Liver, Pancreas and Gall Bladder Pathology SCBM342 Systemic Pathology Witchuda Payuhakrit, Ph.D. (Pathobiology) Email: witchuda.pay@mahidol.ac.th
Objectives 1. Understand etiology and pathogenesis of common disease in liver, pancreas and gall bladder pathology 2. Describe gross and histopathology of common disease in liver, pancreas and gall bladder pathology
Liver: anatomy and function
Bilirubin metabolism
Microscopic anatomy of liver The liver has been divided into 1-2 mm diameter hexagonal lobules The hepatocytes in the vicinity of the terminal hepatic vein are called Centrilobular The hepatocytes are arranged in one-cell layer thick plates separated by sinusoids The portal tracts each contain three tubular structures (portal triad) Hepatic artery Portal vein Bile duct
Microscopic anatomy of liver
Patterns of hepatic injury 1. Degeneration and intracellular accumulation 2. Necrosis and apoptosis 3. Inflammation 4. Regeneration 5. Fibrosis
Hepatic failure The most severe clinical consequence of liver disease Sudden and massive hepatic destruction The morphologic alterations that cause liver failure Massive hepatic necrosis drug or toxin induced Chronic liver disease most common route to hepatic failure Hepatic dysfunction without overt necrosis unable to perform normal metabolic function (Reye syndrome, tetracycline toxicity)
Cirrhosis Top 10 causes of death in the Western world Contributors are alcohol abuse and viral hepatitis As the end-stage of chronic liver disease cirrhosis is defined by three characteristics Hepatic fibrosis with bridging fibrous septa replacing hepatic lobules Parenchymal nodules Micronodular nodules 3 mm Macronodular nodules > 3 mm Disruption of the architecture of entire liver
The etiology of cirrhosis Alcoholic liver disease 60%-70% Viral hepatitis 10% Biliary disease 5%-10% Primary hemochromatosis 5% Wilson disease Rare α 1 -Antitrypsin deficiency Rare Cryptogenic cirrhosis 10%-15%
Pathogenesis of cirrhosis
Pathogenesis of cirrhosis Hepatocytic damages Progressive fibrosis Source of collagen mainly from perisinusoidal stellate cells which transform into myofibroblasts Constriction of sinusoidal spaces leading to disruption of interface between liver cells and the vascular supply and the biliary drainage system
Complications of cirrhosis The major complications of cirrhosis are: 1. Liver failure is characterized clinically by - Hypoalbuminemia - Clotting factor deficiencies - Ascites - Encephalopathy is due to the failure of liver to eliminate toxic nitrogenous products of gut bacteria (ammonia) 2. Portal hypertension 3. Liver cells carcinoma
Portal hypertension Is hypertension in the portal vein system Cirrhosis is the commonest cause of portal hypertension Probably due to a combination of : Increase portal blood flow Increase hepatic vascular resistance Intrahepatic arterio-venous shunting Leads to esophageal varices
Ascites Refers to the collection of excess fluid in the peritoneal cavity Pathogenesis of ascites is complex, involving the following mechanism Sinusoidal hypertension Percolation of hepatic lymph into the peritoneal cavity Normal thoracic duct lymph flow approximates 800-1000 ml/day Cirrhosis, thoracic duct lymph flow may approach 20 L/day Intestinal fluid leakage Renal retention of sodium and water due to secondary hyperaldosteronism
Jaundice and cholestasis Jaundice is the name given to yellowing of the skin and mucosal surfaces due to the presence of bilirubin Many patients with significant liver disease, often severe, are not jaundiced Liver disease is not the only cause of jaundice Cholestasis is the condition where bile cannot flow from liver to duodenum Caused by hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction Also may present with jaundice Symptom are pruritus and skin xanthomas http://www.medicalnewstoday.com
Pathophysiology of jaundice Occurs when the equilibrium between bilirubin production and clearance is disturbed 1. Excess production of bilirubin 2. Reduced hepatic uptake 3. Impaired bilirubin conjugation 4. Decrease hepatocellular excretion 5. Impaired bile flow
Neonatal jaundice Physiologic jaundice of the newborn Is relatively common, particularly in premature infants Rarely severe and it fades as liver function mature (Glucuronyl transferase) But high bilirubin level can be directly harmful Bilirubin encephalopathy or kernicterus http://www.abclawcenters.com/frequently-asked-questions/can-jaundice-cause-cerebral-palsy/
Hepatitis A virus (HAV) The main characteristics of hepatitis A are: faecal-oral spread relatively short incubation period sporadic or epidemic directly cytopathic virus no carrier state mild illness, full recovery usual specific diagnosis is made by seeking an IgM-class antibody to HAV
Hepatitis B virus Spread by blood, blood contaminated instruments, often transmitted between homosexual males, mother to child Relatively long incubation period Liver damage by antiviral immune reaction Carrier state exists Relatively serious infection
Pathogenesis of HAV and HBV
Hepatitis C virus Spread by blood, blood-contaminated instruments, blood products and possibly venereal Relatively short incubation period Often asymptomatic Fluctuating liver biochemistry (transaminase) Tendency to chronicity
Viral hepatitis Ballooning degeneration Area of necrosis in pale yellow Mononuclear inflammatory cells infiltrate
Viral hepatitis Chronic HBV infection. A, Showing the diffuse granular cytoplasm, so-called groundglass hepatocytes. B, Immunoperoxidase stain for HBsAg from the same case, showing cytoplasmic inclusions of viral particles.
