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Q. What rare liver disease primarily affects young men who have inflammatory bowel disease?
Hint: this disease has been in the news lately because a well known football player, Walter Payton, has been diagnosed with it.

A. Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis
     Recently, media attention has focused on a rare liver disease, primary sclerosing cholangitis (PSC), because a world famous football player, Walter Payton, has been diagnosed with it. Exactly, what is this disease and what can we learn about liver pathophysiology in general by describing it?
    PBS belongs to a group of liver diseases called the cholangiopathies. These are hepatobiliary diseases in which the cells that line the bile ducts, cholangiocytes, are affected. The liver has a tremendous system of ducts which transport the bile produced by the liver cells (hepatocytes). These bile ducts are located both intrahepatically (within the liver itself) and extrahepatically (outside the liver tissue proper). Intahepatic bile ducts begin as small ductules, then drain into larger ducts, septal ducts and segmental ducts. Eventually, the bile is collected into the largest ducts of all, the extrahepatic bile ducts that include the hepatic duct, cystic duct and common bile duct. The extrahepatic ducts empty the bile into the duodenum.
      The cholangiocytes, epithelial cells lining the bile ducts, have numerous functions. They participate in bile formation, they contain multiple transport proteins and they are immunologically active in the sense that they can produce cytokines (e.g. inteferons and interleukins including tumor necrosis factor). They can proliferate in response to a variety of stimuli and can cause inappropriate and harmful consequences for the liver. Immune mediated infections, genetic or developmental causes, neoplastic processes, drug exposure and vascular situations can all inappropriately activate and stimulate cholangiocytes so that they cause an inflammation of the bile ducts. Cholangitis is the term used to describe an inflammation of the bile ducts. An inflammation of liver tissue is harmful. Often a cholangitis can result in the stopping of the free flow of bile. When this occurs, then you have a cholestasis. A cholestasis is also very harmful to the liver. It is important to remember that there is a two way street., i.e. a cholangitis can lead to a cholestasis and cholestasis can also lead to a cholangitis
The cholangiopathies include
• Primary Biliary Cirrhosis (PBS) which has an autoimmune origin,
• Viral Cholangitis, caused by infection of liver by a virus, often seen secondary to chronic hepatitis C (in the presence of AIDS many other viruses may lead to this),
• Drug Induced and Toxic Cholangitis (drugs lead to cholestasis which then leads to cholangitis, e.g. ampicillin, barbituates, carbamazepine, hydralizine, phenothiazines, quinidine),
• Ischemic Cholangitis where ischemic damage to liver occurs (often after liver transplantation or exposure to antineoplastic agents),
• Primary Sclerosing Cholangitis (PSC) in which there is progressive inflammation of bile ducts leading to destruction, (an autoimmune origin) and
• Bacterial Cholangitis due to infection of the liver by bacteria

How does liver disease cause pruritis (itching)?
Itch occurs when C fibers (unmyelinated afferent neurons) located in the skin transmit an impulse to the CNS, ultimately to the thalamus and sensory cortex. These C fibers (special itch neurons, so to speak) are stimulated by a variety of mediators. Substances such as histamine (present in an inflammatory response), bradykinin (present in an inflammatory response) and bile salts can all stimulate them. In liver disease if there is inflammation of bile ducts (cholangitis) or blockage of bile ducts (cholestasis), then bile salts can back up into the bloodstream and then be deposited from the blood into tissues, where they can stimulate the C fibers.

What is bile?
Bile is a substance produced by the liver, which contains the following components: water, bile salts, bilirubin, cholesterol and a few products of organic metabolism. The liver produces about 600 – 1200 ml of bile per day. The bile salt component of bile (the liver produces about 0.6 grams per day of this) aids in digestion by emulsifying dietary fats. Bile can be emptied directly into the duodenum or it can be stored in the gallbladder so that a large amount can be released at once in response to a high fat meal.

What are liver enzymes?
Liver function tests include an evaluation of the serum levels of liver enzymes. When the liver is injured these enzymes rise., often before other indicators of liver dysfunction become apparent. Two enzymes, alanine aminotransferase (ALT, previously known as SGPT) and aspartate aminotransferase (AST, previously known as SGOT) often increase in cases of acute hepatocellular injury such as hepatitis, hypoxic or ishemic injury to liver tissue and Reyes’ syndrome. Two other enzymes, alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) tend to rise more in disorders affecting the bile ducts.

Both Primary Biliary Cirrhosis (PBS) and Primary Sclerosing Cholangitis (PSC) are similar in that they have an autoimmune origin, but they are different diseases, involving different etiologies and inflammatory pathways. Interestingly enough a major difference lies in the populations most at risk for each of these two autoimmune cholangitis’s. PBS typically occurs in middle aged females, whereas PSC primarily affects young men with inflammatory bowel disease. With PSC 70% of those afflicted are men and 70% have co-existing inflammatory bowel disease, usually ulcerative colitis. The average age at diagnosis for PBS is 40.

In PSC the inflammatory process of the bile ducts is chronic in nature, it results in the destruction of the bile ducts, fibrosis of liver tissue with subsequent development of cirrhosis. PSC is often complicated by recurrent episodes of bacterial cholangitis. Patients with PBS have an increased risk of cholangiocarcinoma (bile duct cancer).

The symptoms include pruritis, jaundice, fatigue, fever, weight loss . Often the disease is only discovered when a blood test reveals elevated levels of serum alkaline phosphatase and gamma-glutamyltranspeptidase on testing for other reasons. The definitive diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) which reveal characteristic findings that can distinguish this disease from other cholangiopathies (for example PBS). Often a liver biopsy is performed, especially to see if thre patient has already developed cirrhosis. After the time of diagnosis, the median survival time is about ten years. The disease is characterized by recurrent bouts of superimposed bacterial cholangitis. The only effective treatment is a liver transplant.

Resources

Classic Lecture on Liver

Diseases of the Liver This resource is an alphabetical list of liver diseases and conditions with hypertext links to other sites that provide relevant information. It is sponsored by Columbia University.