Lecture 3: Cirrhosis and Choleostasis

-toxic accumulations of metabolic waste (especially ammonia & bilirubin) -drugs & toxins -endogenous hormones (especially estrogen) bleeding, associated with a deficiency of coagulation factors edema, associated with a deficiency of albumin failure to absorb intestinal fat because of a deficiency of bile acids Viral hepatitis is a common contagious disease Cirrhosis is the final endpoint for many liver diseases Portal HTN is the most important consequence of cirrhosis & can be associated with liver failure & severe hemorrhage Stones often form in the gallbladder & may pass into & obstruct the bile duct

Anything that impairs liver function – hepatitis, infection, drugs, toxins May give mixed hyperbilirubinemia Distinguish from extrahepatic causes as there is no obstruction in intrahepatic

Mechanical obstruction of biliary drainage

Prehepatic Before the liver = hyperbilirubinemia = jaundice Intrahepatic Cholestasis From uptake into the hepatocyte to delivery into biliary canaliculi = cholestasis = hyperbilirubinemia = jaundice Extrahepatic Cholestasis From canaliculi to small bowel = cholestasis = hyperbilirubinemia = jaundice

Jaundice, dark urine, pale stools, and generalized pruritus Chronic cholestasis may produce: muddy skin pigmentation excoriations from pruritus a bleeding diathesis, bone pain, and cutaneous lipid deposits

↑ serum bilirubin ↑ serum amylase ↑ ↑ alkaline phosphatase (ALP) ↑ ↑ gamma glutamyl transpeptidase (GGT) Mild ↑ liver transaminases (ALT, AST 2X normal)

“backup” of bile – hepatocyte, liver canaliculus, biliary tract Deposition of bilirubin and other bile constituents due to backup

Intrahepatic cholestasis is suggested by symptoms of hepatitis, heavy alcohol ingestion, recent use of potentially cholestatic drugs, or signs of chronic hepatocellular disease (eg, spider nevi, splenomegaly, ascites). Extrahepatic cholestasis is suggested by biliary or pancreatic pain, rigors, or a palpable gallbladder.

Slowly progressive autoimmune liver disease 90% females Peak incidence in 40’s Portal inflammation and autoimmune destruction of intrahepatic bile ducts Leads to cirrhosis and liver failure 90-95% have antimitochondrial antibody (confirms PBC) Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease

1 Destruction of bile ducts in portal tracts 2 Inflammation beyond portal tracts 3 fibrous septa link portal triads 4 Cirrhosis

AMA titer 1:80 or greater (95% sens/spec) IgM > 1.5 upper limits of normal Liver biopsy: bile duct destruction Symptoms: Pruritus and Fatigue

Starts as hepatocelluar neocrosis and inflammation Complete loss of normal architecture, Replaced by extensive fibrosis (bridging fibrous septa) with, Regenerating hepatocytes from nodules.

• Alcoholic liver disease 2. Viral Hepatitis

Hepatocyte injury leading to necrosis. (Alcoholic, infections including virus, drugs, genetic etc.). Chronic inflammation - (hepatitis). Bridging fibrosis Regeneration of remaining hepatocytes. Proliferate as round nodules. Loss of sinusoids, vascular arrangement rendering regenerating hepatocytes ineffective.

Hepatocyte injury & fibrosis Hepatocyte regeneration but non functional. Vascular disruption Porta systemic shunts (blood bypasses hepatocyte) – Liver failure Portal hypertension Encephalopathy

Hepatocellular failure. Malnutrition, low albumin & clotting factors, bleeding. Hepatic encephalopathy. Portal hypertension. Ascites, Porta systemic shunts, varices, splenomegaly.

GI disturbances, dull pain in RUQ/epigastrium, fever, malaise, enlargement of liver & spleen

Jaundice, skin lesions (spider angiomas, palmar erythema), hematologic problems, endocrine disturbances, peripheral neuropathy

Compression = Portal vein,hepatic veins, sinusoids = Obstruction of portal blood flow = Portal Hypertension = Increased venous pressure, splenomegaly, collateral circulation, ascites, systemic hypertension, esophageal varices

Liver enzymes elevation – ALP, AST, GGT ↑ globulin (due to infection/globin) ↓ cholesterol levels, total protein, albumin Prolonged PT Bilirubin metabolism abnormalities Liver biopsy Liver scan

Globulins: Due to the diminished removal of immunoglobulins by diseased liver allowing gut antigens and endotoxins that bypass the liver and reach the antibody-producing cells. Albumin: is made by liver, so with less hepatocyte mass of functional cells, less albumin made.