What the heck is in bile?

- it's concentrated in the gall bladder.

- bile salts (about half of the solutes), bilirubin, cholesterol, lechithin, and electrolytes.

- water and many electrolytes (besides Ca2+) are reabsorbed by the gallbladder mucosa. (that's a way of concentrating the other solutes as well)

What are the 2 major functions of bile?

- fat digestion and absorption: bile acids help to emulsify large fat particles in food into minute particules allowing the surfaces to be attacked by lipase secreted from the pancreas. They also aid in absorption of digested fat end products through the intestinal mucosal membrane.

- means of excretion of bilirubin and excess cholesterol from the blood.

Where are bile acids synthesized? What are the steps to synthesis?

- they're made in the liver.

- made from cholesterol precursor, (from diet or synthesized in liver during fat metabolism).

- cholesterol is first converted into cholic a. or chenodeoxycholic acid in equal amounts. These acids then combine principally with glycine and to a lesser extent with taurine to form glyco and tauro-conjugated bile acids. The salts of these acids, many are sodium salts, are then secreted in bile.

How is bile acid secreted?

Bile is secreted in the liver in two stages:

-The initial portion is secreted by hepatocytes and contains large amounts of bile acids, cholesterol and other organic constituents. It is secreted into minute bile canaliculi that originate between the hepatic cells.

-Bile then flows in the canaliculi toward the interlobular septa, where the canaliculi empty into terminal bile ducts and then into progressively larger ducts, finally reaching the hepatic duct and common bile duct. Bile is then emptied directly into the duodenum or diverted through the cystic duct into the gallbladder.

An additional secretion is added to the bile as it moves through the bile ducts. This is a watery solution of sodium and bicarbonate ions secreted by secretory epithelial cells that line the ductules and ducts. Secretin stimulates the second secretion, causing the release of additional bicarbonate to supplement pancreatic bicarbonate.

How does the gallbladder decided when to spill its contents?

The gallbladder stores bile until it is needed in the duodenum. It also concentrates the bile that is stored by absorbing water, sodium, chloride and most other small electrolytes through the mucosa. Rhythmical contractions of the wall of the gallbladder with simultaneous relaxation of the sphincter of Oddi results in gallbladder emptying.

Cholecystokinin (CCK) is the most potent stimulus for causing gallbladder contractions. The presence of fatty foods in the duodenum causes the release of CCK into the blood. The gallbladder is also activated less strongly by acetylcholine-secreting nerve fibers from the vagus nerves and intestinal enteric nervous system.

How are gallstones formed in the gallbladder?

Under abnormal conditions, cholesterol (present in the bile) may precipitate in the gallbladder, resulting in the formation of cholesterol gallstones. The amount of cholesterol in the bile is determined partly by the quantity of fat that a person eats, therefore people on a high-fat diet over a period of years are prone to the development of gallstones.

Inflammation of the gallbladder epithelium, often resulting from low-grade chronic infection, may also change the absorptive characteristics of the gallbladder mucosa, sometimes allowing excessive absorption of water and bile salts but leaving behind the cholesterol in the bladder in progressively greater concentrations. The cholesterol begins to precipitate, first forming many small crystals of cholesterol on the inflamed mucosa but then progressing to large gallstones.

Describe the 3 phases of pancreatic secretion

Cephalic Phase: the same nervous signals from the brain that cause secretion in the stomach also cause acetylcholine release by the vagal nerve endings in the pancreas. This causes moderate amounts of enzymes to be secreted into the pancreatic acini. However, only little of the secretion flows immediately through the pancreatic ducts into the intestine because only small amounts of water and electrolytes are secreted along with the enzymes.

Gastric Phase: nervous stimulation of enzyme secretion continues, accounting for another 5-10% of pancreatic enzymes secreted after a meal. Again, only small amounts reach the duodenum because of continued lack of significant fluid secretion.

Intestinal Phase: after chyme leaves the stomach and enters the small intestine, pancreatic secretion becomes copious, mianly in response to the hormone secretin

List the hormones that control pancreatic exocrine output, their site of release, factors stimulating their release, and their effect on the pancreas.

