Multiple Electrolyte Imbalances and Mixed Acid-base Disorder Posing a Diagnostic Dilemma

A Case Report

Fortune O. Alabi; Christopher O. Alabi; Rafaela G. Basso; Nadia Lakhdar; Adebanke O. Oderinde


J Med Case Reports. 2020;14(15) 

In This Article


The management of a 28-year-old woman who presented with acute-onset muscular stiffness, a history of mixed acid-base imbalance, and multiple electrolyte derangement brought a number of differential diagnoses to mind. She denied use of alcohol in her initial history several times, and as a result, we needed to try to explain what other conditions could cause her symptoms.

Some of the differential diagnoses considered included hypothyroid myopathy because of her history of hypothyroidism, but this was easily ruled out because of her normal free T4. On account of her urinalysis showing pyuria, bacteriuria, and elevated leukocyte esterase with lactic academia, a diagnosis of sepsis was considered. The absence of fever, leukocytosis, and the severe electrolyte derangements made sepsis unlikely. The abnormal urinalysis was ascribed to asymptomatic bacteriuria. We also considered thyrotoxic periodic paralysis (TPP) because she was taking thyroid supplement medication, and excessive exogenous intake of levothyroxine can cause TPP, although it is commonly seen in endogenous cases of thyrotoxicosis such as Graves disease.[2] TPP was discounted easily because of normal free T4 and the acid-base disorder, which could not be explained by this entity. Hypokalemic periodic paralysis was also considered but ruled out because it could not explain the other electrolyte imbalances and lactic acidosis. Alcohol abuse remained the best rationale for her constellation of symptoms and provided plausible mechanisms for both the electrolyte disorders and acid-base disorders.

Alcohol abuse has been linked to a variety of abnormalities such as acid-base disorders, dehydration, and electrolyte imbalances.[3] Metabolic acidosis with anion gap, respiratory alkalosis, metabolic alkalosis, and mixed disturbances can be seen in patients who abuse alcohol, and the presence of each varies from patient to patient.[4–6]

The production of lactic acid and ketone bodies (β-hydroxybutyric acid and acetoacetate) is the cause of acidosis in patients who abuse alcohol. The lactic acidosis is due to elevated hepatic nicotinamide adenine dinucleotide + hydrogen (NADH)/reduced nicotinamide adenine dinucleotide (NAD+) ratio that occurs with alcohol metabolism.

The excess NADH favors lactate production from pyruvate.

As a result, less pyruvate will be available for gluconeogenesis.[7] Furthermore, low NAD+ will inhibit the Krebs cycle because three enzymes (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase) in the pathway require NAD+ for their reduction reactions. Severe forms of lactic acidosis resulting from alcohol abuse are seen when the patient has coexisting thiamine deficiency and tissue hypoperfusion, such as in sepsis, hypovolemia, or heart failure. Thiamine deficiency inhibits the formation of acetyl coenzyme A (CoA) from pyruvate because the oxidation of pyruvate to acetyl CoA by pyruvate dehydrogenase requires thiamine as cofactor. Thiamine deficiency inadvertently favors formation of more lactic acid from pyruvate when NAD+ level is low. We believe the cause of severe lactic acidosis in our patient was due to the combination of alcohol-induced lactic acidosis and systemic hypoperfusion due to intravascular volume depletion. Hepatic NADH/NAD+ ratio usually returns toward the normal baseline once ethanol consumption ceases, allowing all the impeded pathways to return to normal.[8]

Acetic acid, one of the oxidative products of alcohol, becomes converted to acetyl CoA in the liver and from there becomes a substrate for fatty acid synthesis or formation of ketones such as acetoacetate, β-hydroxybutyric acid, or acetone. This is the cause of a mild or moderate ketone production initially seen after recent alcohol ingestion.[6,9]

