Pathophysiology of Liver Flashcards
Major functions of the liver
Storage of blood: The liver acts as a blood reservoir, containing about 8% of total blood volume.
Nutrient metabolism: The liver plays a central role in carbohydrate, protein, and lipid metabolism.
Protein synthesis: The liver synthesizes albumin, clotting factors, and other plasma proteins.
Formation and excretion of bile: Bile aids in digestion and absorption of lipids.
Detoxification and excretion: The liver detoxifies harmful substances and excretes bilirubin, drugs, and hormones.
Storage: The liver stores fat-soluble vitamins (A, D, E, K) and minerals like iron.
Immune functions: Kupffer cells in the liver cleanse blood by removing bacteria and antigens.
Jaundice definition and causes
Definition: Yellowish discoloration of the skin and sclera due to elevated bilirubin levels (>1.2 mg/dL).
Causes:
Pre-hepatic: Excess RBC hemolysis (e.g., hemolytic anemia).
Intrahepatic: Liver damage (e.g., hepatitis, cirrhosis).
Post-hepatic (obstructive): Bile flow obstruction (e.g., gallstones, tumors).
Definition, causes and complications of liver cirrhosis
Definition: Irreversible fibrosis of the liver, leading to distorted liver architecture and portal hypertension.
Causes: Chronic viral hepatitis (B, C), alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and others.
Manifestations:
Portal hypertension: Leads to complications like esophageal varices, ascites, and splenomegaly.
Hepatic insufficiency: Results in jaundice, hypoalbuminemia, and coagulopathy.
What is unconjugated and conjugated bilirubin?
Unconjugated bilirubin (90%) is insoluble and binds to serumn albumin. Not excreted in urine, and can be toxic to brain in newborn (kernicterus) if in excess.
Conjugated bilirubin (10%) a.k.a direct bilirubin as it is measured directly by clinical test is soluble, loosely bound to albumin and can be excreted in urine. It cannot be reabsorbed into intestinal lumen (easily excreted)
Stages and pathogenesis of alcoholic liver disease
Alcoholic fatty liver: Reversible with abstinence.
Alcoholic hepatitis: Inflammation and liver cell necrosis, with a worse prognosis.
Alcoholic cirrhosis: Irreversible fibrosis, leading to liver failure and hepatocellular carcinoma.
Pathogenesis: Ethanol metabolism generates toxic metabolites (e.g., acetaldehyde), leading to oxidative stress, inflammation, and fibrosis.
**Significant alcohol consumption = >21 standard drinks for men and >14 standard drinks for women per week
What is non-alcoholic fatty liver disease? including NAFLD and NASH
Non-alcoholic fatty liver diseases: Evidence of steatosis and lack of secondary causes of hepatic fat accumulation such as significant alcohol consumption, log-term use of a steatogenic medication or monogenic hereditary disorder. NAFL and NASH are subsets of NAFLAD
Non-alcoholic fatty liver (NAFL): Hepatic steatosis without significant inflammation, often associated with metabolic syndrome, with
Non-alcoholic steatohepatitis (NASH): Steatosis with inflammation and fibrosis, which can progress to cirrhosis and hepatocellular carcinoma.
Pathogenesis: Insulin resistance leads to lipid accumulation, oxidative stress, and inflammation, causing liver injury.
Risk factors: Obesity, T2DM, dyslipidemia, Met syndrome, polycystic ovary syndrome
Drugs that cause drug-induced immune hemolytic anemia, leading to rises in unconjugated hyperbilirubinemia levels
Cephalosporins
Dapsone
Levodopa
Levofloxacin
Methyldopa
Nitrofurantoin
NSAIDS
Penicillins and derivatives
Phenazopyridine
Quinidine
Disease causes of unconjugated hyperbilirubinemia
G6PD, drug induced, sickle cell anemia, thalassemia, gilbert syndrome, crigler-najjar syndrome, red blood celll membrane disorders, autoimmune hemolyticc anemias
Disease causes of conjugated hyperbilirubinemia
Viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, drug-induced liver injury, genetic diseases, AIDS/HIV, cholangiocarcinoma, cholangitis, biliary-related diseases, autoimmune disorder (autoimmune hepatitis, primary biliary cirrhosis)
Drug induced liver injury leading to conjugated hyperbilirubinemia
Dose-dependent
Paracetamol, salicylates, tetracycline
Non-dose dependent
Anaesthetics (e.g. halothane)
Anti-depressants (e.g. MAOI)
anti-malarials (fansidar)
NSAIDS
Statins
Chlorpromazine, penicillins (flucoxacillin), antithyroid drugs can induced cholestasis
Investigations and tests -
Differentiate the purpose/meaning of ALT, AST, GGT, bilirubin elevation/drop.
ALT/AST elevation > hepatocellular injury
ALP elevations > Intrahepatic and/or extrahepatic
GGT > excretory function of the liver
Synthetic function of liver > albumin/prothrombin time
What are the risk factors for HCC?
Disease toxicity - Alcohol-related cirrhosis, NAFLD/NASH
Metabolic syndrome/obesity - insulin resistance, obesity, dyslipidemia, sedentary lifestyle
Biologic toxicity - hepatitis B/C, alpha-1 antitrypsin deficiency
Environmental toxicity - alcohol, tobacco, aflatoxin
What factors determine hepatic drug clearance?
Hepatic blood flow (drug delivery).
Fraction of unbound drug (free to interact with enzymes).
Intrinsic clearance (enzyme activity).
Extraction ratio: High (>0.7), intermediate (0.3-0.7), low (<0.3).
What is the key mechanism in NAFLD pathogenesis?
Insulin resistance leads to hepatic fat accumulation.
Lipotoxicity causes inflammation, fibrosis, and progression to NASH/cirrhosis.
How does cirrhosis affect drug pharmacokinetics?
Absorption: Altered due to gastropathy, delayed gastric emptying, decreased first-pass effect, pro-drug metabolism diminished, decreased rate of absorption
Distribution: Reduced protein binding, increased volume of distribution.
Metabolism: Reduced phase I/II enzyme activity.
Elimination: Reduced biliary/renal excretion, disrupted enterohepatic recycling, biliary excretion reduced
What is the R ratio and what is it used for?
ALT is more specific for hepatic injury, ALP is more specific for cholestatic injury
R = (ALT / ALT ULN) / ( ASP / ASP ULN ), where >5 means hepatoinjury, <2 means cholestatic injury, 2-5 means mixed pattern
