B2.069 - Big Case Liver Failure Flashcards
What is jaundice clinically
Yellow discoloration of skin and mucosal when bilirubin exceeds 2.5 mg/dL
What causes jaundice
When the equilibrium between production of bilirubin and the metabolism and excretion is disturbed.
How is bilirubin made in the body
Senescent erythrocytes are broken down to heme which is converted to biliverdin by heme oxygenate and biliverdin reductase by mononuclear phagocytic cells
Why cant bilirubin be excreted through the urine
Its water insoluble
How is bilirubin excreted from the body
Bilirubin is complexed with albumin (major carrier protein in the body) and carries it to the liver for further processing. It then is taken up by the liver cell to be processed. Once inside the hepatocyte its conjugated by UGT1A1. Then it becomes water soluble so it can be secreted by urine or feces. Its secreted from the hepatocyte to the canulicular membrane to the biliary tree then to the gut.
what population is at increased risk of jaundice
Premature babies and babies being breastfed
What is Crigler-Najjar syndrome
When you have no UGT1A1 which is needed to conjugate bilirubin albumin complex
What is Gilbert syndrome
When you have 30% of the UGT1A1 enzyme needed and it causes jaundice during stress
What is the final step of heme breakdown
The hepatic ducts join and deposit conjugated bilirubin into the ampulla Vauter
What’s the difference between conjugated and non conjugated bilirubin
Conjugated is water soluble and can be excreted
Unconjugated is not water soluble and cant be excreted regardless of how high the blood levels are
What constitutes unconjugated hyperbilirubinemia
ratio of conjugated bilirubin:Total bilirubin
What constitutes conjugated hyperbilirubinemia
Ratio of conjugated bilirubin:Total bilirubin is >.4
What are causes of overwhelming the first step of heme breakdown
Hemolytic anemia
Resorption from internal hemorrhage
Ineffective erythropoiesis
What are causes of impaired canalicular transport of bilirubin
Rotor syndrome
Dubin-Johnson syndrome
Drugs
What is physiologic jaundice of newborn due to
decreased UGT1A1 activity
What are the two types of Criglar Najjar syndrome
Type I - Absense of UGT1A1 this is incompatible with life
Type II - Decreased presence of UGT1A1
What are other diseases of the liver that can cause jaundice
Hepatitis, hepatocyte, necrosis, cirrhosis
What are the normal ranges of AST and ALT
AST - 7-40
ALT - 7-56
What do AST and ALT do
Live in hepatocyte and they are enzymes that help break things down.
What causes raised AST or ALT levels (generally)
Anything that compromises membrane integrity of the hepatocyte
What is confluent necrosis
Huge zones of hepatocyte necrosis
What happens to the AST and ALT levels of a patient with massive necrosis
It will get really high and then fall off because all the hepatocytes are dead
What is secreted in bile
Serum bilirubin total and direct
What are the plasma membrane proteins of bile ducts
Serum alkaline phosphatase
Serum gamma glutamyl transpeptidase (GGT)
What is the portal triad
Artery, vein, bile duct
What does the bile duct look like on histo
A string of pearls
What happens when bile ducts are damaged
They leak alkaline phosphatase, GGT
What are the lab studies of acute liver disease
Increase AST and ALT
What are the lab studies of acute liver failure
Increased AST, ALT, prolonged PT, increased ammonia
What are the labs of obstructive/biliary liver disease pattern
Increased alkaline phosphate, bilirubin and increased GGTP
What are the labs for cirrhosis pattern
Decreased albumin, decreased platelets, prolonged PT
Why do you seen decreased platelets in patients with cirrhosis?
Portal hypertension and splenomegaly
What does the PT measure
extrinsic coagulation pathway
V, VII, IX, X
What is hepatic encephalopathy due to
Increased in serum ammonia made as a byproduct of hepatocyte processing of nitrogen containing compounds.
