bubble_chart Overview

The human body's stirred pulse: The pH value in the blood is the negative logarithm of the H⁺ concentration in the blood, normally ranging from 7.35 to 7.45, with an equilibrium value of 7.40. The intake of H⁺ in body fluids is minimal, primarily generated endogenously during metabolic processes. The body has a relatively comprehensive regulatory mechanism for acid-base load, mainly including buffering, compensation, and correction. Carbonic acid and bicarbonate are the most important and significant buffer pair in body fluids. During metabolic acid load, H⁺ combines with HCO₃^- to form H₂CO₃. H₂CO₃ is highly unstable, mostly decomposing into CO₂ and H₂O. CO₂ is expelled from the body through respiration, maintaining the ratio of HCO₃^- to H₂CO₃ in the blood at 20:1, thereby keeping the pH value constant. However, compensation has its limits. If the body's compensatory capacity is exceeded, acidosis will further intensify. Metabolic acidosis is the most common type of acid-base imbalance, characterized by a primary decrease in HCO₃^- (<21 mmol/L) and a decrease in pH (<7.35).

bubble_chart Etiology

It is nothing more than excessive production or impaired excretion of H⁺, or excessive loss of HCO₃^-. Common causes include: a. Excessive production of acidic metabolic waste, such as in peritonitis, shock, high fever, or prolonged fasting leading to excessive fat breakdown and ketone accumulation; b. Conditions like diarrhea, intestinal fistula, biliary fistula, and pancreatic fistula, where large amounts of HCO₃^- are lost from the digestive tract; c. Acute renal failure, where the excretion of H⁺ and reabsorption of HCO₃^- are impaired.

When H⁺ levels rise in the body, aside from the buffering system of body fluids, the lungs and kidneys primarily regulate it. The reaction H⁺

+ HCO₃^- → H₂CO₃ → H₂O + CO₂ occurs. When HCO₃^- decreases, H₂CO₃ increases accordingly, dissociating into CO₂, which raises blood PCO₂. This stimulates the respiratory center, causing deep and rapid breathing, thereby increasing CO₂ excretion and reducing H2CO₃ in the blood as compensation. The kidneys excrete H⁺ and NH₄⁺ while reabsorbing HCO₃^- to increase the ratio of HCO₃^- to H₂CO₃ in plasma. If the pH remains normal, it is called compensated metabolic acidosis. However, if this ratio cannot be maintained and the pH drops below 7.35, it becomes uncompensated metabolic acidosis.

bubble_chart Pathogenesis

1. Excessive production of acidic substances

(1) Lactic acidosis: Lactic acidosis can occur in various conditions causing hypoxia. The pathogenic mechanism involves enhanced glycolysis during hypoxia, leading to increased lactate production. Due to insufficient oxidation, lactate accumulates, resulting in elevated blood lactate levels. This type of acidosis is very common.

(2) Ketoacidosis: Ketoacidosis occurs when the body mobilizes large amounts of fat, such as in diabetes, starvation, prolonged vomiting during pregnancy, or alcohol intoxication with vomiting and reduced food intake for several days. In these cases, fatty acid oxidation in the liver increases, leading to excessive ketone body production that surpasses the utilization capacity of extrahepatic tissues, resulting in ketonemia. Ketone bodies include acetone, β-hydroxybutyrate, and acetoacetate, with the latter two being organic acids that cause metabolic acidosis. This type of acidosis also falls under the category of increased anion gap (AG) normal-chloride metabolic acidosis.

Patients with diabetes due to insulin deficiency can develop severe ketoacidosis, which may even be fatal. Normally, insulin counteracts lipolytic hormones, maintaining a constant rate of lipolysis. When insulin is deficient, the effects of lipolytic hormones such as ACTH, cortisol, glucagon, and growth hormone are enhanced, activating large amounts of lipase in adipocytes. This accelerates the breakdown of triglycerides into glycerol and free fatty acids, which then flood the liver, significantly increasing ketogenesis.

The increase in hepatic ketogenesis is associated with elevated activity of acylcarnitine transferase. Normally, insulin inhibits this enzyme, but when insulin is deficient, its activity is markedly enhanced. Fatty acids entering the liver form fatty acyl-CoA, which, under the action of this enzyme, enters mitochondria in large quantities and undergoes β-oxidation to produce substantial amounts of acetyl-CoA, the precursor for ketone body synthesis. Under normal conditions, acetyl-CoA is either condensed with oxaloacetate by citrate synthase to form citrate and enter the tricarboxylic acid (TCA) cycle, or it is converted to malonyl-CoA by acetyl-CoA carboxylase for fatty acid synthesis. Thus, only minimal amounts of acetyl-CoA are used for ketone body synthesis, which can be fully utilized by extrahepatic tissues. Additionally, in diabetic patients, the increased fatty acyl-CoA in hepatocytes inhibits the activity of citrate synthase and acetyl-CoA carboxylase, impairing the entry of acetyl-CoA into the TCA cycle and hindering fatty acid synthesis. Consequently, large amounts of acetyl-CoA are condensed into ketone bodies in the liver.

