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

▪ α1-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

Area of necrosis in pale yellow

Mononuclear inflammatory cells infiltrate

Ballooning degeneration

Viral hepatitis

Chronic HBV infection. A, Showing the diffuse granular cytoplasm, so-called ground-glass 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 diseaseWilson 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

http://www.joplink.net/prev/200103/2.html

Exception: amylase and lipase are secreted in an active form

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 systemto 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 4th 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

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0018956/

▪ Are the organs and ducts that make and store bile

▪ The biliary tract includes▪ Gallbladder▪ Bile ducts inside

and outside the liver

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