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Digestive Systems, Nutrition, and Metabolism > Bile Metabolism > Flashcards

Bile Metabolism Flashcards

1
Q

What is bile?

A

It’s an aqueous solution of bile acids and bile salts (BA ans BS = majority), phospholipids, cholesterol, and bilibubin. Made from liver.

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2
Q

What are the jobs of bile

A
  1. Lipid digestion and absorption, including fat soluble vitamins (ADEK)
  2. It’s a means fro excretion of cholesterol and bilirubin.
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3
Q

Where is bile made? What happens to it after it is made What causes bile to be released after storage in the gallbladder?

A

BA and BS are both made in hepatocytes from cholesterol in the liver. It then enters the common bile duct where it can go straight to second part of duodenum of turn into the gallbladder. it is normally stored during fasting and released when you eat through the stimulation of CCK, whcih contracts the gallbladder, pushing bile into the common bile duct.

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4
Q

What is the job of CCK?

A

Upon Fatty acid presence, it causes gallbladder to contract (increasing flow of bile into common bile duct and causes sphincter of oddi to relax (increasing flow of bile into duodenum.).

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5
Q

What is the main precursor of BA and BS?

A

Cholesterol (FOUR (4) linked ring structures…last of which is a pent, not a hex…with a tail and an OH at the other end.). Very hydrophobic, except for at the area near the OH.

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6
Q

What two products are made from cholesterol (C27, OH is only at 3 position)? AKA what are the primary bile acids?

A

The primary bile acids are:
1. Cholic acid (C24, OH at 7 and 12)
2. Chenocholic acid (C24, OH at 7)
Both these guys have more OH added to them, in addition to 1 COOH added to each one. These guys are thus more hydrophilic, and can dissolve better in water

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7
Q

What is significant about the location of the polar parts (COOH, OH) of the cholic and chenocholic acid?

A

The polar parts are all on one side of the molecule, so there is a designated polar and non-polar side. That makes them AMPHIPATHIC. This is what allows them to emulsify fats.

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8
Q

What is the FIRST step to making a bile acid? Include both names of the enzyme used. What does this step do? What energy is used to foster the reaction? Where is the enzyme found? What is the rate limiting step?

A

Cholesterol is converted to 7-alpha-hydroxycholesterol using the enzyme 7-alpha-hydroxylase = CYP7A1. This step adds OH to C7. It uses NADPH (converted to NADP). Enzyme is in the liver. Cholesterol presence is the rate limiting step. If it has a lot of cholesterol, it will make 7-alpha-hydroxycholeserol. If There is too much cholic acid present, the reaction will not go through (negative feedback).

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9
Q

What molecules does the liver use to conjugate cholic acid (or BA in general)? Compare the resulting pKa’s. What is the of adding these amino acids? What is another name for a conjugated bile acid?

A

Uses taurine (becomes taurocholic acid, pKa 2) or glycine (become glycocholic acid, pKa 4). Note pKa of cholic acid is 6. The goal is to make these bile acids more polar. These guys would be fully unprotonated (fully charged) at pH of 6. Note: these guys are officially bile salts when they lose their proton, and are thus charged.

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10
Q

At pH of 6, what is the status of cholic acid?

A

Half protonated and half unprotonated. The charge version is more hydrophilic.

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11
Q

Which of the following is the least soluble in water? cholesterol, cholic acid, chenodeoxylic acid, glycocholic acid. Which is the most hydrophilic?

A
  1. cholesterol (least polar)

2. glycocholic acid (most polar)

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12
Q

What makes BAs and BSs highly efficient detergents?

A

They help emulsify fats and fat-soluble vitamins. They also form mixed micelles essential for fat digestion and absorption. Breaks does fat globules into smaller fat droplets (emulsifies them) so that they can be digested by lipases. Without bile, you can’t absorb fats as well.

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13
Q

Describe the enterohepatic circulation of BAs.

A

When bile enters duodenum, runs through to distal ileum, most of the bile salts had been absorbed (90-95%) and sent to the liver then gallbladder for storage. This happens every time you eat. Can happen multiple times in one digestion. 5-10% of bile acids reach colon, where they are deconjugated and dehydroxylated by bacteria to become secondary bile acids.

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14
Q

Describe conversion process of primary to secdondary bile acids by gut bacteria.

