Mitochondrial disorders are rare diseases that are caused by mutations of either mitochondrial DNA or nuclear mitochondrial genes.
A 38-year-old woman with long-standing history of hypokalemia and metabolic acidosis was seen in the Nephrology Clinic for a second opinion regarding her electrolyte abnormalities. Her past medical history was notable for acid reflux, polycystic ovarian syndrome, hypertriglyceridemia, Hashimoto’s hypothyroidism, and anxiety. Her home medications included levothyroxine 200 μg daily, liothyronine 5 μg daily, sertraline 50 mg daily, omeprazole 40 mg daily, lubiprostone 24 mg daily, furosemide 20 mg daily as needed, metolazone 5 mg daily as needed, sodium bicarbonate 650 mg twice daily, and potassium chloride 20 mEq daily. She endorsed daily fatigue and muscle weakness and pain, especially with activity.
Her symptoms initially started at age 26 with off-and-on episodes of hypokalemia and metabolic acidosis. She had 2 documented episodes of hypokalemia and anion gap metabolic acidosis when she was 30 and 35 years of age before her current presentation without any identifiable etiology and without measurement of any lactate levels ( Laboratory data ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone.8 yr prior 3 yr prior 12 mo prior 7 mo prior Current visit 2 d later (at dismissal) Reference range Serum Sodium, mmol/l 140 140 136 140 136 143 135–145 Potassium, mmol/l 3.2 3.4 2.3 3.3 2.1 3.8 3.6–5.2 Chloride, mmol/l 108 103 98 105 80 106 98–107 Bicarbonate, mmol/l 13 21 11 19 38 24 22–29 Creatinine, mg/dl 0.67 0.7 0.67 0.7 0.78 0.72 0.59–1.04 Anion gap 19 16 20 16 18 13 7–15 Magnesium, mg/dl 0.7 1.7 2.5 2.2 1.7–2.3 Albumin, g/dl 4.3 3.4–5.4 Lactate, mmol/l 13.9 4.0 5.1 1.9 0.5–2.2 Arterial blood gas pH 7.55 7.43 7.35–7.45 pCO2, mm Hg 39 32 32–45 pO2, mm Hg 105 105 83–108 HCO3, mmol/l 34 22 22–26 Urine pH 6.7 4.5–8.0 Sodium, mmol/l <10 Potassium, mmol/l 10 Chloride, mmol/l 20 Magnesium, mg/dl 4.0 Ammonium, mmol/l 3–65 Creatinine, mg/dl 101 24-h potassium, mmol 22.7 17–77 Endocrine Cortisol, μg/dl 12 (AM) 11 (PM) 7–25 (AM) 2–14 (PM) TSH, mIU/l 1.4 0.3–4.2 ACTH, pg/ml 35 7.2–63 Creatinine kinase, U/l 131 26–192 Aldosterone, ng/dl 7.7 <21 Renin activity, ng/ml 17 2.9–24
At the time of evaluation in the Nephrology Clinic, her physical examination was notable for short stature, blood pressure of 94/64 mm Hg and heart rate of 88 beats per minute. The rest of her physical examination was unremarkable. Laboratory workup was completed, which showed a serum potassium of 2.1 mmol/l (
At the time of hospital admission, the patient had metabolic alkalosis in combination with anion gap metabolic acidosis (unlike her prior episodes when she primarily had a metabolic acidosis). The metabolic alkalosis in combination with low blood pressure, and low urinary sodium and chloride levels were most consistent with previous diuretic use. Patient confirmed that indeed she was taking diuretics (prescribed to her for lower extremity edema) on a regular basis before her current visit but that she had stopped all use a day before her current evaluation. She had started diuretics after her last emergency department visit (7 months before the current evaluation). She denied any diarrhea despite daily use of lubiprostone 24 mg. A potential shift of potassium related to her lactic acidosis also was considered as a potential contributor to her hypokalemia.
A week later, she was seen again in the Nephrology Clinic. At that point, her metabolic acidosis and hypokalemia had resolved. Her prior episodes of metabolic acidosis were most consistent with an anion gap metabolic acidosis secondary to elevated L lactate levels. In the absence of evidence of any shock or systemic hypoperfusion, a type B lactic acidosis was suspected.