Ketoacidosis in non-diabetic patients results from insufficient glycogen replenishment, forcing the body to rely heavily on fat mobilization, such as during starvation.

2. Impaired renal acid excretion and bicarbonate conservation Whether due to reduced H⁺ secretion by renal tubular epithelial cells, decreased bicarbonate generation, or a severe decline in glomerular filtration rate, both acute and chronic renal failure can lead to renal metabolic acidosis. Since the kidneys are the ultimate regulators of acid-base balance, acidosis in renal failure is more severe and represents one of the critical clinical conditions necessitating hemodialysis.

(1) Renal failure: If renal failure is primarily caused by dysfunction of the renal tubules, the resulting metabolic acidosis is mainly due to the reduced production of NH₃ and decreased excretion of H⁺ by the tubular epithelial cells. Normally, renal tubular epithelial cells receive glutamine and amino acids from the blood supply. Under the catalytic action of glutaminase and amino acid oxidase, NH₃ is continuously generated. NH₃ diffuses into the tubular lumen and combines with H⁺ secreted by the renal tubular epithelial cells to form NH₄⁺, which raises the urine pH. This enables the continuous secretion of H⁺ into the tubular lumen, completing the acid excretion process. The Na⁺ in the original urine is continuously exchanged by NH₄⁺ and reabsorbed into the blood along with HCO₃^- to form NaHCO₃. This is the primary acid-excreting and alkali-preserving function of the renal tubules. When tubular dysfunction occurs due to disease, leading to severe impairment of this function, acidosis can result. In this type of acidosis, since the glomerular filtration function remains largely unaffected, no acidic anions accumulate in the body due to filtration impairment. Its characteristic is a normal anion gap (AG) hyperchloremic metabolic acidosis. In other words, anions such as HPO₄⁼ and SO₄⁼ do not accumulate, so the AG does not increase. However, due to insufficient reabsorption of HCO₃^-, another easily regulated anion, Cl^-, takes its place, leading to elevated blood chloride levels.

Renal failure, if primarily due to glomerular lesions leading to impaired filtration function, generally results in the retention and increase of unmeasured anions in plasma, such as HPO₃⁼, SO₄⁼, and some organic acids, when the glomerular filtration rate falls below 20% of normal. The characteristic feature here is an increased anion gap (AG) with normal chloride metabolic acidosis. Reduced filtration of HPO₄⁼ can lead to decreased excretion of titratable acids, causing H⁺ retention in the body.

(2) Carbonic anhydrase inhibitors: For example, when using acetazolamide as a diuretic, the drug inhibits the activity of carbonic anhydrase in renal tubular epithelial cells, weakening the reaction CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃^-. This results in reduced H⁺ secretion and decreased HCO₃^- reabsorption, leading to a normal AG hyperchloremic acidosis. At this time, Na⁺, K⁺, and HCO₃^- excretion in urine is higher than normal, producing a diuretic effect. Prolonged use of the drug may lead to the aforementioned type of acidosis.

(3) Renal tubular acidosis (RTA): Renal tubular acidosis is a disorder of the kidney's ability to acidify urine, resulting in a normal AG hyperchloremic metabolic acidosis. Currently, it is classified into four types based on its pathological mechanism.

Type I – Distal renal tubular acidosis (Distal RTA). This is caused by impaired H⁺ excretion in the distal tubule. Here, the distal tubule cannot establish or maintain the normal steep concentration gradient of H⁺ between the tubular lumen and the peritubular fluid. The formation of H₂CO₃ in the tubular epithelial cells is impaired, and H⁺ in the lumen may diffuse back into the peritubular fluid. This may be due to a series of structural, functional, and metabolic abnormalities in the renal tubular epithelial cells affecting H⁺ excretion. Its disease causes include primary, autoimmune, renal calcification, drug poisoning (e.g., amphotericin B, toluene, lithium compounds, certain analgesics and anesthetics), pyelonephritis, urinary obstruction, kidney transplantation, leprosy, genetic disorders, and cirrhosis.

