tbl 5 physiology: liver

Question 1

[Liver]
•Two lobes separated by the falciform ligament
•Liver mass to body ratio: If liver mass decreases relative to body mass, hepatocytes proliferate. If liver mass increases relative to body mass, hepatocytes undergo __________

Hepatocytes, hepatic plates, sinusoids: 80% of parenchymal volume of human liver is composed of hepatocytes. Hepatocytes form an epithelium, one-cell thick (a plate), which separates the ___________ lumen from the blood sinusoid. During their passage through the hepatic plates, the contents of the sinusoids are modified extensively chemically. Bile is formed on the other side of the hepatic plate. The bile passes into the intestine via the hepatic ducts and common bile duct.

Answer 1

apoptosis;

bile canalicular

Question 2

[Liver]
Dual blood supply but single venous drainage
• An important function of the liver is to serve as a filter between the blood coming from the __________ (presumably containing many toxins) and the blood in the resting of the body.
• Blood comes from the intestines and other viscera via the portal vein. The Portal vein contributes 75% of the total circulation to the liver; the hepatic artery contributes 25%. The portal vein drains the stomach, pancreas, spleen and small and large intestine. Blood from portal venules and hepatic arterioles flow into a complex network of ___________. Blood from these sinusoids converge to form __________ (at the center of each hepatic lobule) that then coalesce into the hepatic vein. The hepatic vein drains into the ______________.
• The arterial supply for the bile ducts arises mainly from the ___________. These arterioles give rise to an extra-ordinary rich plexus of capillaries that surround the bile duct as they traverse the portal tracts. Blood from this peribiliary plexus empties into the sinusoids by way of branches of the portal vein so that this blood may pick up solutes from the bile ducts and cycle them back to hepatocytes.

Answer 2

GI tract;

hepatic sinusoids; central veins; inferior vena cava

right hepatic artery;

Question 3

[Hepatic Sinusoids]
- Vascular system: Blood from portal vein and hepatic artery flow into hepatic sinusoids, which drain into the central vein and eventually into the inferior vena cava.

• Biliary system: Each hepatocyte is juxtaposed to several biliary canaliculi. The canaliculi drain into_____________. These coalesce to form ____________, and then right and left hepatic ducts. After these join cystic duct, the common bile duct is formed. The common bile duct empties into the duodenum at the Ampulla of Vater.
• _________ are specialized tissue (fixed) macrophages that remove particulate matter from the circulation, particularly coming from the gut. They line the hepatic sinusoids.
• Ito cells (__________ cells) also lie within the sinusoidal space. They play a central role in the storage of vitamin A and contribute to hepatic fibrosis in pathological states.

Answer 3

intra-lobular ducts; inter-lobular ducts

Kupffer cells;

hepatic stellate;

Question 4

Hepatic lobule: The central vein lies in the middle of the lobule and the portal triads at the periphery. Blood flows from the portal triad to the central vein. Bile flows from the center towards the portal triad. Regions within lobules based on blood supply and activity. The lobule can be divided into three zones based on the proximity to the blood supply.

• Zone 1 – Periportal Hepatocytes: Hepatocytes close to the vascular core (i.e. blood vessels in portal triad) receive the highest concentrations of oxygen and solutes. These hepatocytes specialize in oxidative metabolism, amino acid catabolism, gluconeogenesis, glycogen degradation, _________ synthesis and _____ synthesis. They are more resistant than other hepatocytes to cell injury due to circulatory compromise and nutrient deficiency (because of their position relative to the blood supply) and are the first to regenerate. ___________ affects this region the most as it spreads from the portal triad into the hepatic lobule.
• Zone 3 – Centrilobular Hepatocytes: Hepatocytes closest to the central vein are perfused by blood already modified (‘used”) by hepatocytes in zones 1 and 2. Therefore they are exposed to lower concentrations of oxygen and nutrients. Hepatocytes of zone 3 are important for general detoxification mechanisms, biotransformation of drugs (i.e. high concentration of ____________), glycolysis, glycogen synthesis, bile acid synthesis and ketogenesis. Liver destruction in ________________ mainly involves zone 3. _________, a mycotoxin from Aspergillus (which can contaminate peanuts) causes liver damage primarily of zone 3.

Answer 4

cholesterol; urea

Viral hepatitis;

cytochrome P450 enzymes;

alcoholic cirrhosis;

Aflatoxin

Question 5

The formation of bile occurs in three discrete steps.
1) _________ actively secrete bile into bile canaliculi.
2) __________ that line hepatic ducts secrete into the lumen a watery HCO3–rich fluid. Steps 1 + 2 produce approximately 900 ml/day of so-called hepatic bile.
3) Between meals, about half the hepatic bile (~450 ml) is diverted to the gall bladder, which stores and concentrates the bile. The 0.5 L of bile that reaches the duodenum per day through the Ampulla
of Vater is a mixture of relatively dilute hepatic bile (450 ml) and concentrated GB bile (~50 ml). Both hepatic bile and gall bladder bile are complex secretions that are ________ with plasma (~300 mOsm/kg). They contain water, electrolytes, and organic solutes including bilirubin, cholesterol, fatty acids and phospholipid. ___________ are present in gall bladder bile concentrations lower than in hepatic bile. Main anions in gall bladder bile are bile salts, large polyanions. Although __________ is actively transported out of the gall bladder into the extracellular space, dragging water and other electrolytes with it, sodium and other cations diffuse back into the gall bladder because of the presence of high concentrations of negatively charged bile salts in the gall bladder.

