asidosis metabolik

46
Introduction Background Understanding the regulation of acid-base balance requires appreciation of the fundamental definitions and principles underlying this complex physiologic process. Basic definitions An acid is a substance that can donate hydrogen ions (H + ), and a base is a substance that can accept H + ions, regardless of the substance's charge. H 2 CO 3 (acid)«H + + HCO 3 - (base) Strong acids are those that are completely ionized in body fluids, and weak acids are those that are incompletely ionized in body fluids. HCl«H + + Cl - Hydrochloric acid (HCl) is considered a strong acid because it is present only in a completely ionized form in the body, whereas H 2 CO 3 is a weak acid because it is ionized incompletely, and, at equilibrium, all 3 reactants are present in body fluids. The law of mass action states that the velocity of a reaction is proportional to the product of the reactant concentrations. H 2 CO 3 (acid)«H + + HCO 3 - (base) On the basis of this law, the addition of H + or bicarbonate (HCO 3 - ) drives this reaction to the left. In body fluids, the concentration of hydrogen ions ([H + ]) is maintained within very narrow limits, with the normal physiologic concentration being 40 nEq/L. The concentration

Upload: sucifitridr

Post on 15-Oct-2014

78 views

Category:

Documents


1 download

TRANSCRIPT

Page 1: asidosis metabolik

Introduction

Background

Understanding the regulation of acid-base balance requires appreciation of the fundamental definitions and principles underlying this complex physiologic process.

Basic definitions

An acid is a substance that can donate hydrogen ions (H+), and a base is a substance that can accept H+ ions, regardless of the substance's charge.

H2 CO3 (acid)«H+ + HCO3 - (base)

Strong acids are those that are completely ionized in body fluids, and weak acids are those that are incompletely ionized in body fluids.

HCl«H+ + Cl-

Hydrochloric acid (HCl) is considered a strong acid because it is present only in a completely ionized form in the body, whereas H2 CO3 is a weak acid because it is ionized incompletely, and, at equilibrium, all 3 reactants are present in body fluids.

The law of mass action states that the velocity of a reaction is proportional to the product of the reactant concentrations.

H2 CO3 (acid)«H+ + HCO3 - (base)

On the basis of this law, the addition of H+ or bicarbonate (HCO3 -) drives this reaction to the left.

In body fluids, the concentration of hydrogen ions ([H+]) is maintained within very narrow limits, with the normal physiologic concentration being 40 nEq/L. The concentration of HCO3 - (24 mEq/L) is 600,000 times that of [H+]. The tight regulation of [H+] at this low concentration is crucial for normal cellular activities because H+ at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function. Under normal conditions, acids and, to a lesser extent, bases are being added constantly to the extracellular fluid compartment, and for the body to maintain a physiologic [H+] of 40 mEq/L, the following 3 processes must take place:

Buffering by extracellular and intracellular buffers Alveolar ventilation, which controls PaCO2 Renal H+ excretion, which controls plasma [HCO3 -]

Buffers

Page 2: asidosis metabolik

Buffers are weak acids or bases that are able to minimize changes in pH by taking up or releasing H+. Phosphate is an example of an effective buffer, as in the following reaction:

HPO4 2- + (H+)«H2 PO4 -

Upon addition of an H+ to extracellular fluids, the monohydrogen phosphate binds H+ to form dihydrogen phosphate, minimizing the change in pH. Similarly, when [H+] is decreased, the reaction is shifted to the left. Thus, buffers work as a first-line of defense to blunt the changes in pH that would otherwise result from the constant daily addition of acids and bases to body fluids.

HCO3 -/H2 CO3 buffering system

The major extracellular buffering system is HCO3 -/H2 CO3; its function is illustrated by the following reactions:

H2 O + CO2 «H2 CO3 «H+ + HCO3 -

One of the major factors that makes this system very effective is the ability to control PaCO2 by changes in ventilation. As can be noted from this reaction, increased carbon dioxide (CO2) concentration drives the reaction to the right, whereas a decrease in CO2 concentration drives it to the left. Put simply, adding an acid load to the body fluids results in consumption of HCO3 - by the H+ added and the formation of carbonic acid, which, in turn, forms water and CO2. CO2 concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO2. The kidneys regenerate the HCO3 - consumed during this reaction.

This reaction continues to move to the left as long as CO2 is constantly eliminated or until HCO3 - is significantly depleted, making less HCO3 - available to bind H+. That HCO3 - and PaCO2 can be managed independently (kidneys and lungs, respectively) makes this a very effective buffering system. At equilibrium, the relationship between the 3 reactants in the reaction is expressed by the Henderson-Hasselbalch equation, which relates the concentration of dissolved CO2 (ie, H2 CO3) to the partial pressure of CO2 (0.03 X PaCO2) in the following way:

pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2)

Alternatively, [H+] = 24 X PaCO2/[HCO3 -]

Note that changes in pH or [H+] are a result of relative changes in the ratio of PaCO2 to [HCO3 -] rather than to absolute change in either one. In other words, if both PaCO2 and [HCO3 -] change in the same direction, the ratio stays the same and the pH or [H+] remains relatively stable. To diminish the alteration in pH that occurs when either HCO3 -

or PaCO2 changes, the body, within certain limits, changes the other variable in the same direction.

Page 3: asidosis metabolik

In chronic metabolic acidosis, intracellular buffers (eg, hemoglobin, bone) may be more important than HCO3 - when the extracellular HCO3 - level is low.

Renal acid handling

Acids are added daily to the body fluids. These include volatile (eg, carbonic) and nonvolatile (eg, sulfuric, phosphoric) acids. The metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO2 per day, which is excreted by the lungs. Failure to do so results in respiratory acidosis (see Respiratory Acidosis). The metabolism of proteins (ie, sulfur-containing amino acids) and dietary phosphate results in the formation of nonvolatile acids, H2 SO4 and H3 PO4. These acids first are buffered by the HCO3 -/H2 CO3 system as follows:

H2 SO4 + 2NaHCO3 «Na2 SO4 + 2H2 CO3 «2H2 O + CO2

The net result is buffering of a strong acid (H2 SO4) by 2 molecules of HCO3 - and production of a weak acid (H2 CO3), which minimizes the change in pH. The lungs excrete the CO2 produced, and the kidneys, to prevent progressive HCO3 - loss and metabolic acidosis, replace the consumed HCO3 - (principally by H+ secretion in the collecting duct). Some amino acids (ie, glutamate, aspartate) result in the formation of citrate and lactate, which, in turn, will be converted to HCO3 -. The net result, in a typical American diet, is an acid load in the range of 50-100 mEq of H+ per day.

To maintain normal pH, the kidneys must perform 2 physiological functions. The first is to reabsorb all the filtered HCO3 - (any loss of HCO3 - is equal to the addition of an equimolar amount of H+), a function principally of the proximal tubule. The second is to excrete the daily H+ load (loss of H+ is equal to addition of an equimolar amount of HCO3 -), a function of the collecting duct.

HCO3 - reabsorption

With a serum HCO3 - concentration of 24 mEq/L, the daily glomerular ultrafiltrate of 180 L, in a healthy subject, contains 4300 mEq of HCO3 -, all of which has to be reabsorbed. Approximately 90% of the filtered HCO3 - is reabsorbed in the proximal tubule, and the remainder is reabsorbed in the thick ascending limb and the medullary collecting duct.

The 3Na+ -2K+ «ATPase (sodium-potassium«adenosine triphosphatase) provides the energy for this process, which maintains a low intracellular Na+ concentration and a relative negative intracellular potential. The low Na+ concentration indirectly provides energy for the apical Na+/H+ exchanger, NHE3 (gene symbol SLC9A3), which transports H+ into the tubular lumen. H+ in the tubular lumen combines with filtered HCO3 - in the following reaction:

HCO3 - + H+ «H2 CO3 «H2 O + CO2

Page 4: asidosis metabolik

Carbonic anhydrase (CA IV isoform) present in the brush border of the first 2 segments of the proximal tubule accelerates the dissociation of H2 CO3 into H2 O + CO2, which shifts the reaction shown above to the right and keeps the luminal concentration of H+ low. CO2 diffuses into the proximal tubular cell perhaps via the aquaporin-1 water channel, where carbonic anhydrase (CA II isoform) combines CO2 and water to form HCO3 - and H+. The HCO3 - formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na+/3HCO3 - cotransporter, NBCe1-A (gene symbol SLC4A4).