Acetylcholine – is released from vagus nerve endings and from other cholinergic nerves in the enteric nervous system

Cholecystokinin – is secreted by the duodenal and upper jejunal mucosa when food enters the small intestine

Secretin – also secreted by the duodenal and jejunal mucosa when highly acid food enters the small intestine

Acetylcholine and cholecystokinin stimulate acinar cells of the pancreas, causing production of large quantities of pancreatic digestive enzymes but relatively small quantities of water and electrolytes to go with the enzymes. Without the water, most of the enzymes remain temporarily stored in the acini and ducts until more fluid secretion comes along to wash them into the dunodenum.

Secretin stimulates secretion of large quantities of water solution of sodium bicarbonate by the pancreatic ductal epithelium.

When all different stimuli of pancreatic secretion occur at once, the total secretion is far greater than the sum of the secretions caused by each one separately.

What are the components of pancreatic fluid?

The enzymatic components of pancreatic juice include:

- trypsin

- chymotrypsin,

- carboxypeptidase

- pancreatic amylase

- pancreatic lipase

- cholesterol esterase

- phospholipase.

Bicarbonate ions and water are two other important components of pancreatic fluid. Bicarbonate serves to neutralize the hydrochloric acid emptied into the duodenum from the stomach.

How do pancreatic enzymes get activated?

When first synthesized in pancreatic cells, the proteolytic digestive enzymes are in the inactive forms trypsinogen, chymotrypsinogen and procarboxypeptidase. They become activated only after they are secreted into the intestinal tract. Trypsinogen is activated by the enzyme enterokinase, which is secreted by the intestinal mucosa when chime comes in contact with the mucosa. Trypsinogen can also be autocatalyticaly activated by trypsin that has already been formed from previously secreted trypsinogen. Chymotrypsinogen is activated by trypsin to form chymotrypsin and procarboxypolypeptidase is activated in a similar manner.

What are the functions of the major enzymes released by the pancreas?

- Trypsin and chymotrypsin split whole and partially digested proteins into peptides of various sizes but do not cause release of individual amino acids

-Carboxypolypeptidase splits some peptides into individual amino acids, thus completing digestion of some proteins all the way to the amino acid state.

-Pancreatic amylase hydrolyzes startches, glycogen and most other carbohydrates to form mostly disaccharides and a few trisaccharides

-Pancreatic lipase is capable of hydrolyzing neutral fat into fatty acids and monoglycerides

-Cholestrol esterase causes hydrolysis of cholesterol esters

-Phospholipase splits fatty acids from phospholipids

How do people think that cholesterol gallstones are formed?

In many individuals, bile contains more cholesterol than can be maintained in a stable solution, and in some of these people, the supersaturated bile starts to form microscopic cholesterol crystals.  Deposition of additional layers of cholesterol within mucin, a mucus gel secreted by the gallbladder epithelium, leads to macroscopic cholesterol gallstones. 

*other stones may be made up of bilirubin pigment (like in RBC hemolysis) and mixed calcium, cholesterol and protein stones.

What are the top 3 causes of liver disease? Describe briefly some functions of the liver.

- First is Hep C, then fatty liver disease, then alcohol.

- Vascular: blod reservoid, lymph synthesis (50% of all lymph), blood filter (PLUS MAJOR BACTERIA FILTER! - Kupffer cells in the liver sinusoids)

- Secretory: bile and bile acids, bilirubin

- Metabolism: carbs, fat prot, sortage of vitamins and iron, elimination of dugs, hormones, toxins. *the liver turns toxic ammonia created during metabolism and converts it to non-toxic urea to be excreted. Aas are also metabolized in the liver where they produce ammonia. 

When someone has gallstones, how will that affect them?

They may have any of the following:

- asymptomatic cholelithiasis

- biliary colic

- acute calculous cholecystits

- choledocholithiasis which is a stone in the common bile duct (jaundice, cholangitis which is an infection)

- gallstone pancreatitis

- gallstone ileus (which means obstruction)- it may form a fistula and go into the bowel

- carcinoma of the gallbladder

What is bilary colic?

