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Classification of liver cirrhosis

Global statistics of liver cirrhosis

Liver cirrhosis is estimated to be responsible for over one million deaths in the world in 2010 [Mokdad 2014]. Liver cirrhosis is estimated to be the $12^{th}$ leading cause of death in 2020 [Murray 1997]. Therefore, it is declared the global burden and steps are taken to reduce the incidence of occurrence of liver cirrhosis. Before entering into deep to the discussion, we must remind the reader about the normal anatomy and physiological role of liver in human.

liver cirrhosis

Liver cirrhosis is the end stage liver disease, associated with replacement of healthy hepatocytes with scar tissue (fibrous). Loss of normal hepatic tissue causes the impairment of normal synthetic and metabolic action of liver, leading to hepatic encephalopathy and coagulopathy

Compensated cirrhosis

Though the liver is heavily scared, but the capacity of liver to perform important physiological roles is not impaired. Generally compensated cirrhosis is asymptomatic. The disease is revealed with the following symptoms: fatigue, loss of energy, loss of appetite, weight loss, nausea and abdominal pain.

Decompensated cirrhosis

Liver cirrhosis with any one of the following symptoms: jaundice, ascites or HE [table 1].

Table 1 ChildPugh score

HE Null Minimal (grade 1-2) Advanced (grade 3-4)
Ascities Absent Controlled Refractory
Total bilirubin (mg/dl) <2 2-3 >3
Plasma albumin (g/dl) >3.5 2.8-3.5 <2.8
Prothrombin time (Seconds) <4 4-6 >6

Classification of liver cirrhosis according to causes

Alcoholic liver cirrhosis

Alcoholic liver cirrhosis is the end stage of fatty liver due to excess alcohol consumption. It accounts for death due to cirrhosis in $40\%$ of that patients in United States [Mashiko 2010]. During consumption of more than two or three drink daily for several days leads to accumulation of fat in liver, followed by cirrhosis with or without hepatic carcinoma. Ethanol is metabolized by three possible pathways in liver:

  • Reversible oxidation into acetaldehyde (toxic product) by either enzyme, alcohol dehydrogenase (predominant), cytochrome $P_{450}$2E1 (CYP2E1), and catalase.
  • Irreversible conversion of actaldehyde into acetate by acetaldehyde dehydrogenase.
  • Break down of acetate into $CO_2$ and $H_2O$.
  • Alcohol dehydrogenase activation is comonly used pathway by mitochondria for the purpose. CYP2E1 activated due to chronic alcohol consumption and leads to aldehyde formation in peroxisomes. Alcohol is converted into acetaldehyde by catalase in microsome. While imbalance between aldehyde production and metabolism, excess aldehyde, due to its electrophilic nature, converted into adducts (covalent chemical addiction products). These adducts are the primary products, responsible for alcoholic lever diseases. These are capable of binding with protein, lipids, DNA and thus damage the cell and promote DNA mutation (example: point mutation in acetaldehyde induced hypoxanthine phosphoribosy tranferase (HPRT1) gene, followed by impaired DNA synthesis. Acetaldehyde adducts produce protein adducts, interacting with a large number of proteins like colagen, tubulin, coagulation factors VII and IX, ketosteroid reductase (responsible for bile acid synthesis). Acetaldehyde binds with glutathione and thus increase the oxydative stress (superoxide, hydrogen peroxide and hydroxyl radicals)of cells, followed by lipid peroxidation and cell death [Mashiko 2010].

