1. portal V. and hepatic A.
2. courses through sinusoids
3. central V. (at zone three, so this zone receivs blood last)
   • most susceptible to hypoxia and hepatotoxic agents
4. hepatic vein
5. IVC

• flows from central areas to portal bile ducts
• canaliculi to coalesce to form bile ductules which form bile ducts

• reticulin network surrounds the sinusoids (act as structural grid)
• allows for regeneration after injury
• without reticulin, regeneration takes place without a frame, so cells cannot "hook up" correctly and liver cannot function normally
  • aka CIRRHOSIS

• sinusoids lined by endothelial cells and Kupfer cells
• spaces of Disse are between the fenestrated endothelium and membrane of hepatocytes
  • within them reside stellate cells (Ito)
    • function- regulate blood blood flow
    • transformed to collagen producers with injury

• removal of metabolic substrates and toxic products from the blood
  • only dysfunctional if most hepatocytes dead/dying or portal blood doesn't reach the hepatocyte
• detox and excrete toxic and waste products (made more water soluble to be easily excreted: bilirubin)
• protein synthesis
  • plasma proteins
  • CF's
  • acute phase reactants to cytokines
• production of carbs, lipids, AA's
• endocrine function
  • inactivates many hormones (convert T4 to T3 and remove estrogen)
  • manufactures substances essential for action of several hormones (ex: angiotensinogen)
  • bindin proteins carrying steroid and thyroid hormoens
• bile acid synthesis
• reticuloendothelial system
  • Kupffer cells remove bacteria and their toxic products from portal blood
  • remove circulating immune complexes

• increased rate of formation of bilirubin
  • liver processes more bilirubin than nomral, leading to more urobilinogen produced by intestinal bacteria and more excreted in urine
  • examples
    • hemolytic anemias
    • blood transfusions
    • hematoma formation
    • skeletal muscle damage
• decreased conjugation of bilirubin (cant make bilirubin water soluble, so increased UCB)
  • examples
    • Gilbert's syndrome
    • Crigler-Najjar syndrome
    • severe damage to liver (cirrhosis, liver failure)
• decreased excretion of conjugated bilirubin (MOST COMMON)
  • obstruction of bile flow
  • Dubin Johnson and Rotor's syndrome (decreased excretion, but both are asymptomatic)

• total bilirubin- measure all forms of bilirubin (adds agent making UCB react with aqueous reagents which create end product)
• direct bilirubin
  • measures end product directly after mixing serum and reagents
  • mainly a measure of conjugated bilirubin (70-90%)
  • indicates liver damage
    • normally should be no conjugated bilirubin in serum, so very sensitive marker for liver dysfunction
• indirect bilirubin (indirect measure)
  • substract direct bilirubin from total bilirubin
• urine bilirubin
  • via dipsticks in urinalysis
  • usually only conjugated enters urine
  • use- evaluate recovery of liver function after period of jaundice
    • becomes negative after liver can excrete conjugated bilirubin into bile

• increase indirect bilirubin due to:
  • increased in UCB due to:
    • increased production of bilirubin
    • decreased conjugation of bilirubin
• increase direct bilirubin due to:
  • increases conjugated bilirubin and biliprotein due to:
    • difficulty in excretion of conjugated form
  • longer problem persists, higher proportion of biliprotein
    • as liver recovers, CB is cleared quickly, so clear biliprotein cleared (and direct bilirubin) may approach 100% total bilirubin

• high cholesterol- bile duct obstruction
• low cholesterol- advanced liver disease

• significance of different half lives of proteins (dependent on constant rate of production)
  • For example, if there is an acute decrease in serum levels of factor VII, but albumin is normal, that means there is ACUTE change in production of liver proteins
  • also, if there is decrease in both factor VII and albumin, this is a problem that has been going on for weeks
• a significant portion of liver has to be damaged in liver failure to cause decrease proteins
  • normal cause of decrease: failure of portal blood to reach liver such as in portal HTN

• blood ammonia levels (if high, liver has decreased function)
• BUN can be decreased in late stages of liver disease (decreased synthesis)

Rarely useful liver function test

• serum enzyme levels
  • AST, ALT
  • alkaline phosphatase
  • LDH
  • gamma glutamyl transferase
• alpha-fetoprotein

Note: serum enzyme levels measure cell integrity, NOT cell function (many times referred to as liver function tests) because these enzymes are not specific to the liver.

