16. Cirrhosis. Causes, mechanisms and consequences. Hepatic cachexia.

Last updated on February 19, 2019 at 22:45

Introduction

Cirrhosis is the disease where functioning liver parenchyme is replaced by connective scar tissue. It’s the final pathway of many chronic liver diseases, like alcohol-induced or viral hepatitis. The normal liver architecture is converted into structurally abnormal nodules. Its development takes years. It involves a chronic injury to hepatocytes that stimulates scarring. As the functioning liver parenchyme is replaced by scar tissue will the liver start to lose its function. It will start to fail.

The causes of cirrhosis are:

  • Chronic hepatitis viral infection (mostly hep C)
  • Alcoholic liver disease
  • Non-alcoholic fatty liver disease
  • Cholestasis
  • Congestion (right-sided heart failure)
  • Cystic fibrosis

In chronic liver diseases does steatosis usually develop first. Later will the hepatocyte injury stimulate fibrosis and inflammation. Hepatic stellate cells (Ito cells) are converted into myofibroblasts that starts to proliferate and deposit collagen.

Stages of development of cirrhosis

Pre-inflammatory (steatotic) phase: Hepatocytes are injured by alcohol, virus or whatever etiology is present. Due to hepatocyte injury will the cells perform less β-oxidation. This suppresses protein synthesis, which reduces the hepatocytes’ ability to release lipids in lipoproteins because they can’t produce apolipoproteins. This causes the hepatocytes to fill with lipids. Stellate cells take up some of these lipids. At this stage is there steatosis. At this point are the changes reversible.

Inflammatory phase: The injured, fat-filled hepatocytes produce free radicals. These stimulate stellate cells to convert into myofibroblasts. These cells proliferate and produce connective tissue. They also produce cytokines which stimulate the Kupffer macrophages, which produce inflammation and start to remodel the parenchyme. Necrotic cell debris from dead hepatocytes also stimulates inflammation.

The connective tissue starts to compress the sinusoids, which increases the pressure in them, damaging the endothelial cells that line them. This increases the fenestration of the sinusoids, which allows more proteins and inflammatory cytokines to enter the interstitium.

Post-inflammatory phase: At this point are most stellate cells converted into myofibroblasts. There is continuous connective tissue proliferation, which compresses the liver parenchyme and damages hepatocytes. The damaged hepatocytes produce more γ-glutamyl transferase (GGT).

Cirrhosis may not cause symptoms initially. If it’s not treated will it progress until it starts to show symptoms like jaundice and oedema, and can eventually develop into liver failure with more severe symptoms. Due to the simultaneous destruction and rebuilding of liver tissue does cirrhosis have the potential to develop into hepatocellular carcinoma.

Liver failure

Liver failure is the condition where the liver loses some or all of its functions. It is a condition with a spectrum – some liver function is lost as soon as liver parenchyme is lost, and the liver failure may progress until liver function is severely decreased. At this point is it called end-stage liver disease.

It can occur acutely but most commonly has a chronic development. Chronic liver failure is basically synonymous with cirrhosis.

Common causes are:

  • Acute liver failure
    • Viral hepatitis
    • Toxins – mushrooms, organic solvents
    • Hepatotoxic drugs – halothane, isoniazid, paracetamol
    • Tumors
  • Chronic liver failure
    • Cirrhosis

When the liver fails are there multiple consequences:

  • Hypoglycaemia (only in acute failure)
  • Decreased protein synthesis
    • Hypoalbuminaemia
    • Coagulopathy – due to decreased clotting factors
  • Cholestasis
    • Jaundice
  • Hepatopulmonary syndrome
  • Hepatorenal syndrome
  • Portal hypertension
    • Hypersplenism
    • Malabsorption
  • Oedema, ascites
  • Hepatic encephalopathy
  • Hepatic cachexia

Hepatic cachexia or wasting occurs due to a combination of:

  • Hypermetabolism due to inflammation
  • Malabsorption due to portal hypertension and porto-caval anastomoses
  • Decreased appetite due to ascites, inflammation and hepatic encephalopathy

Hypoalbuminaemia contributes to the development of oedema and ascites.

As liver failure progresses will the liver’s ability to eliminate ammonia by producing urea decrease. Ammonia is toxic to the brain and contributes to hepatic encephalopathy.

Patients who develop ascites, hepatic encephalopathy or hepatorenal syndrome are considered to be in end-stage liver disease.


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15. Jaundice

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17. Portal hypertension

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