Multiple dyselectrolytemia in a patient with alcohol use disorder (AUD)

Abstract

Alcohol use disorder (AUD) is a chronic disease characterized by an inability to limit alcohol use despite knowledge of the negative health and social impacts. An umbrella entity, AUD encompasses the terms alcohol abuse, alcohol dependence, alcohol addiction, and alcoholism. In patients with AUD, who often have multiple electrolyte abnormalities, hypomagnesemia or magnesium deficiency can lead to prolonged hypokalemia or hypocalcemia, because magnesium is a coenzyme required for renal K excretion or 1,25-(OH)₂D₃ conversion. We experienced a 61-year-old patient with AUD with severe hypomagnesemia combined with hypokalemia and hypocalcemia. The patient had consumed alcohol habitually for about 45 years, and had an extremely irregular diet and chronic diarrheal symptoms for much of that period. When the patient was transported to our hospital for limb weakness and difficulty standing, hypokalemia (1.6 mEq/L), hypomagnesemia (1.0 mg/dL), hypocalcemia (corrected Ca 7.2 mg/dL) and elevated creatine kinase (148000 U/L) were observed. Muscle strength was remarkably reduced, with a manual muscle strength grade of 1/5 and no deep tendon reflex. Trousseau’s sign and tetany symptoms were recognized, and an electrocardiogram showed prolonged QT. Following correction of the multiple electrolyte imbalances by supplementation with magnesium, potassium, calcium and vitamin D, the patient’s urinary excretion of electrolytes was normalized, and improvement of the neurological findings and abnormal electrocardiogram suggested systemic improvement of electrolyte balances as well. In conclusion, when hypomagnesemia, hypokalemia and hypocalcemia are present simultaneously, a multifaceted and comprehensive approach to electrolyte imbalances may be necessary, rather than management for a single electrolyte abnormality.

Introduction

Alcohol use disorder (AUD) is a chronic disease characterized by an inability to limit alcohol use despite knowledge of the negative consequences. Individuals with AUD exhibit various electrolyte disorders and acid–base imbalance, and these conditions must be comprehensively corrected as a whole. In particular, cases complicated by hypomagnesemia or Mg depletion require that Mg abnormalities be corrected simultaneously with other electrolyte disturbances because Mg is involved in the regulation of renal K excretion and parathyroid hormone secretions. We experienced a patient with AUD who showed various electrolyte disturbances that seemed to involve hypomagnesemia or Mg depletion.

Case presentation

This case involves a 61-year-old Japanese man. Beginning at around 16 years of age, he had consumed approximately 720 mL of whisky per day. He lived alone and his food intake was extremely irregular. He ate only one meal each day, usually a simple and inexpensive lunch box or fast food meal for dinner, resulting in a diet lacking properly balanced nutrition for a long period of time. He had chronic diarrhea and a history of hospitalization for cellulitis of the lower extremities, and he was noted to have had multiple electrolyte abnormalities at that time. In early October 2021, his family members were contacted and informed that he had little appetite, but as they were unable to reach him, emergency services were sent to check on him, and found that he had fallen and was in a state of incontinence. Due to his limb weakness and difficulty standing, the patient was transported by ambulance to the emergency unit of our hospital. A blood test at admission showed multiple electrolyte abnormalities along with hypokalemia (1.6 mEq/L), hypomagnesemia (1.0 mg/dL), and hypocalcemia (corrected Ca 7.2 mg/dL), and rhabdomyolysis was also suspected based on his elevated creatine kinase (14,800 U/L). He was hospitalized in the nephrology department.

The patient had a history of hypertension from the age of 20 years. Although his hypertension had been clinically managed, the details of his blood pressure control were unclear. At his most recent visit to a physician he had been prescribed potassium chloride 2400 mg/day, valsartan 160 mg/day, amlodipine 10 mg/day, febuxostat 10 mg/day, benzbromarone 25 mg/day, magnesium oxide 990 mg/day, L-calcium aspartate 800 mg/day, and alfacalcidol 0.5 µg/day. In addition, he routinely took antidiarrheal agents and antiflatulents. Upon admission to the nephrology department his height was 164.2 cm and he weighed 61.4 kg. His consciousness was clear, with blood pressure of 140/77 mmHg, pulse rate of 76 bpm, respiratory rate of 16 breaths per minute, percutaneous arterial oxygen saturation of 98% (room air), and body temperature of 36.6 °C. Neurological examination revealed no significant abnormalities except for a decrease in manual muscle strength score (1/5). He was positive for Trousseau’s sign and tetany symptoms, but muscle atrophy and grasping pain were not clearly observed. The deep tendon reflexes had disappeared bilaterally.

