21. Hepatobiliary Function Flashcards
Main functions of the liver
Bile production and secretion
Metabolism of carbs, proteins, and lipids
Bilirubin production and excretion
Detoxification of substances
Chronic liver disease in which normal liver cells are damaged and replaced by scar tissue (fibrosis)
Cirrhosis
Most common cause of cirrhosis
Excessive alcohol intake
How does excess alcohol intake lead to cirrhosis?
Initial accumulation of fat within hepatocytes leads to steatohepatitis (fatty liver + inflammation) which leads to liver scarring and cirrhosis
Chronic disease that causes bile ducts in liver to become inflamed, damaged, and are eventually lost
Primary biliary cirrhosis
Most common cause of portal HTN
Cirrhosis
Portal HTN develops when there is increased _____ to portal blood flow, which most often occurs in the liver
Resistance
[this increase in resistance is because of loss of connections in parallel]
Complications of portal HTN in the setting of cirrhosis
Hepatic encephalopathy
Esophageal varices
Splenomegaly
Ascites
What changes in the starling forces cause ascites in the setting of cirrhosis?
Cirrhotic liver produces less albumin, thus reducing oncotic pressure
Increased portal pressure leads to increased hydrostatic pressure
Fluid begins leaving mesenteric capillaries into interstitial spaces
Bile is produced and secreted by the ___
Liver
Composition of bile
Bile salts (50%) Bile pigments like bilirubin (2%) Cholesterol (4%) Phospholipids, such as lecithin (40%) Ions Water
Primary function of bile
Solubilizes lipids that are naturally insoluble by forming micelles; vehicle for elimination of substances from the body
Formation of bile salts begins with primary bile acids, then secondary bile acids, then bile salts.
There are relative amounts of bile acids, which ones are most common?
Cholic acid > chenodeoxycholic acid > deoxycholic acid > lithocholic acid
Where are primary bile acids synthesized?
Hepatocytes
Where are secondary bile acids synthesized
Small intestine
Primary bile acids are synthesized in the liver from ________, catalyzed by the ______ enzyme to become cholic or chenodeoxycholic acid
Cholesterol; 7-alpha hydroxylase
Where are bile salts conjugated?
Liver
What is the primary hormonal mediator of bile secretion? What does it cause?
CCK
Causes contraction of gallbladder and relaxation of the sphincter of Oddi
Action of CCK is mediated through extrinsic _____ and intrinsic _____ nerves
_____ may antagonize CCKs actions
Vagal; cholinergic
Secretin
What effect do pancreatic polypeptide and somatostatin have on gallbladder contractility?
Decrease it
How does the parasympathetic nervous system affect bile secretion?
Stimulation via vagus nerve:
Increases bile flow
Induces contraction of gallbladder
[sympathetic system opposes these things]
What is the role of secretin in bile secretion from the liver?
After bile is secreted from the liver, secretin stimulates addition of ions and water, thus diluting the bile
After bile is released from the liver, where does it go? What does it do there?
Gallbladder, which concentrates the bile
CCK stimulates contraction of the gallbladder and relaxation of the sphincter of Oddi. Where does the bile that is released go from there?
Enters duodenum, travels through to ileum, and gets reabsorbed via portal circulation for recycling back to the liver
________ bile is secreted by ductule cells in response to the osmotic effects of anion transport
Newly synthesized and returning bile acids are secreted into the _________ as conjugated bili
Canalicular
Bile canaliculi
Although most bile transported through the small intestine is recycled, some is excreted in ______. The more that is lost, the _____ gets synthesized
Feces; more
[so fecal loss should equal hepatic synthesis of bile]
What transporters in the basolateral membrane of hepatocytes are responsible for bile reuptake/recylcing back into hepatocytes from enterohepatic circulation?
NTCP
OATP
Increased bile secretion should increase the rate of its return via enterohepatic circulation, this will lead to negative feedback on bile synthesis once enough is produced. Thus, the ______ enzyme is inhibited by bile salts
Cholesterol 7-alpha hydroxylase
Interruption of enterohepatic circulation can ______ bile synthesis to values >10x normal
Increase
What is the difference between bile acid-dependent secretion, and bile acid-independent secretion?
Acid-dependent = driven by bile acids
Acid-independent = driven by secretin (small portion of bile)
Secretin stimulates HCO3 and water secretion from ______ cells, which increases volume, ______ pH, and ______ bile salt concentration
Ductile; increases; decreases
______ bile is plasma ultrafiltrate
Cannalicular
Describe bile acid secretion between meals (aka the interdigestion period)
Gallbladder fills with bile
Gallbladder is relaxed
Sphincter of Oddi is closed
Describe bile acid secretion upon ingestion of food
CCK is released from I cells in duodenum
Contraction of gallbladder
Relaxation of sphincter of Oddi
Bilirubin is initially produced from the breakdown of RBCs via the ________ system, forming bilirubin-albumin which travels to the ______ where it is conjugated. Some of the conjugated is excreted in the urine, but some is secreted in the _______ which travels to the small intestine and colon. Conjugated bilirubin that takes the latter route is converted to _______, then either _____ or ______ which are excreted in feces and give stools their darker color
Reticuloendothelial; liver; bile; urobilinogen; urobilin; stercobilin
What enzyme, responsible for the conjugation of bilirubin, is synthesized slowly in newborns, thus explaining the relatively common incidence of neonatal jaundice?