Answer 5

Hepatocytes;

Cholangiocytes;

isosmotic

Chloride and HCO3-;

sodium

Question 6

Production of Bile salts:
• Primary bile acids (_____ acid and ________ acid) are synthesized by hepatocytes from cholesterol. The key enzyme responsible for converting cholesterol to primary bile acids is _____________. When greater quantities of bile salts are recirculated to the liver, there is decreased demand for synthesis, and the enzyme is inhibited. When smaller quantities of bile salts are recirculated, there is increased demand for synthesis and the enzyme is stimulated.

• Conjugation to glycine or taurine: Conjugation of primary bile acids with glycine or taurine in hepatocytes results in bile salts (e.g. taurocholate; tauro chenodeoxycholate; glycocholate; glycochenodeoxycholate), which are more ____________.
• Micelles: Primary bile salts combine with ________ to form micelles, which are delivered via the bile into the duodenum through the Sphincter of Oddi at the Ampulla of Vater. Remember, gall bladder bile contains more bile salts (and therefore also micelles) than hepatic bile. A stone obstructing the ______ could therefore reduce delivery of bile salts and micelles into the common bile duct and thence the intestine. Micelles are involved in the transport and absorption of fats and fat-soluble vitamins. Transport and absorption of fats and fat-soluble vitamins would be impaired by a reduction in micelles in the intestine.
• Secondary bile acids (deoxycholic acid, lithocholic acid) are formed in the intestine. Intestinal bacteria deconjugate and ____________ primary bile acids to secondary bile acids (cholate to deoxycholate; chenodeoxycholate to lithocholate). Secondary bile acids formed in the intestine are _________. These are passively absorbed from the ileum into the portal vein, and from there to the liver. In the liver they are conjugated to ____________ to form more water-soluble secondary bile salts (tauro-deoxycholate, glycol-deoxycholate, tauro-lithocholate, and glycolithocholate). Secondary bile salts join the enterohepatic circulating pool.

Answer 6

cholic; chenodeoxycholic;

cholesterol 7α-hydroxylase;

water-soluble;

liver fats;

cystic duct ;

dehydroxylate;

lipid soluble;

taurine and glycine

Question 7

Production of bile salts

Digestive functions of bile salts
• Emulsification of fats because of their _____________ nature (polar and non-polar surfaces) increases surface-to-volume ratio of lipid droplets and micelles and increases absorption.
• Formation of micelles that disperse fats and make them accessible to pancreatic lipases.
• Activation of an enzyme called _______________, which is present in milk.

• Lipid droplets have a diameter of ~1 mm. They have a surface coating of bile salts and _________. The hydrophilic face of the bile salts faces outwards. Emulsification increases _____________ ratio of droplets and facilitates absorption.
• Micelles are ~5 nM. They contain a surface of bile salts and phospholipids and a core of absorbable fats (fatty acids, ____________, cholesterol, fat-soluble vitamins A, D, E, K). The micelles disperse fats and make them accessible to pancreatic lipases.

Answer 7

amphipathic;

bile-salt-activated lipase

phospholipid; surface-to-volume;

monoglycerides;

Question 8

[Enterohepatic circulation]

Step 1: Synthesis of primary bile salts in hepatocytes. Approximately, 600 mg/day of primary bile salts are synthesized. Approximately 900 ml of hepatic bile is produced per day. _________ simulates hepatic and biliary duct cells to secrete bicarbonate and water, which expands the volume of bile and increases its flow into the intestine

Step 2: Between meals, about half hepatic bile (~450 ml) is diverted to the gall bladder. Since the volume of the GB is only 15-60 ml, the stored gall bladder bile has to be concentrated. The active pumping of sodium out of the GB causes electrolyte and water reabsorption, which concentrates the bile. Bile salts are the main anion in GB bile. The gall bladder has three functions.

1. Stores bile during the fasting state. The ____________ opens to allow bile to enter intestine only when fats are present. At other times, bile is stored in gall bladder until needed.
2. Concentrates bile during the fasting state. Typically, bile is concentrated 10-fold in the gallbladder by absorption of water and small electrolytes. Active pumping of sodium out of the GB causes ___________________, which concentrates the bile. Virtually all the organic molecules are retained. The result is that the gall bladder concentrates the key remaining solutes in bile fluid—bile salts, bilirubin, cholesterol, and lecithin—by 10- to 20-fold.
3. Ejects bile 30 minutes after a meal.

