What are the stages of cirrhosis?1. Latent phase (well compensated stage) 2.

Advanced phase (decompensated stage)

Stages of Liver Cirrhosis

Stage1: During the initial stage of cirrhosis, the body normally does not exhibit any symptoms. Inflammation of the liver and formation of abnormal tissue in the liver can be detected with the help of proper medical tests. The initial stage of liver cirrhosis is called 'compensated stage.

Stage2: During this stage, abnormal tissues developed inside the liver get transformed into stiff bands of connective tissues. This process is known as fibrosis. Fibrosis and inflammation of the liver spreads and affects the portal veins and the surrounding regions.

Stage3: As the disease advances, all the stiff bands begin to merge with each other. This leads to the enlargement of the affected areas. Disruption of liver functions is generally noticed during this stage.

Stage4: The final stage of liver cirrhosis is known as the decompensated stage of cirrhosis. This stage is the most dreaded one. Liver transplant is the only treatment option.

 Fibrogenesis is the natural wound healing response to tissue injury.

The transformation of normal to fibrotic liver and then cirrhosis is a complex process involving key components :Both hepatic parenchymal and non parenchymal cells

Immune system

Proteinases and their inhibitors.

Cytokines

Extracellular matrix composition in normal liver and hepatic scar tissue

Normal liver After hepatic injury
Types I and III, rather than type IV (3

Type IV (nonfibrillary) collagen, glycoproteins (including fibronectin and laminin) and proteoglycans (including heparan sulphate).

These constituents comprise the low-density basement membrane in the space of disse

to 8 fold increase in extracellular matrix, composed predominantly of high-density interstitial fibril-forming collagens) as well as

cellular fibronectin, hyaluronic acid and other matrix proteoglycans and glycoconjugates.

Accumulation of Type I collagen results from both increased synthesis and reduced degradation, and is the hallmark of fibrogenesis.

Stellate cell activation: a central feature of hepatic fibrosis

 Stellate cell activation is a central event in hepatic fibrosis and can be conceptualized as occurring in at least two stages: (1) initiation and (2) perpetuation

Chemotaxis During liver injury, the normally quiescent HSC also Proliferation myogenic features including expression of alpha acquires Since fibrosis is a normal wound-healing response to smooth muscle actin and myosin , which confer With activation, HSCs proliferate rapidly. Plateletencapsulate injury, it is not surprising that the HSCs contractile properties. is the most potent migrate towards derived growth factor (PDGF-) Endothelin-1 and nitric oxide are sites of injury driven by key chemoattractants, mitogenic factor for HSCsImmune interactions . Other stellate cell mitogens Fibrogenesis regulators that control HSC contractility through their which include PDGF, monocyte mutually antagonistic factor (VEGF), thrombin, include vascular Inflammatory endothelialIgrowthactivities .(Contractility is also effected The productionsignalling including angiotensin II, eicosanoids, protein-1 (MCP-1) and CXCR3 ligands of type Macrophages play divergent collagen is the chemotactic liver by many factor (EGF), endothelial growth other factors transforming growth factor- roles inatrial fibrosis HSCs secrete proinflammatory cytokines/ carbon monoxide, among depletion cardinal feature of the activatedfibroblast regression. For example, progression and (TGF-), naturetic peptide, somatostatin and growth keratinocyte growth factor, stellate cell. chemokinesothers ) the mostHSCs, like dendritic cells, induction of fibrosis such as MCP-1.of factor IGF-1 andduring the factor remains TGF-1(FGF), insulin-like growth macrophages CXCL12 potent fibrogenic can also function as professional antigen presenting results in decreased fibrosis cytokine. Cellular sources of TGF-1 in chronic progression, yet when cells .In addition, signalling by TLR4 in HSCs indepleted during recovery, fibrosis macrophages are liver injury bacterial sinusoidal endothelial cells, response to include lipopolysaccharide prolonged due to loss of macrophageregression is further Kupffer cells and HSCs. Other cytokines include implicates and VEGF. Angiotensin II,matrix proteases . Natural killer (NK) cells, derived the main CTGF, FGF innate immune response to injury which contribute effector of the reninangiotensin system, is a to immediate innate responses, functional cytokine that is a may suppress fibrosis by killing activated potential activator of myofibroblasts ,anti- NKT cells can express collagen production in HSCs and a target of while
fibrotic therapies profibrotic activity .

Contractility

Pathway of extracellular matrix production and degradation.