- gallbladder pain

- RUQ or epigastric pain radiating to the right subscapular area

- steady, severe discomfort lasting hours

- onset about 2 hours after a meal

- may have nausea and vomitting

- NO SIGNS OF INFLAMMATION

- it's the contraction of the GB against a stone impacted in the infundibulum or the cystic duct

- the stone falls back more towards the fundus or passes in several hours and the symptoms resolve.

- so this is being "backed up all in your gallbladder" without other complication

How do you diagnose gallstones? How about management?

- U/S is best *here you'll see a sound shaddow type phenomenon!

- plain x ray and CT may also detect

- manage with pain control during attacks

- cholecystectomy or other treatment (doesn't say yet)

What is acute calculous cholecystitis?

- pain in the RUQ and epigastric pain radiating to the right subscapular area initially (just like bilary colic)

- then it becomes sharp, severe and localized to the RUQ (peritoneal pain)

- associated with N/V

- signs of inflammation and infection (fever and high WBC)

- PE shows RUQ tenderness and guarding, and + murphy's sign

- here the gallstone doesn't fall back or pass, it stays impacted in the infundibulum or sytic duct! Causing acute inflammmation of GB, prolonged inflammation (can cause gangrene, perforation and then bile peritonitis!)

If the gall bladder explodes open because of acute calculous cholecystitis, what organisms may you target in treatment for bile peritonitis?

How do you diagnose acute calculous cholecystitis? How do you treat it?

- U/S: will show gallstone impacted in infundibulum or cystic duct, thickenned GB wall, fluid around the GB, air in GB wall, perforation, pain induced by pressure of U/S probe

- CT scan

- Bilary scintigram ( to see cystic duct obstruction)

- MRI-MRCP

- manage with pain control, IV antibiotics and IV fluid

- early or delayed cholecystectomy

- percutaneous cholecystectomy by U/S for higher risk pts.

Choledocolithiasis

- when a gallstone goes and gets impacted in the common bile duct (that's the duct that also comes right from the liver, it's not the cystic duct, blocking that one is more ok)

- can lead to bile stasis and bacterial contamination resulting in bacterial cholangitis (I thought that calculous cholangitis could cause that too, maybe it does, but that's just in the cystic duct remember)

- increased intraductal pressure causes reflux of bacteria up the bilary tree, across bile cannaliculi and into hepatic veins, resulting in hepatic abcesses and bacteremia

- presents with RUQ or epigastric pain and cholestatic jaundice

Bacterial cholangitis

- so calcaneous cholecystitis can cause infection of the gallbladder and possible perforation, but it does not cause THIS specifically

- this is caused by a gallstone in the COMMON BILE DUCT that creates a back up of pressure so that bacteria will get into the liver and circulation

- spectrum from mild to life-threatening

-Charcot triad: RUQ steady pain, fever, jaundice

- Reynold pentad: all above PLUS septic shock and mental status changes

- elevated WBCs

- bacteremia is about half of cases

- Culprits: E.coli, Klebsiella, Enterobackter, B.fragilis, Pseudomonas (Every Kindof ladE B Present in there!)

In someone with Charcot's triad (or Reynold's pentad) - what was that again?- how do you tell if they have gallstones -and where would they be again?

- RUQ pain, fever, jaundice, sepsis, mental changes

- it would be in the common bile duct

- biochemistry: elevated total/direct serum bilirubin levels, elevated serum ALP level, other hepatic enzymes high

- U/S should dilated bile ducts +/- stones

- ERCP (endoscopic retrograde cholangio-pancreatolography), PTC (percutaneous transhepatic cholangiography) *both of those are both diagnositic and therapeutic! And MRCP and CT cound be doen.

*ERCP is upper GI endoscopy

How would you manage someone with Choledocholithiasis?

Supportive:

- resus, if bact with shock

- possibel ICU management, if with shock

- IVF and IVAbio

- pain control

Therapeutic:

- ERCP with stone removal

- PTC with stone removal

- operative exploration of the common bild duct

Gallstone pancreatitis, is it not that bad?