Given this suspicion, urinary organic acid, serum free carnitine (FC), acylcarnitine (AC), and AC/FC ratio were obtained and she was referred to the genetic clinic for further evaluation. Urine organic acid profile was normal. Her total carnitine and FC were slightly low at 33 nmol/l (reference 34–78 nmol/l) and 20 nmol/l (reference 25–54 nmol/l), respectively, but she had a normal AC/FC of 0.7 (reference 0.1–0.8).
During her genetic clinic visit, she was noted to have bilateral hearing loss (on finger rub test), weakness of −1/−2 in the bilateral biceps muscles, hip flexor muscle, and intrinsic hand muscles, in addition to short stature. Her family history was significant for short stature (grandmothers on both sides), hearing loss (mother and maternal aunt), vision problems (mother), and Hashimoto’s hypothyroidism (sister). Quantitative urine analysis of amino acids was normal, as was brain magnetic resonance imaging. Muscle biopsy (left vastus lateralis) showed nonspecific mild myopathy and type 2B fiber atrophy. Mitochondrial full genome analysis was performed, which revealed a large-scale mitochondrial DNA (mtDNA) deletion of approximately 8.1 kb, spanning mitochondrial genome 5791 to 13,917. This deletion was expected to affect partial complex I, and whole complex V and IV, including the following genes:
Mitochondrial disorder is caused by impaired mitochondrial energy production secondary to mutations of either mtDNA or nuclear mitochondrial genes.
Notable in this patient’s presentation were her repeated episodes of hypokalemia in combination with her episodes of lactic acidosis. At the time of her current presentation, even though she had a profound metabolic alkalosis (pH of 7.55), she also had a superimposed anion gap metabolic acidosis (lactate of 5.1 mmol/l and anion gap of 18). This case highlights the importance of calculating the anion gap in all patients with acid-base disorder. When evaluating patients with unexplained hypokalemia, urinary potassium levels can be helpful in evaluating the cause. A low urinary potassium level suggests nonrenal potassium wasting, as could be seen with gastrointestinal losses (e.g., diarrhea), potassium shifting, or when renal potassium wasting has stopped (e.g., after discontinuing diuretic therapy). RTA is a major cause of urinary potassium loss that is typically seen in combination with nongap metabolic acidosis. Schematic of effects of lactic acidosis on plasma K+. Elevation of lactate, an organic acid, causes lactic acidosis, which results in reduction of intracellular pH. The low pH in turn activates the Na+/H+ exchange in the cell, which pushes H+ out in exchange for Na+. The influx of Na+ intracellularly then activates the Na+/K+-ATPase, which results in intracellular shift of K+, leading to hypokalemia. Adapted from Figure 4 in Aronson PS, Giebisch G. Effects of pH on potassium: new explanations for old observations.
When a mitochondrial disease is suspected, other useful screening tests besides an elevated lactate would include urinary organic acid, serum FC, AC, and AC/FC ratio. Urine organic acid test can be helpful to evaluate the intermediates of the Krebs cycle, such as methylmalonate, and dicarboxylic acid, which can be elevated in patients with mitochondrial disorder. Carnitine is necessary for carrying long-chain fatty acids across the mitochondrial membrane and low carnitine levels and elevated AC/FC are suggestive of abnormal free fatty oxidation.
Mitochondrial disorder may have a syndromic or nonsyndromic manifestation.
Presently, there is no curative treatment for mitochondrial disorder. In addition to advising our patient to discontinue her diuretics, proton pump inhibitor, and laxative, she was also started on bicarbonate supplementation. The most commonly used dietary supplement ingredients for mitochondrial disease include vitamin E, coenzyme Q10, riboflavin, and carnitine.
In conclusion, a mitochondrial disorder should be suspected in patients with unexplained lactic acidosis and hypokalemia, and a detailed history and physical examination is important, as it may yield other diagnostic clues, as was the case in our patient ( Teaching pointsA mitochondrial disorder should be suspected in patients with unexplained lactic acidosis. In a patient with unexplained lactic acidosis, it is important to be aware of mitochondrial disorder and to obtain a careful clinical history and physical examination of possible underlying mitochondrial disorder. Certain drugs, such as metformin, can worsen the lactic acidosis. An underlying predisposition should be suspected if lactic acidosis develops in the setting of normal kidney function and on a standard dose of metformin. Hypokalemia associated with lactic acidosis. Unlike inorganic acids that are associated with hyperkalemia, lactic acidosis results in an inward shift of potassium and hypokalemia. This is due to increased activity of Na+-K+-ATPase pump related to the low intracellular pH that develops from lactic acidosis.
All the authors declared no competing interests.