In essence, the filtered HCO3 - is converted to CO2 in the lumen, which diffuses into the proximal tubular cell and is then converted back to HCO3 - to be returned to the systemic circulation, thus reclaiming the filtered HCO3 -.

Acid excretion

Excretion of the daily acid load (50-100 mEq of H+) occurs principally through H+ secretion by the apical H+ «ATPase in A-type intercalated cells of the collecting duct.

HCO3 - formed intracellularly is returned to the systemic circulation via the basolateral Cl-/HCO3 - exchanger, AE1 (gene symbol SLC4A1), and H+ enters the tubular lumen via 1 of 2 apical proton pumps, H+ «ATPase or H+ -K+ «ATPase. The secretion of H+ in these segments is influenced by Na+ reabsorption in the adjacent principal cells of the collecting duct. The reabsorbed Na+ creates a relative lumen negativity, which decreases the amount of secreted H+ that back-diffuses from the lumen.

Hydrogen ions secreted by the kidneys can be excreted as free ions but, at the lowest achievable urine pH of 5.0 (equal to free H+ concentration of 10 µEq/L), would require excretion of 5000-10,000 L of urine a day. Urine pH cannot be lowered much below 5.0 because the gradient against which H+ «ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep. A maximally acidified urine, even with a volume of 3 L, would thus contain a mere 30 µEq of free H+. Instead, more than 99.9% of the H+ load is excreted buffered by the weak bases NH3 or phosphate.

Titratable acidity

The amount of secreted H+ that is buffered by filtered weak acids is called titratable acidity. Phosphate as HPO4 2- is the main buffer in this system, but other urine buffers include uric acid and creatinine.

H2 PO4 «H+ + HPO4 2-

The amount of phosphate filtered is limited and relatively fixed, and only a fraction of the secreted H+ can be buffered by HPO4 2-.

Ammonia

Page 5: asidosis metabolik

A more important urine-buffering system for secreted H+ than phosphate, ammonia (NH3) buffering occurs via the following reaction:

NH3 + H+ «NH4 +

Ammonia is produced in the proximal tubule from the amino acid glutamine, and this reaction is enhanced by an acid load and by hypokalemia. Ammonia is converted to ammonium (NH4 +) by intracellular H+ and is secreted into the proximal tubular lumen by the apical Na+/H+ (NH4 +) antiporter. The apical Na+/K+ (NH4 +)/2Cl- cotransporter in the thick ascending limb of the loop of Henle then transports NH4 + into the medullary interstitium, where it dissociates back into NH3 and H+. The NH3 diffuses into the lumen of the collecting duct, where it is available to buffer H+ ions and becomes NH4 +. NH4 + is trapped in the lumen and excreted as the Cl salt, and every H+ ion buffered is an HCO3 - gained to the systemic circulation.

The increased secretion of H+ in the collecting duct shifts the equation to the right and decreases the NH3 concentration, facilitating continued diffusion of NH3 from the interstitium down its concentration gradient and allowing more H+ to be buffered. The kidneys can adjust the amount of NH3 synthesized to meet demand, making this a powerful system to buffer secreted H+ in the urine.

Pathophysiology

In healthy people, blood pH is maintained at 7.39-7.41, and because pH is the negative logarithm of [H+] (pH = - log10 [H+]), an increase in pH indicates a decrease in [H+] and vice versa. An increase in [H+] and a fall in pH is termed acidemia, and a decrease in [H+] and an increase in pH is termed alkalemia. The underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively. Metabolic acidosis is a primary decrease in serum HCO3 - concentration and, in its pure form, manifests as acidemia (pH <7.40).

Rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance in which 2 or more separate metabolic or respiratory derangements occur together. In these instances, pH may not be reduced or the HCO3 - concentration may not be low.

As a compensatory mechanism, metabolic acidosis leads to alveolar hyperventilation with a fall in PaCO2. Normally, PaCO2 falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum HCO3 - concentration, a compensatory response that can occur fairly quickly. If the change in PaCO2 is not within this range, then a mixed acid-base disturbance is present. For example, if the decrease in PaCO2 is less than the expected change, then a primary respiratory acidosis also is present (see Respiratory Acidosis).

Often the first clue to metabolic acidosis is a decreased serum HCO3 - concentration observed when serum electrolytes are measured. Remember, however, that a decreased serum [HCO3 -] level can be observed as a compensatory response to respiratory alkalosis

Page 6: asidosis metabolik

(see Respiratory Alkalosis). An [HCO3 -] level less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis.

The only definitive way to diagnose metabolic acidosis is by simultaneous measurement of serum electrolytes and arterial blood gases (ABGs), which shows both pH and PaCO2 to be low; calculated HCO3 - also is low. (See Metabolic Alkalosis, for a discussion of the difference between measured and calculated HCO3 - concentrations.) A normal serum HCO3 - level does not rule out the presence of metabolic acidosis because a drop in HCO3 - from a high baseline (ie, preexisting metabolic alkalosis) can result in a serum HCO3 - level that is within the reference range, concealing the metabolic acidosis.

Anion gap in metabolic acidosis

Plasma, like any other body fluid compartment, is neutral; total anions match total cations. The major plasma cation is Na+, and major plasma anions are Cl- and HCO3 -. Extracellular anions present in lower concentrations include phosphate, sulfate, and some organic anions, while other cations present include K+, Mg2+, and Ca2+. The anion gap (AG) is the difference between the concentration of the major measured cation Na+ and the major measured anions Cl- and HCO3 -. Normal values for those ions are 140, 108, and 24 mEq/L, respectively, and the gap is usually between 6 and 12 mEq/L. The AG represents the difference between unmeasured anions and unmeasured cations, as shown in the following:

AG = [Na+]-([Cl-] + [HCO3 -]) = unmeasured anions - unmeasured cations

This equation indicates that an increase in the AG can result from either a decrease in unmeasured cations (eg, hypokalemia, hypocalcemia, hypomagnesemia) or an increase in unmeasured anions (eg, hyperphosphatemia, high albumin levels). In certain forms of metabolic acidosis, other anions accumulate; by recognizing the increasing AG, the clinician can formulate a differential diagnosis for the cause of that acidosis. (See Hypokalemia, Hypocalcemia, Hypomagnesemia, and Hyperphosphatemia for further information.)

HA + NaHCO3 NaA + H2 CO3 CO2 + H2 O

This reaction indicates that the addition of an acid (HA, where H+ is combined with an unmeasured anion A-) results in the consumption of HCO3 - with an addition of anions that will account for the increase in the AG. Metabolic acidosis is classified on the basis of AG into normal- (also called non-AG or hyperchloremic metabolic acidosis) and high-AG metabolic acidosis.

Urinary AG

Calculating the urine AG is helpful in evaluating some cases of non-AG metabolic acidosis. The major measured urinary cations are Na+ and K+, and the major measured urinary anion is Cl-.

Page 7: asidosis metabolik

Urine AG = ([Na+] + [K+]) - [Cl-]

The major unmeasured urinary anions and cations are HCO3 - and NH4 +, respectively. HCO3 - excretion in healthy subjects is usually negligible, and average daily excretion of NH4 + is approximately 40 mEq/L, which results in a positive or near-zero gap. In the face of metabolic acidosis, the kidneys increase the amount of NH3 synthesized to buffer the excess H+ and NH4 Cl excretion increases. The increased unmeasured NH4 + thus increases the measured anion Cl- in the urine, and the net effect is a negative AG, representing a normal response to systemic acidification. Thus, the finding of a positive urine AG in the face of non-AG metabolic acidosis points toward a renal acidification defect (eg, renal tubular acidosis [RTA]).

Caveats

The presence of ketonuria makes this test unreliable because the negatively charged ketones are unmeasured and urine AG will be positive or zero despite the fact that renal acidification and NH4 + levels are increased. Moreover, severe volume depletion from extrarenal NaHCO3 loss causes avid proximal Na+ reabsorption, with little Na+ reaching the lumen of the collecting duct to be reabsorbed in exchange for H+. Limiting H+ excretion reduces NH4 + excretion and may make the urine AG become positive.