- no it's really bad!

- happens in up to 1% of ppl with gall stones, 10% mortality rate

- pancreatid duct obstruction by a gallstone in the lower bile duct, or one that's gone through the sphinter of Oddi into the duodenum

- refux of bilary-pancreatic secretions causes functonal obstruction at the sphinter of Oddi which causes pancreatic duct injury, release of ACITVE ensymes into glandular epithelium, release of cytokines

How would someone with biliary pancreatitis present?

- steady epigastric pain

- jaundice secondary to gallstone blocking the bile duct, of edema of the head of the pancreas blocking it

- high serum lipase level

- edematous to necrotizing pancreas can cause crazy stuff, like respiratory problems, metabolic, ascites, pseudocyst, abscess, sepsis, SIRS, MOFO

How should you manage someone with biliary pancreatitis?

- IVF, pain, nutritional support, abios

- confirm cause of pancreatitis with U/S, CT or MRCP. Assess the bile duct with these, plus you could use ERCP, PTC or cholangiogram.

To treat: do ERCP/sphincterotomy, exploration of bile duct at time of cholecystectomy

- PTC with stone extraction

- timely cholecystectomy once pancreatitis has resolved.

- ursodeoxycholic acid may help with pts who cannot get surgery.

What happens in acute pancreatitis?

- autodigestion from premature activation of enzymes

- mostly trysin activation, it activates other proteases

- acinar cells get damaged and necrosed, then there's pancreatic edema and inflammation (impaired microcirculation and cytokine release)

What is the number 1 and 2 causes of acute pancreatitis, and what are the causes that can be easiest to measure?

- Biliary is the big one, then alcoholic

- hypercalcemia and TG emia and celiac can do it too! You can measure those so think of that!

- if you have a young pt, think genetic

- if you have an older pt, think of ca.

*up to 10% of alcoholics develop pancreatitis, mechanism he said "see notes"

What is pancreas divisum? What are a few other rare things?

- it's when the minor and major pancreatic ducts don't fuse! And the smaller one empties a larger portion of the pancreas

- congenital problems with the sphinter of Oddi can cause similar issues.

- HIV associated CMV, drug induced (top of list acei), trauma

How would someone with acute pancreatitis present?

- acute epigastric pain with radiation to the back, maybe better leaning forward to lying to the left side

- increased with eating

- N/V

- different from biliary colic cause it's worse.

- may have mild tenderness, but on the other end of the spectrum they could have hemodynamic instability, tachypnea, fever, scleral icterus ad jaundice (if choledocholithiasis), look for evidence of sepsos or organ failure. May have ileus, tenderness and guarding, Grey-Turner's sign (eccymosis in one or both flanks), Cullen's sign (periumbilical eccymosis)

* you need 2 of 3:

1- typical symptoms (pain)

2- more than 3 x upper limit of pancreatic lipase

3- diagnose with CT (but do U/S first to look for stones)

Someone comes in with epigastric pain and fever, with abdominal tenderness and guarding. What questions do you ask them and what tests should you do?

- Hx: etoh, meds, HIV, vasculitis, autoimmune, other PMHx, FMHx (esp high TG, cystic fibrosis)

- Check their AST, ALT, ALP, GGT and Bili, Ca2+ (corrected) and TGs.

*a raise is more than 3x upper limit of liver enzymes should raise suspicion about choledocolythiasis, especially ALT and AST

- check their pancreatic lipase

- check their U/S

*actually I sortof messed this question stem up, the top is more what you would do to know the cause of what you already know is acute pancreatitis.

You know someone has acute pancreatitis cause they have pain, high lipase and CT. How do you tell how bad it is?

- pancreatic necrosis (you can tell with Ct with contrast cause dead pancreas won't take up contrast) and organ failure.

- so here organ failure doesn't just mean the pancreas, it can mean circulatory shock, pulmonary insufficiency (O2 sat below 90) and renal failure and GI bleeding. I think he means multiple organ failure. Yes he does. 

- if it's mild then recovery ovvurs withing 5-7 days and I don't think we need to do anything.