Step 3: When food enters the stomach and the duodenum, a hormone called ____________ is released from I cells in the intestine. CCK causes the gall bladder to contract and squirt its contents into the bile duct. At the same time cholecystokinin relaxes the sphincter of Oddi at the Ampula Vater, allowing bile to flow into the duodenum. The 0.5 L of bile that reaches the duodenum per day is a mixture of relatively dilute hepatic bile and concentrated GB bile. In the small intestine, intestinal bacteria dehydroxylate some of the primary bile salts to form secondary conjugated bile salts (which are still water-soluble), deoxycholic acid from cholic acid and _____________ from chenodeoxycholic acid. Intestinal bacteria also deconjugate some primary and secondary conjugated bile salts back to lipid soluble bile acids. In the small intestine, bile salts emulsify and solubilize dietary lipids and fat-soluble vitamins allowing for their absorption.

Step 4: Along the ileum, conjugated primary and secondary bile salts are reabsorbed actively into hepatic portal circulation. The apical _____________ is responsible for active transport. Lipid-soluble secondary bile acids are passively absorbed into hepatic portal circulation. When the ileum is resected, for example in patients with Crohn’s disease, bile salt absorption decreases and the enterohepatic circulation of bile salts ceases. The excess bile salts therefore enter the colon, where they attract water into the lumen (being anions) causing bile salt diarrhea. The disruption of the enterohepatic cycle leads to a loss of bile salts, which results in less formation of micelles and less fatty acid digestion and absorption. The undigested fat is lost in the feces (steatorrhea).

Step 5: Bile salts and bile acids travel to the liver, where ___________ extract them from the portal circulation. The bile salt pool is 2-4 g, and bile salts circulate 6-10 times per day.

Excretion in feces: About 0.6 g of bile salts is excreted in the feces daily, equivalent to the amount of primary bile acids synthesized. This is the only route for elimination of cholesterol from the body.

Answer 8

Secretin;

Ampulla of Vater;

secondary electrolyte and water reabsorption;

cholecystokinin (CCK);

lithocholic acid

sodium-dependent bile salt transporter;

hepatocytes;

Question 9

If the enterohepatic circulation of bile salts fails, excess bile salts enter the colon, where they attract water into the lumen (being anions) causing bile salt diarrhea. _______________ are polymeric cationic bile-salt binding resins that decrease bile salt diarrhea. These drugs are also used for lowering ____________. Side effects:Bloating, constipation, flatulence, and enhances bile salt depletion. Drug interaction: Bind to many drugs and decrease their absorption. Therefore, best they not be given within 2 h of any other drug.

Answer 9

Colestipol, Cholesytramine, Coleselvalam;

LDL cholesterol

Question 10

Cholagogue responses: Cholagogues are substances that cause contraction of the gall bladder thereby emptying its contents. The presence of _____________________ in the small intestine causes the release of cholecystokinin (cholecysto = gallbladder and kinin = movement) from I cells in the intestine. Cholecystokinin stimulates contraction of the gallbladder through direct action on muscle and via activation of vagal afferent fibers leading to a _____________. Cholecystokinin also stimulates the relaxation of the Sphincter of Oddi via activation of ____________________. The result is that bile is ejected into the duodenum in spurts.

Answer 10

fat, amino acids and small peptides;
vago-vagal reflex;
inhibitory enteric nerves

Question 11

Choleretic responses: Choleretics are substances that increase bile formation. Food ingestion stimulates the vagus nerve. Vagal stimulation acts on __________ that line hepatic and biliary ducts and cause them to secrete a watery fluid rich in bicarbonate. Secretin released in response to _______________ simulates hepatic and biliary ductal cells to secrete bicarbonate and water, which expands the volume of bile and increases its flow into the intestine. Bile salts, being anionic, increase fluid accumulation in hepatic bile, thereby increasing bile formation. The higher the bile salt concentration in the enterohepatic circulation, the more bile is produced.

Answer 11

cholangiocytes ; acid in the duodenum

Question 12

Causes of gallstones: substances that are in high
concentration in gallbladder bile are __________ and
bile pigments
- Too much absorption of water from bile – too concentrated
- Too much absorption of bile acids from bile – as bile acids are ________, water is absorbed along, leading to concentration of
bile
- Too much cholesterol in bile – cholesterol stones may lead to irritation
- Inflammation of epithelium – cholecystitis
- ______________ (chenodiol) – naturally occurring bile acid used to dissolve gall stones, treat primary biliary cirrhosis and reduction of weight
o Reduces cholesterol content of bile by reducing hepatic cholesterol synthesis and by stabilizing hepatocyte canalicular membranes

Answer 12

cholesterol;

polyanionic;

Ursodeoxycholic acid

Question 13

Bilrubin metabolism

Step 1: Extravascular hemolysis: Aged RBCs are phagocytosed by macrophages lining the sinusoids of the spleen, liver and bone marrow. Inside the macrophage, the heme molecule is cleaved off from the __________.

Step 2: Heme → Bilirubin: The iron (ferrous) in heme is converted to ferric. The _______ of heme is broken to release the iron and carbon monoxide, resulting in the formation of a toxic product called biliverdin, a green pigment. Biliverdin is converted into a yellow pigment called bilirubin by an enzyme called biliverdin reductase.

