Question

What is the cellular mechanism (cells in the liver that become altered, etc.) leading to this death? Is the type of cell death apoptosis, necrosis, or both?   What is it in the metabolic breakdown of alcohol that causes the liver damage?

Answer 1

The presence of hepatocytes death , is reflected by the increased levels of serum alanine aminotransferase and aspartate aminotransferase ,These are the most widely used parameters to screen for and monitor patient with disease .These   well established the facts that emphasize the importance of cell death as the ultimate driver of the liver disease progression and the development of liver fibrosis , cirrhosis and hepatocellular carcinoma.

In the healthy liver , the cell death controls organ homeostasis with a tight equilibirum between the loss and replacement of hepatocytes . turnover these two parameters are low iin the normal liver , with approximately 0.05% of heapatocytes at any given time being removed by apoptosis This is reflected by almost undetectable ALT level in healthy subject .Despite the fact that the most hepatic cells types rest in Go phase , the liver is endowed with the an astounding ability to regenerate in response to massive hepatocellular death or loss off functional liver mass.THis regenerative ability not only reflects essential metabolic function of the liver but is also directly related to its high vulnerability to insults causing massive hepatic cell death such as food derived toxin or infection with heptatropic viruses ,bacteria , and parasites .

Cell death occurs not only as a passive response to physiochemical stress or noxious insult but may also be actively induced by the host via PCD .PCD plays an active role inthe development and organismal homeostasis . Accordingly , inhibhition of PCD by the genetic ablation of thekey cell death regulators that lead to heapatic hyperplasia , moreover ,PCD   is directly involved in the defense against pathogen that includes hepatotrophic viruses and represent a key mechanism preventing malignant transformation . Traditionally distinct forms of cell death have been recognized ;- apoptosis as the mediator of PCD and actively induced by the specific signaling cascades and occuring in a high controlled fashion and necrosis as the accidental form of death , however PCD  triggers a specific form of necrosis termed a s necroptosis .

HEpatocye apoptosis involves two fundamental pathways ;- The extrinsic pathways which transmits death signals by the death receptor (DR) and the intrinsic pathway which is intitiated by intracellular stimuli ,

THe extrinsic pathways apoptotic pathway is activated by the binding of the death ligand to DR on theplasma membrane . Death ligand belong to tumor necrosis factor (TNF) .The intrinsic apoptosis pathways is charcterized by the release of cytochrome C or other caspase activating factors from th e mitochondria intermembrane space into cytoplasm Mitochondrial dysfuction can intitae hepatocyte apoptosis and other intracellular organelles can also trigger apoptosis through the  mitochondrial dependent mechanism. Inaddition to apoptosis , other cell death modalities also participate in hepatocyte death and liver injury through crosstalk and overlaop , yielding highly heterogeneous death processes . Activation of similar apoptotic pathways can be observed indifferent types and phases of liver disease types and phases of liver disease .

So, cell death inthe liver occurs mainly by apoptosis or necrosis , with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis .

Alcohol is metabolized by several processes or pathways , the most common pathway involves 2 enzymes- alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) . these enzymes help break apart the alcohol molecule s, making it possible to eliminate it form thebody . First ADH metabolizes alcohol to acetaldehyde is further metabolized down to another less active by product called acetate which then broken down into water and carbon dioxide for easy elimination.

the acute or chronic alcohol exposure increase intestinal permeability and elevated systemic level of gut derived endotoxin and other microbial products .Endotoxin activates kupffer cells (the resident macrophage inthe liver) to induce the production of TNFa and subsequent TNFa mediated apoptosis in the liver . In addition to inducing apoptosis in hepatocytes , alcohol exposure also induses apoptosis and inflammation in adipose tissue .