How is it that some people can die from acute pancreatitis?

- sepsis or SIRS (systemic inflammatory response syndrome) and multi organ failure

- early indicators that this might happen would be:

- shock (HR more than 120 and hypotension <90)

- resp failure (RR>24 and O2 sat <90)

- renal failure (Cr > 180 after IVF, oliguria U/O < 50ml/hr)

- encephalopathy

- hemoconcentration (HCt >50%) *shows massive third space loss

*If they have the following 3 things, there's a 98% accuracy of prediction of mild disease:

1- absence of rebound tenderness or guarding

2- normal Hct

3- normal serum Cr

What is a BISAP score?

Within first 24 hours:

- age >60 (1 pt)

- BUN >9 (1 pt)

- SIRS (1 pt)

- Glasgow coma scale < 15 (1pt)

- pleural effusion (1 pt)

Score 0-2: mortality <2%

Score 3-5: mortality >15%

So if a pt seems to have concerning findings re their acute pancreatitis, what do you do about it?

- heavy observation

- remember that even if early U/S showed no necrosis it may show up a bit later so watch for that

- infused CT should be done (and maybe re-done even)

Treatment of acute pancreatitis, what do you do for that?

- FLUIDS!!!!! these pts loose their ECBV like crazy. (SIRS kindof thing I guess). ECBV being low and underperfusing the pancreas sure is not helping!

- monitor vitals, urine output, O2 sat, pain. Give analgesia and anti-emetics. Nasogastric suction if ileus/obstruction becomes an issue.

- consider nutritional support if a longer course is expected. Enteral nutrition is favored all around, less leaky bowel, less infection...

- DO NOT GIVE ABIOS PROPHYACTIALLY, do it if they have fever or high WBC.

- Treat with ERCP if it's caused by gallstones, and arrange surgical consult before discharge, these ppl shoudl eventually get their GB out. 

What are some major complications of acute pancreatitis?

Pancreas: fluid collections (ascites, cysts in the pancreas), necrosis, infection/abcess formation

Non-pancreas: obstruction, hemorrhage

Systemic: Multiorgan failure, SIRS, shock, pulmonary effusion or ARDS, renal failure, encephalopathy, DIC
METABOLIC THEY LIKE TO ASK THIS ON EXAMS: hypocalcemia due to low albuin, peripheral fat necrosis and hyperglycemia due to insulin deficiency.

What findings would indicate that there is a stone in the common bile duct?

- abdominal U/S shows dilated CBD and/or a stone in there

- jaundice (rising bilirubin)

- high ALP, GGT

- failure of AST and ALT to normalize

- serum bilirubin >23 by the second day (that's something they've observed)

*This gets treated with ERCP remember.

What is chronic pancreatitis and what happens with it?

- chronic inflammatory disease and IRREVERSIBLE DESTRUCTION of parenchema and duct stuff. There ends up being fibrosis and calcification.

- on histology you see patchy fibrosis, lots of inflamm cells, acinar cell loss, loss of islet cells, dilation of ducts due to obstruction from li,e, fibrosis istelf, protein plugs, and calcifications..

What causes acute pancreatitis?

Describe the very basics of the pathophysiology hypotheses of chronic pancreatis.

Ductal obstruction: just like what it souds like. Ex; alcohol leads to secretion of pancreatic juice rich in protein, low in HCO3-, and that favors protein precipitate formation or just other protein and Ca2+ containing stone formation. 

Toxic metabolic: like alcohol or it's metabolite, has direct injurious effect  (increased oxidative stress and may stimulate stellate cells to make pancreatic fibrosis) *stellate cells are also in the liver, those are the ones that do that there!

Necrosis-Fibrosis: most popular theory. repeated acute pancreatitis and then necrosis makes it so that healing process replaces necrotic tissue with fibrosis.

Sentinal Acute Pancreatitis Event (SAPE): pancreatic insult in acinal cells (etoh or other oxidative stress), then trypsin activation, then proinflammatory response, then healing, but if cytokine secretion continues it causes collagen secretion from stellate cells and fibrosis.

So do all heavy drinkers get pancreatitis then? Who else is predisposed?