The laboratory findings on admission are shown in the Table 1. In addition to decreased K, Mg, and cCa, metabolic alkalosis with respiratory compensation was observed. The patient had been taking an angiotensin receptor blocker (ARB) prior to admission, and his renin angiotensin aldosterone (RAA) system was suppressed. Elevation of urinary N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin excretion suggested the development of renal tubulointerstitial disorders, and urinary K and Mg excretions were also elevated (see Table 1). Urinary β2-microglobulin levels had progressively decreased after admission and reached the normal range by the day 12. Diarrhea persisted from the time of admission, and it is estimated that despite the low potassium and low magnesium condition, excretion continued outside the body due to persistent diarrhea at the time of hospitalization, but the specific amount of stool excretion is unknown. The value of 25(OH)D was low, but 1,25-(OH)2D3 was within normal range because he had been taking alfacalcidol. Elevated whole PTH was also observed, and urinary Ca excretion was suppressed. Marked elevation of CK was observed, and CK3 (MM type) was observed in 100% of CK fractions. Vitamin-B1 was not measured in this case because no neurological finding such as consciousness disorder was not observed. The clinical course after hospitalization is illustrated for each electrolyte in Figs. 1, 2, 3. He showed strong appetite on the admission. The diarrhea disappeared on the 7th day of hospitalization, and thereafter, normal stools were observed. The serum K concentration was increased following the initiation of intravenous K administration (20 ~ 80 mEq/day) with KCl; on day 9 of hospitalization his serum K concentration was normalized, allowing a switch to oral K supplementation.

Table 1.

Results of blood count, blood biochemistry, general urinalysis, and urine biochemical tests at the time of the patient's admission

Blood cell count		Urinalysis
WBC (per µL)	14,300	Specific gravity	1.021
Hemoglobin (g/dL)	10.3	pH	6.5
Plate (× 104 per µL)	23.7	RBC count (per HPF)	1–4
Blood biochemistry		WBC count (per HPF)	1–4
Total protein (g/dL)	5.8	Granular cast (per WF)	1–4
Albumin (g/dL)	2.5	Protein by dip stick	1
CK (U/L)	13,787	Sugar by dip stick	-
CK3 (%)	100	Ketone by dip stick	-
AST (IU/L)	158	Urine biochemistry
ALT (IU/L)	31	Creatinine (mg/dL)	169.8
LDH (IU/L)	876	Urea protein (mg/dL)	249
ChE (U/L)	119	Na (mEq/L)	99
BUN (mg/dL)	13	Cl (mEq/L)	36
Creatinine (mg/dL)	1.22	K (mEq/L)	17.3
eGFR (mL/min)	48.0	Ca (mg/dL)	1
UA (mg/dL)	9.8	P (mg/dL)	132
Na (mEq/L)	141	Mg (mg/dL)	5
Cl (mEq/L)	92	FENa	0.50
K (mEq/L)	1.6	FECl	0.28
cCa (mg/dL)	7.2	FEK	7.77
iP (mg/dL)	2.8	FECa	0.10
Mg (mg/dL)	1	%TRP	66.13
Glucose (mg/dL)	96	FEMg	3.59
HbA1c (%)	5.5	NAG (IU/L)	90.8
LDL-C (mg/dL)	45	β2MG (μg/L)	200,292
Osmolality (mosm/kg)	287	Osmolality (mosm/kg)	586
Venous blood gas		Myoglobin (ng/mL)	92,000
pH	7.470	Endocrine
pCO2 (mmHg)	46.3	Aldosterone (pg/mL)	< 4.0
pO2 (mmHg)	31.5	Renin (ng/ml/h)	10.3
HCO3− (mmol/L)	32.9	Whole PTH (pg/dL)	158
		25-(OH)D (ng/mL)	10.4
		1,25-(OH)2D (pg/mL)	39.6

Fig. 1.

Changes in serum K concentration and fractional excretion of K (FEK). Closed circles and closed squares indicate serum K concentration and FEK, respectively

Fig. 2.

Changes in serum Mg concentration and fractional excretion of Mg (FEMg). Closed circles and closed squares indicate serum Mg concentration and FEMg, respectively

Fig. 3.