Step 3: Bilirubin-Albumin transport to Liver: Unconjugated bilirubin is poorly soluble in water (lipid soluble) and is transported in blood bound to serum albumin. The unconjugated bilirubin-albumin complex is taken to the liver via the systemic circulation. Serum albumin has the capacity to bind unconjugated bilirubin up to a blood concentration of 20 mg/dL. When unconjugated bilirubin is in excess of 20 mg/dL, the albumin-carrying capacity is saturated. Excess free unconjugated bilirubin (lipid soluble) penetrates the blood-brain barrier and deposits in lipid-rich ______ causing neuronal damage.

Step 4: Bilirubin conjugation in the hepatocyte: In liver sinusoids, unconjugated bilirubin dissociates from albumin to enter liver cells. Unconjugated bilirubin is lipid soluble. Unconjugated bilirubin is conjugated with _________ in the hepatocyte endoplasmic reticulum, making it water-soluble conjugated bilirubin so that it can be excreted in bile.

Step 5: Transport: Conjugated bilirubin is actively transported into biliary canaliculi and through the bile duct into the small intestine. Normally, most of the conjugated bilirubin is excreted in bile. If however, the bile duct is obstructed, conjugated bilirubin may reflux back into the _________. Since conjugated bilirubin is water soluble, it gets filtered by the kidney and appears in the urine. It does not accumulate in the CNS like lipid-soluble unconjugated bilirubin.

Step 6: Conversion of conjugated bilirubin to urobilinogen and stercobilin: Intestinal bacteria in the _________________ convert conjugated bilirubin into colorless urobilinogen (splits off the glucuronide) (a.k.a. stercobilinogen). About 90% of urobilinogen is oxidized to yellow-brown stercobilin and excreted in feces (gives feces its yellow-brown color).

Step 7: Re-excretion: About 10% urobilinogen is reabsorbed into the circulation and either re-excreted by the liver into the bile or excreted in the urine.

Answer 13

globin chains;

porphyrin ring;

basal ganglia;

glucuronic acid;

blood stream;

terminal ileum and colon

Question 14

Processing bilirubin in the liver

Uptake by hepatocytes: Unconjugated bilirubin dissociates from albumin in the liver sinusoids, and is
then taken up by hepatocytes by two mechanisms.
1. Electrogenic uptake of anionic bilirubin by bilitranslocase
2. Exchange of Cl- for bilirubin via the anion exchanger _____________________ (electroneutral), which is encoded by the ____________ gene.

Modification within hepatocytes: In hepatocytes, unconjugated bilirubin is transported to the ER.
Within the ER, bilirubin is conjugated with glucuronic acid to form water-soluble conjugated bilirubin.
The enzyme that catalyzes this reaction is called ____________________.
- UDP glucuronic acid + Bilirubin → UDP + Bilirubin monoglucuronide
- UDP glucuronic acid + Bilirubin monoglucuronide → UDP + Bilirubin diglucuronide (water soluble)

Export into biliary canaliculi: Conjugated bilirubin is actively transported into the biliary canaliculus
via the transporter __________________. The is the rate-limiting step in the entire process of bilirubin excretion.

Answer 14

OATP-1 (Organic Anion Transport Protein 1) ;

SLCO1A1 (solute carrier organic anion transporter);

uridine diphosphate glucuronosyl transferase;

MRP2 (Multidrug Resistance-associated Protein 2)

Question 15

[Hemolytic Jaundice due to Hemolytic Anemia]

Hemolytic anemia causes hemolytic jaundice. This is the most common type of jaundice and it is due to increased RBC destruction. Examples of hemolytic anemia include sickle cell anemia, ___________, and G6PD deficiency

Excess hemolysis leads to excess heme release, which in turns results in excess unconjugated bilirubin generated.
• Blood change: Total bilirubin and unconjugated bilirubin are __________ in blood. The conjugated bilirubin level in blood is ___________ because whatever conjugated bilirubin is generated in the liver is converted into urobilinogen in the intestine.
• Urine change: Increased unconjugated bilirubin is delivered to liver. Consequently, increased _______________ is formed in liver. This leads to increased urobilinogen formation in the intestine. Increased urobilinogen is absorbed into the circulation, resulting in increased ____________ being excreted in urine.

Answer 15

hereditary spherocytosis;

increased;

unchanged

conjugated bilirubin;

urobilinogen

Question 16

[Jaundice due to defect in conjugation]
Defects in bilirubin conjugation in hepatocytes can lead to jaundice. Because of the conjugation defect less unconjugated bilirubin is converted to conjugated bilirubin. The excess unconjugated bilirubin refluxes back into the blood causing an increase in unconjugated bilirubin in the blood.
• Blood changes: _______________________ are increased in blood. _______________ level in blood is unchanged because whatever little conjugated bilirubin is generated in the liver is converted into urobilinogen in the intestine.
• Urine change: Reduced conversion of unconjugated
ilirubin to conjugated bilirubin in the liver results in reduced conjugated bilirubin entering the small intestine. Hence less urobilinogen is formed and less urobilinogen is detected in the urine. Conjugated bilirubin is not formed in urine.