Effect of potassium balance on acid-base status

Renal acid secretion is influenced by serum [K+] and may result from the transcellular shift of K+ when intracellular K+ is exchanged for extracellular H+ or vice versa. In hypokalemia, an intracellular acidosis can develop; in hyperkalemia, an intracellular alkalosis can develop.

Hypokalemia

Renal production of NH3 is increased in hypokalemia, resulting in an increase in renal acid excretion. The increase in NH3 production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease (see Encephalopathy, Hepatic). Correcting the hypokalemia can reverse this process. (For further information, see Hypokalemia.)

HCO3 - reabsorption is increased secondary to relative intracellular acidosis. The increase in intracellular H+ concentration promotes the activity of the apical Na+/H+ exchanger. (For further discussion see Metabolic Alkalosis.)

Patients with hypokalemia may have relatively alkaline urine because hypokalemia increases renal ammoniagenesis. Excess NH3 then binds more H+ in the lumen of the distal nephron and urine pH increases, which may suggest RTA as an etiology for non-AG acidosis. However, these conditions can be distinguished by measuring urine AG, which will be negative in patients who have normal NH4 + excretion and positive in patients with RTA. The most common cause for hypokalemia and metabolic acidosis is

Page 8: asidosis metabolik

GI loss (eg, diarrhea, laxative use). Other less common etiologies include renal loss of potassium secondary to RTA or salt-wasting nephropathy. The urine pH, the urine AG, and the urinary K+ concentration can distinguish these conditions.

Hyperkalemia

Hyperkalemia has an effect on acid-base regulation opposite to that observed in hypokalemia. Hyperkalemia impairs NH4 + excretion through reduction of NH3 synthesis in the proximal tubule and reduction of NH4 + reabsorption in the thick ascending limb, resulting in reduced medullary interstitial NH3 concentration. This leads to a decrease in net renal acid secretion and is a classic feature of primary or secondary hypoaldosteronism. Consistent with the central role of hyperkalemia in the generation of the acidosis, lowering serum the K+ concentration can correct the associated metabolic acidosis. (For further information, see Hyperkalemia.)

Mortality/Morbidity

The causes of metabolic acidosis are varied, and the morbidity and mortality of this disorder are primarily related to the underlying condition.

Clinical

History

Symptoms of metabolic acidosis are not specific. The respiratory center in the brain stem is stimulated, and hyperventilation develops in an effort to compensate for the acidosis. As a result, patients may report varying degrees of dyspnea. Patients, especially children, also may present with nausea, vomiting, and decreased appetite. The clinical history in metabolic acidosis is helpful in establishing the etiology when symptoms relate to the underlying disorder. The age of onset and a family history of acidosis may point to inherited disorders, which usually start during childhood. Important points in the history include the following:

Diarrhea - GI losses of HCO3 - History of diabetes mellitus, alcoholism, or prolonged starvation - Accumulation

of ketoacids Polyuria, increased thirst, epigastric pain, vomiting - Diabetic ketoacidosis (DKA) Nocturia, polyuria, pruritus, and anorexia - Renal failure Ingestion of drugs or toxins - Salicylates, acetazolamide, cyclosporine, ethylene

glycol, methanol Visual symptoms - Methanol ingestion Renal stones - RTA or chronic diarrhea Tinnitus - Salicylate overdose

Physical

Page 9: asidosis metabolik

The best recognized sign of metabolic acidosis is Kussmaul respirations, a form of hyperventilation that serves to increase minute ventilatory volume. This is characterized by an increase in tidal volume rather than respiratory rate and is appreciated as deliberate, slow, deep breathing. Chronic metabolic acidosis in children may be associated with stunted growth and rickets. Coma and hypotension have been reported with acute severe metabolic acidosis. Other physical signs of metabolic acidosis are not specific and depend on the underlying cause. Some examples include the following:

Xerosis, scratch marks on skin, pallor, drowsiness, fetor, asterixis, pericardial rub - Renal failure

Reduced skin turgor, dry mucous membranes, fruity smell - DKA

Causes

Metabolic acidosis is typically classified as having a normal AG (ie, non-AG) or a high AG. Non-AG metabolic acidosis is also characterized by hyperchloremia and is sometimes referred to as hyperchloremic acidosis. 

Causes of non-AG metabolic acidosis can be remembered with the mnemonic ACCRUED (acid load, chronic renal failure, carbonic anhydrase inhibitors, renal tubular acidosis, ureteroenterostomy, expansion/extra-alimentation, diarrhea). 

Causes of non-AG metabolic acidosis are discussed in more detail below. 

The conditions that may cause a non-AG metabolic acidosis are outlined as follows:

GI loss of HCO3 - - Diarrhea, enterocutaneous fistula (eg, pancreatic), enteric diversion of urine (eg, ileal loop bladder), pancreas transplantation with bladder drainage

Renal loss of HCO3 - - Proximal RTA (type 2), carbonic anhydrase inhibitor Failure of renal H+ secretion - Distal RTA (type 1), type 4 RTA, renal failure Acid infusion - Ammonium chloride, hyperalimentation Other - Rapid volume expansion with normal saline, urinary diverting surgical

procedures (eg, ureteroenterostomy)

RTA is a term used to describe those conditions in which metabolic acidosis occurs from decreased net renal acid secretion. Three principal types of RTA occur; they are summarized in the Table.

Comparison of Types 1, 2, and 4 RTA

Open table in new window

[ CLOSE WINDOW ]

Page 10: asidosis metabolik

Table

CharacteristicsProximal (Type

2)Distal (Type 1) Type 4

Primary defect Proximal HCO3 - reabsorption

Diminished distal H+ secretion

Diminished ammoniagenesis

Urine pH <5.5 when serum HCO3 - is low

>5.5 <5.5

Serum HCO3 - >15 mEq/L Can be <10 mEq/L >15 mEq/LFractional excretion of HCO3 - (FEHCO3)

>15-20% during HCO3 - load

<5% (can be as high as 10% in children)

<5%

Serum K+ Normal or mild decrease

Mild-to-severe decrease*

High

Associated features Fanconi syndrome ... Diabetes mellitus, renal insufficiency

Alkali therapy High doses Low doses Low dosesComplications Osteomalacia or

ricketsNephrocalcinosis, nephrolithiasis

...

CharacteristicsProximal (Type

2)Distal (Type 1) Type 4

Primary defect Proximal HCO3 - reabsorption

Diminished distal H+ secretion

Diminished ammoniagenesis

Urine pH <5.5 when serum HCO3 - is low

>5.5 <5.5

Serum HCO3 - >15 mEq/L Can be <10 mEq/L >15 mEq/LFractional excretion of HCO3 - (FEHCO3)

>15-20% during HCO3 - load

<5% (can be as high as 10% in children)

<5%

Serum K+ Normal or mild decrease

Mild-to-severe decrease*

High

Associated features Fanconi syndrome ... Diabetes mellitus, renal insufficiency

Alkali therapy High doses Low doses Low dosesComplications Osteomalacia or

ricketsNephrocalcinosis, nephrolithiasis

...

*K+ may be high if RTA is due to volume depletion.

The following are common causes of high-AG metabolic acidosis:

Azotemia Ketoacidosis Lactic acidosis Salicylate overdose Ethylene glycol poisoning Methanol poisoning

Page 11: asidosis metabolik

Paraldehyde poisoning

A mnemonic to help remember this list is SLUMPED (salicylate, lactate, uremia, methanol, paraldehyde, ethylene glycol, diabetes).

Plasma osmolality can be calculated using the following equation:

Posm = [2 X Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8

Posm can also be measured in the laboratory, and because other solutes normally contribute minimally to serum osmolality, the difference between the measured and the calculated value (osmolar gap) is no more than 10-15 mOsm/kg. In certain situations, unmeasured osmotically active solutes in the plasma can raise the osmolar gap (eg, mannitol, radioactive contrast agents). The osmolar gap can also help to determine the nature of the anion in high-AG acidosis because some osmotically active toxins also cause a high-AG acidosis. Methanol, ethylene glycol, and acetone are classic poisons that increase the osmolar gap and AG; measuring the osmolar gap can help narrow the differential diagnosis of high-AG acidosis.

