Cirrhosis Biol E-163 TA session 1/8/06

Cirrhosis Fibrosis (accumulation of connective tissue) that progresses to cirrhosis Replacement of liver tissue by regenerative nodules (areas of proliferating hepatocytes) surrounded by fibrous scar tissue, leading to progressive loss of liver function Occurs as a consequence of chronic liver disease normal cirrhotic From: Current Diagnosis & Treatment in Gastroenterology - 2nd Ed. (2003)

Causes of cirrhosis. Autoimmune hepatitis Alcohol-induced liver injury Drug- or toxin-induced liver injury (ie, methotrexate) Viral hepatitis B, C, or D Metabolic diseases  1 -Antitrypsin deficiency Wilson's disease Hemochromatosis and other copper disorders Tyrosinemia Nonalcoholic steatohepatitis (NASH) or fatty liver Vascular derangements Chronic right heart failure Budd-Chiari syndrome Long-standing portal vein thrombosis Biliary disorders (bile ducts or gallbladder) Primary biliary cirrhosis Cystic fibrosis Sarcoidosis Biliary cirrhosis secondary to chronic large bile duct obstruction Primary sclerosing cholangitis Biliary atresia Congenital paucity of intrahepatic ducts Progressive familial intrahepatic cholestasis Malnutrition and postjejunoileal bypass surgery Cryptogenic disease From: Current Diagnosis & Treatment in Gastroenterology - 2nd Ed. (2003) Common causes in developed countries Alcoholism Chronic Hepatitis C infection Asia and Africa Chronic Hepatitis B infection associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications

Pathophysiology Variation from individual to individual in rate of progression from fibrosis to cirrhosis, even from the same underlying cause –Reason unknown Growth regulators = cytokines, epithelial growth factor, hepatocyte growth factor, transforming growth factor- , tumor necrosis factor ** influenced by insulin, glucagon, and patterns of intrahepatic blood flow injury hepatocellular hyperplasia arterial growth (angiogenesis) regenerative nodules growth regulators **

Due to ↑ estradiol resulting from impaired estrogen metabolism From: Current Diagnosis & Treatment in Gastroenterology - 2nd Ed. (2003) Symptoms & Complications Accumulation of fluid in peritoneal cavity due to hepatic hypertention Due to portal hypertension Other non-specific symptoms weakness, fatigue, anorexia, weight loss speckled mottling of the palm Umbilical vein opens, blood from portal- venous system gets shunted through here Portal blood flow through vessels here, likely to bleed Due to ↓ processing of bilirubin

Main consequences of hepatic hypertension 1.Ascites = accumulation of fluid in intraperitoneal cavity 2.Formation of porto-systemic shunts = new blood vessels channel blood from intestines to heart instead of first passing through liver. –Ex: esophageal varices, caput medusae. –Esophageal varices are most dangerous because they often rupture. 3.Congestive splenomegaly = enlargement of the spleen 4.Hepatic encephalopathy = swelling of the brain caused by accumulation of toxic substances in the blood (esp. ammonia) due to porto-systemic shunts (blood bypasses cleaning by the liver) and decreased liver function –Signs can include impaired cognition, decreased level of consciousness, and coma

Diagnosis Displaying signs of portal hypertension Liver function tests If clinical data and lab tests suggest cirrhosis, confirm by liver biopsy

Treatments Eliminating injurious drugs, such as alcohol and hepatotoxic drugs Reducing intake of drugs metabolized by the liver Providing adequate nutrition Therapy for patients with varices Treatments to slow fibrosis End stage disease requires liver transplant

Primary Biliary Cirrhosis (PBC) Autoimmune liver disease Progressive destruction of intrahepatic bile ducts –Leads to cholestasis (blocked flow of bile), cirrhosis, liver failure Most common chronic cholestatic liver disease in adults –More common in women than men –Clusters in families (genetic) Specific cause is unknown

PBC Pathophysiology CD4 and CD8 T lymphocytes cause inflammation of the epithelial cells that line the small bile ducts in the liver Bile ducts proliferate Bile acids are retain and cause inflammation in the liver Fibrosis occurs  cirrhosis

PBC Symptoms 30-50% asymptomatic Abnormal liver function test (esp. elevated alkaline phosphatase) Fatigue Pruritus (itchy skin) Complications of cirrhosis and portal hypertension

PBC Diagnosis Abnormal liver function tests (esp. elevated alkaline phosphatase) Elevation of certain antibodies, particularly IgM and antimitochondrial antibodies Liver biopsy to confirm diagnosis

PBC Prognosis Usually progresses to terminal stage over years, though rate varies Median life expectancy is ~ 10 years once symptoms develop

PBC Treatment Halting or reversing liver damage Treating complications of chronic cholestasis and liver failure Eventually will need a liver transplant Eliminate use of alcohol and hepatotoxic drugs Treatment with ursodeoxycholic acid (facilitates bile flow through liver) –decreases liver damage, prolongs survival, and delays need for liver transplant Pruritus can be treated with cholestyramine (prevents bile reabsorption from the gut)