Cirrhosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. Early disruption of the normal hepatic matrix results in its replacement by scar tissue, which in turn has deleterious effects on cell function.

Pathophysiology

The pathogenesis of cirrhosis is as follows:

• When an injured tissue is replaced by a collagenous scar, it is termed as fibrosis. The development of fibrosis requires several months, or even years, of ongoing injury.
• The pathological hallmark of cirrhosis is the development of scar tissue that leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
• When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver. If the damage progresses, panlobular cirrhosis may result.
• The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
• Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
• Cirrhosis involves the following steps:
  • Inflammation
  • Hepatic stellate cell activation
  • Angiogenesis
  • Fibrogenesis
• Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury.
• The stellate cell, (also known as the perisinusoidal cell or Ito cell) is a cell type that normally stores vitamin A and plays a pivotal role in the development of cirrhosis.
• Hepatic stellate cells (HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury. This contractile cell (known as a myofibroblast) obstructs blood flow in the circulation.
• The stellate cell secretes TGF-β₁, which leads to a fibrotic response and proliferation of connective tissue.
• Connective tissue proliferation leads to the formation of extracellular matrix around hepatocytes and is composed of collagens (especially type I, III, IV), glycoprotein and proteoglycans.
• Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells (HSC).
• Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
• Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
• The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
• Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by matrix breakdown and replacement by connective tissue-secreted matrix.
• Matrix metalloproteinase (MMP) are calcium dependent enzymes that specifically degrade collagen and non collagenous substrate.
• MMP-2 and stromyelysin-1 are produced by stellate cells.
• MMP-2 degrades collagen and stromelysin-1 degrades proteoglycan and glycoprotein.
• Cirrhosis leads to hepatic microvascular changes characterised by:
  • Formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
  • Hepatic endothelial dysfunction
• Sinusoidal endothelial cells are also important contributors of early fibrosis. Endothelial cells from a normal liver produces collagen, laminin and fibronectin.
• The endothelial dysfunction is characterised by
  • Insufficient release of vasodilators, such as nitric oxide due to oxidative stress
  • Increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
• The liver responds to injury with new blood vessel formation. Mediators involved in angiogenesis include:
  • Platelet derived growth factor (PDGF)
  • Vascular endothelial growth factor (VEGF)
  • Nitric oxide
  • Carbon monoxide
• Angiogenesis in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that further exacerbate liver injury.
• Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature.
• A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow).
• Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.
• These mechanisms simultaneously occurring in the liver lead to fibrous tissue band (septa) and regenerative hepatocyte nodule formation, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
• The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
• Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
• The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.
• Due to portal hypertension, the spleen becomes congested, which leads to hypersplenism and increased platelet sequestration.
• Pathogenesis of cirrhosis based upon the underlying cause is as follows:
  • Alcoholic liver disease: Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. Liver damage due to alcoholic hepatitis may progress to cirrhosis.
  • Chronic hepatitis C: Infection with the hepatitis C virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis.
  • Non-alcoholic steatohepatitis (NASH): In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications.
  • Primary sclerosing cholangitis: PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease.
    • There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis.
  • Autoimmune hepatitis: Immunologic damage to the liver leads to inflammation, scarring and cirrhosis.

• Portal hypertension may result from a combination of the following:
  • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
  •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

Pathophysiology of Alcoholic liver disease

Pathogenesis of Cirrhosis due to Alcohol:

• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

• Ethanol metabolism in the liver is carried out mainly by two enzymes:
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
• Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.
• The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide (NADH). This changes the reduction-oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.
• Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.

• The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.

• There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O₂^-, H₂O₂, OH^- and hydroxyethyl radical (HER).

• Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.

• Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:
  • Endotoxin
  • Gut permeability
• Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.
• Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.
• The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.

• After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.
• The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
• Activation of these Kupffer cells requires 3 main cellular proteins:
  • CD14 (monocyte differentiation antigen)
  • Toll-like receptor 4 (TLR4)
  • MD2, a protein, binds TLR4 with LPS-LPS binding protein
• The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.
• The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.
• EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
• In mice the absence of EGR1 prevents alcohol induced liver injury.

• Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.
• The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.
• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

Pathology

• There are four stages of Cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
  • Development of biliary stasis and fibrosis
• Periportal fibrosis progresses to bridging fibrosis
• Increased proliferation of smaller bile ductules leading to regenerative nodule formation.