• function- intermediate metabolism of AA's
  • AST- cytoplasm, mitochondria
  • ALT- cytoplasm
• mechanism of increase in liver damage
  • when hepatocytes rupture, these enzymes leak out into blood, causing increase in serum levels (ex: hepatitis)
• ALT increase>AST increase or ALT increase = AST increase strongly suggests a liver problem
  • due to differences in half life (AST half life < ALT) leading to preferential increase even though AST is in higher levels in the hepatocytes than ALT
• if preferential elevation of AST in alcholism (damage to mitochondria)
  • changes in AST usually dont change quickly (mitochondrial damage is cleared slowly)

• function- in general, on surface of cells for energy dependent transfer of substances
  • in liver, used for transport of substances into bile (loc.-at canalicular surface of hepatocyte)
• when damge to canalicular surface, serum levels begin to rise in 1-2 days (delay due to need to synthesize moe enzyme)
  • obstruction of drainage (stones)
  • direct damage to hepatocytes (drugs, virus)

• function- convert pyruvate to lactate
• uncommonly elevated with liver damage because its conc. is much lower than AST or ALT and isoenzyme in liver has short half life

• location- canalicular surface and microsomes
• increases due to:
  • canalicular damage
  • exposure to agents that cause microsomal enzyme induction (P450 induction)

• elevation with liver disease associated with regneration or proliferation
• very high levels = primary liver cancer

Predominant plasma protein early in fetal life, but fall after birth and usually low at age 2-3 mnths

• jaundice
• portal HTN
  • ascities
  • venous anastomoses
• hepatic encephalopathy
• hepatorenal syndrome

• obstruction of bilirubin excretion
  • productng jaundice
• portal HTN

• definition- yellow discoloration of skin
• cause- deposition of bilirubin in CT (esp. elastic fibers)
  • sclera has large amount of elastic fibers with no melanin, so first place of detection
• becomes visible when serum bilirubin is 2-3x normal
• effect on stool- several days before jaundice, because lack of release of CB, there is stool that becomes pale colored until eventually white (clay colored)
• effect on urine- soon after clay colored stool, CB appear in urine, causing dark urine (detectable before noticable jaundice

• multiple causes: anything increasing resistance to flow in the portal veins
  • thrombosis of:
    • portal V.
    • hepatic V's
    • IVC
  • CHF
  • cirrhosis (most common cause)

• decreases ability of liver to remove active hormones from circulation such as estrogen
  • women- leads to increase gonadotropin production, causing amenorrhea in younger women
  • men- decreases testosterone production leading to impotence and testicular atrophy
    • breast growth
    • gynecomastia
• splenomegaly lead ot trapping of platelets, leading to thrombocytopenia

Usually, patients have signs of portal HTN long before symptoms develop.

• definition- accumulation of fluid in peritoneal cavity
• pathogenesis
  • increase venous and lymphatic pressure generated by resistance to flow of blood through portal V.
  • decrease in albumin lower oncotic pressure, favoring fluid retention

1. increase in portal pressure
2. body attemptos to divert blood away from high P portal system to lower pressure systemic system
3. if sever enough portal HTN, anastamoses between systemic and portal circulation become very large
   • esophagus and stomach = esophageal varicies
   • superior rectal and mid/inf. rectal = internal hemorrhoids
   • paraumbilical V. and inferior epigastric = caput medusae

• pathogenesis
  1. accumulation of metabolites normal removed by the liver leads to alteration in brain function
  2. initially, there is confusion, memory loss, and personality change
  3. eventually, patients level of consciousness and ability to perform skills decrease until coma develops
• tx
  • reduce dietary protein intake
  • decrease intestinal transit time
  • decrease bacterial flora
• prognosis
  • if portal HTN, has many exacerbations and relapses
  • if acute liver disease, its a pre-terminal event

1. for unknown reasons, blood flow to renal cortex decreases
2. production of renin
3. activate RAA
4. eventually, profound vasoconstriction
5. leads to decreasing urine ouput
6. as urine output falls, renal failure results and death usually occurs in a few days

• acute
  • causes
    • complete obstruction of bile ducts
    • acute necrosis of hepatocytes
  • clinical symptoms caused by defects in handling bilirubin
• non acute
  • usually dont see jaundice until late in course of disease