Type II—Proximal Renal Tubular Acidosis (Proximal RTA). It is caused by impaired reabsorption of HCO₃^- in the proximal tubule. In this case, a large amount of HCO₃^- is excreted in the urine, and plasma HCO₃^- levels decrease. If we artificially raise and maintain the plasma HCO₃^- of such patients to normal levels, it can be observed that the renal loss of HCO₃^- exceeds 15% of the filtered load, which is a significant amount. This can lead to severe acidosis. When plasma HCO₃^- drops significantly and acidosis becomes severe, the patient's urinary HCO₃^- also becomes minimal. The aforementioned method can then be used to identify the site of the impairment. The pathogenesis of this type of RTA may be due to insufficient energy for active transport, often resulting from inherited metabolic disorders.

Type III – also known as the I-II mixed type, involves both dysfunction in the distal tubule's ability to acidify urine and impairment in the proximal convoluted tubule's reabsorption of HCO₃^-.

Type IV – Current data suggest that this type is caused by a cation exchange disorder in the distal convoluted tubule. In this case, the luminal membrane has an impaired passage of H⁺. Patients exhibit hypoaldosteronism with low renin levels and hyperkalemia. When K⁺ levels are high, they compete with H⁺, leading to reduced renal excretion of NH₄⁺ and retention of H⁺. This condition is commonly seen in aldosterone deficiency, decreased renal responsiveness to aldosterone, or other causes such as those seen in Type I or II.

(4) Adrenal cortical insufficiency (Addison's disease): On one hand, due to decreased renal blood flow, the filtration of buffer substances is reduced, resulting in less titratable acid formation. On the other hand, reduced Na⁺ reabsorption leads to decreased excretion of NH₃ and H⁺, as there is an exchange relationship between Na⁺ reabsorption and the excretion of NH₃ and H⁺.

3. Extrarenal loss of alkali: The [HCO₃^-] levels in intestinal fluid, pancreatic juice, and bile are higher than those in plasma. Therefore, conditions such as diarrhea, intestinal fistulas, or intestinal decompression suction can lead to significant loss of [HCO₃^-], resulting in hyperchloremic metabolic acidosis with a normal anion gap (AG). Postoperative ureterosigmoidostomy can also cause substantial loss of HCO₃^-, leading to this type of acidosis. The mechanism may involve passive reabsorption of Cl^- and excessive excretion of HCO₃^-, i.e., a Cl^-–HCO₃^- exchange.

4. Excessive intake or administration of acidic or acid-forming drugs  Ammonium chloride can decompose in the liver to form ammonia and hydrochloric acid. Prolonged use of this phlegm-expelling formula in large doses may lead to acidosis. NH₄Cl→NH₃＋H⁺＋Cl^-. This results in a normal anion gap hyperchloremic metabolic acidosis. Prolonged use of calcium chloride in large doses can also cause this type of acidosis. The mechanism is that Ca⁺⁺ is poorly absorbed in the intestine, while Cl^- is absorbed along with H⁺, with the amount absorbed exceeding that of Ca⁺⁺. Ca⁺⁺ can combine with HPO₄⁼, one of the buffer bases, in the intestine, reducing the absorption of HPO₄⁼. Ca⁺⁺ can also combine with H₂PO₄^- to form non-absorbable Ca₃（PO₄）₂ and H⁺, while H⁺ is absorbed along with Cl^-.

Salicylate preparations such as aspirin (acetylsalicylic acid) can rapidly decompose into salicylic acid in the body. It is an organic acid that consumes plasma HCO₃^-, leading to an AG-increased normochloremic metabolic acidosis.

In methanol poisoning, methanol is metabolized in the body to form formic acid, which can cause severe acidosis. Some case reports indicate that blood pH can drop to 6.8. Poisoning can occur from mistakenly drinking industrial alcohol containing methanol or consuming methanol as alcohol. A large-scale poisoning incident occurred in China in 1987. Aside from other toxic effects of methanol, AG-increased normochloremic metabolic acidosis is one of the major causes of death in acute poisoning. The rationale for aggressively administering NaHCO₃ as emergency treatment lies in this.

Acidic foods, such as proteins, can ultimately metabolize into sulfuric acid, keto acids, etc. Of course, this is not a problem for healthy individuals. However, when renal function is impaired, a high-protein diet may lead to metabolic acidosis. This is also an AG-increased normochloremic metabolic acidosis.

Excessive infusion of amino acid solutions or hydrolyzed protein solutions can also cause metabolic acidosis, particularly with the hydrochloride salts of amino acids, which release HCl during metabolism. Although these solutions are adjusted to a pH of 7.4 during preparation, it is important to note that their hydrochloride salts can release hydrochloric acid during metabolism. Clinically, supplementing patients with a certain amount of NaHCO₃ is based on this rationale.