Drug-and Toxin-induced liver disease At least 10% of drug reactions involve the liver injury Injury may results from direct toxicity via hepatic conversion of xenobiotic to an active toxin through immune mechanism Principle reaction predictable (intrinsic) or dose-related unpredictable (idiosyncratic) depend on idiosyncrasies of host
Drug- and toxin-induced hepatic injury
Drug- and toxin-induced hepatic injury Acetaminophen toxicity: extent hepatic necrosis
Alcoholic liver disease Common cause of acute and chronic liver disease Ethyl alcohol is a common cause of liver injury The spectrum of alcoholic liver injury observed in biopsies includes: fatty change (steatosis) hepatitis cirrhosis Mechanism include diversion of metabolic resources, direct hepatotoxicity and stimulation of collagen synthesis
Alcoholic liver disease
Pathogenesis of alcoholic liver disease Cellular energy Fat metabolism alcohol metabolism ( fat accumulation ) Acetaldehyde main product of alcohol metabolism binds to liver cells injured hepatocyte and inflammatory reaction Alcohol stimulates collagen synthesis fibrosis and eventually cirrhosis
Metabolic liver disease Hemochromatosis Characterized by the excessive accumulation of body iron (genetic defect causing excessive iron absorption) Hereditary hemochromatosis chromosome 6 at 6p21.3 Secondary hemochromatosis most common cause are hemolytic anemias Excessive iron appears to be directly toxic to host tissue Lipid peroxidation via iron-catalyzed free radical reactions Stimulation of collagen formation Interactions of reactive oxygen species and of iron itself with DNA lethal injury hepatocellular carcinoma
Metabolic liver disease Wilson disease Autosomal-recessive disorder (chromosome 13) Accumulation of toxic levels of copper (liver, brain and eye) Excess metallothionein-binding capacity toxic liver injury through copper-catalyzed formation of reactive oxygen species The red-brown granular material of copper
Tumors of the liver Benign tumors Rarely of significance Just cause confusion with their malignant counterparts Liver cell adenoma (hepatocytes) Other benign tumors angioma, bile duct hematoma and focal nodular hyperplasia Malignant tumors Hepatocellular carcinoma (liver cells) Cholangiocarcinoma (bile ducts) Angiosarcoma (vascular endothelium) Hepatoblastoma (primary liver tumor in childhood)
Liver cell adenoma Developing from hepatocytes Tend to occur in young woman who used oral contraceptives Have a tendency to rupture (during pregnancy) Cause severe intraperitoneal hemorrhage
Hepatocellular carcinoma (HCC) HCC is one of the commonest tumor in certain parts of the world Known or suspected etiological factors include Aflatoxins, carcinogenic produced by the fungus Aspergillus flavus, which contaminates food Hepatitis B and C viruses Hepatic cirrhosis
Cholangiocarcinoma Is an adenocarcinoma of bile duct epithelium Opisthorchis sinensis, liver fluke as a major risk of cholangiocarcinoma http://biodidac.bio.uottawa.ca/thumbnails/filedet.htm/file_name/trem072p/file_type/jpg
Pancreas Endocrine and exocrine function Exocrine (acinar cells) Trypsinogen Chymotrypsinogen Procarboxypeptidase, etc Endocrine (islet cells) Insulin Glucagon Somatostatin http://www.webmd.com/digestive-disorders/picture-of-the-pancreas
Exception: amylase and lipase are secreted in an active form http://www.joplink.net/prev/200103/2.html
Disorders of pancreas Endocrine pancreas Diabetes mellitus Tumors Exocrine pancreas Congenital anomalies (Pancreas divisum) Acute pancreatitis Tumors (Pancreatic carcinoma)
Pancreas divisum The most congenital anomaly that caused by the failure of fetal duct system to fuse together
Acute pancreatitis Is the a group of reversible lesions, severity ranging from edema and fat necrosis -> parenchymal necrosis -> severe hemorrhage Most common cause are biliary tract disease and alcoholism Less common cause include Obstruction of pancreatic duct system Medications (>85 drugs) these include estrogens, sulfonamides, methyldopa, etc. Mumps virus infection Vascular insufficiency (e. g. shock)
Pathogenesis of acute pancreatitis
Pancreatic carcinoma The 4 th leading cause of cancer death the United States (Lung, colon, and breast cancers) Has one of the highest mortality rates of any cancer Is primary disease in elderly (60-80 years) Little is known about the causative agent Smoking is believed to double the risk of this cancer http://kritiscanningcentre.com
The biliary tract Are the organs and ducts that make and store bile The biliary tract includes Gallbladder Bile ducts inside and outside the liver http://www.ncbi.nlm.nih.gov/pubmedhealth/pmht0018956/
Disorders of the biliary tract Gallbladder Cholelithiasis = gallstones Cholecystitis = Inflammation of gallbladder Carcinoma of the gallbladder Extrahepatic bile ducts Choledocholithiasis and ascending cholangitis Biliary atresia Carcinoma of the extrahepatic bile ducts
Cholelithiasis Risk factors include female gender, obesity, diabetes melitus Gallstones consist of pure cholesterol, bile pigment, calcium or a mixture Possible mechanism of gallstones may result when: bile contains too much cholesterol bile contains too much bilirubin Complications include cholecystitis, obstructive jaundice, carcinoma of the gallbladder http://www.celebritydiagnosis.com
Cholecystitis Acute cholecystitis Usually associated with gallstones Initially sterile, then infected Complications include empyema and/or rupture Chronic cholecystitis Invariable associated with gallstones Fibrosis
Carcinoma of the gallbladder Gallstones are present in 60% to 90% of cases Most carcinomas are adenocarcinomas The tumors is often advanced at the time and invasion of the liver
Disorder of Extrahepatic bile ducts Choledocholithiasis Defined as the presence of stones within the bile ducts of biliary tree Cholangitis Is the term used for bacterial infection of bile ducts Biliary atresia Defined as a complete obstruction of the lumen of extrahepatic biliary tree in neonate