Chap 18- Liver and Gallbladder Flashcards
what is the functional unit of the liver
lobule
liver circulation
- portal vein supplies 70%
- hepatic artery supplies 30%
how does hepatic BF change with aging?
significantly declines
result of hepatic ischemia/ hypoxia
- temporary protection of hepatocytes
- cellular acidosis protects against hepatocyte death
- adenosine is a hepatoprotector against liver damage by CCl4/ ethanol
major functions of liver
- detoxification
- metabolism of CHO, fats, proteins
- form coagulation factors
- form bile
- filter/ store blood
- store vitamins and Fe
kupffer cells
- macrophages found in liver
- located in sinusoids
- removes 99% of bacteria from gut that flows to liver
glycogenesis
excess glucose after meal is converted to glycogen
glycogenolysis
decreased glucose between meals stimulates breakdown of glycogen
gluconeogenesis
exhaustion of glycogen reserves stimulates glucose production from AA and sugars
liver protein metabolism
- deamination of AA
- removal of ammonia by making urea
- formation of plasma proteins
- synthesis of nonessential AA
where does ammonia come from?
bacterial degradation of amines, AA, purines, and urea in gut
liver fat metabolism
- conversion of CHO and proteins to fat
- beta oxidation of fatty acids
- synthesis of lipoproteins
- cholesterol
- phospholipids
what coagulation factors does the liver make
- prothrombin
- VII
- IX
- X
- requires vitamin K to do so
effect of abnormal liver function on coagulation factors
- abnormal synthesis
- dysfunctional coagulation factors
- increased consumption
- platelet disorders
bilirubin
- formed from breakdown of heme
- heme found in hemoglobin, myoglobin, cytochromes, catalase, peroxidase
what is the role of heme oxygenase
convert heme to unconjugated bilirubin
where is heme oxygenase found
- spleen
- kupffer cells
what is the role of bilirubin conjugation?
- unconjugated bilirubin is poorly soluble in water and toxic
- conjugation allows for elimination
how does bilirubin conjugation occur
through glucuronic acid conjugation in liver
urobilinogen
- produced in intestines by bacterial breakdown of bilirubin
- partially absorbed in bowel
- mainly excreted in urine
when is urinary urobilinogen excretion increased?
- excessive bilirubin production
- inefficient hepatic clearance of urobilinogen
- excessive exposure of bilirubin to intestinal bacteria
when is urinary urobilinogen excretion reduced?
- biliary obstruction
- severe cholestasis
causes of elevated serum bilirubin
- overproduction
- impaired uptake, conjugation, or excretion
- backward leak from damaged hepatocytes or bile ducts
beneficial effects of bilirubin
- antioxidant
- protective against CV disease and cancer
- heme oxygenase reduces replication of Hep C virus
ways to protect against bilirubin toxicity
- binding to plasma albumin
- rapid uptake
- conjugation
- clearance
jaundice
- yellowish tint of body tissues
- classified as either hemolytic or obstructive
- occurs when bilirubin concentrations are 3 times normal
hemolytic jaundice
- due to increased destruction of RBC
- rapid release of bilirubin into blood
obstructive jaundice
- obstruction of bile ducts or damage to liver cells
- results in inability to excrete bilirubin into GIT
biochemical markers of liver injury
- serum aminotransferases (ALT* and AST)
- bilirubin and bile acids
- alkaline phosphatase
liver function markers
- albumin
- prothrombin time
tests to detect injury to hepatocytes
- serum aminotransferases (ALT* and AST)
- released when hepatocyte gets injured
tests for livers capacity to transport organic anions and metabolize drugs
- bilirubin and bile acids
tests for the livers biosynthetic capacity
- serum albumin
- prothrombin time
what enzyme reflects cholestasis
alkaline phosphatase
hepatic lymphatic vascular system
- 50% of lymph formed in liver
- fenestrations in sinusoidal endothelial cells leak fluid and proteins into space of disse
- lymph flows through space of disse
what is the result of increased sinusoidal pressure?
- increases lymph production
- fluid accumulates in abdominal cavity -> ascites
what signals hepatocytes to enter mitosis
- macrophages
- hepatic stellate cells
- liver sinusoidal endothelial cells
- hepatic stellate cells are not active in healthy liver
acute liver failure
- occurs suddenly
- also see encephalopathy and elevated prothrombin time
- no cirrhosis or preexisting liver disease
- duration of <26 weeks
what are the main cause of acute liver failure?