The AG equation clearly indicates that for a patient with metabolic acidosis (with a decrease in HCO3 -) to maintain a normal AG, an equal increase in [Cl-] must occur, prompting this disorder to sometimes be called hyperchloremic metabolic acidosis.

AG = [Na+] - ([Cl-] + [HCO3 -])

Hyperchloremic metabolic acidosis occurs principally when HCO3 - is lost from either the GI tract or the kidneys or because of a renal acidification defect. Some of the mechanisms that result in a non-AG metabolic acidosis are the following:

Addition of HCl to body fluids: H+ buffers HCO3 - and the added Cl- results in a normal AG.

Loss of HCO3 - from the kidneys or the GI tract: The kidneys reabsorb sodium chloride to maintain volume.

Rapid volume expansion with normal saline: This results in an increase in the chloride load that exceeds the renal capacity to generate equal amounts of HCO3 -.

Specific causes of hyperchloremic metabolic acidosis

Loss of HCO3 - via the GI tracto The secretions of the GI tract, with the exception of the stomach, are

relatively alkaline, with high concentrations of base (50-70 mEq/L). Significant loss of lower GI secretions results in metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion.

Page 12: asidosis metabolik

o Such losses can occur in diarrheal states, fistula with drainage from the pancreas or the lower GI tract, and sometimes vomiting if it occurs as a result of intestinal obstruction. When pancreatic transplantation is performed, the pancreatic duct is sometimes diverted into the recipient bladder, from where exocrine pancreatic secretions are lost in the final urine. Significant loss also occurs in patients who abuse laxatives, which should be suspected when the etiology for non-AG metabolic acidosis is not clear.

o Replacing the lost HCO3 - on a daily basis can treat this form of metabolic acidosis.

o Urine pH will be less than 5.3, with a negative urine AG reflecting normal urine acidification and increased NH4 + excretion. However, if distal Na+ delivery is limited because of volume depletion, the urine pH cannot be lowered maximally.

Distal RTA (type 1)o The defect in this type of RTA is a decrease in net H+ secreted by the A-

type intercalated cells of the collecting duct. As mentioned previously, H+ is secreted by the apical H+ –ATPase and, to a lesser extent, by the apical K+/H+ –ATPase. The K+/H+ –ATPase seems to be more important in K+ regulation than in H+ secretion. The secreted H+ is then excreted as free ions (reflected by urine pH value) or titrated by urinary buffers, phosphate, and NH3. A decrease in the amount of H+ secreted results in a reduction in its urinary concentration (ie, increase in urine pH) and a reduction in total H+ buffered by urinary phosphate or NH3.

o Type 1 RTA should be suspected in any patient with non-AG metabolic acidosis and a urine pH greater than 5.0. Patients have a reduction in serum HCO3 - to various degrees, in some cases to less than 10 mEq/L. They are able to reabsorb HCO3 - normally, and their FE of HCO3 - is less than 3%. The disorder has been classified into 4 types—secretory, rate dependent, gradient, and voltage dependent—based on the nature of the defect.

o Several different mechanisms are implicated in the development of distal RTA. These include a defect in 1 of the 2 proton pumps, H+ –ATPase or K+ -H+ –ATPase, that can be acquired or congenital. This may lead to loss of function (ie, secretory defect) or a reduction in the rate of H+ secretion (ie, rate-dependent defect).

o Another mechanism is a defect in the basolateral Cl-/HCO3 - exchanger, AE1, or the intracellular carbonic anhydrase that can be acquired or congenital. This also causes a secretory defect.

o Back-diffusion of the H+ from the lumen via the paracellular or transcellular space is another mechanism; this occurs if the integrity of the tight junctions is lost or permeability of the apical membrane is increased (ie, permeability or gradient defect). With a urine pH of 5.0 and an interstitial fluid pH of 7.4, the concentration gradient facilitating back-diffusion of free H+, under conditions of increased permeability of the collecting duct epithelia, is approximately 250-fold.

Page 13: asidosis metabolik

o A defect in Na+ reabsorption in the collecting duct would decrease the electrical gradient favoring the secretion of H+ into the tubular lumen (ie, voltage-dependent defect). This can occur, for instance, in severe volume depletion with decreased luminal Na+ delivery to this site.

o The serum potassium level typically is low in patients with distal RTA because defects in H+ secretion or back-diffusion of H+ tend to increase urinary K+ wasting. Potassium wasting occurs from one or more of the following factors:

Decreased net H+ secretion results in more Na+ reabsorption in exchange for K+ secretion.

The drop in serum HCO3 - and, therefore, filtered HCO3 -, reduces the amount of Na+ reabsorbed by the Na+/H+ exchanger in the proximal tubule, leading to mild volume depletion. The associated activation of the renin-angiotensin-aldosterone system increases K+

secretion in the collecting duct. A possible defect in K+/H+ –ATPase results in decreased H+

secretion and decreased K+ reabsorption.o The serum K+ level can be high if the distal RTA is secondary to

decreased luminal Na+ in the distal nephron. Na+ reabsorption in the principal cells of the collecting duct serves as the driving force for K+ secretion. In this case, the patient has hyperkalemia and acidosis; the disorder is also called voltage-dependent or hyperkalemic type 1 acidosis.

o The causes of distal RTA are shown as follows. Type 1 RTA occurs sporadically, although genetic forms have been reported.

Primary - Genetic or sporadic Drug-related - Amphotericin B, lithium, analgesics, ifosfamide,

toluene Autoimmune disease - Systemic lupus erythematosus, chronic

active hepatitis, Sjögren syndrome, rheumatoid arthritis, primary biliary cirrhosis

Related to other systemic disease - Sickle cell disease, hyperparathyroidism, light chain disease, cryoglobulinemia, Wilson disease, Fabry disease

Tubulointerstitial disease - Obstructive uropathy, transplant rejection, medullary cystic kidney disease, hypercalciuria

o The genetic forms of type 1 RTA are the following: Autosomal dominant: Heterozygous mutations in the basolateral

Cl-/HCO3 - exchanger, AE1 (Online Mendelian Inheritance in Man), cause a dominant form of distal RTA with nephrocalcinosis and osteomalacia. Some patients with this disorder can be relatively asymptomatic and present in later years, while others present with severe disease in childhood. The disorder is allelic with one form of hereditary spherocytosis, but each disease is caused by distinct mutations in the same gene. (For further information, see Spherocytosis, Hereditary.)

Page 14: asidosis metabolik

Autosomal recessive: This form of the disease may occur with or without sensorineural deafness. The type that occurs with deafness involves homozygous mutations in the B subunit of H+ –ATPase (gene symbol ATP6B1) in the A-type intercalated cells (Online Mendelian Inheritance in Man). The type that occurs without deafness involves homozygous mutations in the accessory N1 subunit of H+ –ATPase (gene symbol ATP6N1B; Online Mendelian Inheritance in Man). Homozygous or compound heterozygous mutations in AE1 also cause a recessive form of distal RTA that manifests in childhood with growth retardation and nephrocalcinosis that may lead to renal insufficiency. Heterozygous carriers have autosomal dominant ovalocytosis but normal renal acidification.

o Urine AG is positive secondary to the renal acid secretion defect. Urine pH also can be high in patients with type 2 RTA if their serum HCO3 - level is higher than the renal threshold for reabsorption, typically when a patient with type 2 RTA is on HCO3 - replacement therapy. Administration of an HCO3 - load leads to a marked increase in urine pH in those who have type 2 RTA, while those with type 1 RTA have a constant urine pH unless their acidosis is overcorrected.

o Patients with type 1 RTA may develop nephrocalcinosis and nephrolithiasis. This is thought to occur for the following reasons:

Patients have a constant release of calcium phosphate from bones to buffer the extracellular H+.

Patients have decreased reabsorption of calcium and phosphate, leading to hypercalciuria and hyperphosphaturia.

Patients have relatively alkaline urine, which promotes calcium phosphate precipitation.

