LIVER Flashcards
Types of cells
in liver
Hepatocytes: (70%)
Stellate cells: 8%
Store vitamin A
Regulate blood flow in sinusoids
On damage, transform into collagen-producing myofibroblasts, causing fibrosis of liver
Kupffer cells: Macrophages present in sinusoids
Biliary drainage system
Canaliculi (in center of liver cell plates)
Terminal bile ductules (Canals of Hering or cholangioles)
Intra-hepatic bile ducts
Extra-hepatic bile ducts
Vasculature
Portal vein supplies 70% of blood flow
Hepatic artery supplies 30% of the blood flow
Sinusoids are lined by fenestrated endothelium
Hepatic venules and veins drain into inferior vena cava
secretory, metabolic, storage, synthetic, detox
Functions of Liver
The liver has several functions, including …
1. Secretory
Bile: 600 ml to 1 L of bile produced in a day
Stored in gallbladder and discharged through common bile duct into duodenum
Composition of bile
Water: 97–98 %, bile salts: 0.7%, bilirubin: 0.2%, fats (cholesterol, fatty acids, andlecithin): 0.51%,and inorganic salts: 200 mEq/L
2. Metabolic
Carbohydrate, lipid, amino acid, mineral, vitamin, nucleic acid metabolism
Cholesterol synthesis and esterification
Interconversion of sugars
3. Storage
Glycogen, vitamin B12 and vitamin A
4. Synthetic
Albumin, alpha-1 and gamma-2 globulins, clotting factors, binding proteins, transport proteins
5. Detoxification
Xenobiotics, steroids, thyroid hormone, endogenous metabolites
Liver Metabolism
- Oral drugs are metabolized in liver, some extensively, through first-pass or pre-systemic metabolism
- Most drugs are metabolized by liver enzymes called cytochrome (CYP) P450 or microsomal enzymes
- They catalyse reactions such as
Phase I: Oxidation, reduction, hydrolysis
Phase II: Conjugation with glucuronic acid or sulfate
cyp system
CYP system
Consists of 12 groups with approx. 57 functional enzymes
-Nine of them metabolize endogenous substances
-Three of them metabolize drugs
CYP1 to CYP3
CYP3 metabolizes 50% of drugs,
CYP2 45%, and
CYP1 5%
on liver metabolism
Effect of age
- Liver function in neonates (until 1 year) is immature as the organs are not fully developed
- Children of 1–12 years have increased activity of metabolizing enzymes
- After 12 years, children handle drugs similarly to adults
- In elderly, physiologic changes alter all pharmacokinetic processes in liver
-Many drugs are metabolized slowly, causing accumulation
Drug effects on Liver
1. Enzyme induction
Chronic administration of some drugs can increase metabolizing enzymes in liver
Accelerates drug metabolism requiring larger doses
Increased metabolism increases toxic metabolites
Enzyme induction does not occur for 1–3 weeks because new enzymes must be synthesized
E.g.
rifampin and cigarette smoking
2.** Enzyme inhibition**
Due to co-administration of drugs that compete for same metabolizing enzymes
Smaller doses of drug is needed to avoid toxicity
May occur within hours/days of starting an inhibiting agent
**E.g.
Cimetidine
**
-
Some drugs indirectly affect liver function
-Epinephrine decreases blood flow by constricting hepatic artery and portal vein
-β-blockers decrease blood flow by decreasing cardiac output
Many drugs change liver function tests without clinical signs of liver dysfunction
Morphological patterns of liver injury
1. Degeneration
Ballooning degeneration (hydropic change)
Feathery degeneration (bile-induced damage)
Intracellular accumulations
-Fat (steatosis), iron, copper, bile, Mallory’s hyaline
2. Necrosis (coagulative or lytic) and apoptosis
Massive: Involving almost all of the liver
Sub-massive: Involving most of the liver
Bridging (bridging hepatic necrosis, e.g. portal to venular)
Randomly focal (spotty necrosis)
Zonal. E.g. zone 3 which is most prone to injury
-Zone 3 is farthest from blood supply
-It contains most drug-metabolizing enzymes
3. Inflammation
Acute, chronic or granulomatous
May be portal, periportal (interface hepatitis) or acinar (focal, or panacinar)
4. Fibrosis
Forms in response to inflammation or direct toxic injury
Can be portal or perivenular, form bridging fibrosis, and finally cirrhosis
Effects of liver impairment
Decrease in synthesis of metabolizing enzymes
Decrease in metabolism of lipid-soluble drugs
Decrease in excretion of these drugs
May require reduction in dosage of these drugs including:
Cimetidine,Diazepam,Morphine, etc
Decrease in protein binding
-Protein binding affects drug distribution
-Impaired liver is unable to synthesize plasma proteins (albumin) adequately
-Also causes accumulation of substances (e.g. bilirubin) that displace drugs from protein-binding sites
-Decrease in protein binding increases free drug
-Increases drug action :Can cause adverse effects
-Increases elimination :Decreases duration of action
Investigation of liver diseases
1. Biochemical
Enzymes (ALT: Alanine transaminase, AST: Aspartate transaminase)
Proteins (albumin)
Bilirubin
2. Haematological
Coagulation factors among others
3. Immunological
Antibodies (viruses, autoimmune)
4. Imaging
Ultrasound, CT (Computed Tomography), MRI (Magnetic Resonance Imaging), ERCP (Endoscopic Retrograde Cholangiopancreatography), MRCP (Magnetic Resonance Cholangiopancreatography)
5. Liver biopsy
Percutaneous needle biopsy, transjugular biopsy, wedge biopsy using laparoscopy or open surgery
Useful in :
Providing information on aetiology and severity of disease
Ruling out presence of other concomitant diseases
Monitoring response to therapy
Risk factors for impaired liver function include
- Hepatotoxic drugs
- Primary liver disease (e.g., hepatitis, cirrhosis)
- Diseases that impair blood flow to the liver
-Heart failure, shock, major surgery, or trauma - Malnourished people or those on low-protein diets
Major Diseases of Liver
Jaundice and cholestasis
Fatty liver
Liver fibrosis
Cirrhosis
Liver failure
Jaundice and Cholestasis
Jaundice (or icterus)
Yellow discoloration of skin, sclerae and mucous membranes due to excess plasma bilirubin (hyperbilirubinemia)
Jaundice appears when plasma bilirubin exceeds 50 µmol/L (Normal: 3–17 µmol/L)
Liver disease is not the only cause of jaundice
Many liver disease patients are anicteric (no jaundice)
Cholestasis
Arrest of bile flow
A failure of adequate amounts of bile to reach the duodenum
Due to interference anywhere from liver cell microsomes to the duodenum
Jaundice mechanism
- Increased bilirubin production
- Decreased uptake by hepatocytes
- Impaired conjugation
- Impaired excretion
-Intrahepatic
-Extrahepatic
