Etiology and Pathogenesis

Liver cirrhosis conventionally is classified into three typed, they are macro
nodular (size of nodul more than 3 mm), micro nodular (size of nodul less than 3
mm), and mixed both macro and micro nodular in the same proportion. 1,2 Another
classification divided liver cirrhosis according to its etiology and morphologic.
Michitaka K studied result that held in Japan, Hepatitis B virus (HBV) 13.9%,
hepatitis C virus (HCV) 60.9%, alcohol 13.6%, primary biliary cirrhosis (PBC)
2.4%, autoimmune hepatitis (AIH) 1.9%, and nonalcoholic steatohepatitis
(NASH) 2.1% patients are correlated as liver cirrhosis etiology.3 HBV, HCV, and
alcohol are primary etiology of liver cirrhosis worldwide. In Europe HCV and
alcohol are the primary etiology.3 In western country, alcohol, chronic HCV
infection, and non-alcoholic fatty liver diseases (NAFLD) as the primary etiology
of liver cirrhosis.2 Meanwhile in North America and developing countries (Asia
and Africa) HBV leads as the primary etiology.2,3 In this paper we will discuss the
pathogenesis of the most common etiology HBV, HCV, alcohol, and NAFLD.

Pathogenesis of liver cirrhosis due to its etiology

1. Cirrhosis due to chronic HBV and HCV infections
Chronic infection of HBV and HCV will lead to damage of liver cells. HBV
and HCV infections increase level of oxidative stress markers. Lipid peroxidation
products are increased in serum, peripheral blood mononuclear cells (PBMC), and
liver specimen. They can also induce oxidative stress intracelularlly in
hepatocytes.4,5 Due to this chronic inflammation, infiltration, and activation of
stress oxidative, the hepatocytes undergo apoptosis. Kupffer cell will be activated
and release fibrogenic mediators such as cytokine.5,6 Apoptosis of damaged
hepatocytes also stimulates the fibrogenic actions of liver myofibroblasts.
Inflammatory cells, either lymphocytes or polymorphonuclear cells, and activate
hepatic stellate cells (HSCs).2 Activation of HSCs is characterized by cell
proliferation, migration, contraction and transforming into myofibroblast generate
large amount of collagen (commonly type I and III) and extracellular matrix
(ECM).
If the hepatic injury persists, then eventually the liver regeneration fails, and
hepatic hepatocytes are substituted with abundant collagen and ECM, it will lead
2,5,7
to liver fibrosis. Liver fibrosis is part of hepatic wound healing, and if it
undergo progressively ultimately leading to liver cirrhosis.

Figure []. Activation to HSCs lead to fibrosis

2. Cirrhosis due to alcohol consumption

Excessive alcohol consumptions is well known to be associated with cirrhosis
liver disease. Among heavy drinkers, 820% will develop cirrhosis in 10 years of
period.8 Definition of heavy drinkers are people who drink more than 35 glasses
per week. Alcohol will lead to prolong destruction of hepatocytes, perivenular
fibrosis continued into panlobular cirrhosis.1 Hypoxia of sentrilobular, metabolism
of acetaldehyde etanol increase the usage of lobular oxygen causing relative
hypoxia and cells damage in the area that located far from the oxidized blood flow
(i.e pericentral region). Infiltration or activation of neutrophils, causing the release
of chemoattractan neutrophils by hepatocytes that metabolite etanol. Tissue
damage can be caused from neutrophils and hepatocytes that release intermediate
reactive oxygen, protease, and cytokine. Formation of acetaldehyde-protein
adducts acts as neoantigen and produce the sensitized lymphocytes and specific
antibody against hepatocytes that bring this antigen. The formation of free radicals
by alternative from etanol metabolism, it is called system that oxidize microsomal
enzyme.

4. Cirrhosis due to NAFLD

Fatty liver is the result of an intracellular accumulation of triglycerides
because of increased uptake of free fatty acids and liponeogenesis in the
hepatocytes. At the same time, there is a reduction in the hepatic secretion of very
low density lipoproteins. The liver damage consists of cellular necrosis and
inflammation, and these disorders result from an increase in mitochondrial
oxidative stress on triglycerides with the consequential generation of free radicals
and peroxisomes.9 Almost the same with the mechanism of chronic viral infection,
inflammation and activated of oxidative stress will lead to hepatocytes apoptosis,
activation of Kupffer cells, and activating of HSCs. HSCs will transformed into
myofibroblasts and generate abundant amount of collagen and other ECM leading
to fibrosis and cirrhosis.
Figure []. General mechanism of liver fibrosis and lead to cirrhosis
Source

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