tomaintain a h ig h h yd ro ge n io n gradient across th e renaltubule cell m em branes and therefore w ill not be able tolo w er t he ir urinary pH to

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    + P LA SM A IH CO I + pH

    A NIO N G AP

    ii IEXCLUDE Renal failure

    Respi ra tory alkalosis Ketoacidosisclinicalb lood gases Lact ic ac idos is

    Ing estion s T ab le 1PLASMA IKI

    N-.-4 I IE a rl y u rem ic ac idosis EXCLUDEObstructive uropathy Vesico-colic fistulaDiabetic ketoacidosis U reterosigmoidostomy

    M ineralocortico id deficiency Obstructed ilea l bladderIngestions/ infusions Table 2

    F UR INE pHduring ac idem ia5.3

    P ro xim al R TAA c ut e d ia rr he a

    P o st -h y po ca p ni c a ci do si sCarbonic anhydrase inhib ition D istal RTAFigure 1 . Sugges ted s ch em e f or t he e va lu at io n o f a n o rm a l a n io n ga pmetabolic acidosisRTA:rena l tubu laracidosis

    CLIN ICAL CHEM ISTRY , Vol. 31, No. 2, 1985 31 3

    Plasma lactate and ketones: In the absence of severe renalfailure plasma creatinine concentration >0.4 mmol /L) ahigh-anion-gap a cid osis in dic ates ke toa cid osis, la ctic acid o-s is , o r an acidosis due to ingestion of some toxin Ta ble 1 .Estim ation of plasma lactate or kethnes, or both, aids inevaluation o f th es e cases if the pathophysiology is unclear.

    Urinary acidification test: The defin itive diagnosis ofrenal tubular acidosis requires investigation of the renalresponse to acidem ia, e .g ., estimation of H and ammoniumion excretion after an ammonium chloride load. However, ifthe patient is already acidem ic pH 5.3indicates classical d ista l renal tubular acidosis type 1). ApH