Chemical pathology case conference: acid-base disorders

Ching-Wan Lam 林青雲, Tony W L Mak 麥永禮, Albert Y W Chan 陳恩和, Rossa W K Chiu 趙慧君, Morris H L Tai 戴學良, Michael H M Chan 陳浩明, Anthony C C Shek 石志忠, Sidney Tam 譚志輝

HK Pract 2005;27:294-299

Summary

The human body is a net-producer of acids. Both intracellular and extracellular proton concentrations are physiologically tightly regulated because many important steps in intermediary metabolism, including ATP synthesis, are pH dependent. This chemical pathology case conference on acid-base disturbance will provide basic knowledge to interpret disturbances in acid-base homeostasis in clinical practice. This will be achieved by (1) a brief review of basic concepts, (2) an introduction of laboratory investigations used to diagnose acid-base disturbances, and (3) the analysis of clinical examples of disturbances in acid-base homeostasis.

摘要

在新陳代謝中，不少重要過程，包括ATP合成，都是依賴一個適中的pH值。因此，無論在細胞內或外， 質子的濃度在生理上都受到嚴密調控。 本期有關酸鹼平衡失調的化學病理學個案研討將會提及在臨床上解說酸鹼內環境穩定失衡的基本知識它包括 (1)簡論其基本概念(2)介紹在臨床診斷上的實驗室檢測，和(3)臨床病例分析。

What is pH?

pH is a measure of hydrogen ion activity. The definition of pH was proposed by Sorenson in 1909.¹ The pH of whole blood is defined as the common logarithm of the reciprocal of hydrogen ion activity [H⁺] expressed in mol/L. The reference interval of arterial pH is 7.35-7.45. pH is not an arithmetic scale, e.g. for a 2-fold change in [H⁺], the pH will only be changed by 0.30. An intuitive expression of blood acidity is to use [H⁺]. The reference interval of arterial [H⁺] is 35-45x10^-9 mol/L. The narrow range of pH is illusionary (0.1) when compared to that of the actual [H⁺], i.e., 10 nmol/L. While pH should be viewed as a conventional scale, it is important to note that cellular metabolism is critically influenced by [H⁺] and not pH, which is an artifact.

Acid-base interpretation

Acidaemia simply means that pH is <7.35 (not 7.0) or [H⁺]>45 nmol/L. However, acidaemia is not equivalent to acidosis, which is a biological process or clinical condition leading to acidaemia. Clinical acidaemia can be caused by a combination of acidosis and alkalosis culminating in acidaemia.

A change in [H⁺] affects the equilibrium of all extracellular and intracellular buffer systems. A shift in the equilibrium of one buffer system will reflect the shift in all other biological buffer systems - isohydric principle. The bicarbonate/carbonic acid (pCO₂) buffer has been chosen for investigations of disturbed acid-base balance because the components of this buffer are easy to measure and are physiologically tightly regulated.

The essence of acid-base homeostasis is to stabilize [H⁺] changes by minimizing the changes of [HCO₃-]/pCO₂ ratio when the body is perturbed by excessive amounts of acids or bases. This can be easily appreciated by the Henderson-Hasselbalch equation:

pH=6.1+Log10		[HCO3-] in mmol L-1
		0.03 in mmol L-1 mmHg-1 x pCO2 in mmHg

The term 0.03 x pCO₂ is directly proportional to the [H₂CO₃] concentration - the conjugate acid of HCO₃-. The normal {[HCO₃-]/0.03 x pCO₂} ratio is 20.

To minimize the change in the ratio, the premise is that [HCO₃-] and pCO₂ have to be changed in the same direction. If [HCO₃-] and pCO₂ are changed in different directions, a mixed acid-base disturbance occurs. A simple metabolic acidosis (low [HCO₃-] and low pH) will be partially compensated by lowering the blood pCO₂ (increased lung ventilation). A simple respiratory alkalosis (low pCO₂ and high pH) will be partially compensated by lowering the blood [HCO₃-] (increased renal excretion of bicarbonate). Based on the aforementioned pathophysiological principles, abnormal acid-base patterns can be easily derived (Table 1).

Anion gap and organic acidosis

Anion gap is defined as [Na⁺]+[K⁺]-[Cl^-]-[HCO ₃-] in plasma or serum. The reference interval of serum anion gap is 7-17 mmo/L. The sum of circulating anions and cations must be the same - law of electroneutrality. The "gap" consists of other ions, mainly calcium, magnesium, phosphates, sulfates, and organic anions (e.g. lactate, acetoacetate). Accumulation of organic acids in circulation will increase the serum anion gap, therefore, an increased anion gap is a marker of organic acidosis or high-anion gap metabolic acidosis. The beauty of anion gap is that the diagnosis of organic acidosis can be reached irrespective of the values of pH, pCO₂, and [HCO₃-]; if a patient with high anion gap has normal values of pH, pCO₂, and [HCO₃-], the results suggested that the patient has equipotent organic acidosis and metabolic alkalosis. The difference between the increases in anion gap and the decreases in [HCO₃-] will help us to diagnose mixed high-anion gap and normal-anion gap metabolic acidosis. Lactate is accumulated in lactic acidosis, and beta-hydroxybutyrate is accumulated in diabetic ketoacidosis and alcoholic ketoacidosis.