Metabolic acidosis and hypokalemia lead to hypocitraturia, a risk factor for stones. Citrate in the urine complexes calcium and inhibits stone formation.

For more information, refer to Nephrocalcinosis, Nephrolithiasis, and Hypocitraturia.

Proximal (type 2) RTAo The hallmark of type 2 RTA is impairment in proximal tubular HCO3 -

reabsorption. In the euvolemic state and in the absence of elevated levels of serum HCO3 -, all filtered HCO3 - is reabsorbed, 90% in the proximal tubule. Normally, HCO3 - excretion occurs only when serum HCO3 - exceeds 24-28 mEq/L. Patients with type 2 RTA, however, have a lower threshold for excretion of HCO3 -, leading to a loss of filtered HCO3 - until the serum HCO3 - concentration reaches the lower threshold. At this point, bicarbonaturia ceases and the urine appears appropriately acidified. Serum HCO3 - typically does not fall below 15 mEq/L because of the ability of the collecting duct to reabsorb some HCO3 -.

o Type 2 RTA can be found either as a solitary proximal tubular defect, in which reabsorption of HCO3 - is the only abnormality (rare), or as part of a

Page 15: asidosis metabolik

more generalized defect of the proximal tubule characterized by glucosuria, aminoaciduria, and phosphaturia, also called Fanconi syndrome. (For more information, see Fanconi Syndrome.)

o Dent disease or X-linked hypercalciuric nephrolithiasis is one example of a generalized proximal tubular disorder characterized by an acidification defect, hypophosphatemia, and hypercalciuria and arises from mutations in the renal chloride channel gene (CLCN5) .

o The proximal tubule is the site where bulk reabsorption of ultrafiltrate occurs, driven by the basolateral Na+/K+ –ATPase. Any disorder that leads to decreased ATP production or a disorder involving Na+ -K+ –ATPase can result in Fanconi syndrome. In principle, loss of function of the apical Na+/H+ antiporter or the basolateral Na+/3HCO3 - cotransporter or the intracellular carbonic anhydrase results in selective reduction in HCO3 - reabsorption.

o The follow are causes of proximal RTA: Primary - Genetic or sporadic Inherited systemic disease - Wilson disease, glycogen storage

disease, tyrosinemia, Lowe syndrome, cystinosis, fructose intolerance

Related to other systemic disease - Multiple myeloma, amyloidosis, hyperparathyroidism, Sjögren syndrome

Drug- and toxin-related - Carbonic anhydrase inhibitors, ifosfamide, gentamicin, valproic acid, lead, mercury, streptozotocin

o Isolated proximal RTA occurs sporadically, although an inherited form has recently been described.

Homozygous mutations in the apical Na+/3HCO3 - cotransporter have been found in 2 kindreds with proximal RTA, band keratopathy, glaucoma, and cataracts (Online Mendelian Inheritance in Man).

A form of autosomal recessive osteopetrosis with mental retardation (Online Mendelian Inheritance in Man) is associated with a mixed RTA with features of both proximal and distal disease (called type 3). The mixed defect is related to the deficiency of carbonic anhydrase (CA II isoform) normally found in the cytosol of the proximal tubular cells and the intercalated cells of the collecting duct. (For more information, see Osteopetrosis.)

The most common cause of acquired proximal RTA in adults follows the use of carbonic anhydrase inhibitors.

o Patients with type 2 RTA typically have hypokalemia and increased urinary K+ wasting. This is thought, in part, to be due to an increased rate of urine flow to the distal nephron caused by the reduced proximal HCO3 - reabsorption and, in part, to be due to activation of the renin-angiotensin-aldosterone axis with increased collecting duct Na+ reabsorption from the mild hypovolemia induced by bicarbonaturia. Administration of alkali in

Page 16: asidosis metabolik

those patients leads to more HCO3 - wasting and can worsen hypokalemia unless K+ is replaced simultaneously.

o The diagnosis of type 2 RTA should be suspected in patients who have a normal-AG metabolic acidosis with a serum HCO3 - level usually greater than 15 mEq/L and acidic urine (pH <5.0). Those patients have an FEHCO3 - less than 3% when their serum HCO3 - is low. However, raising serum HCO3 - above their lower threshold and closer to normal levels results in significant HCO3 - wasting and an FEHCO3 exceeding 15%.

FEHCO3 - = (urine [HCO3 -] X plasma [creatinine] / plasma [HCO3 -]) X urine [creatinine] X 100

o Some patients with type 2 RTA tend to have osteomalacia, a condition that can be observed in any chronic acidemic state, although it is more common in persons with type 2 RTA. The traditional explanation is that the proximal tubular conversion of 25(OH)-cholecalciferol to the active 1,25(OH)2-cholecalciferol is impaired. Patients with more generalized defects in proximal tubular function (as in Fanconi syndrome) may have phosphaturia and hypophosphatemia, which also predispose to osteomalacia. 

Type 4 RTAo This is the most common form of RTA in adults and results from

aldosterone deficiency or resistance. The collecting duct is a major site of aldosterone action; there it stimulates Na+ reabsorption and K+ secretion in the principal cells and stimulates H+ secretion in the A-type intercalated cells. Hypoaldosteronism, therefore, is associated with decreased collecting duct Na+ reabsorption, hyperkalemia, and metabolic acidosis.

o Hyperkalemia also reduces proximal tubular NH4 + production and decreases NH4 + absorption by the thick ascending limb, leading to a reduction in medullary interstitial NH3 concentration. This diminishes the ability of the kidneys to excrete an acid load and worsens the acidosis.

o Because the function of H+ –ATPase is normal, the urine is appropriately acidic in this form of RTA. Correction of hyperkalemia leads to correction of metabolic acidosis in many patients, pointing to the central role of hyperkalemia in the pathogenesis of this acidosis. (For more information, see Hyperkalemia.)

o Almost all patients with type 4 RTA manifest varying degrees of hyperkalemia, which commonly is asymptomatic. The etiology of hyperkalemia is multifactorial and related to the presence of hypoaldosteronism in conjunction with a degree of renal insufficiency. The acidosis and hyperkalemia, however, are out of proportion to the degree of renal failure.

o The following findings are typical of type 4 RTA: Mild-to-moderate chronic kidney disease (stages 2-3) in most

patients, with a creatinine clearance of 30-60 mL/min Hyperkalemia

Page 17: asidosis metabolik

Hypoaldosteronism Diabetes mellitus (in approximately 50% of patients)

o The following are causes of type 4 RTA: Hypoaldosteronism (low renin) - Hyporeninemic

hypoaldosteronism (diabetes mellitus/mild renal impairment, chronic interstitial nephritis, nonsteroidal anti-inflammatory drugs, beta-blockers)

Hypoaldosteronism (high renin) - Primary adrenal defect (isolated: congenital hypoaldosteronism; generalized: Addison disease, adrenalectomy, AIDS), inhibition of aldosterone secretion (heparin, ACE inhibitors, AT1 receptor blockers)

Aldosterone resistance (drugs) - Diuretics (amiloride, triamterene, spironolactone), calcineurin inhibitors (cyclosporine, tacrolimus), antibiotics (trimethoprim, pentamidine)

Aldosterone resistance (genetic) - Pseudohypoaldosteronism (PHA) types I and II

o Although type 4 RTA occurs sporadically, familial forms have been reported. The genetic forms are called PHA; PHA type 1 is characterized by hypotension with hyperkalemia and acidosis and includes an autosomal recessive and autosomal dominant form. PHA type 2 is characterized by hypertension with hyperkalemia and acidosis and is also known as Gordon syndrome and familial hyperkalemic hypertension.

Autosomal recessive PHA type 1: Homozygous mutations in the alpha, beta, or gamma subunits (gene symbols SCNN1A, SCNN1B, and SCNN1G) of the collecting duct epithelial sodium channel cause a syndrome that manifests in infancy with severe salt wasting, hypotension, hyperkalemia, and acidosis (Online Mendelian Inheritance in Man). A pulmonary syndrome characterized by recurrent respiratory infections, chronic cough, and increased respiratory secretions has also been noted in some individuals.

Autosomal dominant PHA type 1: Heterozygous mutations in the mineralocorticoid receptor lead to a milder phenotype that is restricted to the kidneys (Online Mendelian Inheritance in Man). Unlike the autosomal recessive form, the clinical symptoms improve with age.