5. Dilutional acidosis: Infusing large amounts of normal saline can dilute the body's HCO₃^- and increase Cl^-, thereby causing an AG-normal hyperchloremic metabolic acidosis.

bubble_chart Clinical Manifestations

The manifestations vary depending on the disease cause, and mild cases are often masked by the primary condition. The main symptoms include: a. Deep and rapid breathing, increased ventilation, decreased PCO₂, which may mitigate the drop in pH; sometimes, the breath may have a ketone odor. b. Facial flushing, increased heart rate, often low blood pressure, confusion, or even unconsciousness, often accompanied by severe symptoms of dehydration. c. Reduced myocardial contractility and decreased sensitivity of peripheral blood vessels to Black Catechu phenethylamine, leading to arrhythmias, vasodilation, hypotension, acute renal insufficiency, and shock. d. Decreased muscle tone, diminished or absent tendon reflexes. e. Decreased blood pH, carbon dioxide combining power (CO₂CP), SB, BB, and BE; serum Cl^- and K⁺ may increase. Urinalysis typically shows an acidic reaction.

bubble_chart Diagnosis

If a patient has a history of severe diarrhea, intestinal fistula, or ureterosigmoidostomy, along with deep and rapid breathing, metabolic acidosis should be suspected. Blood gas analysis can confirm the diagnosis and provide information on compensation status and the severity of acidosis. In decompensated cases, blood pH and [HCO₃^-] are significantly decreased, while PCO₃ remains normal. In partial compensation, blood pH, [HCO₃^-], and PCO₂ all show varying degrees of reduction. If this test is not feasible, measuring carbon dioxide combining power can also confirm the diagnosis and roughly assess the severity of acidosis. Measurements of serum Na⁺, K⁺, and Cl^- are also helpful in evaluating the condition.

bubble_chart Treatment Measures

1. Actively prevent and treat the primary diseases causing metabolic acidosis, correct typical edema and electrolyte imbalances, restore effective circulating blood volume, improve tissue perfusion, and enhance renal function.

2. Administer alkali to correct metabolic acidosis: Severe acidosis that is life-threatening requires prompt alkali correction. Sodium bicarbonate (NaHCO₃) is commonly used to supplement HCO₃^- and buffer H⁺. Sodium lactate can also be used, but it is avoided in cases of liver dysfunction or lactic acidosis because sodium lactate must be metabolized by the liver to produce NaHCO₃. Tris-hydroxymethyl aminomethane (THAM or Tris) is frequently used nowadays. It does not contain Na⁺, HCO₃^-, or CO₂. Its molecular formula is (CH₂OH)₃CNH_2, and it neutralizes H⁺ through its OH^-. One gram of NaHCO₃ contains 11.9 mmol of HCO₃^-, one gram of sodium lactate is equivalent to 9 mmol of HCO₃^-, and one gram of THAM is equivalent to 8.2 mmol of HCO₃^-. NaHCO₃ solution acts rapidly, has a definite therapeutic effect, and causes minimal side effects.

The amount of alkali required to correct metabolic acidosis can be calculated using the following formulas:

Alkali supplementation (mmol) = (Normal CO₂CP - Measured CO₂CP) × Body weight (kg) × 0.2

or = (Normal SB - Measured SB) × Body weight (kg) × 0.2

Clinically, one-half to one-third of the calculated dose may be administered initially, and the remaining amount can be adjusted based on symptoms and laboratory results. During acidosis correction, large amounts of K⁺ shift into cells, leading to hypokalemia, which must be promptly addressed.

3. Manage hyperkalemia in acidosis and hypokalemia in potassium-deficient patients: Acidosis is often accompanied by hyperkalemia. When alkali is administered to correct acidosis, H⁺ moves from intracellular to extracellular spaces and is continuously buffered, while K⁺ shifts back into cells, causing serum potassium levels to decrease. However, it is important to note that some patients with metabolic acidosis may have concurrent potassium loss, resulting in hypokalemia despite acidosis. Correcting acidosis in such cases can further lower serum potassium levels, leading to severe or even life-threatening hypokalemia. This scenario is observed in diabetic patients with osmotic diuresis-induced potassium loss or diarrhea patients with potassium depletion. Potassium supplementation should be adjusted according to the degree of serum potassium decline during acidosis correction.

For acidosis caused by severe renal failure, peritoneal dialysis or hemodialysis is required to correct fluid, electrolyte, acid-base imbalances, and metabolic waste retention.