Stratification of Risk of Death in Severe Acute Alcoholic Hepatitis Using a Panel of Adipokines and Cytokines

Abstract

Background: Dysregulated adipose tissue metabolism has been implicated in the pathogenesis of alcoholic liver disease in murine models. We aimed to characterize serum markers of adipose tissue metabolism and inflammation in patients with severe acute alcoholic hepatitis (AAH) and determine their utility to predict survival in severe AAH. Methods: A prospective, case control study design was used. Seventy-six patients hospitalized with severe AAH and twenty-five ambulatory patients with alcoholic cirrhosis as controls were included. Serum samples were collected for biochemical analyses. Patients were followed for 180 days after enrollment to determine survival. Results: AAH patients exhibited higher serum glycerol and free fatty acid levels, suggesting enhanced adipose tissue triglyceride hydrolysis. Patients with AAH demonstrated a distinct serum lipidomic profile compared with alcoholic cirrhosis but not in systemic and adipose-specific insulin resistance. AAH patients had higher serum resistin and plasmin activation inhibitor-1 levels, while serum leptin was decreased. Serum levels of the prolipolytic cytokines tumor necrosis factor α (TNF- α), interleukin (IL)-6, IL-8 and IL-15 were significantly higher in AAH patients. Only 53% of AAH patients survived 180 days after admission, while all cirrhotic patients were alive at the end of the study period. Among patients with severe AAH, white blood cell count, hemoglobin, resistin, IL-6, and TNF-α were associated with 180-day survival, and all five markers demonstrated accuracy by area under receiver-operator curve (AUC) analysis. Serum IL-6 levels ≥ 38.66 pg/ml most precisely identified deaths in severe AAH. Patients with IL-6 ≥ 38.66 pg/ml had significantly decreased mean survival compared to those with lower levels. Conclusions: AAH patients demonstrate evidence of increased adipose tissue lipolysis and altered serum lipidomic profile compared with alcoholic cirrhosis patients. IL-6 may be a useful biomarker to risk-stratify severe AAH patients at the highest risk of mortality.

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study

“…Of the 12 dysregulated cytokines/chemokines identified in our study, the proinflammatory cytokines/chemokines (TNF-a, IL-6, IL-8, and IP10), the antiinflammatory cytokines (IL-4 and IL-10), and the growth factor (IL-15) have been shown to be elevated in patients with ALD in comparison to HC or those with stable alcoholic cirrhosis. (13,14,18,27,28) Serum IL-7 concentration is higher in alcohol-dependent individuals without clinical AH than HC. (29) We found that IL-8, a potent neutrophil chemotactic factor, was the most highly up-regulated cytokine in AH patients and remained higher in abstinent AH patients.…”

“…Consequently, AH patients have elevated circulating levels of a variety of proinflammatory factors in association with elevated anti‐inflammatory and hepatoprotective cytokines, such as interleukin 10 (IL‐10) . Studies have demonstrated that circulating levels of tumor necrosis factor alpha (TNF‐α), IL‐6, IL‐8, macrophage/monocyte chemotactic protein 1, and macrophage inflammatory protein 3α correlate with the severity of AH and that two of them (TNF‐α and IL‐6) also correlate with AH mortality . Abstinence from alcohol improves clinical symptoms for most AH patients and has been shown to reduce IL‐6 level .…”

“…(11,12) Studies have demonstrated that circulating levels of tumor necrosis factor alpha (TNF-a), IL-6, IL-8, macrophage/monocyte chemotactic protein 1, and macrophage inflammatory protein 3a correlate with the severity of AH and that two of them (TNF-a and IL-6) also correlate with AH mortality. (13)(14)(15)(16) Abstinence from alcohol improves clinical symptoms for most AH patients and has been shown to reduce IL-6 level. (17,18) Increased hepatic oxidative stress and overactivation of liver cells, including resident macrophages (Kupffer cells) and hepatocytes, have also been observed in AH patients.…”

Pathogenesis of alcoholic liver disease

“…showed serum leptin levels in chronic moderate drinkers were increased, but another by Rachakonda et al . reported lower serum leptin levels in acute alcoholic steatohepatitis patients compared to alcoholic cirrhosis patients . Although leptin is strongly suspected to be responsible for the pathogenesis of ALD to some extent, the precise roles need to be investigated further.…”

Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice

“…Several processes have been identified as being involved in ALD pathogenesis. Alcohol intake stimulates adipose lipolysis, thus increasing lipid trafficking into the liver to induce steatosis (3)(4)(5)(6)(7)(8). Alcohol consumption also promotes hepatic de novo lipogenesis, further worsening liver steatosis (9).…”