Hepatobiliary Disease Flashcards
Macrostrucure of Liver
Liver is the largest visceral organ in the body
- Right lobe is the largest
- 75 to 85% of blood supply is from the portal vein
Which lobe is the largest in liver?
Right lobe
The Liver Function
- Metabolic
- Storage
- Excretory/Secretory
- Protective
- Circulatory
- Coagulation
Metabolic Functions
- Carbohydrate Metabolism
– Gluconeogenesis
– Glycogenolysis and glycogenesis - Synthesis of fatty acid, lipoproteins, cholesterol
- Ketogenesis (breakdown of fatty acids to keytones)
- Protein Metabolism
- Synthesis of plasma protein (albumin, globulin, fibrinogen)
- Urea synthesis
- Hormone Metabolism
- Red blood cell production (in fetal liver during the first trimester of pregnancy)
Storage Function
- Glycogen
- Vitamins
– A, D, E, K (Lipid Soluble)
– B12 (water soluble) - Iron
- Copper
Excretory/Secretory Functions
Bile
- Water, Cholesterol, Bile pigments, Anions of the bile acids, Phospholipids (mainly lecithin), Bicarbonate and other ions
Insulin-like Growth Factor 1 (IGF-1)
Most blood protein
Cholesterol, fatty acids
Protective Function
- Purification, Transformation, and Clearance
– Endogenous (hormones, ammonia)
– Exogenous drugs and chemical - Kupffer cells (residential macrophages)
– Bacteria and other foreign material from the portal blood
Circulatory Function
Antechamber of the heart
- Collecting portal blood from the GI tract
Coagulation
Production of coagulation factors
- Fibrinogen I
- Prothrombin II
- Factors (V, VII, IX, X, XI)
- Protein C
- Protein S
- Antithrombin
Liver Enzymes—Indicators of Liver Function
Transaminases (from damaged/dead hepatocytes)
- Aspartate aminotransferase (AST or SGOT)
- Alanine aminotransferase (ALT or SGPT)
Cholestatic Enzymes (from injured biliary epithelial cells)
- Alkaline phosphotase (ALP)
- Gamma-glutamyl transferase (GGT)
Viral Hepatitis
Acute Liver Injury
HAV & HEV: direct disruption of hepatocytes
HBV and HCV: immuno attack of hepatocytes
- HCV: 75% asymptomatic
Direct disruption of hepatocytes
HAV & HEV
Immuno-attack of hepatocytes
HBV and HCV
Drug-induced Liver Injury (DILI)
Acute Liver Injury
High incidence
- 10% adverse drug reaction: DILI
- Hepatocellular (the most common type of primary liver cancer): tylenol
- Cholestatic (flow of bile from the liver is slowed or blocked) : methyl testosterone
Most common drugs for DILI
- Amoxicilin/Clavulanate
- Diclofenac
- Azathiopurin
- Infliximab
- Nitrofurantoin
Chronic Liver Injury
hepatitis, fibrosis, cirrhosis, HCC Etiology
- Hepatitis
– Viral
– Alcohol
– Drugs
– Autoimmune
– Obesity - Iron overload
- Copper overload: Wilson’s disease (hepatolenticular degeneration)
- Alpha1-antitrypsin deficiency
- Autoimmunue
– PSC-progressing sclerosing cholangitis
– PBC-progressing biliary cholangitis
ASH and NASH
ASH: Alcoholic Steatohepatitis
NASH: Non-alcoholic steatohepatitis
Cause:
- Steatosis (Fatty liver disease)
- Inflammation
- Hepatocyte ballooning (cell swelling and enlargemen)
Specutrum of NADLD
Fatty Liver (fat accumulates in the liver) ==> NASH (Fat plus inflammation and scarring) ==> Cirrhosis (scar tissue replaces liver cells)
Alcoholic Hepatitis
Normal liver => Steatosis => Fibrosis => Cirrhosis => HCC
Risk Factors:
- Female
- Obesity
- Dietary Factors
- Polymorphisms
- Drinking
- Smoking
Comorbidity:
- Viral hepatitis
- Hemochromatosis
- HIV
What happens in NASH + ASH
Macrovesicular steatosis + inflammation => Infiltration of both lymphocytes and Kupffer cells => Ballooned hepatocytes that also contain Mallory-Denk bodies => Perivenular/pericellular (chicken wire) fibrosis
Epidemiology
Fatty liver diseases is the most common cause of abnormal liver enzyme tests
- Lean NASH (happens in the absence of overweight)
Liver steatosis affect 30-40% of population in developed countries
- Fibrosis, cirrhosis, hepatocellular carcinoma
Affect 2-3% of children (25-50% of obese children)
N. American Incidence of NAFLD and NASH +/- Fibrosis
N. American prevalence of NASH + fibrosis – 2.1%
- US Census Estimated Population in July 2017 - 325,719,178
- Number of individuals in US with or will have NASH + fibrosis 7,078,411
NAFLD (by ultrasonography) – 25.2%
NASH among NAFLD patients – 21%
NASH patients who experience fibrosis (global) - 41%
Molecular Mechanism of NASH
Two-hit (multi-hit) theory
- First Hit: fat accumulation in the liver
