Ethanol is metabolised mainly in the liver, and the injury it causes begins with acetaldehyde and the oxidative stress that follows.
Metabolism of ethanol
The liver metabolises alcohol through three enzymes:
- alcohol dehydrogenase (ADH) — the main enzyme at low concentrations of alcohol
- CYP2E1 — the main enzyme at high concentrations, above 10 mM; it is up-regulated in people who drink heavily over time
- catalase
ADH and CYP2E1 both convert ethanol to acetaldehyde, a potentially toxic compound. Aldehyde dehydrogenase (ALDH) then converts acetaldehyde to acetate. Most of the immediate side effects of drinking — nausea, headache and flushing — come from acetaldehyde.
Cellular mechanisms of liver damage
Four cellular processes drive the hepatic damage in ALD: acetaldehyde toxicity, oxidative stress in the mitochondria, failure of the proteasome pathway, and the action of gut-derived toxins through the gut–liver axis.
Acetaldehyde is one of the central molecules in the pathogenesis of ALD. It forms chemical adducts with proteins and other molecules, changes the redox state of the cell by altering the ratio of NADH to NAD, and damages the mitochondria’s protective mechanisms against cell death. That shift in the NADH/NAD ratio also pushes the liver toward fat accumulation, because it increases fatty acid synthesis and decreases fatty acid oxidation; this is how ethanol produces steatosis.
Oxidative imbalance — an imbalance between pro-oxidant and anti-oxidant mechanisms — is considered one of the most important pathogenic pathways in ALD. The main pro-oxidant changes come from an increase in free radicals generated by the activity of CYP2E1 and from increased activity of polymorphonuclear (PMN) cells.
Microscopic studies of hepatocytes in ALD show megamitochondria, caused by oxidative damage to the mitochondria. Normally this damage is offset by mitochondrial anti-oxidant defences such as glutathione, which is imported from the cytosol into the mitochondrial intermembrane space through the voltage-gated anion channels of the mitochondria. In ALD these channels are disrupted and do not work, so oxidative stress rises inside the mitochondria without anti-oxidant defence.
Methionine is the main source of methylation in the liver, and the enzyme methionine adenosyltransferase converts it to S-adenosylmethionine (SAMe). In ALD, methionine adenosyltransferase activity is depleted and SAMe is severely reduced. SAMe is crucial for regenerating and using the glutathione anti-oxidant pathway, so this loss is another mitochondrial route to liver damage. Increased sensitivity of the mitochondria to TNF-related cell death contributes to the same pathway.
Endoplasmic reticulum and the proteasome
Besides the mitochondria, the endoplasmic reticulum (ER) also plays an important role in hepatocyte damage. In ALD the ER’s protective handling of unfolded proteins is diminished. The main mechanism for degrading mis-folded proteins is the proteasome, and proteasome activity in ALD is reduced, so mis-folded proteins accumulate in hepatocytes, form Mallory bodies, and trigger cell death with production of interleukin-8 (IL-8) and interleukin-18 (IL-18). IL-8 recruits neutrophils, while IL-18 increases local hepatic inflammation.
The gut–liver axis
Another important mechanism is the gut–liver axis. In people who drink alcohol, the intestinal barrier becomes leakier. Alcohol and its metabolites such as acetaldehyde act directly on the tight junctions of the intestinal barrier, and overgrowth of gram-negative bacteria adds to the effect. The result is endotoxaemia: pathogen-associated molecular patterns (PAMPs) derived from the gut microbiota, mainly lipopolysaccharide (LPS), leak into the circulation, are recognised by Toll-like receptors (TLRs) on hepatocytes, and drive the hepatic inflammation that underlies ALD.
Genetic and epigenetic factors
Several genes may relate to the pathogenesis of ALD, mainly the genes of the enzymes involved in alcohol metabolism. Some ALDH polymorphisms reduce or abolish enzyme activity, so acetaldehyde accumulates. CYP2E1 has two common polymorphisms, C1 and C2; the C2 variant is biologically more active than C1 and therefore predisposes the person to more oxidative stress.
An epigenetic change in histone deacetylase (HDAC) also matters. The balance of acetylation and deacetylation of histones determines how open the DNA is for expression: heavily acetylated histones are expressed, and vice versa. Binge drinking alters the expression of HDAC mRNA in hepatocytes, which increases the expression of genes associated with steatosis.
Emerging mechanisms are also involved in ALD: studies show that inhibition of cannabinoid receptors such as CB1 causes weight loss and attenuation of fatty liver and steatosis.
Malnutrition is another mechanism. Some micronutrients and macronutrients are involved in both protecting and damaging hepatocytes in ALD — in particular zinc, whose deficiency and loss of zinc-finger protein function are well established in ALD, as well as vitamin A, vitamin D and dietary fats.
Fibrosis
Fibrosis in ALD can be mild to severe, as in cirrhosis. It occurs with increased deposition of the extracellular matrix (ECM). The total amount of fibrotic tissue in the liver, as in other tissues, reflects the balance between production and degradation.
In the liver, fibrotic tissue is made by activated stellate cells. Stellate cells are resident cells of the liver, and when activated they become myofibroblasts, which produce collagen type I. In ALD the total production of collagen type I rises because stellate cells are activated by the oxidative stress caused by alcohol and by the inflammatory signals made by inflammatory cells. Degradation of collagen type I is carried out by MMP-1. In ALD the level of tissue inhibitors of MMP-1 rises, so the enzyme cannot degrade the deposited collagen, and fibrosis results.