(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21–65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.

(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-1β, 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 β, 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.

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Pathways underlying the gut-brain axis and pro-inflammatory cytokine production influence brain functions and behavior. Alcohol use disorder (AUD) patients exhibit domains such as alcohol withdrawal, depression, and craving; and the gut-immune response may play a significant role in these domains of AUD. This study examined the role of intestinal permeability, pro-inflammatory cytokines, and hormones levels on the domains of AUD.Forty-eight AUD patients [male (n=34) and female (n=14)] aged 23-63 yrs. were grouped categorically using the Clinical Institute Withdrawal Assessment of alcohol scale (CIWA) as either clinically significant CIWA group (CS-CIWA [score>10] Gr.1 [n=22]), and clinically not-significant group (NCS-CIWA [score≤10] Gr.2 [n=26]). A sub-set of 13 AUD patient were also tested for reward response for drug-seeking using Penn-Alcohol Craving Score (PACS). Clinical data and blood samples were collected upon enrollment. Blood samples were analyzed for pro-inflammatory cytokines, and hormones, and markers of intestinal permeability. CIWA, 90-day timeline followback (TLFB90), and lifetime drinking history (LTDH) were also collected for comparison.As expected, recent and chronic heavy drinking were significantly higher in Gr.1: HDD90 (heavy drinking days), NDD90 (number of drinking days), as was LTDH, especially in Gr.1 females. Further, in Gr.1, adiponectin (associated with withdrawal) was significantly higher; and numerically higher levels of lipopolysaccharide (LPS) and LPS-binding protein (LBP) were also reported. Gr.1 patients exhibited higher effects of association on the withdrawal-associated depression domain for the parameters of LPS, sCD14, IL-6 and IL-8. Leptin also showed a significantly high effect of association with HDD90 in those AUD patients with craving. The craving domain (assessed by PACS, Penn-Alcohol Craving Scale) could be described as a gut-immune-brain model by the gut-dysregulation (LBP and Leptin) markers, and specific pro-inflammatory activity (IL-1β and TNF-α). Such pathway model describes the heavy drinking phenotype, HDD90 with even higher effects (R2=0.955, p=0.006) in the AUD patients who had higher ratings for craving (PACS>5).Interaction of gut-dysfunction, cytokines involved in both inflammation and in mediating-chemotactic activity constitute a novel pathophysiological gut-brain axis for withdrawal, and alcohol-associated depression and craving domains of AUD. AUD patient with higher craving show higher reinforcing effects of the gut-brain axis response for heavy drinking.