Gordon syndrome (PHA type 2). This disorder is characterized by hypertension and hyperkalemia with variable degrees of metabolic acidosis. Heterozygous mutations in 1 of 2 kinases, WNK1 or WNK4, cause this syndrome. A third locus on band 1q has been described, but the genetic defect at this locus has not yet been identified.

o Type 4 RTA should be suspected in any patient with a mild non-AG metabolic acidosis and hyperkalemia. The serum HCO3 - level is usually greater than 15 mEq/L, and the urine pH is less than 5.0 because these patients have a normal ability to secrete H+. The primary problem is

Page 18: asidosis metabolik

hyperkalemia from aldosterone deficiency or end organ (collecting duct) resistance to the action of aldosterone. This can be diagnosed by measuring the transtubular potassium gradient (TTKG). 

TTKG = urine K+ X serum osmolality/serum K+ X urine osmolalityA TTKG greater than 8 indicates that aldosterone is present and the collecting duct is responsive to it. A TTKG less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance. For the test to be interpretable, the urine Na+ level should be greater than 10 mEq/L and the urine osmolality should be greater than or equal to serum osmolality.

o The hyperkalemia suppresses renal ammoniagenesis, leading to a lack of urinary buffers to excrete the total H+ load. The urine AG will be positive. Note that patients with hyperkalemic type 1 RTA have a urine pH greater than 5.5 and a low urine Na+.

Early renal failureo Metabolic acidosis is usual in patients with renal failure, and, in early to

moderate stages of chronic kidney disease (glomerular filtration rate of 20-50 mL/min), it is associated with a normal AG (hyperchloremic). In more advanced renal failure, the acidosis is associated with a high AG.

o In hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load. In addition, NH3 reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH3 concentration.

o In general, patients tend to have a serum HCO3 - level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO3 -.

o Note that patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO3 - loss from an extrarenal source (eg, diarrhea) and severe metabolic acidosis can develop rapidly.

Urinary diversiono Hyperchloremic metabolic acidosis can develop in patients who undergo a

urinary diversion procedure, such as a sigmoid bladder or an ileal conduit.o This occurs through 1 of the following 2 mechanisms:

The intestinal mucosa has an apical Cl-/HCO3 - exchanger. When urine is diverted to a loop of bowel (as in patients with obstructive uropathy), the chloride in the urine is exchanged for HCO3 -. Significant loss of HCO3 - can occur, with a concurrent increase in serum Cl- concentration.

Intestinal mucosa reabsorbs urinary NH4 +, and the latter is metabolized in the liver to NH3 and H+. This is particularly likely to occur if urine contact time with the intestinal mucosa is prolonged, as when a long loop of bowel is used or when the stoma is obstructed and when sigmoid rather than ileal loop is used. Presumably, the creation of a continent bladder also increases

Page 19: asidosis metabolik

HCO3 - loss. This disorder is not observed very frequently anymore because short-loop incontinent ureteroileostomies are used now.

Infusion of acidso The addition of an acid that contains Cl- as an ion (eg, NH4 Cl) can result

in a normal-AG acidosis because the drop in HCO3 - is accompanied by an increase in Cl-.

o The use of arginine or lysine hydrochloride as amino acids during hyperalimentation can have the same result.

Specific causes of high-AG metabolic acidosis

Lactic acidosiso A more detailed discussion is available in Lactic Acidosis. Briefly, L-

lactate is a product of pyruvic acid metabolism in a reaction catalyzed by lactate dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD+).

o Daily lactate production in a healthy person is substantial (approximately 20 mEq/kg/d), and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low.

o The major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the citric acid cycle. In the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced.

o Lactic acid accumulates in blood whenever production is increased or use is decreased. A value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis.

o Type A lactic acidosis occurs in hypoxic states, while type B occurs without associated tissue hypoxia.

o D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D-lactate by intestinal bacteria. It is observed in association with intestinal bacterial overgrowth syndromes. D-lactate is not measured routinely when lactate levels are ordered and must be requested specifically when such cases are suspected.

Ketoacidosiso Free fatty acids released from adipose tissue have 2 principal fates. In the

major pathway, triglycerides are synthesized in the cytosol of the liver. In the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway. Ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased.

Page 20: asidosis metabolik

o This pathway is favored when insulin is absent (as in the fasting state), in certain forms of diabetes, and when glucagon action is enhanced.

o Alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor nutrition. Alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels. These patients tend to have a mild degree of lactic acidosis. This diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive. Patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting). For more information, see Alcoholic Ketoacidosis.

o Starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by exercise

o DKA is usually precipitated in patients with type 1 diabetes by stressful conditions (eg, infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes.

Hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis.

The metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood. However, after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO3 -, which was consumed during the acidosis).

For more information, see Diabetic Ketoacidosis. Advanced renal failure

o Patients with advanced chronic kidney disease (glomerular filtration rate of less than 20 mL/min) present with a high-AG acidosis. The acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H+ buffered in the urine. The increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function. For more information, see Acute Renal Failure and Chronic Renal Failure.

o In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO3 - level usually remains greater than 12 mEq/L. This bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia.

Salicylate overdoseo Deliberate or accidental ingestion of salicylates can produce a high-AG

acidosis, although respiratory alkalosis is usually the more pronounced acid-base disorder.

o The increase in AG is only partly from the unmeasured salicylate anion. Increased ketoacid and lactic acid levels have been reported in persons with salicylate overdose and are thought to account for the remainder of the AG.

Page 21: asidosis metabolik

o Salicylic acid ionizes to salicylate and H+ ion with increasing pH; at a pH of 7.4, only 0.004% of salicylic acid is nonionized, as follows:

Salicylic acid (HS)«salicylate (S) + H+ (H+)

o HS is lipid soluble and can diffuse into the CNS; with a fall in pH, more HS is formed. The metabolic acidosis thus increases salicylate entry to the CNS, leading to respiratory alkalosis and CNS toxicity.

o For more information, see Toxicity, Salicylate. Methanol poisoning

o Methanol ingestion is associated with the development of a high-AG metabolic acidosis. Methanol is metabolized by alcohol dehydrogenase to formaldehyde and then to formic acid.

o Formaldehyde is responsible for the optic nerve and CNS toxicity, while the increase in AG is from formic acid and from lactic acid and ketoacid accumulation.

o Clinical manifestations include optic nerve injury that can be appreciated by funduscopic examination as retinal edema, CNS depression, and unexplained metabolic acidosis with high anion and osmolar gaps.

o For more information, see Toxicity, Alcohols. Ethylene glycol poisoning

o Ingestion of ethylene glycol, a component of antifreeze and engine coolants, leads to a high-AG acidosis. Ethylene glycol is converted by alcohol dehydrogenase first to glycoaldehyde and then to glycolic and glyoxylic acids. Glyoxylic acid then is degraded to several compounds, including oxalic acid, which is toxic, and glycine, which is relatively innocuous.

o The high AG is primarily from the accumulation of these acids, although a mild lactic acidosis also may be present.

o Patients present with CNS symptoms, including slurred speech, confusion, stupor or coma, myocardial depression, and renal failure with flank pain.

o Oxalate crystals are usually observed in the urine and are an important clue to the diagnosis, as is an elevated osmolar gap.

o For more information, see Toxicity, Ethylene Glycol.

Differential Diagnoses

Acute Renal Failure Lactic AcidosisAzotemia Metabolic AlkalosisChronic Renal Failure Respiratory AlkalosisDiabetes Mellitus, Type 1Toxicity, SalicylateDiabetes Mellitus, Type 2

Page 22: asidosis metabolik

Other Problems to Be Considered

Hyperosmolar nonketotic acidosisMixed acid-base disturbancesRenal tubular acidosisToxicity, ethylene glycolToxicity, methanolToxicity, paraldehyde

Workup

Laboratory Studies

The diagnosis is made by evaluating serum electrolytes and ABGs.o A low serum HCO3 - and a pH of less than 7.40 upon ABG analysis

confirm metabolic acidosis.o The AG should be calculated to help with the differential diagnosis of the

metabolic acidosis and to diagnose mixed disorders.o In general, a high-AG acidosis is present if the AG is greater than 10-12

mEq/L, and a non-AG acidosis is present if the AG is less than 10-12 mEq/L.

