Elevated anion gap metabolic acidosis due to starvation ketoacidosis, in the setting of lactation.
This patient presented with symptoms of nausea, vomiting, and decreased oral intake, in the setting of a recent cold. Additionally, she recently had a baby and had been breastfeeding her daughter throughout her illness, prior to presenting to the emergency department. Her initial lab results were notable for hyperkalemia, decreased total CO2, leukocytosis and a urinalysis with elevated ketones and WBCs. A venous blood gas showed decreased bicarbonate, PvCO2, and pH, indicating the presence of a metabolic acidosis, with the patient's electrolyte levels revealing an elevated anion gap (1,2,6,8). The patient responded well to interventions to resolve her hyperkalemia and high anion gap metabolic acidosis. Toxicological causes of a metabolic acidosis were ruled out, and volatile alcohol testing showed an elevated acetone level. The patient's beta-hydroxybutyrate level was also elevated, and urine organic acids showed lactic aciduria and ketonuria. Taken together, the clinical and laboratory findings led to the patient ultimately being diagnosed with an elevated anion gap metabolic acidosis attributed to starvation ketoacidosis, in the setting of lactation (3,4).
Normal acid-base homeostasis is complex and managed by a variety of physiologic mechanisms, including multiple buffering systems within the blood, and active homeostatic responses involving the kidneys and lungs (1,3,5,8,10). Acid-base disorders can be classified as either metabolic or respiratory, depending on whether the initial acid-base derangement is due to changes in the bicarbonate concentration or PCO2, respectively (8). Metabolic acidosis is a disorder, "characterized by a primary reduction in the serum concentration of bicarbonate (HCO3-), a secondary decrease in the arterial partial pressure of carbon dioxide (PaCO2), and a reduction in blood pH," (1). Metabolic acidosis may present acutely or develop chronically over a period of time, result from a variety of different etiologies, and thus present with a wide range of signs and symptoms (1-10). The development of metabolic acidosis is due to increased levels of acid in the blood, relative to base, and may result from either ingestion of acid precursors (e.g., methanol, ethylene glycol, etc.), dysregulation of metabolism favoring the production of acids (e.g., lactic acid, ketones), decreased ability to excrete acids, or base (i.e., bicarbonate) loss (1-10). In response to a metabolic acidosis, the body attempts to maintain acid-base homeostasis through hyperventilation to lower the PCO2 - and thus carbonic acid - in the blood relatively quickly, and through mechanisms within the kidney to retain base and get rid of acid, that act more slowly (1,3,5,8,10).
Some cases of metabolic acidosis may have an elevated anion gap, as was seen in this patient's case. A patient's anion gap can be calculated by subtracting the concentration of the major serum anions, bicarbonate and chloride, from the concentration of the major serum cation, sodium (potassium may sometimes be used as well) (1,6,8). There are many causes of an elevated anion gap. Anion gaps result from the presence of an acid (e.g., lactic acid, beta-hydroxybutyrate, etc.) within a patient's serum that does not dissociate into chloride or bicarbonate, and is thus unaccounted for in the aforementioned calculation (1-4, 6-10). In this patient's case, the initial electrolyte values were sodium 135 mmol/L, chloride 103 mmol/L, and a very low total CO2, measured as <5.0 mmol/L. Total CO2 can be used clinically as a surrogate for plasma bicarbonate levels, although it is technically comprised of both the dissolved carbon dioxide and bicarbonate concentrations (8). Using 5 mmol/L as an estimate for the patient's bicarbonate, her anion gap would be calculated as 135-(103+5)=27 mmol/L and would be considered elevated, as the reference range at our lab is 7-15 mmol/L, which may differ from reference ranges at other labs as different authors denote various normal ranges in the literature(1,3,6,8,10). The differential diagnosis for an elevated anion gap metabolic acidosis is broad and one common, helpful mnemonic to remember some of the potential etiologies is MUDPILES, which stands for Methanol ingestion, Uremia, Diabetic (and alcoholic) ketoacidosis, Paraldehyde/Paracetamol (acetaminophen)/Propylene glycol poisoning, Isoniazid/Iron poisoning, Lactic acidosis, Ethylene glycol poisoning, and Salicylate overdose (2,8). Additionally, it is important to note that not all cases of ketoacidosis will present with an elevated anion gap (1,6,7). One of the initial concerns in this case was the potential of a toxic alcohol ingestion, hence the initiation of fomepizole while awaiting toxicology results. Fomepizole is a drug that blocks the enzyme alcohol dehydrogenase, and prevents the metabolism of certain alcohols (e.g., methanol, ethylene glycol, etc.) into toxic, acidic metabolites (1,2,8,10).
As mentioned above, ketoacidosis can cause an elevated anion gap metabolic acidosis (1-4, 6-8, 10). Ketoacidosis can be, "defined as an increase in ketone body concentration, together with a decrease of serum bicarbonate and pH," (2). Certain conditions are more likely to cause ketoacidosis, such as "diabetes, starvation coupled with physiologic stress, ethanol toxicity, other alcohol ingestions, drug toxicities, and inborn errors of ketone metabolism," (2). Normally, when the body has plenty of dietary carbohydrates, insulin is released and stimulates glucose storage while preventing the breakdown of stored fats (4-6). During this well-fed state, pyruvate is produced through glycolysis and utilized in the citric acid cycle to produce ATP, which will be used as an energy source for cells (6). During periods when glucose is significantly decreased the body will adapt to utilizing ketones (e.g., acetoacetate, acetone, and beta-hydroxybutyrate), derived from acetyl-CoA - which is produced when fatty acids undergo beta oxidation in the liver - as an additional source of energy (2-4,6,8,10). The ketone bodies acetoacetate and beta-hydroxybutyrate are anions (acetone is neutral) and may decrease serum pH as their concentrations rise (1-10). Although ketones can be measured in both the patient's blood and urine, it is important to realize that urine levels of ketones may not provide an accurate assessment of ketone concentration in the blood, and common urine tests may not assess all three types of ketone bodies (1,2,6). For example, urine dip stick testing for urinary ketones utilizes a method known as the nitroprusside reaction (2,6). While this reaction can determine the presence of acetone and acetoacetate in the urine, it cannot detect beta-hydroxybutyrate (1,2,6).
