Iron and iron-related proteins in alcohol consumers: cellular and clinical aspects

Abstract

Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases. Its pathological spectrum includes the overlapping stages of hepatic steatosis/steatohepatitis that can progress to liver fibrosis and cirrhosis; both are risk factors for hepatocellular carcinoma. Moreover, ALD diagnosis and management pose several challenges. The early pathological stages are reversible by alcohol abstinence, but these early stages are often asymptomatic, and currently, there is no specific laboratory biomarker or diagnostic test that can confirm ALD etiology. Alcohol consumers frequently show dysregulation of iron and iron-related proteins. Examination of iron-related parameters in this group may aid in early disease diagnosis and better prognosis and management. For this, a coherent overview of the status of iron and iron-related proteins in alcohol consumers is essential. Therefore, here, we collated and reviewed the alcohol-induced alterations in iron and iron-related proteins. Reported observations include unaltered, increased, or decreased levels of hemoglobin and serum iron, increments in intestinal iron absorption (facilitated via upregulations of duodenal divalent metal transporter-1 and ferroportin), serum ferritin and carbohydrate-deficient transferrin, decrements in serum hepcidin, decreased or unaltered levels of transferrin, increased or unaltered levels of transferrin saturation, and unaltered levels of soluble transferrin receptor. Laboratory values of iron and iron-related proteins in alcohol consumers are provided for reference. The causes and mechanisms underlying these alcohol-induced alterations in iron parameters and anemia in ALD are explained. Notably, alcohol consumption by hemochromatosis (iron overload) patients worsens disease severity due to the synergistic effects of excess iron and alcohol.

Keywords: ALD; Alcohol; Alcohol-associated liver disease; Carbohydrate-deficient transferrin; Ferritin; Hemoglobin; Hepcidin; Iron; Transferrin; Transferrin receptor-1.

Fig. 1

Mechanisms of alcohol-induced hepcidin downregulation. The figure depicts a few mechanisms of alcohol-induced hepcidin suppression. These include events induced by hypoxia, oxidative stress, and reduced IL-6. Indeed, there are other hepcidin-suppressing mechanisms that may work alongside these events. Hepcidin downregulation leads to uncontrolled iron entry into plasma via ferroportin. Red crosses inside the macrophage, hepatocyte, and duodenal enterocyte indicate normal mechanism of hepcidin-mediated degradation of ferroportin (shown as green structures), which prevents iron entry into the circulation and thereby regulates systemic iron homeostasis under excess iron conditions. The normal hepcidin-ferroportin axis is disturbed due to alcohol-induced hepcidin suppression. C/EBP-α: CCAAT/enhancer-binding protein alpha. The figure was created with BioRender.com

Fig. 2

Events causing alcohol-induced anemia. There are several alcohol-induced events that can lead to anemia, for example, alcohol-induced nutritional deficiencies (e.g., B12 and B9 deficiencies) and impaired erythropoiesis in the bone marrow. Also, alcohol directly exerts toxic effects and reduces the number of RBC precursors in the bone marrow. Chronic alcohol consumption can produce defective RBCs that are swiftly destroyed via hemolysis. Moreover, loss of liver functionality can decrease serum transferrin levels leading to inefficient iron delivery to developing RBCs. Gastrointestinal bleeding in advanced ALD leads to direct loss of RBCs resulting in anemia. The figure was created with BioRender.com

Fig. 3

Putative reasons for alcohol-induced decrement in serum transferrin. During early ALD when there is no major liver dysfunction, alcohol and other metabolic factors such as malnutrition and vitamin A deficiency may suppress hepatic (hepatocyte) transferrin synthesis [55, 91, 92] and thereby reduce transferrin in circulation. As ALD progresses, inflammation may also decrease transferrin synthesis by hepatocytes [93]. In the later stages of ALD when there is significant liver damage, reduction in liver mass and/or the number of functional hepatocytes may be the main reason for decreased serum transferrin levels. The figure was created with BioRender.com

Fig. 4

Putative reasons for alcohol-induced increment in serum ferritin. During the early stages of ALD, increased systemic iron levels followed by increased cellular iron content increase ferritin synthesis. Upon disease progression, inflammation may additionally trigger ferritin synthesis. In the later stages of ALD, alcohol may directly stimulate (de novo) ferritin synthesis via an unknown mechanism. The figure was created with BioRender.com

Fig. 5

Overview of alcohol-induced alterations in iron parameters. The figure shows alcohol-induced alterations in iron parameters, as indicated via red upward and downward arrows. Essentially, alcohol decreases hepcidin synthesis, which causes decrement in serum hepcidin. This allows excessive iron absorption into the circulation via the duodenal enterocytes and increased iron egress from the iron storing macrophages and hepatocytes leading to elevation in serum iron levels. Serum iron is also partly elevated due to alcohol-induced upregulations of duodenal DMT-1 and ferroportin that facilitate iron entry and exit into and from the enterocyte, respectively. Resultantly, intracellular and serum ferritin levels increase and so does the iron saturation of serum transferrin. Interestingly, ferritin is elevated by both increased iron levels and inflammation, the latter often found in heavy or chronic alcohol consumers. Inflammation also reduces transferrin synthesis. Alongside, alcohol can decrease hematopoietic activity in the bone marrow leading to reduction in the number of functional red blood cells (RBCs), thereby contributing to the many causes of anemia, as observed in some ALD cases. Carbohydrate-deficient transferrin (CDT) levels increase, but alcohol does not seem to alter soluble transferrin receptor (sTfR) levels. Distinct from the depiction in this figure, serum iron levels may decrease or remain unaltered in ALD. Also, levels of transferrin and transferrin saturation may remain unaltered. Hemoglobin levels (not shown in the figure) may increase, decrease, or remain unaltered. The figure was created with BioRender.com