Two distinct mechanisms drive severe alcoholic liver disease

2022

Challenge

Severe alcoholic hepatitis (SAH) is a common and life-threatening liver ailment that develops as a consequence of alcohol abuse, so there is a strong need to develop new treatments for SAH and other forms of liver damage induced by chronic alcohol drinking. SAH patients often have elevated numbers of white blood cells in their blood and livers, but how white blood cells contribute to SAH remains poorly understood. Diagnosis and treatment may be complicated by the existence of different types of SAH involving distinct underlying molecular mechanisms.

Advance

Jing Ma, Ph.D., and colleagues in the laboratory of IRP senior investigator Bin Gao, M.D., Ph.D., examined SAH patients and used a mouse model of SAH to characterize changes in white blood cell function in two varieties of SAH. Analyzing the livers of SAH patients revealed that, despite similar symptoms, some of the patients had high levels of white blood cells called neutrophils in their livers but low levels of cells known as CD8-positive T cells, while the rest of the patients had the opposite balance of the two types of cells. The scientists also demonstrated that neutrophils produce toxic substances that promote liver inflammation and worsen SAH, and they identified a small 'microRNA' molecule’s role in that process.

Impact

The varying number of neutrophils in the livers of SAH patients may have different effects in driving downstream liver injury and liver failure by regulating inflammation and production of harmful substances. These findings likely explain the variation among SAH patients in the response to anti-inflammatory corticosteroid medications in clinical studies of alcohol-associated liver damage. Therefore, the results suggest that future clinical trials may need to take into account the number and type of white blood cells in patients’ livers. In addition, the findings highlight the need to find easily measurable biomarkers that will allow clinicians to separate patients with the two distinct types of SAH.

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