- viral
- drug induced- APAP
clinical manifestations of acute liver failure
- liver test abnormalities*
- hepatic encephalopathy*
- prolonged prothrombin/INR*
- jaundice
- hepatomegaly
- r upper quadrant tenderness
- coagulopathy
- increased portal HTN
hepatic encephalopathy
- impaired brain function
- reversible
pathogenesis of hepatic encephalopathy
- hyperammonemia
- oxidative stress
- oxindole
hyperammonemia
- increases brain uptake of AA -> altered synthesis of DA, NE, and serotonin
- increases intracellular osmolarity in astrocytes
- alters neural electric activity
oxindole
- tryptophan metabolite
- formed by gut bacteria
- causes sedation, muscle weakness, hypotension, coma
how does APAP cause liver injury?
- converted to NAPQI which is cytotoxic
- NAPQI binds to proteins and DNA to form adducts
acute alcohol ingestion and APAP
- protective to liver
- alcohol competes with APA for CYP enzymes -> decreased NAPQI produced
chronic alcohol ingestion and APAP
- increases CYP activity two fold
- reduces glutathione levels
what are the three possible fates of APAP metabolism?
- produce free NAPQI via CYP
- renal excretion
- conjugation of NAPQI urinary excretion
cirrhosis
- late stage progressive hepatic fibrosis
- distortion of hepatic architecture
- irreversible
- requires liver transplant
- associated with chronic liver failure
etiology of chronic liver failure and cirrhosis
- chronic viral hepatitis (B and C)
- alcoholic liver disease
- hemochromatosis
- nonalcoholic fatty liver disease
what is the main source of hepatic fibrosis
stellate cells that become activated
portal HTN
- resistance to portal BF
- often develops in cirrhosis
- develop structural and dynamic changes
structural changes with portal HTN
- fibrosis
- angiogenesis
- vascular occlusion
dynamic changes with portal HTN
- increased production of vasoconstrictors
- reduced release of endothelial vasodilators
main clinical consequences of portal HTN
- ascites
- congestive splenomegaly
- hepatic encephalopathy
ascites
- accumulation of excess fluid in peritoneal cavity
- most often caused by cirrhosis
- portal HTN causes changes in splanchnic circulation
liver alcohol metabolism
- generates acetaldehyde in liver via alcohol dehydrogenase (ADH)
- acetaldehyde metabolized to acetate via ALDH
- acetaldehyde can produce liver injury
gastric alcohol metabolism
- stomach has ADH activity
- h pylori and gastritis can reduce activity of gastric ADH
alcoholic steatosis
- reduced oxidation of hepatic fatty acids
- increased lipogenesis
- chronic consumption of alcohol increases expression of genes like fatty acid synthase
alcoholic steatohepatitis
- cytokine release and inflammation
- antigenic adduction formation- acetaldehyde and hydroxyethyl radicals
- immunologic
types of alcoholic liver disease
- alcoholic steatosis
- alcoholic steatohepatitis
where are iron stores normally found
- Hb in circulating RBC
- iron containing proteins other than Hb
- iron bound to transferrin in plasma
- storage iron as ferritin or hemosiderin
causes of iron overload
- increased intake- blood transfusion
- increased absorption- hereditary hemochromatosis and chronic liver disease
what is the main clinical consequence of iron overload?
- organ damage
- when taken into organs it creates hydrogen peroxide
- OH is a ROS -> damage, inflammation, fibrosis
transferrin
protein in the blood that transfers iron throughout body
what happens when iron burden increases?
- tranferrin becomes saturated
- iron binds to other molecules - non-transferrin bound iron
- NTBI taken up in liver, heart, endocrine organs
cause of hereditary hemochromatosis
mutation in HFE gene
what is the clinical outcome of hemochromatosis
- increased absorption of iron from intestine
- fibrosis and cirrhosis due to iron
mechanism of liver injury in hereditary hemochromatosis
- lipid peroxidation due to increased ROS
- interaction of ROS with DNA
- activation of stellate cells
hemochromatosis pathogenesis
- hepcidin activity is reduced
- have unchecked iron-export by ferroportin in macrophages
- excess iron -> accumulation in tissues and organ damage
hepatitis A virus
- self limited
- does NOT become chronic infection
- can prevent with vaccine, immune globulin, proper hygiene
- complete recovery within 6 mo in most pts
how is HAV spread?
- contaminated water and food
- shed in stool
- consumption of raw or steamed shellfish
pathogenesis of HAV
- replication occurs in hepatocyte
- damage mediated by CD8+ and NK cells
- interferon-gamma promotes clearance of infected hepatocytes
what is the incubation period for HAV
- 28 days
- contagious during incubation pd and 1 week after jaundice appears
symptoms of HAV
- N/V
- anorexia
- fever
- malaise
- abdominal pain
- jaundice
- scleral icterus
- hepatomegaly
Hep B virus
- global problem
- clinical manifestations vary from either acute or chronic
- outcome depends on age, level of HBV replication, immune status
how is HBV spread?