Answer 16

Total bilirubin and unconjugated bilirubin;

Conjugated bilirubin;

Question 17

[Jaundice due to defect in conjugation]

Gilbert syndrome is the most common hereditary cause of increased bilirubin and is an autosomal recessive condition that is characterized by intermittent jaundice (especially following ___________) in the absence of hemolysis or underlying liver disease. Patients have a mild deficiency of ______________. No treatment is needed.

Crigler-Najjar type-2: Marked deficiency in uridine diphosphate glucuronosyl transferase results in jaundice soon after birth. Treatment includes phototherapy (exposure of skin to blue light causes photoisomerization of unconjugated bilirubin to water-soluble lumirubin), __________ (which induces the UGT enzyme and increases its activity), and liver transplant.

Crigler-Najjar type-1 and Kernicterus: Uridine diphosphate glucuronosyl transferase is absent.
Unconjugated bilirubin cannot be converted to conjugated bilirubin. Unconjugated bilirubin levels can exceed 20 mg/dL. _________ has the capacity to bind unconjugated bilirubin up to a blood concentration of 20 mg/dL. When unconjugated bilirubin is in excess of 20 mg/dL, the albumin-carrying capacity is saturated. Excess free unconjugated bilirubin (lipid soluble) penetrates the blood-brain barrier and causes a neurological disorder called ________ due to deposition of bilirubin in lipid-rich basal ganglia (damage to brain centers of infants by deposition unconjugated bilirubin). Treatment includes exchange transfusion (replace all the blood), phototherapy 12 hours per day, _____________ to form complexes with bilirubin in the gut, inhibitors of heme synthesis and liver transplantation.

Neonatal jaundice: In the normal fetus, bilirubin is removed from the circulation by the _______ (into the mother’s circulation). At birth, the newborn has to excrete its own bilirubin suddenly, but its hepatic conjugation of bilirubin is inadequate due to reduced UDP glucuronyl transferase activity. As a result ___________ bilirubinemia can occur during the first 2-5 days after birth. The hyperbilirubinemia subsides as the liver matures. Treatment includes phototherapy.

Answer 17

fasting; uridine diphosphate glucuronosyl transferase;

phenobarbital;

Serum albumin; Kernicterus; oral calcium phosphate

placenta; unconjugated

Question 18

[Jaundice due to defect in export]
Defective transport of conjugated bilirubin into biliary canaliculi → conjugated bilirubin refluxes back into blood → increased ______________ in blood.

Blood changes: Total bilirubin and conjugated bilirubin are increased in blood. _______________ level in blood unchanged because whatever unconjugated bilirubin presented to the liver is converted to conjugated bilirubin.

Urine changes: Reduced export of conjugated bilirubin into bile → decreased conjugated bilirubin reaches intestine → reduced urobilionogen generated → reduced urobilinogen in urine.

Increased conjugated bilirubin refluxed into blood → being water-soluble, increased conjugated bilirubin excreted into urine → urine has a dark color due to presence of _______________.

Feces (clay colored): Reduced export of conjugated bilirubin into bile → decreased conjugated bilirubin reaches intestine → reduced urobilionogen generated → reduced stercobilin in feces → feces has a clay color.

Because conjugated bilirubin is water soluble, most of the excess is excreted in urine. Conjugated bilirubin does not cross into the brain, unlike unconjugated (lipid soluble) bilirubin and therefore does not cause ____________.

Answer 18

conjugated bilirubin;

Unconjugated bilirubin;

conjugated bilirubin;

kernicterus;

Question 19

[Jaundice due to defect in export]
Dubin Johnson syndrome: Absence or mutation of transporter ____________________ responsible for transporting conjugated bilirubin into the biliary canaliculi. Jaundice is mild with increase in conjugated bilirubin in blood and urine. No treatment is required.

Rotor syndrome: Simultaneous mutations of two genes SLCO1B1 (solute carrier organic anion transporter family, member 1B1; encodes _______) and SLCO1B3 (encodes ________) that contribute to transport of conjugated bilirubin into the biliary tree. Similar clinical phenotype as Dubin-Johnson syndrome.

Kernicterus can never occur in these patients because conjugated bilirubin that accumulates in the blood of these patients is water soluble, is filtered by the kidney and appears in the urine. It does not accumulate in the brain.

Answer 19

MRP2 (Multidrug Resistanceassociated Protein 2);

OATP2; OATP1B3

Question 20

[Hepatocellular jaundice due to liver damage]

Parenchymal liver disease (e.g. acute hepatitis A infection) causes ____________ of the liver resulting in obstruction of biliary canaliculi (causing increased conjugated bilirubin in blood).

Defects can also occur in uptake of unconjugated bilirubin into hepatocytes (causing increased unconjugated bilirubin in blood). Blood changes: Total bilirubin and both unconjugated and conjugated bilirubin levels will be increased because of the variable way in which bilirubin transport is disturbed. The severity of jaundice and clinical features depends on the underlying disease.

