Novel insights into alcoholic liver disease: Iron overload, iron sensing and hemolysis

Abstract

The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.

Confounders of Serum Phosphatidylethanol: Role of Red Blood Cell Turnover and Cirrhosis

“…Moreover, PEth levels are associated with indirect signs of hemolysis which is increased during heavy alcohol consumption. 41 …”

“…CD163 was measured in serum by ELISA using Human CD163 DuoSet ELISA delivered by R&D Systems, Inc. (Minneapolis, USA) using standard protocols and as described recently. 41 It is important to note that CD163 was only measured in a smaller group of patients (N=21). For liver apoptosis, the M30-Apoptosense ELISA according to the manufacturer’s instructions (Peviva, Bromma, Sweden) and the M65 ELISA (Peviva) were used to quantify both uncleaved and caspase-cleaved K18.…”

“… 43–46 These data also show that RBC turnover is not primarily due to deficiency eg of folic acid or vitamin B12 but rather to direct toxicity to RBCs and the bone marrow stem cell compartment of precursor cells. 41 , 46 Moreover, enhanced alcohol-mediated RBC turnover can be evidenced by increased serum levels of the hemoglobin-haptoglobin scavenger receptor CD163 and by elevation of LDH, ferritin and MCV. 46 …”

Active Components of Pueraria lobata through the MAPK/ERK Signaling Pathway Alleviate Iron Overload in Alcoholic Liver Disease

“…[4] Therefore, iron excess is an independent factor in the progression and deterioration of alcoholic liver disease and determines patient survival. [5][6] Current research on pharmacological interventions against iron overload has focused on deferoxamine, deferiprone, and antioxidant drugs to effectively prevent iron overload and its mediated oxidative stress. [7][8] However, deferoxamine is not efficiently absorbed by the gut and has occasional adverse effects that may lead to stunted growth and metaphyseal dysplasia.…”

“…This process intensifies alcohol‐induced oxidative stress and worsens alcohol‐induced liver damage [4] . Therefore, iron excess is an independent factor in the progression and deterioration of alcoholic liver disease and determines patient survival [5–6] …”