– Obesity, Long term fasting
- Additional/parallel hit: injury leading to inflammation
– Drugs, Pathogenes, Leaky Guts (LPS), Genetic abnormalities (PTEN, FXR or..), Oxidative stress
ASH Pathophysiology
- Hepatic fat storage
- Inflammation: Increased hepatic uptake of gut-derived endotoxins triggering Kupffer cell activation and release of proinflammatory factors
- Oxidation: Induction of cytochrome P4502E1 producing toxic acetaldehyde and reactive oxygen species
- ER stress: ethanol-mediated endoplasmic reticulum stree, protein mis-folding
Why is inflammation Important in ASH
Because it increased hepatic uptake of gut-derived endotoxins
- This end up triggering Kupffer cell activation
- Which will cause the release of proinflammatory factors
What Cytochrome do oxidation induce
P4502E1
- Produce toxic acetaldehyde and reactive oxygen species
Mechanism of ALD-Inflammation
- Activation of innate immunity
- Increase pro-inflammatory cytokine production in all cells in the liver
- Increase adaptive immunity
Liver Fibrosis
- Presitent HSC activation
- Fibrosis potentially irreversible
- Low hepatic blood flow
- Numerous sequelae
- No therapeutic agents
- Requires liver transplantation
Cirrhosis induced by NASH
“burnt out” NASH
Some features of NASH will no longer exist
- Steatosis
- Ballooned hepatocytes,
- Lobular inflammationt
The characteristic perivenular/ pericellular fibrosis may still be present
25% of patient never develop cirrhosis
Liver Cysts
Cysts: closed sac filled with liquid or other tissue
Types:
- Simple Cyst
- Hydatid Cyst: Due to parasite (Echinococcus granulosus)
- Choledochal Cyst: Congenital, Dilation of bile duct
– Common in east Asia
Primary Biliary Cholangitis (PBC)
Cholangiopathies Intrahepatic Bile Duct
T-cell mediated apoptotic destruction of biliary epithelial cells
- Middle Aged Women
4 Stages:
- Florid duct lesion
- Ductular proliferation
- Fibrotic septa
- Cirrhosis
Primary Sclerosing Cholangitis (PSC)
Inflammation, progressive fibrosis and destruction of bile duct
- 10-30 yrs old male
- Duct affected: all ducts
- Associated with IBD
Histology
- Onion skin fibrosis
- Inflammatory infiltrate is typically mild and limited to biliary epitherlum and portal tracts
T-cell mediated apoptotic destruction of biliary epithelial cells
Bile Duct
Primary Biliary Cholangitis (PBC)
Duct affected: all ducts
Bile Duct
Primary Sclerosing Cholangitis (PSC)
Common in 10-30 yrs old males
Bile Ducts
Primary Sclerosing Cholangitis (PSC)
Middle aged females are affected
Bile Duct
PBC
Onion skin fibrosis
Bile Duct
PSC
Congenital Gall Bladder Pathology
Most sever case: Biliary atresia
- Biliary tree fail to develop
– Toxins involved (isoflavonid) biliatresone from plants: Dysphania genus, tight junction disruption
extrahepatic biliary atresia
Inflammation with stricture of hepatic or common bile ducts.
- Leads to marked cholestasis
- intrahepatic bile duct proliferation
- fibrosis
- cirrhosis
This liver was rock hard. The dark green color comes from formalin acting on bile pigments in the liver from marked cholestasis, turning bilRUBIN to bilIVERDIN
Diseases of Gall Bladder
Cholelithiasis (gallstone)
Carcinoma of the bile duct
Carcinoma of the gall bladder
Biliary obstruction
Gallstone Disease: Cholelithiasis
Cholesterol stones form if there is an imbalance between the ration of Cholesterol and Bile Salt
- Normally bile salt enclose the hydrophobic cholesterol => this mean gallstone result from EXCESS cholesterol or DEFICIT of bile salt
Risk Factors for Gallstone Disease
- Female
- Forties
- Fat
- Fertile
- FXR mutation
Liver tumors
Benign tumors
- Liver cell adenoma
- Angioma
- Bile Duct hamartoma
- Focal nodular hyperplasia
Liver Tumors
Malignant
Primary:
- Liver cell carcinoma (hepatocellular carcinoma-HCC)
- Cholangiocarcinoma (adenocarcinoma of bile ducts)
- Angiosarcoma (malignant neoplasm of vascular endothelium)
- Hepatoblastoma (primary liver tumor in childhood)
Secondary: Metastases from
- GI
- Lung
- Breat cancer
Molecular Mechanisms of Hepatocellular Carcinoma
Heterogenic
Screen Shot
HCC Types
Well Differentiated
- Tumor cell resemble hepatocytes
- Form trabeculae, cords and nests
- May contain bile pigment in cytoplasm
Poorly Differentiated
- Malignant epithelial cells are discohensive
- Plemorphic anaplastic and giant
Cholangiocarcinoma
Malignant Tumors in the Bile Duct