Answer 20

inflammation and edema

Question 21

[Obstructive jaundice blockade of biliary tree]
_______ law: In a patient with obstructive jaundice, a palpable gall bladder suggests that jaundice is NOT due to gallstones. This is because gallstones develop over a prolonged period, and the repeated cholecystitis results in a _______________ gall bladder that is not easily palpable. When a gall bladder is palpated, it suggests a pathology that has caused obstruction of the biliary tree over a shorter period of time such as pancreatic malignancy leading to passive distention from back-pressure.

Block in bile duct → reflux of conjugated bilirubin into blood → increased conjugated bilirubin in blood.
Blood changes: ______________ are increased in blood. Unconjugated bilirubin level in blood unchanged because whatever unconjugated bilirubin presented to the liver is converted to conjugated bilirubin.

Urine: Reduced export of conjugated bilirubin into bile → decreased conjugated bilirubin reaches intestine → reduced urobilionogen generated → reduced urobilinogen in urine.
Increased conjugated bilirubin refluxed into blood → being water-soluble, increased conjugated bilirubin excreted into urine → urine has a __________ due to presence of conjugated bilirubin.

Feces (clay colored): Reduced export of conjugated bilirubin into bile → decreased conjugated bilirubin reaches intestine → reduced urobilionogen generated → reduced stercobilin in feces → feces has a clay color.

Causes:

1. Cancer of the head of the pancreas can obstruct the common bile duct as it traverses the pancreas to join with the pancreatic duct at the Ampulla of Vater.
2. A stone in the bile duct can cause cholestasis.
3. Liver flukes (____________) can obstruct the biliary tree in many developing countries,
4. Cholangiocarcinoma (cancer of the bile duct),
5. Primary biliary cirrhosis (chronic, progressive liver disease strongly associated with the presence of serum autoantibodies against mitochondria, AMA).

Clinical:

1) Obstructive Jaundice
2) Steatorrhea (absence of bile salts in the intestine, fatty stool)
3) _________ (itching; because bile salts reflux into the blood stream and deposit in the skin)
4) Deficiency of fat-soluble vitamins (A, D, E, K) and malabsorption of fats (absence of bile salts in the intestine). Vitamin K, for example, is required for the function of pro-coagulant factors (prothrombin, VII, IX and X) in the clotting system, and vitamin K deficiency therefore leads to bruising and a prolonged prothrombin time.

Answer 21

Courvosier;

shrunken, fibrotic;

Total bilirubin and conjugated bilirubin;

dark color;

Opisthorchis viverrini;

Pruritus

Question 22

[Detox: organic anions ]
Organic Anions: Organic anions include bile salts, prostaglandins, thromboxane and several drugs.

• Uptake into hepatocytes: OATP-1 (encoded by _____) and OATP2 (encoded by ________) transport organic anions from blood into hepatocytes in exchange for Cl- (electroneutral).
• intracellular transport: Organic anions bind to intracellular binding proteins (e.g. fatty acid-binding protein) and travel to the ER.
• Chemical modification occurs in two phases to render them more hydrophilic.
• Phase I: Cytochrome P450 in the ER add polar groups to the organic lipophilic anion. Phase I reactions include oxidation reactions (deamination, dealkylation, oxidation and hydroxylation) and hydrolysis reactions. The Cytochrome P450 monoxygenase system consists of around 50 enzymes. Drug-drug interactions with clinical consequences occur because of drug impact on cytochrome enzymes. For example, the anti-TB drug __________ induces cytochrome P450 enzymes and enhances the metabolism of coumarin anti-coagulants, oral contraceptives and steroids, so that more of these drugs are needed. As another example, ________, the antihistamine receptor blocker used for peptic ulcer disease treatment, inhibits cytochrome P450 enzymes and suppresses the metabolism of coumarin anti-coagulants and the anti-epilepsy drug phenytoin, so that less of these drugs are needed.
• Phase II: Organic anions are conjugated with glycine, taurine, glucuronic acid, sulfates, acetyl groups, glutathione and methyl groups to make them more hydrophilic.
• Export into the bile canaliculus: Hydrophilic organic anions are exported into biliary canaliculi via the transporter called ___________________. The products are then emptied through the biliary system into the intestine.

Answer 22

SLCO1A1; SLCO1B1;

rifampin; cimetidine;

MRP2 (Multidrug Resistance-associated Protein 2)

Question 23

[Detox: organic cations]
Organic cations: Major organic cations transported into hepatocytes include cholinergic drugs, local anesthetics, antibiotics and endogenous compounds (choline, thiamine, nicotinamide).
• Uptake into hepatocytes: ___________ mediates electrogenic uptake of small organic cations. Bulkier organic cations are transported into hepatocytes by a variant) of OATP1.
• Export into bile canaliculi: Organic cations are exported into biliary canaliculi via ___________________ and related family members.

