Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients

Abstract

(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death.

Characterization of Hypomagnesemia in Alcoholic Hepatitis Patients and Its Association with Liver Injury and Severity Markers

“…Previously, we found that hypomagnesemia in the early stages of alcohol-associated liver disease could be one of the factors leading to progression of the disease [3]. In our subsequent clinical longitudinal study on early-stage ALD, we found that magnesium levels could be a valuable indicator of liver cell death and the recovery of liver health with standard of care magnesium supplementation in AUD patients with early-stage liver disease [7]. In this study, we found that there could be a deficiency level of magnesium that would provide vital clues for the detection of AH.…”

“…Earlier, we reported that such levels of magnesium (sub-clinical) are also present in AUD patients with early-stage ALD or no liver injury [7], thus such levels may not conclude differentiating AUD patients who may have AH or not in an initial clinical review of laboratory charts. We know that when the severity of alcohol-associated liver disease is higher, the homeostasis of magnesium is altered [26].…”

“…Factors contributing to hypomagnesemia in patients with acute and chronic alcohol abuse include a poor nutritional status leading to decreased absorption [21][22][23], increased urinary losses [22][23][24], and impaired magnesium homeostasis [25]. Our previous study noted an independent association of lower magnesium levels with higher levels of hepatic apoptosis (quantified by K18M30) and necrosis (quantified by K18M65) in early alcoholic liver disease patients admitted for an inpatient rehabilitation program [7]. Considering that the magnesium levels corresponded with increased liver cell death in these patients, it also led to our investigation of magnesium as a possible prognostic indicator in acute alcoholic patients.…”

“…However, there remains a paucity of data on electrolyte imbalances in acute alcoholic hepatitis including magnesium. We believe that this is an area of keen clinical interest as our previous studies have shown a reduction in markers of hepatic necrosis and apoptosis after just 2 weeks of standard of care magnesium supplementation in early alcoholic liver disease patients [7]. Thus, understanding the extent of deficiency in the magnesium level in AH is important.…”