If the AG is elevated, the osmolar gap should be calculated by subtracting the calculated serum osmolality from the measured serum osmolality.

o Ethylene glycol and methanol poisoning increase the AG and the osmolar gap.

o Other tests can be performed, including a screen for toxins (eg, ethylene glycol, salicylate) and tests for metabolic disorders (eg, ketoacidosis, lactic acidosis), that are known to elevate the AG.

If the AG is not elevated, then a urinalysis should be performed and a urine pH obtained with a pH electrode on a fresh sample of urine collected under oil or in a capped syringe.

o A urine AG is calculated from the measurement of urine Na+, K+, and Cl-.o This helps to differentiate between GI and renal losses of HCO3 - in non-

AG metabolic acidosis. The change in AG (or delta AG) helps in detecting the presence of a second acid-

base disorder in patients with an elevated AG. It is calculated by the following equation: (AG-10)/(24-HCO3 -)

o A value less than 1 indicates that the drop in serum HCO3 - is not accompanied by a corresponding increase in the AG. This suggests that a portion of the H+ load is not accompanied by an unmeasured anion and indicates the presence of a mixed metabolic acidosis (eg, a non-AG acidosis and a high-AG acidosis).

o A value greater than 1.6 indicates that the drop in serum HCO3 - is associated with a larger-than-expected increase in the AG. This would occur if the serum HCO3 - level was higher than normal prior to the onset

Page 23: asidosis metabolik

of the metabolic acidosis and then dropped below normal with the addition of H+ coupled to an unmeasured anion. This indicates the presence of a mixed metabolic acidosis and metabolic alkalosis.

Special testso Measuring the TTKG is useful in determining the etiology of

hyperkalemia or hypokalemia associated with metabolic acidosis.o Plasma renin activity and plasma aldosterone levels are useful in

determining the etiology of the hyperkalemia and hypokalemia that accompany metabolic acidosis.

o FEHCO3 - is useful in the diagnosis of proximal RTA.o The NH4 Cl loading test is useful in patients with nephrocalcinosis and/or

nephrolithiasis, who may have an incomplete form of distal RTA. These patients may not have a pH less than 7.35 or a drop in serum HCO3 -; metabolic acidosis can be induced by administration of NH4 Cl (0.1 g/kg for 3 d). Under these circumstances of induced acidemia, a urine pH greater than 5.3 indicates distal RTA.

o A recently described alternative to the NH4 Cl loading test involves the simultaneous oral administration of furosemide to increase distal Na+ delivery and fludrocortisone to increase collecting duct Na+ absorption and proton secretion.1 Under these circumstances, a urine pH greater than 5.3 indicates distal RTA.

o Measuring the urine-blood PaCO2 gradient following an HCO3 - load is useful in some patients with classic distal RTA to differentiate a permeability defect from other defects. This test is useful in patients with nephrocalcinosis in whom distal RTA is suspected but urine is acidified appropriately in the face of metabolic acidosis. Some of these patients have a rate-dependent defect in proton secretion, revealed by a low urine-blood PaCO2 gradient following HCO3 - loading.

Imaging Studies

Abdominal radiographs (eg, kidneys, ureters, bladder), CT scans, and/or renal ultrasound images may show renal stones or nephrocalcinosis in patients with distal RTA.

Treatment

Medical Care

General principles for treating acute acidosis include the following:

Treatment of acute metabolic acidosis by alkali therapy is usually indicated to raise and maintain the plasma pH to greater than 7.20. In the following 2 circumstances this is particularly important:

Page 24: asidosis metabolik

o When the serum pH is below 7.20, a continued fall in the serum HCO3 - level may result in a significant drop in pH. This is especially true when the PCO2 is close to the lower limit of compensation, which, in an otherwise healthy young individual is approximately 15 mm Hg. With increasing age and other complicating illnesses, the limit of compensation is likely to be less. A further small drop in HCO3 - at this point thus is not matched by a corresponding fall in PaCO2, and rapid decompensation can occur. For example, in a patient with metabolic acidosis with a serum HCO3 - level of 9 mEq/L and a maximally compensated PCO2 of 20 mm Hg, a drop in the serum HCO3 - level to 7 mEq/L results in a change in pH from 7.28 to 7.16.

o A second situation in which HCO3 - correction should be considered is in well-compensated metabolic acidosis with impending respiratory failure. As metabolic acidosis continues in some patients, the increased ventilatory drive to lower the PaCO2 may not be sustainable because of respiratory muscle fatigue. In this situation, a PaCO2 that starts to rise may change the plasma pH dramatically, even without a significant further fall in HCO3 -. For example, in a patient with metabolic acidosis with a serum HCO3 - level of 15 and a compensated PaCO2 of 27 mm Hg, a rise in PaCO2 to 37 mm Hg results in a change in pH from 7.33 to 7.20. A further rise of the PaCO2 to 43 mm Hg drops the pH to 7.14. All of this would have occurred while the serum HCO3 - level remained at 15 mEq/L.

o Sodium bicarbonate (NaHCO3) is the agent most commonly used to correct metabolic acidosis. The HCO3 - deficit can be calculated by using the following equation:

HCO3 - deficit = deficit/L (desired serum HCO3 - - measured HCO3 -) X 0.5 X body weight (volume of distribution for HCO3 -)

This provides a crude estimate of the amount of HCO3 - that must be administered to correct the metabolic acidosis; the serum HCO3 - level or pH should be reassessed frequently.

o HCO3 - can be administered intravenously to raise the serum HCO3 - level adequately to increase the pH to greater than 7.20. Further correction depends on the individual situation and may not be indicated if the underlying process is treatable or the patient is asymptomatic. This is especially true in certain forms of metabolic acidosis. For example, in high-AG acidosis secondary to accumulation of organic acids, lactate, and ketones, these anions are eventually metabolized to HCO3 -. When the underlying disorder is treated, the serum pH corrects; thus, caution should be exercised in these patients when providing alkali to raise the pH much higher than 7.20 because an overshoot alkalosis may occur.

o To minimize the risk of hypernatremia and hyperosmolality, two 50-mL ampules of 8.4% NaHCO3 (containing 50 mEq each) are added to 1 L of

Page 25: asidosis metabolik

0.25 normal saline or 3 ampules are added to 1 L of 5% dextrose in water. (For information about treating hypernatremia, see Hypernatremia.)

o Volume overload can be a consequence of alkali therapy, and loop diuretics can be used in these circumstances.

o Another consequence of treatment with NaHCO3 is a rise in PaCO2. This can become a very important factor in patients who have reduced ventilatory reserve.

o Other important forms of alkali therapy for acute treatment include the following:

Carbicarb: This compound has an equimolar concentration of NaHCO3 - and sodium carbonate. Because carbonate is a stronger base, it buffers H+ in preference to HCO3 -, resulting in the generation of HCO3 - rather than CO2. This drug is not available in the United States.

THAM is a sodium-free alkalizing solution containing 0.3N tromethamine. It buffers acids and limits the generation of CO2 and has been used in some clinical situations to treat severe metabolic acidosis. Major adverse effects include hyperkalemia and hypoglycemia, and the drug should not be used in patients with oliguria or poor renal function. This drug is not used widely in the United States.

Oral NaHCO3 can be administered in some acute metabolic acidemic states in which correction of metabolic acidosis is unlikely to occur without exogenous alkali administration.

Oral alkali administration is the preferred route of therapy in persons with chronic metabolic acidosis. The most common alkali forms for oral therapy include NaHCO3 tablets. These are available in 325 and 650 mg strengths (1 g of NaHCO3 is equal to 11.5 mEq of HCO3 -). Citrate salts are available in a variety of formulations, as mixtures of citric acid with sodium citrate and/or potassium citrate. These solutions generally contain 1-2 mEq of HCO3 - per mL. Potassium citrate is useful when the acidosis is accompanied by hypokalemia but should be used cautiously in persons with renal impairment and must be avoided in those with hyperkalemia.

