Last updated on May 11, 2019 at 17:07
The most important causes of cirrhosis are alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD). Both progress from a steatosis to a hepatitis to cirrhosis.
The morphology of alcoholic liver disease and NAFLD is indistinguishable. The different alterations seen in fatty liver can be present in these stages:
1. Hepatocellular steatosis
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.
These changes are often more prominent in an alcoholic liver than in NAFLD, and they include:
- 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.
3. Steatohepatitis with fibrosis
A distinctive pattern of scarring occurs with fatty liver disease. 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.
Alcoholic liver disease
Excessive ethanol consumption causes more than 60 % of chronic liver diseases in the Western countries (and probably higher in Hungary), and is the 5th leading cause of death.
Chronic alcohol consumption has many adverse effects, as you may know now. Among the most important are the forms of alcoholic liver disease, as discussed earlier:
- Hepatic steatosis
- Alcoholic hepatitis
- Fibrosis and cirrhosis
Some “fun facts” about alcohol drinking: women take more damage to the liver from drinking, and binge drinking every weekend now and then is more damaging than drinking a little every day.
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:
- Reactive oxygen species generated during oxidation of ethanol
- Cytokine-mediated inflammation and cell injury
- Alcohol itself
Hepatitis C is also very often found in chronic alcoholics and leads to acceleration of alcoholic liver disease.
Morphology: 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 blood test, commonly higher than 2. Macrocytic anaemia can also occur.
Complications: Alcoholic hepatitis can progress into cirrhosis. Almost every heavy drinker develops hepatic steatosis, but cirrhosis only develops in 1 of 5. The best treatment is abstinence from alcohol.
Non-alcoholic fatty liver disease
This condition develops in persons who don’t drink alcohol but are obese. The liver may suffer the same changes as described above, but the changes are less prominent. The aetiology is however different. NAFLD is associated with insulin resistance and metabolic syndrome. Metabolic syndrome is defined to have at least two of the following: obesity, insulin resistance, dyslipidaemia and hypertension.
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.
Symptoms: Most patients with steatosis are asymptomatic. Some can also experience malaise, fatigue, discomfort in the right upper quadrant. The treatment for this is like treating coronary artery disease, helping the patient getting a healthy lifestyle and controlling the insulin.
Complications: NAFLD can progress into cirrhosis.
Cirrhosis refers to the replacement of normal liver tissue by scar tissue. It develops in a small fraction of people with hepatitis. Regression of cirrhosis is not possible. The most common causes are excessive alcohol consumption and hep C infection.
- Alcoholic liver disease
- Non-alcoholic fatty liver disease
- Chronic viral hepatitis
- Hepatitis C, B or D
- Wilson’s disease
- Budd-Chiari syndrome
Pathomechanism: Continous necrosis and regeneration of the liver parenchyme replaces the functioning liver parenchyme with fibrosis.
Morphology: 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.
Clinical manifestations: Cirrhosis causes hepatic failure, the symptoms of which you can read about below. Laboratory findings in cirrhosis show:
- elevated serum aminotransferases (ALT and AST),
- elevation of alkaline phosphatase,
- hypoproteinaemia (globulins, albumins and clotting factors)
Classification: There are 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
Hepatic or liver failure describes the condition where the liver is unable to perform its normal functions. This occurs because the liver parenchyme is damaged or replaced by scar tissue. Chronic hepatic failure is almost synonymous with cirrhosis, as cirrhosis is the most common cause.
- Loss of hepatocytes
- Massive necrosis – like in fulminant hepatitis or by toxic agents
- Poisonous mushrooms, phosphorous, CCl4 and halothane
- Paracetamol overdose
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
- Coagulopathy – Low fibrinogen and clotting factors
- Hyperbilirubinaemia (jaundice)
- Increased levels of oestrogen
- Hepatorenal syndrome
- Hepatopulmonary syndrome
- Hepatic encephalopathy
- Vascular decompensation – due to congestion of the portal circulation
- Portal hypertension
- Oesophageal varices
- Caput medusae
Cirrhosis also increases the risk for hepatocellular carcinoma.
You can read more about these consequences in pathophysiology 2.
13. Chronic viral hepatitis (aetiology, types), pathomorphology and differential diagnostics, detection of virus associated antigens and their significance)
15. Tumours and tumorlike conditions of the liver