What does high levels of serum ammonia cause
Its toxic to neurons so it causes encephalopathy
What are clinical manifestations of increased ammonia
Alterations in mental status
Disordered sleep
Asterixis (flapping tremor)
Coma and death
What constitutes hepatic failure
80-90% of hepatic functional capacity is gone
What is the mortality of hepatic failure
70-95% without transplant
What causes hepatic failure
Sudden or massive destruction
End point of progressive damage to liver as part of chronic liver disease
What is cirrhosis
Scarring of the liver
What are symptoms of cirrhosis
Decrease of protein synthesis
Portal hypertension
Decreased detoxification
What is hyperesterinemia
When the liver cant break down estrogen
It causes gynecomastia in men and testicular atrophy
What is cirrhosis most commonly caused by
Viral hepatitis (50% of HCV develops cirrhosis)
Alcoholic liver disease
NAFLD/NASH
What’s the pathogenesis of cirrhosis
Progressive fibrosis and reorganization of vascular micro architecture of the liver
Types I and III collagen are deposited in the lobule
What does the dying hepatocyte activate
Kupffer cells which secrete cytokines and activate stellate cells to become myofibroblasts (secrete mostly type I collage) which is an irreversible process
What causes splenomegaly
Portal systemic shunts
Blood backs up from liver bc its hard and fibrous which goes into the spleen and causes it to enlarge which sequesters platelets
Why do patients with cirrhosis have low platelets
Because the spleen is enlarged with blood and it sequesters platelets
What is periumbilical caput Medusa
When collaterals in the abdominal wall become engorged caused by chronic liver disease
What’s a normal reference range for Tylenol
Less than 20
What are located in the points of each hexagon in the liver lobule
Portal tracts
What zone does the blood come to in the liver
Zone 1
Rank the zones of the liver in order of most oxygen to least
1>2>3
What zone has the most cytochrome p450?
Zone 3
What does cytochrome p450 do with respect to this big case
it breaks down acetometaphen
What is the first thing you think of when you thing of centrilobular (zone 3) necrosis
Tylenol poisoning
Acetometaphen is converted to what toxic enzyme
NAPQI
How is NAPQI taken care of in the body normally
GSH binds with it
What is one way to treat acetaminophen overdose?
Giving NAC which is converted to GSH which combines with NAPQI to make a non toxic conjugate
After the hepatocyte dies can you give NAC
No it wont work, most effective in first 12 hours
What are the types of drugs that cause liver injury
Antibiotics Minocycline is big, its for acne Isoniazid - for TB Phsychotropic meds Birth Control pills
What is are drugs that cause a cholestatic acute injury
Cause canalicular plugs
Caused by anabolic or contraceptive steroid use
Alcoholic induced liver disease causes what
Steatosis which is fat deposition in the liver
What causes steatosis in the liver with alcoholism
Production of excess reducing equivalents (NADH and H+) due to metabolism of alcohol
How does excess reducing equivalents derived from alcohol metabolism cause steatosis
Shunting of normal substrates away from catabolism and toward lipid biosynthesis
How many deaths related to cirrhosis are due to alcohol
40%
Steps of alcohol induced liver disease
Steatosis
Steatohepatitis - inflammation of the liver cell
Cirrhosis
What is the irreversible point in liver disease
Cirrhosis
Where is steatosis initially seen
Centrilobular
Histologically what does inflammation and steatosis of the liver look like in alcoholism
Ballooned hepatocytes
Fat droplets large and small
Intermediate filaments called Mallory hyaline
What is non alcoholic fatty liver disease due to
Obesity
Dyslipidemia
Hyperinsulinemia
Insulin resistance
What constitutes Metabolic syndrome
One of these DM Impaired glucose tolerance Impaired fasting tolerance Insulin resistance Two of High blood pressure Dyslipidemia Central obesity Microalbuminuria
Steps of NAFLD
Steatosis, steatohepatitis, fibrosis
