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.

(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.

Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1ß, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 ß, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut-immune-thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut-thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut-brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.