Liver

- Largest organ of the body

- Receives dual blood supply
- Majority of cells are hepatocytes
- Organized in lobules with portal areas at the
periphery and central veins at the center of
lobule
• Anatomic considerations:

- Organized in lobules within which blood flows

past hepatic cells via sinusoids from branches
of portal vein to the central vein
- Central veins coalesce to form the hepatic
veins which drain into the inferior vena cava
- Each liver cell is also apposed to several bile
canaliculi, the canaliculi drain into intralobular
then interlobular bile ducts to form the right
and left hepatic ducts; common hepatic duct.
• From a functional point of view:
- Organized into acini with hepatic artery and
portal venous blood entering the acinus from
portal areas (zone 1) then flowing through the
sinusoids to the
- Terminal hepatic veins(zone 3), the
intervening hepatocytes constitutes Zone 2
• Advantages:

• -helps to explain the morphologic patterns

and zonality of many vascular and biliary
diseases
 Functions of the Liver
1. Formation of bile
2. Carbohydrate storage and release
3. Formation of urea
4. Cholesterol metabolism
5. Manufacture of plasma proteins
6. Fat metabolism
7. Inactivation of some polypeptide hormones
8. Reduction and c onjugation of adrenocortical and
gonadal steroid hormones
9. Synthesis of 25 hydroxycholec alciferol
10. Detoxification of many drugs and toxins
• Classification of Liver Diseases:
1. Hepatocellular
• - features of liver injury :inflammation, and
necrosis predominate,viral, alcoholic dse
1. Cholestatic Diseases
• - inhibition of bile flow
predominance;gallstone,malignant
obstruction,drug-induced liver diseases
1. Mixed
• - features of both hepatocellular and cholestatic
• injury are present
 Toxic and Drug-Induced Liver
Disease
• Liver Injury:

- may follow inhalation,ingestion or parenteral

administration of a number of pharmacologic
and chemical agents.
• - essential that any patient presenting with
jaundice or altered biochemical liver tests be
asked carefully about
• a. drug use (prescription /OTC)
• b. use of vitamins and hormones
• c. exposure to environmental or industrial
toxins
a. Industrial toxins- carbon tetrachoride
,trichloroethylene,yellow phosphorus
b. Heat-stable toxic bicyclic octapeptides of
certain species of amanita and galerina
c. Pharmacologic agents used in medical
therapy
• Types of Chemical Injury to the Liver:
• 1. Dose -related-
• a. -produce tissue injury that results in
• metabolic defects ,cell death of
• dysfunction
• -chlorinated hydrocarbons,paracetamol
• b. Due to agents that act indirectly by
• interfering with a metabolic activity
• essential to cell function and survival
• 2. Injuries due to chemical agents which
• depend on idiosyncrasy of the host for
• their toxicity eg.dapsone – induced
3. Injuries which depends on a metabolic
idiosyncracy that leads to accumulation
of a metabolite that is capable of either
inciting intrinsic liver damage or an
allergic reaction eg.phenytoin-induced
liver damage
Liver Biopsy:
-generally shows a cytotoxic or cholestatic injury
- Other types of injury could be vascular,
- granulomatous or neoplastic lesions
Purpose:
1. Establish the diagnosis
2. Suggest of establish another cause for
liver injury
3. occasionally,to stage the degree of injury
-
• Treatment:
- 1.largely supportive,except acetaminophen
poisoning
- 2.In fulminant hepatitis,liver transplantation
- 3.Withdrawal of suspected agent is
• indicated at the first sign of adverse reaction
A. Removal of offending dietary constituents
eg.. galactose-containing CHO in galactosemia
B. Removal of toxic endogenous substances
eg. Iron,Copper
-accumulate as a result of intermediary
metabolism of liver injury

• .
• Principles Of Treatment of Liver disease
• 1. Replacement of Depleted Constituents
• 3 Categories of Deficiencies:
a. vitamins and minerals that are depleted due
to dietary deficiencies
b. vitamins and nutrients that are diminished as
a result of impairment of
the enterohepatic circulation
• C. endogenous substances that become
• depleted as a results of impairment
• of hepatic function
• 2. Temporizing
• - deliberate decision not to treat with
• drugs
• - allowing normal physiologic processes
• to reestablish homeostasis
 Acetaminophen Poisoning
- causes severe centrilobular hepatic
necrosis
- single dose of 10-15 gms can cause liver injury
- 25 gms or more causes fatal fulminant
disease
- blood level of more than 300ug/ml 4 hrs after
ingestion-severe liver injury
- Blood levels less than 150ug/ml liver injury unlikely
• Acetaminophen Metabolism:
• Ac-glucuronide---Ac---Ac sulfate
• Cytochrome P450
• N-acetyl-p-benzoquinoneime
•
• GSH cell protein