- blood
- semen
- other bodily fluids
- child birth
- needle sharing
pathogenesis of HBV
- CD8 mediated
- HBV mutations can affect severity of liver disease
- development of chronic infection
acute hepatitis clinical manifestations
- subclinical or anicteric hepatitis
- more severe in pts with co-infection or underlying liver disease
phases of chronic HBV infection
- immune tolerance
- immune clearance- HBeAg pos
- inactive carrier
- reactivation- HBeAg neg
hepatitis C virus
- majority of infected are not clinically ill
- no vaccine
- persistent infection and chronic hepatitis are hallmarks
how is HCV spread?
- blood borne
- mostly through sharing needles
pathogenesis of HCV
- acute spread through hepatic a, viral replication and INF increase
- chronic hep c
- liver cirrhosis
- hepatocellular carcinoma
HCV associated carcinogenesis
- combo of indirect host mediated and direct HCV mediated mechanisms
- persistant inflammation -> ROS damage
- impaired DNA repair
- repeated cycles of destruction and fibrosis -> cancer field
nonalcoholic fatty liver disease
- spectrum of disorders
- nonalcoholic fatty liver (NAFL)
- nonalcoholic steatohepatitis (NASH)
effect of visceral adipose and intrahepatic fatty acids
- induce gluconeogenesis
- increase production of FFA
- insulin resistance
progression of NAFLD
- simple steatosis -> steatohepatitis -> fibrosis
- simple steatosis is low risk for significant fibrosis
pathogenesis of inflammation in NAFLD
- free cholesterol -> liver injury
- kupffer cells secrete pro-inflammatory mediators
- stellate cells increase liver fibrogenesis
- hepatocytes induce lipid peroxidation and lipotoxicty
- mitochondrial dysfuntion
insulin resistance and hepatic steatosis
- increased FFA released from adipose
- accumulation in liver
- decreased glucose uptake
- net result=increase glucose production and decreased uptake
- hyperglycemia and hyperinsulinemia -> lipogenesis
clinical features of NAFLD/ NASH
- simple steatosis generally asymptomatic
- clinical presentation related to insulin resistance or diabetes
- AST and ALT elevated
- CVD is frequent cause of death
bile
- liver secretes 1L/day
- fat emulsification and absorption
- medium for excretion of bilirubin and cholestrol
bile salts
- amphipathic
- emulsification of lipids
- transport of lipids
cholelithiasis classifications
- pure cholesterol stones
- pigmented- mainly bilirubin
- mixed- varying cholesterol, bilirubin, calcium carbonate, calcium phosphate
major risk factors of cholelithiasis
- age and sex- age >40 and female
- environmental factors- estrogen
- acquired disorders
- hereditary factors- ABC transporters
conditions that contribute to formation of cholesterol gallstones
- suppression of bile with cholesterol
- hypomotility of gallbladder
- defective conversion of cholesterol to bile acids
- hypersecretion of mucus in gallbladder
pathogenesis of pigmented stones
- elevated unconjugated bilirubin in bile from bacterial contamination
- e coli increases likelihood of stone formation
clinical features of cholelithiasis
- most are asymptomatic
- most common sx- biliary colic
- pain in RUQ or epigastrium, can radiate to shoulder
- inflammation
cholecystitis
- inflammation of gallbladder
- either acute, acalculous, or chronic
acute calculous cholecystitis
- chemical irritation and inflammation of gallbladder obstructed by stones
- mucus layer is disrupted
- prostaglandins released in wall
acute acalculous cholecystitis
- d/t ischemia
- inflammation and edema of wall, gallbladder stasis and accumulation of biliary sludge causes obstruction
chronic cholecystitis
- associated with presence of gallstones
- result of mechanical irritation or recurrent attacks of cholecystitis
- results in fibrosis and thickening of gallbladder
carcinoma of gallbladder
- uncommon
- highly fatal
- most are dx at advanced stage
risk factors for carcinoma of gallbladder
- pt demographics- age, female
- gallbladder abnormalities
- pt exposure i.e. smoking
- infections- salmonella and h pylori
- common thread= chronic inflammation
pathogenesis of gallbladder carcinoma
- cholelithiasis
- mutations in KRAS and p53
cholestatic disease
- decrease in bile flow
- due to hepatocellular impairment of bile formation or obstruction of bile flow
clinical presentation of cholestatic disease
- jaundice
- scleral icterus
- pruritis
pathogenesis of pruritis in cholestasis
- retention of bile salts
- release of endogenous opioids
- lysophosphatidic acid and autotaxin
risk factors for hepatocellular carcinoma
- cirrhosis
- HBV
- HCV
- hereditary hemochromatosis
