Pathologies of the Liver

This page describes some of the pathologies of the liver that can lead to liver transplantation and/or the possible need for liver therapy.

Table 1: Main Indication for Liver Transplantation (by percent of Liver Transplants)

Primary Biliary Cirrhosis 16.5%

Other cirrhosis (nonalcoholic) 11.8%

Biliary atresia 10.9%

Retransplantation 10.5%

Chronic Active Hepatitis 8.1%

Primary Sclerosing cholangitis 4.9%

Alcoholic Liver disease 4.0%

Budd-Chiari Syndrome 3.8%

α- antitrypsin deficiency 3.1%

Hepatocellular carcinoma 9.2%

Cholangiocarcinoma 4.1%

Other Diseases 10%

Primary biliary cirrhosis is an autoimmune disease in which there is T cell mediated destruction of the bile ducts of the liver. Due to the autoimmune nature of the disease, there is infiltration of the liver with macrophages and other lymphocytes which results in an intense inflammatory response. This results in the bile ducts becoming clogged or destroyed, resulting in fibrosis and degeneration of the hepatocytes. Transplantation is the most effective treatment currently for PBC; however, the disease may recur after transplantation.

Fig. 4 Note the lymphocyte infiltration and the absence of bile ducts Fig. 5 A liver with macronodular cirrhosis

Cirrhosis (figs 4 and 5) is the liver’s end-stage response to ongoing injury. When hepatocytes are injured, they fibrose. It results in diffuse fibrosis of the hepatocytes; this fibrosis is then converted into nodules in the healing process. These nodules often affect the blood flow through the liver. In addition, when the cells fibrose, they no longer actively interact with their environment. These two factors together cause liver failure as a result of cirrhosis. In addition, cirrhosis can lead to elevated blood pressure which can often lead to edema in the abdomen, and most seriously hepatic encephalopathy, in which toxins normally removed by the liver build up in the brain, leading to cognitive impairments and possibly death. Multiple factors can lead to cirrhosis, including hypoxia, drugs and alcohol abuse, infections such as hepatitis, and metabolic conditions such as α- antitrypsin deficiency. It is important to note that as cirrhosis is the end stage of the liver healing process, almost any recurrent chronic condition can lead to it. Cirrhosis is irreversible; it can be slowed down, but a liver transplant is the only effective way to return full function to the liver.

Biliary Atresia a congenital defect in which children are born with part of their bile duct system missing. Thus, the bile cannot flow, which leads to damage to the hepatocytes and subsequent fibrosis and cirrhosis within the liver. While surgery is adequate in a few forms of biliary atresia, in which there is still connection with the gallbladder, for all others transplantation is required, and without it most children with the condition will not live past the age of 3. In the US, approximately 300 children per year are born with biliary atresia.

Chronic Active Hepatitis can be caused by many factors, including the hepatitis B, C, or D virus, autoimmunity and idiosyncratic drug prescriptions. All of these causes can lead to the inflammation of the liver, specifically around the portal veins. The hallmark of chronic active hepatitis is piecemeal necrosis, in which the cells at the border between the connective tissue of the portal system and the hepatocytes are destroyed. This necrosis leads to cirrhosis and liver failure. While viral hepatitis can recur after a liver transplant, if often recurs at a much slower rate.

Fig. 8 This bile duct shows the narrowing involved in primary sclerosing cholangitis

Primary Sclerosing Cholangitis occurs when the bile ducts undergo sclerosis, forming multiple layers of connective tissue surrounding their lumens, as well as distension as a result of inflammation and fibrosis. This leads to a stoppage of bile production, which in turn causes hepatocyte death. Eventually this will lead to fibrosis and cirrhosis. Currently the cause of primary sclerosing cholangitis is unknown, as are treatment options other than transplantation.

Alcohol leads to an assortment of diseases in the liver. In the US 10 % of men and 3 % of women may have liver problems due to chronic alcohol abuse. In the Western world, alcohol is the leading underlying cause of liver disease. The three main conditions that can result in liver failure due to alcohol abuse are:

Steatohepatitis: fatty liver, the accumulation of lipid within the hepatocytes, accompanied with inflammation. These two factors can lead to fibrosis and cirrhosis.

Fig. 9 Alcoholic fatty liver, note the deposition of lipids within the hepatocytes

Alcohol abuse can also lead directly to cirrhosis; the repeated exposure of the hepatocytes to toxin can lead directly to fibrosis and cirrhosis, most frequently micronodular cirrhosis

Alcoholic hepatitis is when alcohol leads directly to hepatocyte injury and swelling, accompanied by necrosis. There is also infiltration by lymphocytes, which often leads to more cell death, fibrosis and cirrhosis.

Budd-Chiari Syndrome is the condition in which there is a thrombosis within the hepatic vein. This leads to hepatomegoly, which results from the congestion of blood in the liver. Most people who exhibit Budd-Chiari are predisposed in some way to having blood clots. Transplantation often leads to good outcomes for those with vascular disorders such as Budd-Chiari syndrome.

Fig. 11 The dark bodies are collections of the α- antitrypsin protein within the hepatocytes

α- antitrypsin deficiency is a genetic disease that results in the degradation and buildup of the protease inhibitor α- antitrypsin within the endoplasmic reticulum of the hepatocytes. This creates tangles within the cells that cannot be removed, and eventually lead to cirrhosis in childhood. Transplantation yields good outcomes for those with metabolic disorders such as α- antitrypsin deficiency.

Hepatocellular carcinoma is cancer of the hepatocytes, the cell that make up most of the liver. While HCC is not common in the US it is one of the most prevalent cancers worldwide, especially in Asia and Africa. There is an association between HCC and cirrhosis and there is thought to be an association between HCC and the hepatitis B virus. Usually transplantation is only available as an option if the tumor is fairly small and has not spread.

Cholangiocarcinoma, cancer of the bile ducts both inside and outside the liver, accounts for approximately 20% of liver tumors. There are often pre-existing conditions that may dispose a patient to CC, including obstruction of ducts, malformation of ducts, inflammation of ducts and biliary atresia. While cholangiocarcinoma can be treated with a liver transplantation, there is a high rate of recurrence.

Arias, Irwin M. ed. Liver; Biology and Pathobiology. 3^rd ed. Raven; New York, 1994.

Wight, Derek G.D. ed. Liver, Biliary Track and Exocrine Pancreas. Vol. 11. Churchill Livingstone; Edinburgh, 1994.