Fibrinolysis
a net increase in Activated HSCs are interstitial collagenase the main source of activity occurs as a result MMP-2 , MMP-3 (stromelysin) of both increased MMPSand MMP-13, interstitial and decreased tissue inhibitors ofcollagenase MMP-1 MMPS (TIMPS) .

Fibrogenesis
TIMP-1, levels are TIMP-1
increased resulting in TIMP-2, both decreased and MT1degradation of type 1 MMP.

TIMP-1 plays a central role in fibrosis progression and regression. The imbalance between matrix synthesis and degradation plays a major role in ECM accumulation during hepatic fibrogenesis . The net result of the changes during hepatic injury is increased degradation of the normal basement membrane collagen, and reduced degradation of interstitial-type collagen.

collagen as well as persistence of activated stellate cells.

Definition
Cirrhosis of the liver is a pathologic entity characterized by (1) necrosis of liver cells, slowly progressive over a long period and ultimately causing chronic liver failure and death; (2) fibrosis, which involves both central veins and portal areas; (3) regenerative nodules, the result of hyperplasia of surviving liver cells; (4) distortion of normal hepatic lobular architecture; and (5) diffuse involvement of the whole liver.

 A regenerative nodule is an abnormal mass of liver cells without a normal cord pattern or central venule and surrounded completely by fibrosis Cirrhosis is defined anatomically as a diffuse process with fibrosis and nodule formation. It is the end result of the fibrogenesis that occurs with chronic liver injury.

Fibrosis is not synonymous with cirrhosis.

Fibrosis may be in acinar zone 3 in heart failure, or in zone 1 in bile duct obstruction and congenital hepatic fibrosis, or interlobular in granulomatous liver disease, but without a true cirrhosis. In schistosomiasis, the ova excite a fibrous tissue reaction in the portal zones but this does not usually evolve into cirrhosis.

Nodule formation without fibrosis, as in partial nodular transformation, is not cirrhosis.

INDIRECT MARKERS OF LIVER FIBROSIS

The aminotransferase-to-platelet ratio index (APRI)

Bonacini cirrhosis discriminant score 1. Platelets 2. Alanine aminotransferase to aspartate aminotransferase (ALT/AST) ratio: 3. International normalized ratio (INR)

FIBROTEST, based on 1. Bilirubin, 2. Gamma-glutamyl transferase, 3. Apolipoprotein A1, alpha-24. Macroglobulin, and 5. Haptoglobin.

FORNS INDEX, based on 1. Age, 2. Platelets, 3. AST,and 4. Cholesterol.

Therapeutic strategies for hepatic fibrosis

Remove injurious stimuli Suppress hepatic inflammation

Corticosteroids in autoimmune and alcoholic Abstinence from alcohol for alcoholic liver Downregulate stellate cell activation liver diseases diseases Neutralizing inflammatory cytokines using Antiviral therapy for viral hepatitis Gamma Interferon specific receptor antagonists: IL-1 receptor Antihelminthic therapy for schistosomiasis Antioxidants: alpha-tocopherol, resveratrol, quercetin, Nantagonists, soluble TNF-alpha receptor Copper chelation for Wilson's disease acetylcysteine, silymarin, OC-15161 Ursodeoxycholic acid (UDCA) Phlebotomy for hemochromatosis Cytokine-directed therapy: Discontinue hepatotoxins (eg, methotrexate) in Others: prostaglandin E, colchicine and TGF-beta antagonists colchiceine, milotilate, translast, IL-10 drug-induced liver injury Endothelin receptor antagonists Hepatic growth factor Disrupt ECM-HSC interactions: Arg-Gly-Asp (RGD) analogue Collagen synthesis inhibitors: TGF-beta antagonists, relaxin, halofuginone Others: Dilinoleylphosphotidylcholine (DLPC), HMG CoA reductase, Pentoxyphylline, HOE077, Safironil Retinoids?

Causes of fatty liver according to size of fat deposits

Microvesicular fat
Alcoholic foamy degeneration Acute fatty liver of pregnancy Reye's syndrome Valproic acid Tetracycline Jamaican vomiting sickness Indian childhood cirrhosis Haemochromatosis Viral hepatitis B and C 1-antitrypsin deficiency

Macrovesicular fat
Alcohol Malnutrition Obesity Diabetes mellitus Corticosteroids Total parenteral nutrition Wilsons disease Viral hepatitis B and C 1-antitrypsin deficiency