Generating Differential Diagnoses

Identifying the primary process is important because it helps you to generate differential diagnoses and decide on work-up and management. The basic differential diagnoses for the primary acid-base abnormalities are as follows:

Elevated Anion Gap Metabolic Acidosis

It is common for students and physicians to use a mnemonic to remember the common causes of an elevated anion gap acidosis. One common mnemonic is as follows:

• M: Methanol intoxication
• U: Uremia
• L: Lactic acidosis
• E: Ethylene glycol intoxication
• P: Paraldehyde intoxication
• A: Alcoholic Ketoacidosis
• K: Ketoacidosis (diabetic, starvation, alcoholic)
• S: Salicylate intoxication, Seizures, Shock

It is important to recognize that in the case of seizures and shock, it is actually the accumulation of lactic acid that is responsible for the development of the elevated anion gap acidosis.

Some people use an alternative mnemonic:

• M: Methanol intoxication
• U: Uremia
• D: Diabetic Ketoacidosis
• P: Paraldehyde intoxication
• I: Infection (sepsis)
• L: Lactic acidosis
• E: Ethylene glycol intoxication
• S: Salicylate intoxication, Seizures, Shock

Other diagnoses that don’t fit in these mnemonics can also cause an elevated anion gap acidosis and should be considered in cases where your initial work-up does not identify an underlying cause. These other diagnoses would include:

• Cyanide or carbon monoxide poisoning
• Excess inhaled beta-agonists
• Hereditary disorders (eg. glucose-6-phosphatase deficiency)
• D-Lactic acidosis (jejuno-ilea bypass, small bowel resection)
• Medications (iron, isoniazid, zidovudine)
• Toluene intoxication
• Massive Rhabdomyolysis

As noted above, in several of these cases (eg. carbon monoxide poisoning, excess beta-agonists), the elevated anion gap derives from accumulation of lactate.

You should also be aware that there is a differential diagnosis for a low serum anion gap. It includes the following items:

• Fall in unmeasured anions (eg. Hypoalbuminemia)
• Increased unmeasured cations (hyperkalemia, hypercalcemia, hypermagnesemia)
• Lithium
• Multiple Myeloma
• Bromide (found in Pyridostigmine Bromide used in the treatment of myasthenia gravis and some herbal medications)

Normal Anion Gap Metabolic Acidosis (non-gap acidosis)

The differential diagnosis includes:

• Gastrointestinal bicarbonate losses:
  • Diarrhea
  • Ureteral Diversion (ileal loop)
• Renal bicarbonate losses:
  • Carbonic anhydrase inhibitors (eg. acetazolamide)
  • Renal tubular acidosis
  • Aldosterone inhibitors or hypoaldosteronism

If the cause of the non-gap acidosis is not clear based on the patient history, you can identify whether the problem is renal or gastrointestinal losses by calculating a urine anion gap:

Urine Anion Gap (UAG) = (Urine Na⁺ + Urine K⁺) – Urine Cl^-

A positive value (UAG >0) suggests the metabolic acidosis is due to a renal etiology, whereas a negative value (UAG <0) points to a gastrointestinal source.

Metabolic Alkalosis

The differential diagnosis includes:

• Chloride Responsive Alkaloses:
  • - Vomiting
  • - Nasogastric suction
  • - Diuretics
• Chloride Unresponsive Alkaloses:
  • - Hyperaldosteronism
  • - Cushing’s syndrome
  • - Licorice ingestion
  • Bartter’s syndrome
  • Excess alkali intake (e.g., milk alkali syndrome)

If the cause of the metabolic alkalosis is not clear based on the patient history, you can obtain a urine chloride level to help determine the cause. If the urine chloride level is <15 the patient has a "chloride responsive alkalosis" which can be corrected with saline (NaCl) administration. This typically happens with gastrointestinal losses or intravascular volume depletion (i.e., a contraction alkalosis with diuretic use). If the urine chloride is >15, the patient has a "Chloride Unresponsive Alkalosis."

Respiratory Acidosis

A primary respiratory acidosis implies that the patient is hypoventilating or not ventilating enough in the face of high CO₂ production. This can be seen in the following settings:

• Acute intoxication with narcotics or other sedative medications
• Severe metabolic encephalopathy
• Obesity hypoventilation
• Severe chronic obstructive pulmonary disease
• Acute upper airway obstruction
• Neuromuscular disorders (e.g., Guillan Barre, Myasthenia Gravis, Botulism, Amyotrophic Lateral Sclerosis)
• Later stages of a severe asthma exacerbation (e.g., the patient is tiring out)
• Thoracic cage trauma (flail chest)
• Inappropriately low minute ventilation settings on mechanical ventilation

Respiratory Alkalosis

A primary respiratory alkalosis implies that the patient is hyperventilating. This can be seen in the following settings:

• Early stages of an asthma exacerbation
• Anxiety attack
• Acute hypoxia (hypoxic ventilatory response)
• Pregnancy or other cases of elevated progesterone
• Cirrhosis and/or hepatic encephalopathy
• Salicylate intoxication
• Central nervous system disease

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