Answer 23

OCT1 (Organic Cation Transporter 1);

MDR1 (MultiDrug Resistance protein 1)

Question 24

[Storage: iron]
Haptoglobin-Hemoglobin complex and Hemopexin-Heme complex: If red blood cells are destroyed in the circulatory system (intravascular hemolysis), hemoglobin and heme are released. Free hemoglobin is bound to _____________ to form a Haptoglobin-Hemoglobin complex. Free heme is bound to _________ to form a Heme-Hemopexin complex.

Uptake of iron into hepatocytes. Iron is transported in the blood as Ferric (Fe3+) coupled to transferrin in the form of a TF-Fe3+ complex. The TF-Fe3+ complex binds to transferrin receptors (TF-R; transferrin receptor 2) on the basolateral membrane (sinusoidal facing surface) of hepatocytes, and is then internalized. Transferrin is stripped from the complex. Free iron joins the free iron pool. The Haptoglobin- Hemoglobin and the Hemopexin-Heme complexes are taken into the hepatocyte. Iron is freed by the enzyme heme ___________.

Storage of iron in the liver. Free iron is toxic to cells, so iron in cells is stored as ___________________. Ferritin is made of an iron-free apoferritin (protein) shell with a hollow central cavity containing iron. A fully saturated ferritin molecule can hold up to ~4500 iron atoms. When iron levels are low, ferritin releases iron required by the body. Hemosiderin, a dense aggregate of ferritin crystals formed inside lysosomes, does not release iron easily.

Hemochromatosis: Excess iron is deposited in tissues, primarily liver, pancreas and skin.
• Hereditary Hemochromatosis: Mutations of many genes can cause hereditary hemochromatosis including ____________ (a transporter involved in iron absorption in the duodenum), transferrin receptor 2, hepcidin, human factors engineering protein (HFE) and hemojuvelin.
• Acquired Hemochromatosis may arise as a consequence of multiple blood transfusions ( e.g. for thalassemia and other chronic hemolytic anemias), dietary overload of iron, alcoholic cirrhosis, or a disease affecting heme synthesis called ________

Answer 24

haptoglobin; hemopexin;

oxygenase;

ferritin or hemosiderin;

ferroportin;

porphyria cutanea tarda.

Question 25

[copper storage in liver]

1. Copper is absorbed in the _________.
2. In the blood it is complexed to albumin or to the amino acid _____. These complexes travel to the liver.
3. Copper enters hepatocytes via specific transporters in the basolateral membrane (sinusoidal facing surface) of hepatocytes. Inside the hepatocyte it is bound to low-molecular weight proteins called ____________.
4. The copper is then used in the liver to synthesize copper-containing enzymes, for example cytochrome C oxidase, superoxide dismutase and ceruloplasmin.
5. Ceruloplasmin enters the blood stream and transports copper to ______________.
6. Excess copper is actively transported via the biliary system into the duodenum.
7. If copper intake is greater than the bile excretion capacity, the free excess copper induces the production of cysteine-rich proteins called ____________, which complexes with the free copper.
8. The complex gets excreted through the bile into the intestine. About 1-2 mg/day (~80% of dietary intake) is excreted in bile.

In Wilson’s disease, copper accumulates and deposits in the liver, cornea (_________ ring), CNS, kidney, heart, blood cells, and bones. It is an autosomal recessive disease in which a defect in a copper-transporting ATPase leads to impaired biliary excretion of copper

Answer 25

jejunum;

histidine;

copper chaperones;

extra-hepatic tissues;

methallothioneins;

Kayser-Fleischer

Question 26

Vitamin A storage
• Absorbed in the jejunum.
• Transported in blood packaged in chylomicrons or VLDL.
• Stored in the liver as ___________
• In vitamin A deficiency, retinyl ester is converted to retinol, which is released into the the blood where it binds retinol-binding protein and is transported to tissues.
• Excess vitamin A leads to _____ due to increased liver storage.

Answer 26

retinyl ester;

hepatotoxicity

Question 27

Vitamin K is derived from leafy vegetables (as _______), and partly from the bacterial flora in the intestine (as _________). Dietary vitamin K is fat-soluble and requires bile salts for absorption.

Bacterial vitamin K is water-soluble. The physiologically active form, _________ (reduced hydroquinone), is formed in the liver. The liver has stores for a month.

Vitamin K is required for the activity of Vitamin K dependent proteins (VKDP) involved in the clotting cascade (prothrombin, VII, IX and X) and some anti-coagulant proteins.

Vitamin K cycle: VKDPs undergo post-translational modification involving the carboxylation of about 10 of their terminal glutamic acids residues γ-carboxyglutamate, which enables them to enables interact with membrane phospholipids on platelets or fibroblasts. This reaction is catalyzed by ______________ and requires vitamin KH2. When Vitamin KH2 helps carboxylation of VKDPs, it gets oxidized to Vitamin K oxide, which is inactive. Vitamin KH2 is regenerated in the liver from vitamin K
oxide by the enzyme epoxide reductase.

