Cause of overproduction of acids with an increased anion gap metabolic acidosis

Cause of overproduction of acids with an increased anion gap metabolic acidosis

A list of the causes of metabolic acidosis is provided below in detail.

Causes of Metabolic Acidosis

Acid gain

With retention of anions in plasma:

  • 1. l -lactic acidosis
    • A. Due predominantly to overproduction of l -lactic acid
      • Hypoxic lactic acidosis
      • Inadequate delivery of O (cardiogenic shock, shunting of blood past organs [e.g., sepsis], or excessive demand for oxygen [e.g., seizures])
      • Increased production of l -lactic acid in absence of hypoxia
      • Overproduction of NADH and accumulation of pyruvate in the liver (e.g., metabolism of ethanol plus a deficiency of thiamin)
      • Decreased pyruvate dehydrogenase activity (e.g., thiamin deficiency, inborn errors of metabolism)
      • Compromised mitochondrial electron transport system (e.g., cyanide, riboflavin deficiency, inborn errors affecting the electron transport system)
      • Excessive degree of uncoupling of oxidative phosphorylation (e.g., phenformin)
    • B. Due predominantly to reduced removal of l -lactate: liver failure (e.g., severe acute viral hepatitis, shock liver, drugs)
    • C. Due to a combination of reduced removal and overproduction of l -lactic acid
      • Antiretroviral drugs (inhibition of mitochondrial electron transport plus hepatic steatosis)
      • Metastatic tumors (especially large tumors with hypoxic areas plus liver involvement)
  • 2. Ketoacidosis (diabetic ketoacidosis, alcoholic ketoacidosis, hypoglycemic ketoacidosis including starvation, ketoacidosis due to a large supply of short-chain fatty acids [i.e., acetic acid from fermentation of poorly absorbed carbohydrate plus inhibition of acetyl-coenzyme A carboxylase])
  • 3. Kidney insufficiency (metabolism of dietary sulfur-containing amino acids and decreased kidney excretion of NH )
  • 4. Metabolism of toxic alcohols (e.g., formic acid from metabolism of methanol, glycolic acid, and oxalic acid from metabolism of ethylene glycol)
  • 5. d -lactic acidosis (and other organic acids produced by gastrointestinal bacteria)
  • 6. Pyroglutamic acidosis

With a high rate of excretion of anions in urine:

  • 1. Glue sniffing (hippuric acid overproduction)
  • 2. Diabetic ketoacidosis with excessive ketonuria

NaHCO loss

Direct loss of NaHCO :

  • 1. Via the GI tract (e.g., diarrhea, ileus, fistula)
  • 2. Via the urine (proximal renal tubular acidosis or low carbonic anhydrase II or IV activity)

Indirect loss of NaHCO (low urinary NH secretion):

  • 1. Low glomerular filtration rate
  • 2. Renal tubular acidosis
    • A. Low availability of NH (urine pH ∼5) = problem in PCT ammoniagenesis: hyperkalemia, alkaline pH in PCT cells
    • B. Defect in net distal H secretion (urine pH often ∼7):
      • ATPase defect or alkaline α-intercalated cells (a number of autoimmune disorders or disorders with hypergammaglobulinemia; e.g., Sjögren syndrome)
      • back-leak (e.g., amphotericin B)
      • HCO secretion in the collecting ducts (e.g., a molecular defect in the Cl-/HCO − anion exchanger leading to its mistargeting to the luminal membrane of α-intercalated cells, as in some patients with Southeast Asian ovalocytosis)
    • C. Problem with both distal H secretion and medullary NH (urine pH <6): Diseases involving the kidney interstitial compartment (e.g., sickle cell disease)

PCT , Proximal convoluted tubule.

A secret heuristic for the causes of an elevated anion gap is “KULT”:

  • • Ketones (diabetic, fasting and alcoholic ketoacidosis)
  • • Uremia (with retained phosphate and sulfate and others)
  • • Lactate (e.g., with hypoxia and septic shock)
  • • Toxic ingestions (especially ethylene glycol and methanol)

While ketones are typically detected from the clinical history, a secret is that ketonuria may not be detected on a standard urinalysis if there is a high NADH/NAD ratio (e.g., contaminant, ethanol intake). The reason is that beta-hydroxybutyrate (BHB) is favored when NADH is abundant, and BHB is not detected by the nitroprusside test, which is the urinalysis-based assay. The next test to be sought is the venous lactate measurement. When a VBG is available, also take note of the PvCO 2 , as noted previously. Lastly, consider assessing for toxic ingestions by calculating a serum osmolal gap (P Osmolal gap ). This will determine whether new uncharged particles are present in plasma:

However, as the toxic alcohols ethylene glycol and methanol are metabolized to oxalate and formic acid, the osmolal gap falls as the anion gap rises. Early after ingestion, before metabolism has occurred, the osmolal gap is present. Subsequently, metabolism leads to a rising anion gap such that the time of the peak for both anion and osmolal gaps may not coincide

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