14. Cirrhosis and hepatic failure (+ alcoholic and fatty liver disease)

From greek.doctor

Cirrhosis

Introduction and epidemiology

Cirrhosis is a chronic liver disease characterised by replacement of normal liver tissue by scar tissue. It’s an irreversible end-stage of hepatitis which cause significant morbidity and mortality. There is continuous loss of functional liver tissue, which is initially compensated and asymptomatic as the remaining liver can compensate. However, acute insults precipitate decreases in liver function, causing hepatic decompensation and development of dramatic and life-threatening complications.  Cirrhosis is also an important risk factor for hepatocellular carcinoma.

Cirrhosis is a common condition worldwide.

Etiology

  • Alcoholic liver disease
  • Metabolic associated fatty liver disease
  • Chronic viral hepatitis (C, B or D)
  • Haemochromatosis
  • Biliary obstruction (primary biliary cholangitis, primary sclerosing cholangitis)
  • Autoimmune hepatitis
  • Wilson’s disease
  • Heart failure
  • Alpha-1 antitrypsin deficiency

The most common causes are alcoholic liver disease and hep C infection.

Pathology

Continous necrosis and regeneration of the liver parenchyme replaces the functioning liver parenchyme with fibrosis. The pattern of fibrosis eventually forms fibrous septa. The more prominent they become, the more the liver takes on a nodular cirrhotic appearance. Histology shows pseudolobules separated by fibrosis. These pseudolobules can be distinguished from hepatic lobules by the fact that they don’t have a central vein.

The liver will now be a brown, shrunken, nonfatty organ composed of cirrhotic nodules.

We can distinguish multiple types of cirrhosis:

  • Micronodular cirrhosis (Laennec cirrhosis) – caused by alcoholism
  • Macronodular cirrhosis – caused by chronic hepatitis B or C or by autoimmune hepatitis
  • Pigment cirrhosis – Caused by hemochromatosis (iron accumulation) or Wilson disease (copper accumulation)
  • Biliary cirrhosis – Caused by damage to the biliary tree

Clinical features

Cirrhosis causes hepatic failure, the symptoms of which you can read about below, but the most significant are jaundice, ascites, and hepatosplenomegaly. Laboratory findings in cirrhosis show:

  • Elevated serum aminotransferases (ALT and AST) and alkaline phosphatase
  • Hyperbilirubinemia,
  • Hypoproteinaemia (globulins, albumins and clotting factors)
  • Anaemia
  • Elevated INR – due to decreased production of clotting factors

Hepatic failure

Introduction

Hepatic or liver failure, also called hepatic decompensation, describes the condition where the liver is unable to perform its normal functions. This occurs because the liver parenchyme is so damaged or replaced by scar tissue that the remaining liver cannot compensate for the loss. It may be acute or chronic, but chronic is much more common. Chronic hepatic failure is almost synonymous with cirrhosis, as cirrhosis is the most common cause.

Etiology

  • Acute hepatic failure
    • Acute viral hepatitis (A, E)
    • Drug effects
    • Poisonous mushrooms, phosphorous, CCl4 and halothane
    • Paracetamol overdose
  • Chronic hepatic failure (cirrhosis)

Complications

The complications of hepatic failure are many, and it can be divided into two types:

  • Parenchymal decompensation – due to decreased function of the parenchyme
    • Hypoproteinaemia
      • Hypoalbuminaemia -> oedema, ascites
      • Decreased production of clotting factors -> coagulopathy -> excessive bleeding
    • Hyperbilirubinaemia -> jaundice
    • Hepatic encephalopathy -> confusion and altered mental status
    • Hepatorenal syndrome
    • Hepatopulmonary syndrome
  • Vascular decompensation – due to congestion of the portal circulation
    • Ascites
    • Portal hypertension
    • Oesophageal varices -> can cause significant bleeding
    • Caput medusae
    • Splenomegaly
    • Malabsorption

You can read more about these consequences in pathophysiology 2.

Alcoholic liver disease

Alcoholic liver disease and non-alcoholic fatty liver disease don’t have their own topics, but they’re important disorders to know.

Introduction and epidemiology

Alcoholic liver disease (ALD) is an umbrella term for liver conditions caused by significant and chronic alcohol abuse. It initially causes liver steatosis, which progresses to alcoholic hepatitis to cirrhosis unless alcohol consumption stops.

