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
