Hepatic Zinc Deficiency Dampens the Acute Phase Response in Patients with Alcohol-Associated Hepatitis

Scott A Read^1*Mehdi Ramezani Moghadam²Brian Gloss³Romario Nguyen³Benjamin Woodham⁴Vincent Lam⁵Lawrence Yuen⁵Jimin Yoon⁶Liang Qiao³Thomas Tu³Jacob George⁵Matthew Shoulders⁶Golo Ahlenstiel⁴

• ¹Western Sydney University, Penrith, Australia
• ²Western Sydney Local Health District, North Parramatta, Australia
• ³Westmead Institute for Medical Research, Westmead, Australia
• ⁴Blacktown & Mount Druitt Hospital, Blacktown, Australia
• ⁵Westmead Hospital, Westmead, Australia
• ⁶Massachusetts Institute of Technology, Cambridge, United States

Zinc deficiency affects ~17% of the population globally, contributing to deficits in growth, metabolism and immunity. Serum zinc is greatly reduced in alcohol-associated hepatitis, driven by hepatic dysfunction and poor zinc retention. While zinc is an essential micronutrient with many beneficial anti-inflammatory and anti-oxidant properties, its role in the progression of alcohol-related liver disease (ALD) remains uncertain. To determine how hepatic zinc deficiency contributes to disease pathogenesis in humans, a transcriptomic zinc signature was generated from publicly available datasets. The zinc signature identified hepatic zinc deficiency among ALD patients that was associated with a down-regulation of the acute phase response pathway (e.g., SAA1, CRP and C9 genes). In vitro studies using hepatocyte and immune cell cultures depleted of zinc demonstrated that macrophage induction of the acute phase response by LPS was dampened by zinc depletion. Together, these data suggest that hepatic zinc stores among patients with alcohol-associated hepatitis are reduced, resulting in deficient acute-phase responses. Increasing hepatic zinc stores via supplementation and dietary modulation may improve acute responses to infection, and thus, long term outcomes in this patient group.