Severe ketoacidosis usually occurs when blood alcohol levels begin to reduce, and decreased oral food intake causes reduced insulin release, which triggers an increase in counterregulatory hormones glucagon, norepinephrine, and cortisol, resulting in the formation of more ketone bodies from the broken-down fatty acids.[10–13] An elevated NADH/NAD+ ratio associated with alcohol intoxication further encourages the conversion of acetoacetate to β-hydroxybutyrate, making β-hydroxybutyrate the predominant ketoacid in alcoholic ketoacidosis.[14]

Alkalosis in patients with alcohol abuse may be due to loss of hydrogen chloride as a result of protracted vomiting or respiratory alkalosis associated with alcohol withdrawal.[15] The respiratory alkalosis tends to be more significant in patients with sepsis, pain, or cirrhosis because of hyperventilation. A mixed acid-base disturbance is seen when the alkalosis coexists with acidemia from the aforementioned mechanisms. Our patient presented with an elevated anion gap of 31 mmol/L and had a blood pH of 7.48, which is alkalemic and fits the description. According to a study, about 78% of patients admitted with acid-base disorders related to alcohol present with mixed disturbances.[9] An increased anion gap greater than the decrease in bicarbonate concentration will be seen when this occurs, just as in our patient.

The hypokalemia seen in our patient could have been caused by gastrointestinal loss from vomiting. Aldosterone release in response to hypovolemia leads to increased kaliuresis and can be more severe with associated hypomagnesemia, as in our patient. A normal magnesium level is required to block the renal intracellular renal outer medullary potassium (ROMK) channels, which are located on the apical membrane of the distal nephron and limit outward potassium secretion from the distal tubular cells. Hypomagnesemia reduces intracellular magnesium, thereby affecting the inhibition of the ROMK channels and causing urinary potassium wasting, which worsens hypokalemia.[16,17] Hypokalemia with concomitant hypomagnesemia as described above will be refractory to correction until the magnesium is corrected.[18]

Hypomagnesemia in our patient can be explained by the direct magnesiuric effect of alcohol consumption[19,20] or alcohol-induced renal tubular dysfunction, which causes urinary loss of magnesium.[16] Intracellular magnesium shift can also cause hypomagnesemia, possibly brought on in our patient when acidosis was being corrected in the hospital with fluids and by the release of insulin in response to glucose-containing fluids. Elisaf et al. found hypomagnesemia in about 30% of patients with chronic alcohol abuse in their cohort study, and it should be noted that magnesium levels help regulate levels of other electrolytes, such as phosphate, calcium, and potassium, and parathyroid hormone resistance can be seen in hypomagnesemia.[21,22]

Hypophosphatemia in our patient may be explained by ethanol directly causing structural changes in the phospholipid bilayer of the membrane of renal tubular cells and generalized tubular dysfunction, which decreases renal threshold for phosphate excretion. The tubular dysfunction usually improves within days of abstinence from alcohol.[23] Stimulation of phosphofructokinase by a rise in body pH resulting from excessive vomiting or respiratory alkalosis (from alcohol withdrawal) can also cause reduction in phosphate levels because it is used as a substrate in glycolysis. Additionally, intravenous dextrose fluid, which stimulates insulin release, promotes phosphate uptake by the cells as phosphorylated glucose intermediates.[24]

Hypocalcemia in our patient could have been due to direct effect of alcohol, which causes urinary calcium loss.[25] Alcohol also decreases the activity of Na+,K+-ATPase in the renal proximal convoluted tubule cells, causing a decrease in the tubular reabsorption of calcium, which could have been worsened by concomitant hypomagnesemia.[26,27] Another proposed mechanism that links hypocalcemia to hypomagnesemia is the peripheral resistance of parathyroid hormone secondary to hypomagnesemia, which prevents normal physiologic maintenance of normal serum calcium level.[22] Also, alcohol has a direct effect in reducing vitamin D metabolism, which results in decreased intestinal calcium absorption.[28] Even though our patient's serum vitamin D level was not checked in the course of this admission, the possibility of a low vitamin D level cannot be ruled out. At 1 month after discharge, our patient remained symptom-free.