    Liver damage induced by alcohol have various pathways:
  • Aldehyde protein adducts bind with lysin and interfere with lysin dependant enzyme $\alpha$ tubulin and impair microtubulin function of hepatocytes [Mashiko 2010].
  • Hybrid adducts (example Malondialdehyde (MDA)-acetaldehyde protein adducts) accumulated in the extracellular area of liver and depletes the collagen, followed by the scar tissue formation by fibrosis and cirrhosis in end stage [Mashiko 2010].
  • Immune system becomes active against protein adduct and hydroxyl radicals and cytokine induced hepatic inflammation leads to liver cirrhosis, following liver cell injury and fibrosis. Elevated levels of IgG, IgM and IgA are found in clinical examination of cirrhotic patients [Mashiko 2010].
  • Another hybrid adduct (malondialdehyde-acetaldehyde (MAA) adducted proteins), along with free radicals stimulate hepatic fixed macrophages (Kuffer cells) to release cytokines and chemokines, including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2), followed by the damage of hepatocytes by inflammatory pathway and leading to scar tissue formation [Mashiko 2010].
  • Additionally, MAA is capable of activating fibronectin, responsible of extracellular matrix deposition and cirrhosis [Mashiko 2010].
  • Adducts activate activating protein 1 (AP1 transcription factor), responsible for the production of collagen 1 synthesis and deposition in liver. Adduct scavenger, chlormethiazole inhibits the synthesis and deposition of collagen in liver [Mashiko 2010].
  • Usually, triglycerides (TGs) are stored in liver. TGs is converted into lipoprotein, conjugating with apoprotein, to circulate in the blood. During heavy alcohol consumption, apoprotein formation is impaired and it leads to excess TGs accumulation in liver, a popular cause of cirrhosis [Kumar 2004].
  • Clinical representation and management of liver cirrhosis

    Hepatitis C induced liver cirrhosis

    The detail mechanism of progression of Hepatitis C induced liver cirrhosis is shown in figure 5 [WHO 2016]. It is worthy to mention here, co-infections along with Hepatitis C, specially immunodeficiency (T CD4 cells count $<$ 200 per $mm^3$ of blood) increases the risk of suffering from cirrhosis in the patients [WHO 2016].

    progression of Hepatitis C induced liver cirrhosis

    Non alcoholic steato-hepatitis (NASH) and liver cirrhosis

    Tissue necrosis occur near to central vein. So, the blood flow through out liver is affected, causing elevated pressure in portal vein (above 12 mm Hg, where as normal is 1-9 mm Hg) [Barbara 2009] [Kumar 2008]. This situation is called portal hypertension. But, actually the pressure gradient between portal vein and inferior vena ceva rises above 5 mmHg causes portal hypertension [Arguedas 2003]. Intrahepatic shunting of blood flow results in ascites, varices (dilated blood vessels), impaired synthetic and metabolic function of liver, coagulopathy and hepatic encephalopathy (HE) [Barbara 2009].

    Reference

    [Barbara 2009] Barbara GW, Joseph TD, Terry LS, Cecily VD, Pharmacotherapy Handbook, $7^{th}$ Edition, Mc Growhill, 239-320, 2009.
    [WHO 2016] World Health Organization: Guidelines for the screening, care and treatment of persons with chromin hepatitis C infections, WHO Document Production Services, Geneva, Switzerland, ISBN 978 92 4 154961 5, updated version 2016.
    [Murray 1997] Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990 - 2020: Global Burden of Disease Study, Lancet, vol. 349, pp.1498- 1504, 1997.
    [Mokdad 2014] Mokdad A, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis, BMC Med., 12, 145, 2014.
    [Mashiko 2010] Mashiko S, Jack RW, Suzanne MM, Acetaldehyde adducts in alcoholic liver disease, Oxidative Medicine and Cellular Longevity, 3(3), 178-185, 2010.
    [Kumar 2004] Kumar V, Abbas AK, Fausto N, Robbins and Cotran Pathologic Basis of Disease, $7_{th}$ Edition, Elsevier, 2004.
    [Kumar 2008] Kumar A, Sharma P, Sarin SK, Indian J Gastroenterol,Hepatic venous pressure gradient measurement, vol. 27, no. 2, pp. 74-80, 2008.
    [Arguedas 2003] Arguedas M, The critically ill liver patient: the variceal bleeder, Semin Gastrointest Dis., 14(1), 34-8, 2003.

    Anatomy and Physiological roles of liver

    Classification of liver cirrhosis

    Phenomena associated with liver cirrhosis

    Clinical representation and management of liver cirrhosis