Changes in serum corrected Ca (cCa) concentration and fractional excretion of Ca (FECa). Closed circles and closed squares indicate serum cCa concentration and FECa, respectively

The manual muscle strength test (MMT) score improved with the increase of K concentration, and the patient was able to begin independent walking, probably due to the improvement of leg muscle strength. Despite the continued K supplementation, the K excretion rate remained generally constant, and an increase in the K excretion rate, possibly indicating the improved body K deficiency, was not observed until after day 20 of the hospitalization.

For severe hypomagnesemia, intravenous Mg sulfate administration was initiated. Unlike the K excretion rate, the Mg excretion rate increased with the initiation of supplementation and remained high even after the Mg dose was reduced. On hospitalization day 8, the serum Mg level was generally normalized, and the deep tendon dysreflexia was resolved. Since the Mg excretion rate was decreased after day 12, it appeared that the Mg reabsorption in the kidney was recovered and the systemic Mg deficiency was corrected. The intravenous supplementation for K was switched to oral supplementation on day 9, and for Mg on day 14. The switch to oral supplementation was comprehensively judged based on the observed increase in serum K and Mg levels, the shortening of the prolonged QTc interval on the ECG, and the changes in FEK and the transtubular potassium gradient (TTKG), which suggested a reduction in renal K loss.

The serum concentration of corrected Ca was gradually normalized by administration of vitamin D and oral supplementation of Ca for hypocalcemia. The tetany and positive Trousseau’s sign disappeared with the changes in serum Ca levels. Like the Mg excretion rate, the Ca excretion rate also tended to increase after the start of vitamin D and Ca administration, suggesting that the renal Ca reabsorption capacity was attenuated at this time. The Ca excretion rate was subsequently decreased, in apparent synchrony with the decrease in Mg excretion rate. These clinical processes may indicate that a mechanism related to Mg deficiency was involved in the attenuation of renal Ca reabsorption capacity in this case.

Discussion

AUD is a comprehensive concept encompassing traditional alcohol abuse and alcohol dependence. It is characterized by an impaired ability to stop or control alcohol intake despite its adverse social, occupational, or health-related consequences. Chronic alcohol intake is known to be associated with various electrolyte and acid–base disturbances, including hypokalemia, hypocalcemia, and hypomagnesemia [1, 2]. Among these, hypomagnesemia is the most frequently observed electrolyte abnormality, occurring in approximately 11–30% of hospitalized patients with AUD-related conditions [3, 4]. Magnesium is an essential element that serves as a cofactor for over 300 enzymatic reactions [5]. Its deficiency influences renal potassium excretion, vitamin D metabolism, and parathyroid hormone (PTH) secretion [6–8]. Indeed, patients with AUD and hypomagnesemia have been reported to exhibit a higher prevalence of hypokalemia, hypocalcemia, hypophosphatemia, and respiratory alkalosis compared to those with normomagnesemia [1, 4]. This clinical profile is consistent with the findings in the present case.

The predisposition of patients with AUD to hypomagnesemia has been attributed to several mechanisms, including (1) increased renal excretion of magnesium, (2) insufficient dietary intake due to anorexia, and (3) impaired intestinal absorption of magnesium [1, 4]. AUD has been associated with various tubular dysfunctions, including impaired urinary acidification, reduced urine concentrating ability, decreased renal glucose reabsorption, and increased urinary excretion of uric acid, magnesium, calcium, and amino acids [3, 9, 10]. One proposed mechanism linking alcohol consumption to proximal tubular dysfunction involves mitochondrial damage induced by alcohol, which in turn impairs Na/K ATPase activity in proximal tubular cells [11]. Given that these functional abnormalities improve after four weeks of alcohol abstinence, it is suggested that alcohol directly contributes to tubular dysfunction [3, 9].

Approximately 30–50% of orally ingested magnesium is absorbed in the intestine, primarily in the distal small intestine, with additional absorption occurring in the ileocecal region and colon [12, 13]. Magnesium absorption occurs via two distinct pathways: passive diffusion through the paracellular route in the small intestine and facilitated diffusion via transporters in the ileocecal region and colon [12, 13]. Reduced intestinal magnesium absorption in AUD is involved in chronic diarrhea and binding to unabsorbed fatty acids in steatorrhea, both of which are commonly observed in patients with AUD [14]. These mechanisms may have contributed to the hypomagnesemia observed in our patient, whose magnesium deficiency may have been partially due to insufficient levels of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. The patient’s diarrhea was considered to be attributable to long-standing habitual heavy alcohol consumption rather than to electrolyte disturbances. Importantly, several electrolyte abnormalities persisted even on day 7, when the diarrhea had already resolved. Therefore, we believe that a direct causal relationship between these gastrointestinal symptoms and the electrolyte disturbances is unlikely.