• Ga-Ac Ac-protein

• Ac-mercapturate hepatic cell death

• Acetaminophen:
- metabolized predominantly by phase II reaction to
sulfate and glucuronide metabolites
- Small proportion is metabolized by phase I reaction
to a hepatotoxic metabolite
• N-acetyl-benzoquinone-imide (NAPQI)
• - NAPQI is detoxified by binding to glutathione to
become mercapturic acid ,excreted in the urine
• Clinical Manifestations:
- nausea, vomiting, diarrhea, abdominal pain,
shock
- 4-12 hrs –early manifestations
- 24-48 hrs. later- hepatic injury becomes
• apparent
• - 4-6 days later maximal abnormalities and
hepatic failure becomes evident
• Treatment:
1. Gastric lavage
2. Supportive measures
3. Oral administration of activated charcoal or
cholestyramine –to prevent absorption of
residual drug
• - neither appears to be effective if given
more than 30 mins after ingestion
• N-acetylcysteine,cysteine,cysteamine:
- In patients with high acetaminophen levels (more
than 200 ug/ml at 4 hrs, or more than 100ug/ml at 8
hrs)
- Reduce severity of necrosis
• a. Provides a reservoir of sulfhydryl groups to
• bind to toxic metabolites
• b. stimulating synthesis and repletion of
• hepatic glutathione
- Should be given within 8 hrs.
• N-acetylcysteine:
• -orally, diluted to yield 5% solution
• -loading dose of 140 mg/kg,followed by
• 70 mg/kg every 4 hrs for 15 to 20 doses
 Cirrhosis
-cardinal pathologic features reflect
irreversible injury of hepatic parenchyma
and include extensive fibrosis in
association with formation of hepatic
nodules.
• Features:
• 1. hepatic necrosis
• 2. collapse of supporting reticulin network
• a. connective tissue deposition
• b. distortion of vascular bed
• c. nodular regeneration of remaining
• liver parenchyma
• Types of Cirrhosis:
a. Alcoholic
b. Cryptogenic and posthepatic
c. Biliary
d. Cardiac
e. Metabolic,Inherited, and Drug-related
• Clinical Features:
• -jaundice,edema,coagulopathy,metabolic
• abnormalities,fibrosis,portal hypertension,
• gastroesophageal varices,splenomegaly,
• ascites,hepatic encephalopathy
• Alcoholic Cirrhosis:
• -aka Laennec’s cirrhosis
• -most common type
• -characterized by diffuse fine scarring,
• uniform loss of liver cells, small regenerative
nodules
• Laboratory Findings:
- Anemia
- Hyperbilirubinemia
- Elevated serum alkaline phosphatase levels
- Prolonged PT
- Serum albumin,decreased , elevated globulins
- Elevated blood ammonia levels
•
• Diagnosis:
• -strongly suspected in patient’s with a
• history of prolonged and excessive alcohol
• intake and physical signs of chronic liver
• disease

• Treatment:
- Large supportive
- Specific treatment is directed at particular
• variceal bleeding and ascites
 BILIARY SYSTEM:

• Gallbladder:
• - where bile from the liver is stored

• Bile =secreted by the cells of the liver

• into the bile duct to duodenum
 Composition of Bile

• -made up of bile salts,bile pigments,

substances dissolved in and alkaline
electrolyte solution
• About 500ml secreted per day
• Some are reabsorbed in the intestine and
excreted again in the liver(enterohepatic
circulation)
 Composition of Human Hepatic Duct
Bile
• 1. water
• 2. bile salts
• 3. bile pigments
• 4. cholesterol
• 5. inorganic salts
• 6. fatty acids
• 7. lecithin
• 8. fat
• 9. alkaline phosphatase
• Glucuronides of bile pigment
• A. biliverdin
• B. bilirubin

- Responsible for the golden yellow color

• of bile
• Bile Salts:
- Sodium and potassium salts of bile acids
- 4 bile acids in human:
• a. cholic acid 50%
• b. Chenodeoxycholic acid 30%
• c. Deoxycholic acid 15%
• d. Lithocholic acid 5%
• Conjugation of acids in the liver results to
• Formation of Na and K salts in alkaline hepatic
bile
• -eg. Glycine –glycholic acid
• taurine- taurocholic acid
• Actions of bile salts:
1. Reduce surface tension
2. Emulsification of fats preparatory to its digestion
and absorption in the small intestine
• 3. Ampipathic
• - they form micelles ,with the hyprophilic
surfaces facing out
• - above a certain concentration,aka critical
micelle concentration, all bile salts added to a
solution form micelles

• micelles - role in keeping lipids in solution and

transporting them to the brush border of the
intestinal epithelial cells where they are absorbed
• ENTERO-HEPATIC CIRCULATION:

• 95% of bile salts are absorbed from the small

intestines,mostly terminal ileum
- Remaining 5% enter the colon and are
converted to salts of deoxycholic acid and
Lithocolic acid
- The absorbed bile salts are transported back
to the liver in the portal vein and re excreted
in the bile
 GALLSTONES:

- Concretions that form in the biliary tract

- One of the most common afflictions of
humans
- Spans a clinical spectrum from
asymptomatic gallstone to the potentially
lethal complications
 Types of Gallstones

Classified into two major types based on

composition:

a. Cholesterol gallstones
b. Calcium pigment gallstone
• Four Factors in Gallstone Formation:
1. Bile must be supersaturated with cholesterol
2. Precipitation of cholesterol as solid crystals must
occur
3. Crystals must be trapped within a mucin gel in
which they grow and fuse to form macroscopic
stones
4. Crystal-containing gel must be retained in the
gallbladder for a substantial period of time
 Measures for Gallstone Dissolution:

1. Use of Bile Acids for Gallstone Dissolution

2. Extracorporeal Shock Wave Lithotripsy
3. Contact Solvent Dissolution of Gallstones
• Extracorporeal Shock Wave Lithotripsy
• -- combined with oral ursodiol,produced
gallstone clearance in up to 80% of patients
with small,solitary,radiolucent gallstones over
a period of weeks to
• months of treatment
• Contact Solvent Dissolution of Gallstones:
- An invasive therapy
- Methyl ter-butyl ether (MTBE)placed in the
gallbladder using percutaneous transhepatic
approach
- Complete or near-complete dissolution of
gallstones observed in more than 90% in
about 7 hrs.