A
  1. Remove conjugation (glysine, taurine, etc) (deconjugation). Becomes cholic acid and chenocholic acid
  2. Remove OH at C7 (dehydroxylation). Becomes deoxycholic acid and lithocholic acid (from chenocholic acid). These are now secondary bile acids…they are not something our body made…bacteria made it.
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15
Q

Which is more soluble in water? Cholesterol, primary bile acids, secondary bile acids?

A

CHolesterol = least solublem
Primary BA is most soluble due to conjugation. Secondary BA is in he middle because it lost the conjugation but still have more OH.

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16
Q

Where does hydroxylation and conjugation occur? Where does deconjugation and dehydroxylation occur?

A
  1. Liver, by hepatocytes

2. Colon, by bacteria

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17
Q

Difference between bile in our tissue and bile that is excreted?

A

Excreted bile lacks conjugations. We only use bile with conjugations added.

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18
Q

Lithocholic acid is a primary BA, secondary BA, or bile pigment?

A

Secondary BA.

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19
Q

When the distal ileum is removed, there will be an increase in bile acid: levels in hepatic venous blood, levels i portal venous blood, absorption by enterocytes, storage in gallbladder, synth by hepatocytes?

A

Synthesis by hepatocytes. Less distance for BS absorption, so the bile does not have as much space for absorption into the hepatic portal vein. So they get excreted more. Meaning, the liver has to make more bile to replace it. Level in portal venous blood would be lower. Less is stored in the gallbladder because the system is always using the bile that’s being made because the bile keeps getting excreted.

20
Q

Consequences of ileal resections

A
  1. Bile salt pool shrinks (varies by dissection length)
  2. Fat malabsorption (due to less bile) and steatorrhea (fatty stool)
  3. Deficiency in fat soluble vitamins.
21
Q

How do you manage patients who had an ileal resection?

A
  1. Limit dietary fat intake

2. Supplement diet with medium-chain triglycerides and fat soluble vitamins (ADEK)

22
Q

What is the principal mech for eliminating cholesterol from body?

A

Excretion of BS.

23
Q

What is the purpose of cholesterol?

A
  1. Steroid hormones
  2. BA, BS
  3. VItamin D
  4. Cell membrane
24
Q

How is cholesterol eliminated in feces?

A
  1. As BA
  2. As unmodified cholesterol
  3. As a reduced cholesterol by bacteria (cholestanol and coprostanol)
25
Q

What is a bile acid sequestrant/bile acid resin?

A

It reduces the amount of cholesterol in your system. It binds to bile acids and reduces BA reabsorption. This causes liver to make more bile from cholesterol, as the bile acids bound to BAS (the resins) are excreted. Note that dietary fiber also sequesters BAs.

26
Q

How are conjugated BAs secreted and reabsorbed in cells?

A

Through membrane transporters found in hepatocytes and enterocytes.

  1. Hepatocyte uses Bile Salt Export Pump (BSEP aka ABCB11) (happens to be an ABC transporter…meaning it uses ATP) to tranport bile into bile caniliculi
  2. After entering caniliculi, it’s transported to gallbladder
  3. Eventually, bile is secreted into enterocytes upon reaching duodenum. At this point, it is reabsorbed. Absorption is done through apical sodim-coupled bile acid transporter (ASBT). This sucks up the bile into the enterocyte
  4. Organic solute transporter (OSTalpha/beta) takes the bile form the enterocyte into the portal vein
  5. The bile travels through the portal vein to get to the last transporter, Na-dependent Taurocholate Cotransporting Polypeptide (NTCP), which brings the bile back into the hepatocytes. You need to know all of these steps. there are 4 of them…just know the order of the transporters.
27
Q

True/false: bile acids are dehydroxylated by intestinal epithelial cells

A

Fells. The dehydroxylation occurs in the colon by bacteria.

28
Q

Where does the maximal bacterial transformation of primary BA to secondary BA take place?

A

Colon

29
Q

Cholelithiasis

A

Stone in the gallbladder. Most of the cases are cholesterol stones. 12% present with symptoms, but 80% have it. stats are of western countries.

30
Q

Choledocholithiasis

A

stone in the common bile duct

31
Q

Cholecystitis

A

inflammation of the gallbladder

32
Q

What is keeping the cholesterol in solution if cholesterol is not soluble in water/hydrophilic liquids?