UDP-gucuronyl transferase
[forms bilirubin glucuronide which is yellow]
What are the steps of bilirubin formation from RBCs via the reticuloendothelial system?
RBCs —> hemoglobin released —> broken down to biliverdin —> bilirubin —> leaves via bloodstream as bilirubin-albumin
______ = icturus
Jaundice
Jaundice is a sign of what SPECIFIC medical condition
Hyperbilirubinemia
What are the 5 known hereditary defects in bilirubin metabolism
Gilbert’s syndrome Dubin-Johnson syndrome Rotor syndrome Crigler-najjar syndrome type 1 Crigler najjar syndrome type 2
Is the following condition associated with conjugated or unconjugated bilirubin?
Biliary tree obstruction
Conjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Dubin Johnson syndrome
Conjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Gilbert’s syndrome
Unconjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Rotor syndrome
Conjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Crigler najjar syndrome
Unconjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Hemolytic anemia
Unconjugated
Is the following condition associated with conjugated or unconjugated bilirubin?
Heart failure
Unconjugated (decreased delivery of bilirubin for conjugation)
Why does hemolytic anemia lead to increased unconjugated bilirubin leading to jaundice?
With more hemolysis, more bilirubin gets produced which at that point is unconjugated
2 main causes of neonatal jaundice
Elevated bilirubin production d/t breakdown of fetal erythrocytes
Low activity of UDP glucuronyl transferase
What condition is characerized by increased levels of unconjugated bilirubin in the blood due to a mutation in the gene that codes for UDP glucoronyltransferase, is often asymptomatic and episodes of jaundice are typically brought on by physiologic stress?
Gilbert’s syndrome
What is Crigler Najjar syndrome? What is the difference between the 2 types?
Increased levels of unconjugated bilirubin in the blood due to mutation in the gene that codes for glucuronyltransferase
Type 1 = severe
Type 2 = less severe
Form of brain damage caused by neural accumulation of unconjugated bilirubin, leading to permanent neurologic sequelae of bilirubin-induced neurologic dysfunction
Kernicterus
Which type of crigler-najjar syndrome starts earlier in life, is associated with kernicterus, and does not respond to phenobarbitol?
Type 1
Which type of Crigler Najjar starts later in life, has less than 20% function of UDP glucuronyltransferase, is less likely to develop kernicterus and can be treated with phenobarbitol?
Type 2
Dubin Johnson syndrome is associated with ________ bilirubin in the serum without elevation of liver enzymes. This condition results from a mutation in _____ which affects the ability of hepatocytes to secrete conjugated bilirubin into bile. Another characteristic sign is _____ pigmentation in the liver
Conjugated; MRP2; black
Rotor syndrome is associated with both unconjugated and conjugated bilirubin in the blood but the majority is ______, due to mutations in _____ and _______. It is similar to Dubin Johnson, except that ____ cells are not pigmented
Conjugated; OATP1B1; OATP1B3; liver
What is the primary treatment in neonates with unconjugated hyperbilirubinemia? How does this work?
Phototherapy
Process of isomerization that changes trans bili to cis bili
4 primary causes of gallstones
- Too much absorption of water from bile
- Too much absorption of bile acids from bile
- Too much cholesterol in bile
- Inflammation of epithelium
Which of the following is the most common?
A. Small gallstones impacted in cystic duct; causing acute cholecystitis
B. Small stones intermittently blocking cystic duct; causing intermittent biliary pain
C. Large gallstones that stay in the gallbladder; usually asymptomatic
D. Small stones impacted in distal bile duct; causing jaundice, biliary type pain, and risk of cholangitis and pancreatitis
E. Cannot be determined
C. Large gallstones that stay in the gallbladder; usually asymptomatic
(Followed by B, A, then D]
The liver modifies drugs or toxic substances through the “____ _____ metabolism”
First pass
Liver enzymes can modify both drugs, endogenous, and exogenous toxins to render them water soluble, which allows the excretion of these substances through bile or urine
What are the 2 possible phases of metabolism?
Phase 1 = drugs are processed via cytochrome p450 enzymes
Phase 2 = conjugation with glucuronide, sulfate, amino acids, or glutathione for further detox of drug
One type of LFT is liver enzymes tests, which are commonly measured in the serum. What are these tests and what might they indicate?
Serum aminotransferase (ALT and AST) - when elevated, indicates hepatocyte injury
Alkaline phosphatase - when elevated indicates cholestasis
Abnormal serum levels of what compounds might indicate impaired hepatic synthetic function?
Bilirubin
Albumin
Prothrombin time
Why is albumin used as a liver indicator?
Severe impairment in liver function/hepatocyte function reduces albumin levels (i.e., liver failure)
Albumin is exclusively synthesized in the liver and levels will fall with worsening cirrhosis
What LFT reflects the degree of hepatic synthetic dysfunction based on its increase as the ability of cirrhotic liver to synthesize clotting factors diminishes?
Prothrombin time (PT)
[also known as INR]
