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Liver Disease in Alpha-1 Antitrypsin Deficiency
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EXCELLENCE IN RESEARCH
Ethyl alcohol, also known as ethanol, is a product of yeast fermentation. Unlike carbohydrates and fats, ethanol is not stored in the tissues of the body. A minimal amount can be eliminated through the lungs and kidneys, but the body essentially rids itself of ethanol through metabolic processes. Because the liver contains the necessary enzymes to break down ethanol, this organ is heavily relied upon for the metabolism of ethanol. More than 90% of ethanol intake will be oxidized to acetic acid via two major metabolic pathways within the liver. The remaining ethanol that is not metabolized is excreted in urine, sweat, and breathing.
Within the cytoplasm of liver cells, 2 hydrogen atoms are removed from an ethanol molecule by the enzyme alcohol dehydrogenase, forming acetaldehyde. This is oxidized in mitochondria by aldehyde dehydrogenase to form acetic acid, which is further broken down into CO2 and H2O. The reaction pathway is as follows:
CH3CH2OH + NAD+ -> CH3CHO + NADH + H+
Another route of ethanol metabolism within the liver is known as the microsomal ethanol-oxidizing (MEOS) system, which involves ethanol oxidation by cytochrome P450. The MEOS system does not have as large a role in ethanol metabolism as the alcohol dehydrogenase pathway, but it begins to become more important when concentrations of ethanol become very high. This pathway results in the same byproducts of acetaldehyde and acetic acid, but uses NADPH instead of NAD+ as a reducing factor. The process also uses O2, which generates free radicals that can damage tissues. The reaction pathway due to MEOS catalysis is:
CH3CH2OH + NADPH + O2 -> CH3CHO + NADP+ + H2O
The single most common cause of liver disease is the chronic consumption of ethanol. The damage results from the alcohol itself and also from the byproducts produced from its breakdown. These damaging byproducts include acetaldehyde and free radicals. A buildup of the reactive acetaldehyde leads to covalent bonding with protein functional groups, impeding protein function. High levels of this compound lead to cell death and liver damage.
Because the liver has an enormous regenerative capacity, liver damage usually occurs only in alcoholics who have been drinking excessive amounts of alcohol for many years. Three main categories of liver disease include: fatty liver, alcohol hepatitis, and alcoholic cirrhosis. Fatty liver is the result of fat deposits in the liver and is reversible. This can result from just one incidence of heavy drinking, but usually does not lead to any further problems. Alcoholic hepatitis is the inflammation and destruction of liver cells due to chronic alcohol consumption. While it may be fatal it can be reversed simply by cessation of alcohol intake. Alcoholic cirrhosis is the extensive scarring of the liver, often following alcoholic hepatitis when the affected individual continues drinking. The replacement of normal functioning liver tissue with fibrotic scar tissue results in the loss of liver function and also the stiffening of blood vessels, leading to portal hypertension as the internal structure of the liver is destroyed.
Alcoholic Hepatitis is an inflammation of the liver resulting from the continual consumption of alcohol. As with inflammation of other organ systems, alcoholic hepatitis results in an increased blood flow to the liver, swelling of the liver, an influx of white blood cells, and pain. In addition to the damage caused by alcohol, those alcoholics who develop hepatitis or cirrhosis may also suffer from malnutrition due to the consumption of alchol which contains many calories without any of the essention nutrients, proteins or vitamins. This malnutrition can contribute to liver disease. While Alcoholic Hepatitis does not directly lead to cirrhosis, cirrhosis is most commonly found in those who are alcoholics, which is also the main group affected by alcoholic hepatitis.
The following figure is a normal Liver tissue. Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.
Below is the normal image of the liver with normal hepatocytes.
The following are the images of liver with alcoholic hepatitis and the presence of swollen, degenerative hepatocytes. The tiny black dots are white blood cells indicating inflammation of hepatocytes. Furthermore, the lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining.
And here is the image of a cut surface of liver with alcoholic hepatitis. The green color results from bile pigment.
Cirrhosis is characterized by the replacement of functional liver tissue with fibrotic scar tissue. This leads to a decrease in functional liver mass. While cirrhosis is usually seen after fatty liver or alcholoic hepatitis occur, this is not a cause and effect relationship. The liver tissue is replaced by nodules (either microscopic, macroscopic, or mixed) separated by fibrous septa. Micronodular cirrhosis is usually the result of chronic alcohol consumption while macronodular cirrhosis is normally due to infectious agents such as viral hepatitis. These nodules are a result of the regeneration process gone slightly off course. The new hepatocytes are displaced and the normal lobular structure of the liver, so critical to its function, is interrupted. After chronic injury and replacement the cells continue to regenerate but they are not replaced within their normal structure. The normal structure of a portal triad is show below. We can see the portal vein, the hepatic artery and the bile duct.
In this next picture we can see that the lobulated structure of the liver has been destroyed. New hepatocytes seem to be strewn about in a disorderly manner. These regenerated nodules are separated by fibrous septa as denoted in the picture.
Below is a schematic picture taken from the Mayo Clinic's web site. We can see on the left is a normal healthy looking liver. On the right is what the liver of a patient with cirrhosis would look like. Note the lobules separated by fibrous septa. The entire internal structure of the liver is also destroyed.
Here we can see two schematics; on the right, a healthy liver showing the portal triad structure while on the left is a schematic of the early stages of cirrhosis. Hepatocytes die and are replaced by scar tissue, damaging the liver structure.
Hepatitis C is a liver disease that is caused by hepatitis C virus and is found in the blood of the infected person. It is spread by contact with the blood of the infected person. This virus is an RNA virus and there is no relationship between hepatitis C virus and the other hepatitis causing viruses. There are several ways to share this virus including transmission of infected blood, sexual intercourse and needle sharing.
Hepatitis C is the most prevalent viral liver disease in the United States. It is often called the “silent epidemic”, because the symptoms might not become visible for some years. Hepatitis C virus emerged in the United States first in the 1960s as a result of a blood transfusion. It was only in the 1990s when the researchers first discovered a blood test for this virus. According to a study, 20% of people who suffer from chronic hepatitis will end up with liver cirrhosis and liver cancer.
There are 270-300 million people suffering from Hepatitis C worldwide; 4 million of which live in the United States. Hepatitis C virus accounts for 20% of the acute hepatitis cases, 70% of chronic hepatitis cases and 40% of end-stage cirrhosis cases. For every person infected with AID, there are 4 people who are infected with HCV. There are 26000 cases every year. HCV accounts for 10000 to 12000 deaths per year.
It has been estimated that the chronic HCV will become one of major diseases affecting many people. It has been estimated that in the United States, there will be a 60% increase in the incidence of cirrhosis, 68% increase in hepatoma incidence, and a 223% increase in liver death rate.
Most acutely and chronically infected people with the virus are free of symptoms for years. Unfortunately by the time the liver damage is diagnosed, it is usually irreversible and results in liver cancer. In the first few years, the only way to detect hepatitis C is through liver biopsy.
There are two forms of hepatitis C: acute and chronic. Acute hepatitis C is a newly acquired infection and can be cleared within 6 months. Some of the symptoms of acute hepatitis are headache, nausea, vomiting, jaundice, weakness and fatigue. Acute form of hepatitis might last from several weeks to several months. Some may recover from the infection and have no long lasting problems.
However, chronic hepatitis C is a long term infection that can last for years. In the beginning, some of the symptoms of the chronic form may include anxiety, blurred vision, vomiting, weakness and weight loss. The symptoms usually progress very slowly but usually end up in severe liver disease such as liver cirrhosis and liver cancer.