Alcoholic liver disease: A current molecular and clinical perspective

Abstract

Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.

Keywords: Alcoholic cirrhosis; Alcoholic hepatitis (AH); Alcoholic liver disease (ALD); Corticosteroids; Liver transplantation.

Fig. 1. The progression of ALD.

The spectrum of ALD ranges from steatosis to fibrosis, cirrhosis, and then hepatocellular carcinoma (HCC). Approximately 90% of heavy drinkers develop alcoholic steatosis. This stage is reversible when alcohol use ceases. Risk factors, such as gender, drinking pattern, obesity, viral hepatitis, and genetics, can contribute to ALD progression. About 20%–40% of patients with alcoholic steatosis will progress to alcoholic steatohepatitis, which is histologically characterized by the infiltration of inflammatory cells, especially neutrophils, the appearance of Mallory-Denk bodies, ballooning degeneration, and hepatocyte death in the liver parenchyma. Some of those patients will develop liver fibrosis and subsequently cirrhosis. Fibrosis begins at perivenular region (zone 3) and extends to the neighboring central or portal areas (bridging fibrosis). The surface of cirrhotic liver is irregular. Cirrhosis may further progress to HCC. AH, an acute-on-chronic condition of ALD, presents with clinical symptoms, such as jaundice, infection, and decompensation. AH can occur at any stage of ALD. Treatments for AH include abstinence and corticosteroids, but they are not always effective. However, liver transplantation can be a curative therapy. Abbreviations: ALD, alcoholic liver disease; HCV, hepatitis C virus; AH, alcoholic hepatitis; ALDH2, aldehyde dehydrogenase 2; PNPLA3, patatin-like phospholipase domain-containing protein 3; TM6SF2, transmembrane 6 superfamily member 2; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13.

Fig. 2. Ethanol consumption increases hepatic steatosis.

In hepatocytes, ADH oxidizes ethanol to acetaldehyde and converts NAD⁺ to NADH. Acetaldehyde entering the mitochondria is converted to acetate and NADH by ALDH through the reduction of NAD⁺. Ethanol is also degraded by CYP2E1 through the conversion of NADPH to NADP⁺. CYP2E1 upregulates ROS production, leading to mitochondria damage, ER stress, DNA damage and the production of protein adducts, resulting in apoptosis. Ethanol reduces AMPK levels, which increases ACC1 activity, decreases PPARa levels, and increases mTORC1 activity. Increased mTORC1 further increases SREBP-1c activity and decreases autophagy. These signaling pathways lead to increased fatty acid synthesis, decreased fatty acid b oxidation, and lipophagy as well as the induction of steatosis. Ethanol also impairs VLDL secretion by inhibiting MTP. Ethanol promotes lipolysis in adipose tissues, resulting in FFA flux to the liver. Excessive intake of dietary fat also promotes alcohol-induced steatosis. Abbreviations: ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; NAD⁺, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NADP⁺, nicotinamide adenine dinucleotide phosphate; CYP2E1, cytochrome P450 2E1; ROS, reactive oxygen species; ER, endoplasmic reticulum; AMPK, adenosine monophosphate-activated protein kinase; ACC1, acetyl-Co A carboxylase 1; PPAR, peroxisome proliferator-activated receptor; mTORC1, mammalian target of rapamycin complex 1; SREBP-1c, sterol regulatory element-binding protein-1c; VLDL, very-low-density lipoproteins; MTP, microsomal triglyceride transfer protein; FFA, free fatty acid; PGC, peroxisome proliferator-activated receptor gamma coactivator; SIRT1, sirtuin 1; TFEB, transcription factor EB; DNA, deoxyribonucleic acid.

Fig. 3. Gut-adipose tissue-liver network in ALD.

Excessive alcohol consumption can affect the composition of intestinal microbiota and increase intestinal permeability by disrupting intestinal epithelial barrier functions. Intestine-derived PAMPs, such as LPS, translocates to the liver via portal veins. In the liver, translocated LPS binds TLR4 to stimulate neutrophils. Kupffer cells and HSCs produce ROS and pro-inflammatory cytokines, such as TNFα, IL-1, and chemokines, leading to hepatocyte damage and liver inflammation. Chronic LPS stimulation facilitates liver fibrosis by causing Kupffer cells and HSCs to downregulate MMPs and produce extracellular matrix, including collagen. Ethanol and acetaldehyde can damage hepatocytes, leading to release of DAMPs, such as HMGB1, and EVs that contain mitochondrial DNA. Ethanol can promote lipogenesis and inhibit lipid degradation by suppressing β-oxidation and autophagy. Hepatic FXR and intestinal FXR that induces FGF15/19 production regulate bile acid and lipid homeostasis in the liver. Ethanol induces lipolysis and adipokine production in adipose tissues. Fatty acids released from adipocytes promote hepatic steatosis. Adipose-tissue-derived free fatty acids also activate Toll-like receptor 4 (TLR4) signaling. Abbreviations: PAMPs, pathogen-associated molecular patterns; LPS, lipopolysaccharide; HSCs, hepatic stellate cells; MMPs, matrix metalloproteinases; DAMPs, damaged-associated molecular patterns; EVs, extracellular vesicles; FGF, fibroblast growth factor; FXR, farnesoid X receptor; HMGB1, high mobility group box 1; IL, interleukin; miRNA, microRNA; mtDNA, mitochondrial DNA; FFA, free fatty acid; ROS, reactive oxygen species; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor; DNA, deoxyribonucleic acid.