Type 1 RTAo Administration of an alkali is the mainstay of treatment. Adult patients

should be administered the amount required to buffer the daily acid load from the diet. This is usually approximately 1-3 mEq/kg/d and can be administered in any form, although the preferred form is as potassium citrate.

o Correction of acidosis usually corrects the hypokalemia, but K+ supplements may be necessary.

Type 2 RTAo Correcting this form of acidosis with alkali is difficult because a

substantial proportion of the administered HCO3 - is excreted in the urine, and large amounts are needed to correct the acidosis (10-30 mEq/kg/d).

Page 26: asidosis metabolik

o Potassium is also required when administering HCO3 -.o Correction is essential in children for normal growth, while in adults

aggressive correction to a normal level may not be required.o Thiazide diuretics can be administered to induce diuresis and mild volume

depletion, which, in turn, raises the proximal tubule threshold for HCO3 - wasting.

Type 4 RTAo Because hyperkalemia is central to the etiology of this disorder, a major

treatment goal is to lower the serum K+ level. This can be achieved by placing the patient on a low-K+ diet (1 mEq/kg K+/d) and by withdrawal of drugs that can cause hyperkalemia (eg, ACE inhibitors, nonsteroidal anti-inflammatory drugs).

o Loop diuretics can be helpful in reducing serum potassium levels as long as the patient is not hypovolemic.

o In resistant cases, fludrocortisone, a synthetic mineralocorticoid, can be used to increase K+ secretion, but this may increase Na+ retention.

o Alkali therapy is not usually required because, in many patients, the mild degree of acidosis is corrected by achieving normokalemia.

o Hyperkalemia and acidosis worsen as renal function declines further; eventually, the patient develops a high-AG renal acidosis.

o Renal replacement therapy should be considered once the measures described fail to control hyperkalemia or acidosis.

Early renal failureo Treatment of chronic metabolic acidosis in persons with renal failure is

indicated for the following reasons: It can help prevent bone loss that can progress to osteopenia or

osteoporosis. In children, growth retardation can occur. (For more information, see Osteoporosis.)

Treatment slows the progression of hyperparathyroidism (see Hyperparathyroidism).

It helps reduce the high-protein catabolic state associated with uremic acidosis, which leads to loss of muscle mass and malnutrition.

o NaHCO3 is the most frequently used agent. It is administered in an amount necessary to keep the serum HCO3 - level greater than 20 mEq/L. The average requirement is approximately 1-2 mEq/kg/d. Sodium citrate should be avoided if the patient is taking aluminum as a phosphate binder because citrate increases aluminum absorption and, hence, the risk for aluminum toxicity.

Ketoacidosiso Starvation and alcohol use resulting in acidosis is treated with intravenous

glucose, which is administered to stimulate insulin secretion and stop lipolysis and ketosis.

o For DKA, insulin is administered, usually intravenously, to facilitate cellular uptake of glucose, reduce gluconeogenesis, and halt lipolysis and production of ketone bodies. In addition, normal saline is administered to

Page 27: asidosis metabolik

restore extracellular volume; potassium and phosphate replacement also may be necessary. The acidosis is corrected partly by the metabolism of ketones to HCO3 -, partly by increased H+ secretion by the collecting duct, and partly by H+ excretion as NH4 +. For more information about treating this condition, see Diabetic Ketoacidosis.

Lactic acidosiso Correction of the underlying disorder is the mainstay of therapy.o In patients with tissue hypoxia, restoration of tissue perfusion is essential.o The role of alkali therapy is controversial; some authors recommend

raising the serum pH to 7.20 when possible. Some evidence suggests, however, that HCO3 - therapy produces only a transient increase in the serum HCO3 - level and that this can lead to intracellular acidosis and worsening of lactic acidosis. Furthermore, large amounts of NaHCO3 are commonly required, and volume overload and hypernatremia can occur. In such situations, hemodialysis or continuous venovenous hemofiltration can be used to correct the metabolic abnormalities.

o If the process leading to lactic acidosis is corrected, lactic acid can be used again by the liver to produce HCO3 - on an equimolar basis. This is important because rebound alkalosis can occur if the patient has received an excessive amount of alkali during the acidemia.

o For more information about treating this condition, see Lactic Acidosis. Salicylate poisoning: Alkali therapy is an important component of therapy in

salicylate overdose for the following reasons:o Correcting the acidemia decreases the amount of salicylate crossing the

blood-brain barrier. Care should be exercised to avoid inducing or worsening the alkalosis that may be present.

o Increasing urine pH increases the excreted salicylate. Alkaline diuresis can be initiated by intravenous NaHCO3 administration or by acetazolamide therapy. The goal is to maintain the urine pH at greater than 7.5 until the salicylate level falls below 30-50 mg/dL.

o Multiple dosing of activated charcoal at 0.25-1 g/kg every 2-4 hours can also be used to increase the excretion of salicylate.

o In acute intoxication, hemodialysis should be considered when the blood level is greater than 80 mg/dL or when renal failure or severe CNS depression is present.

o For more information about treating this condition, see Toxicity, Salicylate.

Methanol or ethylene glycol poisoningo Treatment should be started promptly to prevent any neurological

sequelae.o 4-methylpyrazole (fomepizol) is a potent inhibitor of alcohol

dehydrogenase and is now the preferred therapy, although it is much more expensive than ethanol.  Fomepizol is given as a loading dose and continued over several doses until toxin levels decline substantially. Fomepizol levels do not need to be monitored.

Page 28: asidosis metabolik

o Ethanol competes for alcohol dehydrogenase and can be used as an alternative to fomepizol. It is administered orally or intravenously to saturate alcohol dehydrogenase, to which it has a higher affinity, thus inhibiting metabolism of methanol or ethylene glycol to its toxic metabolites. The blood ethanol level should be maintained at 100-150 mg/dL.

o HCO3 - therapy can be administered to correct severe acidosis, but large amounts of HCO3 - may be required and fluid overload can compromise therapy.

o Patients with methanol overdose should receive folate to enhance the metabolism of formic acid.

o Patients with ethylene glycol overdose should receive thiamine and pyridoxine.

o Hemodialysis should be considered in any patient with significant metabolic acidosis, renal failure, visual symptoms, a high blood toxin level, or a suspected large overdose. Hemodialysis is effective in clearing methanol, ethylene glycol, and their toxic metabolites; in correcting the acidosis; and in restoring extracellular volume. 

o For more information about treating these conditions, see Toxicity, Alcohols and Toxicity, Ethylene Glycol.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Alkalinizing agents

Acute metabolic acidosis is usually treated with alkali therapy to raise plasma pH and to maintain it at greater than 7.20.

Sodium bicarbonate (Neut)

Systemic and urinary alkalinizer used to increase serum or urinary HCO3 - concentration and raise pH. Dosing based on clinical setting, blood pH, serum HCO3 - level, and PaCO2.

Dosing Interactions Contraindications Precautions

Adult

Page 29: asidosis metabolik

Calculate as follows:HCO3 - deficit = deficit/L (desired serum HCO3 - - measured HCO3 -) X 0.5 X weight (kg)(volume of distribution for HCO3 -)

Pediatric

Not established

Follow-up

Complications

In general, acute metabolic acidosis is well tolerated when blood pH exceeds 7.20. When blood pH is less than 7.20, cardiovascular complications can occur, including vasodilatation, myocardial depression, and decreased cardiac output, which manifest as hypotension.

Chronic metabolic acidosis can have long-term complications if left untreated. The main complication is bone disease (osteomalacia and osteopenia) caused by continual buffering of hydrogen ions.

Chronic metabolic acidosis increases the rate of skeletal muscle breakdown; this high catabolic state may contribute to loss of body mass and muscle weakness.

Miscellaneous

Medicolegal Pitfalls

In high-AG acidosis secondary to accumulation of organic acids, lactate, and ketones, these anions are eventually metabolized to HCO3 -. When the underlying disorder is treated, the serum pH corrects; thus, caution should be exercised in these patients when providing alkali to raise the pH much higher than 7.20 because an overshoot alkalosis may occur.

Potassium citrate is useful when the acidosis is accompanied by hypokalemia but should be used cautiously in the presence of renal impairment and must be avoided in the presence of hyperkalemia.