These two organic anions can be measured in clinical laboratories.² The ketostix results have to be interpreted with caution because ketostix only detects acetoacetate in urine, which is not the predominant form of ketone bodies accumulated in blood during ketoacidosis. Normal anion gap metabolic acidosis usually signifies renal tubular or gastrointestinal problems.

Approach for diagnosis of acid-base disturbances

The aim of interpreting acid-base disturbances is to unveil the clinical conditions leading to the acid-base disturbances, particularly those that are obscured, e.g. toxic agents.³ The first step of interpreting acid-base data is to select the simple disturbance which appears to be the sole or dominant contributor to the observed pattern of indices. The selection is based on the fact that in any simple disturbance the compensatory response fails to restore the blood [H⁺] completely to normal. The next step is to compare the observed compensatory response with the response which would be anticipated in the selected disturbance. If the observed response differs from the anticipated response then it is described as inappropriate. An inappropriate response is not consistent with a simple disturbance and indicates the presence of an additional disorder. Detailed calculations of the expected response may not be required. The assumption in this step is that compensatory response has developed fully and that the disturbance is in a stable state. Other supporting acid-base parameters include serum anion gap, urine pH, urine ammonium concentration, urine anion gap, and plasma potassium concentration. Laboratory investigation of acid-base disturbances is shown in Table 2.

Case illustrations

Metabolic or renal compensation: chronic obstructive airway disease

An 80 years old female with chronic obstructive airway disease for 20 years had the following biochemical results: pH 7.30 (reference interval: 7.35-7.45) pCO₂ 10.6 kPa (reference interval: 4.70-6.00 kPa) 80.6 mmHg (reference interval: 36-46 mmHg) [HCO₃-] 39 mmol/L (reference interval: 22.0-26.0 mmol/L)

Comments:

The patient has respiratory acidosis with partial metabolic/renal compensation. The body attempts to reduce pH changes by minimizing alteration in the [HCO₃-]/0.03xpCO₂ ratio, which is 16.1 mmol/L [39/(0.03 80.6)] in this case. This change is relatively small compared with changes in [HCO₃-] and pCO₂.

Calculation of renal compensation is as follows (Table 3): change in pCO₂ is 80.6-40=40.6 mmHg. Renal compensation leads to an increase of [HCO₃-], i.e., 14.2 mmol/L (40.6x0.35). Therefore, the predicted [HCO₃-] is 38.2 mmol/L (14.2+24). The predicted value is close to the measured value; therefore, no primary metabolic component for the acidaemia.

If [HCO₃-] is changed to 30 mmol/L (pH will be 7.19 with pCO₂ unchanged), the patient then has chronic respiratory acidosis and metabolic acidosis. The additional 9 mmol/L decrease in [HCO₃-] could be due to metabolic acidosis secondary to acute hypoxia.

Two cases of alcoholic ketoacidosis

Case 1

A 54 years old male chronic alcoholic with Child's C liver cirrhosis was admitted with complaints of nausea, vomiting, abdominal pain, and shortness of breath. Alcohol had been ingested 2 days prior to admission. On admission, he was noted to be jaundice, with spider naevi, palmar erythema, mild epigastric tenderness and hepatomegaly. The chests were clear. The blood pressure was 120/70 mmHg with a pulse rate of 112 bpm. Arterial blood gas analysis revealed pH 7.06, pCO₂ 2.1 kPa, [HCO₃-] 4.3 mmol/L, random plasma glucose 6.0 mmol/L, blood lactate 9.1 mmol/L, amylase 106 U/L and serum osmolality 305 mmol/kg. Both the anion and osmolal gaps were raised at 38.2 mEq/L and 34.7 mmol/kg respectively. Urine was strongly positive for ketone and tests for both methanol and ethanol were negative. Within the first 4 hours of admission, 900 mL of vomitus was collected and only 100 mL of urine passed. The diagnosis of alcoholic ketoacidosis was made. Treatment consisted of intravenous fluid replacement with administration of intravenous thiamine and bicarbonate. Subsequently, the blood gases and electrolytes almost completely normalized within 12 hours. The patient was then discharged uneventfully.