A

Other amphipathic components of bile (phospholipids, BA, and BS)

33
Q

What color is cholesterol?

A

yellow

34
Q

What are the main components of bile?

A

Phospholipids (lecithin), cholesterol, and BA/BS. You need these guys because hey are all amphipolor. keeps cholesterol in solution. If not present, choesterol would precipitate out and form stone. For insance, if acid pool is lowered by ileal dissection, you are increasing your chances of having cholesterol precipitate out to form stones since the ratio needed is tampered.

35
Q

What does admirand’s triangle show? What is usually the culprit leading to cholesterol stone formation?

A

It shows the ratio of BS to Lecithin (phospholipids) to cholesterol that need to be maintained to keep cholesterol from precipitating out. Really specific. Normally caused by an increase in cholesterol concentration, a decrease in phospholipids (lecithin), or a decrease in BS concentration.

36
Q

What is the channel for cholesterol?

A

ABCG5/G8

37
Q

What is the channel for phospholipids (Lecithin)

A

ABCB4

38
Q

What are the 5 factors (that you apparently don’t to memorize) that predispose you to cholelithiasis?

A
  1. Genetic factors: Lith genes (like BSEP channel gene screw that inhibits BS pumping out) that impact composition of bile or enterohepatic circulation of bile
  2. Hepatic hypersecretion: Hypersecretion of mucous/ supersaturation concentrations of cholesterol in bile.
  3. Gallbladder hypomotility: disrupted gallbladder motility (that may be accompanied with hypersecretion of mucous glycoproteins) –> biliary sludge…which can lead to stones
  4. Rapid Phase transition from liquid to crystal: factors that accelerate nucleation time of cholesterol crystal s
  5. Intestinal Factors: high efficiency of intestinal cholesterol absorption and high dietary cholesterol are risk factors for cholesterol gallstone formation
39
Q

Explain biliary obstruction due to gallstones.

A

Note that gallstones usually form in the gallbladder, but are asymptomatic. They can obstruct in 3 areas tho:

  1. Cystic bile duct: leads to painful gallbladder contract…pain comes upon eating
  2. Common bile duct: leads to inhibition of bile release into duodenum, this leads to steatorrhea (failure to digest fats) and jaundice (failure to excrete bilirubin)
  3. Pancreatic duct: leads to inhibited release of bile or pancreatic secretions into duodenum. Serious malnutrition (failure to digest food) could occur. Could also develop acute pancreatitis.
40
Q

What are the symptoms of cholelithiasis?

A
  1. Abdominal pain and dyspepsia, esp after a fatty meal. Nausea, with or without vomiting, might be present.
  2. Murphy sign - pain on palpation of the right upper quadrant (RUQ) when the patient inhales
  3. Episodes of acute abdominal pain, called biliary colic.
41
Q

What are the treatments for those with cholelithiasis?

A

Only gallstones that cause symptoms or complications require treatment - generally no reason for prophylactic treatment in an asymptomatic person
Removal of the gallbladder in the case of symptoms: laparoscopic cholecystectomy is the treatment of choice for symptomatic gallbladder disease.
Endoscopic retrograde cholangiopancreatography (ERCP) has both diagnostic and therapeutic applications in management of choledocholithiasis.

42
Q

What are 3 predisposing factors to getting gallstones?

A
  1. Being a woman. Occurrence is 2:1 when compared to males.

2, Being obese, middle-ages, female. The incidence is also increased in pregnancy. Link is estrogen

43
Q

What’s something to note about the bile and blood stream?

A

When bile gets back to the liver, a small amount is sent to the bloodstream.

44
Q

What are the morphological features of cholestasis?

A

Note: cholestasis is the reduction or stoppage of bile flow at some point between the liver cells an the duodenum. Signs include:

  1. Enlarges cholestatic hepatocytes
  2. Dilated canalicular spaces with accumulation of bile pigments
  3. Apoptotic cells
  4. Kupffer cells with bile pigments
45
Q

Why would patient use chenodeoxycholic acid to treat gallstones?

A

Increases cholesterol solubility in bile. Note that conjugated bile salt as lower pKa.

Digestive Systems, Nutrition, and Metabolism (20 decks)

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