Almost all who abuse alcohol develop liver steatosis, which is reversible, but only a few progress to hepatitis and cirrhosis. Hepatitis C is often found in chronic alcoholics and leads to acceleration of alcoholic liver disease.

Excessive ethanol consumption causes more than 60 % of chronic liver diseases in the Western countries and is the 5th leading cause of death. Alcoholic liver disease is a major cause of liver transplantation.

Etiology

Alcoholic liver disease is caused by significant alcohol consumption over long periods of time. The risk increases proportionally with the amount of alcohol consumed. There is no threshold above which ALD invariably develops, as this varies from person to person, but most people with ALD have been drinking ~10 units daily for decades.

When talking about alcohol consumption, it’s important to define how much a unit of alcohol is. In Europe in general, one unit is 10 g of alcohol, while it’s 14 g in the US. This corresponds to one 0,33 L beer, one glass of wine, or one small glass of hard liquor.

Some “fun facts” about alcohol drinking: women are more susceptible to alcohol-induced liver injury, and binge drinking may be as harmful as daily drinking.

Pathomechanism

Hepatocellular steatosis results from shunting substrates away from catabolism and towards lipid synthesis, because alcohol dehydrogenase generates so much NADH from all the ethanol that lipid synthesis is favoured by the metabolism. You can read more about this pathophysiology 2.

The causes of alcoholic hepatitis are most likely toxic products and metabolites from ethanol metabolism, like:

  • Acetaldehyde
  • Reactive oxygen species generated during oxidation of ethanol
  • Cytokine-mediated inflammation and cell injury
  • Alcohol itself

The progression of alcoholic liver disease is as follows:

  • Hepatocellular steatosis
    • Steatosis refers to fatty change of the liver. Fat accumulates in the hepatocytes, and the centrilobular ones are the first ones to acquire this change. The lipid accumulation in hepatocytes spreads outward from central veins to the midlobular and periportal hepatocytes. The lipid droplets that accumulate expand the cells and displace the nucleus.
    • Macroscopically, the liver is very big (4-6 kg or more), soft, yellow and greasy.
  • Steatohepatitis
    • Steatohepatitis refers to the presence of both inflammation and steatosis.
    • Hepatocyte ballooning, where single or scattered foci of hepatocytes undergo swelling and necrosis.
    • Mallory-Denk bodies, which consists of damaged intermediate filaments, and can be seen as very eosinophilic inclusion bodies in degenerating hepatocytes
    • Neutrophil infiltration – neutrophils accumulate around the degenerating hepatocytes. Especially around the Mallory-Denk bodies.
  • Cirrhosis
    • A distinctive pattern of scarring occurs. It appears first as central vein sclerosis, and spreads outwards, encircling individual or small clusters of hepatocytes. It looks like a chicken wire fence in the microscope.

The area around the central veins are most susceptible to toxic injury because the generation of acetaldehyde and free radicals is biggest there. Pericellular and sinusoidal fibrosis develop in this area as well. Both steatosis and alcoholic hepatitis can be reversible if the patient stops drinking alcohol.

Alcohol-induced liver damage usually has an increased AST/ALT ratio on labs, commonly higher than 2.

Metabolic associated/non-alcoholic fatty liver disease

Introduction and epidemiology

Metabolic associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), refers to liver disease which develops due to obesity and diabetes mellitus type 2. The pathology and progression is similar as with ALD, but there is no alcohol abuse involved. It progresses similarly as ALD, from steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis.

Recently (2020), it’s been proprosed that NAFLD needs a new name to better describe its pathogenesis, namely metabolic associated fatty liver disease (MAFLD).

It’s a very common condition in the Western world.

Pathomechanism

Insulin resistance results in accumulation of triglycerides in hepatocytes due to these mechanisms:

  • Impaired oxidation of fatty acids
  • Increased synthesis and uptake of fatty acids
  • Decreased hepatic secretion of VLDL cholesterol.

The fat-loaded hepatocytes are very sensitive to lipid peroxidation products generated by oxidative stress, which can damage mitochondria and plasma membranes. This leads eventually to apoptosis of the hepatocytes. A consequence of oxidative stress or release from visceral adipose tissue is that the levels of TNF and IL-6 increase, contributing to liver damage and inflammation.