1,25-(OH)₂D₃ is known to facilitate the intestinal absorption of not only calcium but also magnesium [15]. Additionally, magnesium is essential for the hepatic and renal hydroxylation required to convert vitamin D into its active form, 1,25-(OH)₂D₃[16]. Consequently, the coexistence of magnesium deficiency and vitamin D insufficiency may have exacerbated the pathological condition in the present case. Indeed, in cases of hypocalcemia unresponsive to vitamin D supplementation, it has been recommended that magnesium deficiency be considered [17]. Although our patient had been prescribed alfacalcidol, the relatively low parathyroid hormone (PTH) level in the context of hypocalcemia suggests that impaired intestinal absorption may have led to vitamin D deficiency as well. Such vitamin D deficiency could in turn have decreased the absorption of calcium and magnesium, thereby playing a significant role in the development of severe magnesium depletion and hypomagnesemia. In addition, estimating from the urine biochemical test results at the time of admission, the patient's salt intake just before hospitalization was considered to be approximately 4 g/day. Furthermore, considering that the majority of the patient's oral intake before hospitalization consisted of fast food and snacks high in salt content, it is estimated that the intake of potassium, magnesium, calcium, vitamin D, and other nutrients was significantly low before hospitalization. The significant reduction in both the absorption and intake of minerals and nutrients is also thought to have played a major role in the formation of the multiple electrolyte imbalances in this case. Notably, with the correction of magnesium deficiency, calcium reabsorption improved, leading to the stabilization of serum calcium levels, suggesting that magnesium deficiency contributed to both the development and persistence of hypocalcemia in this case.

Coexistence of hypokalemia and hypomagnesemia is not a rare phenomenon in daily clinical practice, with magnesium depletion being implicated in approximately 40–50% of cases of severe hypokalemia [18, 19]. Conversely, it is also known that hypokalemia frequently accompanies hypomagnesemia [20]. More than 90% of potassium filtered by the glomerulus is reabsorbed in the proximal tubule and thick ascending limb of the loop of Henle, while less than 10% reaching the distal nephron. Potassium secretion in the cortical collecting duct is primarily regulated by renal outer medullary potassium (ROMK) channels, which are negatively modulated by magnesium [21]. In hypomagnesemia, loss of the inhibitory control of potassium leads to increased potassium secretion via ROMK channels, predisposing patients to potassium depletion [19]. Additionally, hypomagnesemia has been reported to stimulate aldosterone secretion, further contributing to potassium loss [19]. Prolonged hypokalemia induces morphological changes in renal tubular cells, resulting in impaired urine concentrating ability and declining renal function, a condition known as hypokalemic nephropathy [22]. In the present case, the patient had persistent hypotonic polyuria (4–8 L/day), which required a large amount of fluid replacement. It was thought that the polyuria was due to impaired urinary concentration resulting from tubular dysfunction due to hypokalemic nephropathy. Hypokalemia associated with hypomagnesemia often exhibits resistance to potassium supplementation alone [18, 19], highlighting the importance of simultaneous magnesium replacement [23]. However, as most of the magnesium exists intracellularly in a protein-bound form, serum magnesium levels may not accurately reflect the total body magnesium status [22, 24]. Therefore, when magnesium deficiency is suspected, even if the decrease in serum Mg²⁺ concentration appears mild, continuous magnesium supplementation for several days or more is recommended [25].

In the present case, despite the presence of hypokalemia, urinary potassium excretion remained relatively elevated, suggesting persistent renal potassium loss. The extent to which magnesium deficiency contributed to this increased potassium excretion resulting from impaired renal potassium reabsorption remains unclear. However, the disappearance of ECG abnormalities associated with magnesium deficiency as a result of magnesium supplementation, along with the maintenance of serum potassium levels even after discontinuing potassium supplementation, suggests a correlation between magnesium deficiency and increased renal potassium excretion. This suggests that magnesium deficiency played a significant role in both the development and persistence of severe hypokalemia in this case.

In conclusion, we experienced a case of an AUD patient who developed symptomatic hypokalemia, hypomagnesemia, and hypocalcemia. If hypomagnesemia is associated with multiple electrolyte disturbances, hypokalemia and hypocalcemia may be interrelated with magnesium deficiency. Therefore, a multifaceted approach with simultaneous supplementation of magnesium, potassium, and vitamin D may be needed rather than management for a single electrolyte.

Declarations

Conflict of interest

The authors have stated they have nothing to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.