Case 2

A 44 years old male, known for a habit of consuming 6-7 bottles of double-distilled Chinese wine daily for over ten years, presented with acute confusion, blurring of vision, nausea, vomiting and abdominal pain after having a binge for 7 days prior to admission. On examination, he was confused but arousable, with blood pressure 90/66 mmHg, pulse rate 95 bpm, and respiratory rate 28 per minute. The pupils were equal in size of 3 mm and reactive to light, fundoscopy was normal. Mild upper abdominal tenderness and bi-basal lung crepitations were also noted. The biochemical investigations on admission revealed pH 6.89, pCO₂ 3.1 kPa, [HCO₃-] 4.3 mmol/L, random plasma glucose 5.4 mmol/L, amylase 88 U/L and raised blood lactate 17.6 mmol/L. Other results were: serum osmolality 327 mmoL/kg, plasma ethanol 19 mmol/L, and serum salicylate and paracetamol were not detectable. Ketone results were not documented. The anion and osmolal gaps were 46.1 mEq/L and 46.6 mmol/kg respectively. The patient was suspected of methanol poisoning and empirical treatment was commenced, consisting of intravenous thiamine and antibiotic administration, intravenous infusion of ethanol and haemodialysis. However, analysis of the patient's serum and an aliquot of the wine sample were both negative for methanol. Infusion of ethanol was subsequently discontinued and the patient succumbed on day 3 of admission. Post-mortem findings were suggestive of aspiration pneumonia and fatty liver, but no other significant findings.

Comments:

Alcoholic ketoacidosis is a syndrome that presents with nausea, vomiting, abdominal pain, in association with signs of volume depletion and the presence of high anion and osmolal gaps. It is vital to distinguish alcoholic ketoacidosis due to ethanol poisoning from the ingestion of other toxic alcohols, such as methanol and ethylene glycol, as the accepted management of the latter may adversely affect the outcome of the former. Such conditions can be differentiated by the estimation of the ketone levels (particularly b-hydroxybutyrate), presence or absence of serum methanol or ethylene glycol, and as for ethylene glycol intoxication, the demonstration of oxalate crystals in the urine. In addition, diabetic ketoacidosis should also be considered, especially in those cases accompanied by hyperglycaemia. The direct measurement of b-hydroxybutyrate should be advocated.^2,5

The key to the diagnosis of alcoholic ketoacidosis is the presence of high anion and osmolal gaps and the demonstration of a raised b-hydroxybutyrate level, together with a high index of suspicion. Osmolal gap is the difference between measured osmolality and calculated osmolality - 2x[Na₊]+[glucose]+[urea]. Normal osmolal gap is less than 10 mmol/L. Elevated osmolol gap signifies the presence of unmeasured osmoles, such as methanol, and ethanol. Ethanol assay is readily available in most clinical laboratories and the presence of a high osmolal gap in such cases should prompt one to consider ethanol poisoning and, more rarely, toxicity from other exotic alcohols.

Note:

The mnemonic MUDPILES helps us remember the causes of a high anion gap metabolic acidosis

Renal tubular acidosis caused by a toxic agent

A 22 years old female was suspected of hypokalaemic periodic paralysis requiring intensive care. She had the following biochemical results:

Comments:

The patient had metabolic acidosis with normal anion gap and respiratory acidosis due to paralysis of the respiratory muscles. The presence of severe hypokalemia and normal anion gap metabolic acidosis indicates renal tubular or gastrointestinal problems. The patient's urine pH of 6.0 indicated that the patient had distal renal tubular acidosis. In the absence of renal tubular acidosis, the urine pH should be around 5.0-5.5 in the face of acidaemia. Metabolic acidosis due to toxic agents was suspected. Massive hippurate and benzoate in the urine was screened out by high-performance liquid chromatography and confirmed by gas chromatography mass spectrometry (Figure 1). A large unknown peak found in the serum was subsequently identified as toluene.³

Conclusion

Acid-base disturbances can be easy to interpret if the underlying pathophysiology principles are applied in the interpretation. In the rare circumstances where the underlying abnormality is obscure, special laboratory investigations and assistance from chemical pathologists should be sought.

Key messages

1. The aim of interpreting acid-base disturbances is to unveil the clinical conditions leading to the acid-base disturbances, particularly those that are obscured, e.g. toxic agents.
2. Acid-base disturbances can be easy to interpret if the underlying pathophysiology principles are applied in the interpretation.
3. To minimize the change in the ratio, the premise is that [HCO₃-] and pCO₂ have to be changed in the same direction.
4. If [HCO₃-] and pCO₂ are changed in different directions, a mixed acid-base disturbance occurs.
5. Before interpreting acid-base data, we have to eliminate the possibility of any preanalytical errors, such as bubbles and excessive amounts of heparin in sample syringes, because they may lead to erroneous interpretation.
6. If a patient is diagnosed to have simple metabolic acidosis, he or she can have more than one condition leading to metabolic acidosis, e.g. renal tubular acidosis and diarrhoea.
7. The difference between the increases in anion gap and the decreases in [HCO₃-] will help us to diagnose mixed high-anion gap and normal-anion gap metabolic acidosis.
8. It is vital to distinguish alcoholic ketoacidosis due to ethanol poisoning from the ingestion of methanol, as the accepted management of the latter may adversely affect the outcome of the former.
9. Elevated osmolol gap signifies the presence of unmeasured osmoles, such as methanol, and ethanol.
10. Ketostix only detects acetoacetate in urine, which is not the predominant form of ketone bodies accumulated in blood during ketoacidosis.
11. Acid-base disturbances can occur in the presence of normal pH, pCO₂, [HCO₃-], and anion gap values.
12. In the rare circumstances where the underlying abnormality is obscure, special laboratory investigations and assistance from chemical pathologists should be sought.