Anti-coagulants: Warfarin (Coumadin) and dicoumarol inhibit epoxide reductase and prevent the regeneration of vitamin KH2. Warfarin does not anti-coagulate blood immediately. Instead, onset of its effect requires about a day before the VKDP clotting factors (prothrombin, VII, IX, X) that are being normally made by the liver have time to naturally disappear in metabolism, and the duration of action of a single dose of warfarin is 2 to 5 days. ___________ has the shortest half-life (4-6 hours) of the vitamin K dependent clotting factors. Since factor VII is a key component of the extrinsic pathway tenase, its deficiency after warfarin therapy results in an early prolongation of the prothrombin time, so it is used to track Warfarin therapy. Also, in vitamin K deficiency, the prothrombin time is prolonged.

Answer 27

phyloquinone;

menaquinone;

vitamin KH2;

glutamyl carboxylase;

Factor VII;

Question 28

[Liver and Lipid metabolism]
Uptake of fatty acids into the liver
• Free fatty acids and lipoproteins from the plasma
• During fasting, fatty acids move from adipose tissue into liver where hepatocytes use them to provide energy through ___________.

Fatty acid synthesis
• The liver is one of the main organs involved in fatty acid synthesis.

Cholesterol metabolism
• Cholesterol is synthesized in the liver
• Cholesterol attached to _______ are taken up and metabolized

Ketone Bodies
• Ketone bodies are __________ compounds that are produced as by-products when fatty acids are broken down for energy in the liver. Ketone bodies are increased during fasting or in patients with diabetes.

Lipoproteins
• Important source of lipoproteins, principally VLDL (VLDL particles contain glycerol, cholesterol, apolipoprotein B-100). These are important component of the fat transport vehicles in the blood stream.

Answer 28

beta-oxidation;

lipoproteins;

water-soluble

Question 29

[Liver and glucose]

Uptake and storage of glucose: Hepatocytes take up glucose by a facilitated carrier-mediated process involving a protein called Glut2. Glucose is converted to _______________ and used for glycogenesis. Glycogen is the main carbohydrate stored in the liver (10% of weight of normal healthy liver).

Insulin: The pancreas secretes insulin into the portal blood making the liver the first organ to respond to changes in plasma insulin levels. About half of the insulin in portal blood is removed in its first pass through the liver. Insulin lowers blood glucose by stimulating glycogenesis and suppressing _____________.

Clinical Correlate: Because of the large reserve of hepatic function, patients with liver damage usually don’t have trouble regulating blood glucose. Patients with portal hypertension may have elevated insulin and glucagon as a result of decreased removal by the liver.

Answer 29

G-6-P and UDP-glucose;

glycogenolysis and gluconeogenesis;

Question 30

[Liver enzymes]
Aminotransferases: The serum levels of two transaminase enzymes—Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)—are often measured to assess liver function. These enzymes transfer amino groups from Alanine and Aspartate to a Ketoacid, producing ____________, respectively. Both enzymes are found in the hepatocyte cytoplasm. Hepatocyte damage releases these enzymes into the blood stream where they can be measured.

Alkaline phosphatase: This group of enzymes hydrolyze ________ at alkaline pH. They are widely distributed in the body with significant activities in the liver, GI tract, bone and placenta. Alkaline phosphatases in the liver are localized in sinusoidal and biliary canalicular membranes. Damage to these membranes releases alkaline phosphatases into the blood stream where they can be measured.

Gamma-glutamyl transferase (GGT): This enzyme transfers ____________ from g-glutamyl peptides to other peptides and amino acids. It is found in many tissues. In the liver it is found in microsomes of epithelium of small bile ducts and in hepatocytes. Damage to these cells releases GGT into the blood stream where it can be measured.

Answer 30

pyruvate and oxaloacetate;

phosphate esters;

glutamyl groups

Question 31

[Diagnostic tests in jaundice]

AST/ALT versus AP/GGT: Blood levels of these enzymes should be considered together.
• Hemolytic Jaundice: No change in liver enzyme levels in blood because the pathology (hemolytic anemia) does not occur in the liver.
• Hepatocellular damage: Large increases of ________________ (hepatocyte cytoplasmic enzymes) in the blood with small increases of AP (biliary canalicular enzyme) favor hepatocellular damage.
• Biliary Obstruction: Large increases of ____________ (microsomal enzyme in small bile ducts and hepatocytes) in the blood with small increases of ALT and AST favors biliary obstruction.

Serum Bilirubin: Total, direct and indirect bilirubin should be considered together.
• Hemolytic Jaundice: _____________ bilirubin increase, with no change in direct bilirubin.
• Hepatocellular damage: Mixed picture with an increase in both direct and indirect bilirubin.
• Obstructive jaundice: ___________ bilirubin increase with no change in indirect bilirubin.

Urine Urobilinogen and Bilirubin:
• Hemolytic Jaundice: Increased urine urobilinogen and no urine bilirubin.
• Hepatocellular damage: No or reduced urine urobilinogen, increased urine bilirubin.
• Obstructive Jaundice: No urobilinogen, increased urine bilirubin.

Answer 31

ALT and AST;

AP and GGT ;

Total and Indirect; Total and Direct