Starvation, in healthy adults, typically does not lead to a severe ketoacidosis (1-4,6,7,10). If starvation is prolonged, or occurs alongside additional stressors, including pregnancy, substantial bouts of emesis, intense exercise, chronic alcohol abuse, lactation, gastric banding, or particular cases of hyperthyroidism, it can lead to a dangerous and severe metabolic ketoacidosis (2-4,6,7,10).
In the case described above, the patient was vomiting and unable to tolerate food or fluids (i.e., undergoing starvation) and developed a metabolic ketoacidosis. One of the unique physiological stressors in this case was that the patient was continuing to breast feed her newborn during her fasting state, which has been reported in the literature as a relatively uncommon stressor associated with the development of metabolic ketoacidosis during periods of starvation (3,4). Compared to non-lactating women, women who are producing milk face a higher demand for energy that leads to, "enhanced gluconeogenesis, decreased insulin secretion, lipolysis, and can subsequently induce ketogenesis," (3). Some authors liken this to a similar condition in the world of veterinary medicine, known as bovine ketosis, which may be seen when milk producing dairy cows cannot meet their body's increased demand for energy through dietary intake (3, 4). In humans, milk production typically continues during periods of starvation, as the process "is generally resistant to caloric insufficiency as additional energy reserves are normally met from diet, body fat, and energy-sparing metabolic adaptations," and may become disrupted only in cases of extreme and/or prolonged periods of starvation (4). Decreased intake of calories or carbohydrates is the underlying stressor most often reported in cases of lactating women who develop ketoacidosis (4). It has been observed that lactating women, when compared to non-lactating women, produce greater levels of the ketone beta-hydroxybutyrate due to decreased oxidation of carbohydrates, and greater oxidation of fats, when placed on a diet low in carbohydrates or participate in a prolonged fast (4). Although the clinical presentation varies amongst patients who present with ketoacidosis during lactation, all cases that have been reported have had favorable recoveries, even though roughly 50% of patients have had pH less than 7.1, and one patient even had a pH reported as low as 6.64 (3,4). Similar to cases seen in the literature, this case involved the development of a severe metabolic ketoacidosis secondary to starvation, in the setting of lactation, with the patient responding well to therapy (3,4).
A final point of interest in this case was the patient's concurrent hyperkalemia, which also responded well to treatment. Hyperkalemia can present with a variety of neurologic and cardiac abnormalities including altered mental status, weakness, and abnormal cardiac rhythms (5,8). While the kidneys play an important role in intra- and extracellular potassium homeostasis, there are many extra-renal variables that contribute as well, including insulin, catecholamines, aldosterone, intra- and extracellular tonicity, and the body's acid-base status (1,5,8,9). In general terms, hyperkalemia occurs during acidosis and hypokalemia occurs during alkalosis (5,8,9). During acidosis, serum potassium is elevated due to the "inhibition of potassium secretion by the distal tubule," as well as, the "shift of potassium from intracellular to extracellular space as hydrogen ions move into cells to be buffered," (5). The resulting hyperkalemia is more profound in metabolic acidosis compared to respiratory acidosis (5). Additionally, the specific acid underlying the acidosis plays a role in the magnitude of the intra- and extracellular potassium shifts (5,9). Organic anions, such as those produced in ketoacidosis, are able to easily permeate cells (5,9). This allows the organic anion to enter the cell with its accompanying hydrogen ion and maintain electroneutrality (5,9). In comparison, when there is a rise in hydrochloric acid, the hydrogen ions are allowed to enter the cell while the chloride anion is not, leading to a disruption in electroneutrality and the extracellular shift of potassium (5,8,9). Overall, this usually leads to a less severe degree of hyperkalemia in cases of organic acidosis (5,9). In fact, some authors in the past have gone so far as to argue that "uncomplicated organic acidemias do not produce hyperkalemia," (9). During starvation, insulin levels may be decreased and glucagon may be increased (2-4,6,10). Insulin affects potassium levels by promoting the shift of potassium from the extracellular compartment to the intracellular compartment, thus lowering serum potassium (5,8,9). In cases where insulin is decreased, the opposite effect may occur, leading to hyperkalemia (5,8,9). Glucagon, on the other hand, has been shown to cause hyperkalemia in animal studies (9). Additionally, dehydration may play a role in the development of hyperkalemia (8,9). Thus, the etiology of hyperkalemia may be complex and multifactorial (1,5,8,9). After determining and addressing the underlying causes, hyperkalemia can be treated with drugs that promote the intracellular shift of potassium, including insulin with glucose or beta-2 agonists (5,8,9). In cases of hyperkalemia due to acidosis, restoration of normal acid-base status often leads to a quick return of normal serum potassium concentrations (8). In this case, the etiology of the patient's hyperkalemia was likely multifactorial, with her starvation ketoacidosis playing a substantial role.
Contributed by Andrew Freeman, MD and Kenichi Tamama, MD, PhD