- only about 10% of chronic alcoholics get chronic pancreatitis. May also have to do with smoking and bad diet.

- you can also have a hereditary form, AD, and the gene is CTG (cationic Trypsingen gene) which codes of the trypsin hydrolysis binding site so that trypsin can get destroyed by stuff. When it's mutated then trypsin hangs around more than it should. Those ppl have higher risk of pancreatic ca. 

- CF pts. CFTR gene codes for a Cl channel that allows you to hydrate mucus.

How would someone wiht chronic pancreatitis present to you?

- pain (intermittent or constant, moderate to severe, epigastric with radiation to back. This is cause of infiltration of peri-neural space by inflammatory cells, and increased size and number of peri-pancreatic nerves. Can also be caused by a sortof like compartment syndrome where there is pancreatic hypertension from ductal obstruction and then pancreatic ischemia.

- pancreatic insufficiency which is mostly steahtorrhea and DM. For the first you have decreased [] of lipase and colipase, and also a relative drop in lipase compared to pancreatic protease and amylase. You bicarb secretion is lower than normal, and the lipase isn't good with acid. Bile acids are also this way. You can see this type of stuff on a Sudan stain. 

- evidence of malabsorption, like weight loss,

Talk about the maldigestion that occurs as a result of chronic pancreatitis.

- EXAM: you need 90% reduction of lipase secretion to get steatorrhea

- absorption of vit A, E and K is usually preserved (so maybe bile salts are more important than lipase for those guys), but there is significant vit D deficiency noted, and we will see osteopenia and osteoporsis commonly.

- vit B12 deficiency is uncommon, but the pancreas is needed to remove that R protein, so you'd see it in extreme cases.

How do you test pancreatic function?

Direct stimulation test: secretin produced by duodenal S cells in response to acidic cyme entering smalll bowel, travels in the circulation and stimulated H2O and HCO3- secretion from ductal epithelial cells. So in this test you would inject IV secretin, then measure the peak HCO3- from fluid around the ampulla (modified endoscopic method). This is very rarely done.

72 hr fecal fat (quantitative) or spot fecal fat (qualitative): For the 72 hour, you give a diet of 100g fat/day for 3 days and measure fat (abN >7g/day). That one is done rarely. For the spot one, you'd do a Sudan III stain of random stool and it's abN if >6 globules of fat/hpf. 

You treat pancreatic insuffiency in different way blah blah, but how do you treat steatorrhea specifically?

- non-enteric coated or enteric coated pancreatic enzymes. If you give non-enteric coated, give with a PPI.

- in general, the best ways to treat pan insuff is analgesia, anti-oxidants, pseudocyst drainage and duce decompression/stone removal. Neuropathic pain tx is sortof controversial as to whether or not it works. It woud be a celiac plexus nerve block (EUS guided) or a Thoracoscopic splanchiectomy.

- in a Coustaux procedure, the divide the main pancreatic duct and the sew over a lip of jejunum over it, so you can drain the pancreatic juice.

What is a Whipples procedure?

How should we look at an elevation of cholestatic and hepatocellular enzymes being raised if all of them are high? Also what are the 3 liver function tests?

- know that cholestatic enzymes are more difficult to raise, so when all else is more or less equal then those are the once you're more concerned about

- that is unless the heptocellar are more than 2X higher than the cholestatic enz are raised.

- LFTs are: total and direct bilirubin, INR and albumin

Are LEs super specific to the liver always? What Liver problems cause a raise in LEs? Also describe what you would do to r/i or r/o each cause.

- it is more if both AST and ALT are high, but not as much if just 1 of them are.

- AST is also in the heart and lots of other places. It will go up in hemolysis.

Aquired: Hepatitis (viral)* do Hep screen, Alcohol (AST will go up twice as high) *history, Drugs *history, Fatty liver and NASH *wt changes and U/S

Primary: autoimmune hepatitis *ANA, SMA (smooth muscle abs), IgG, Wilson's disease *ceruloplasmin would decrease, Hemochromatosis * ferritin, Fe/TIBC, alpha1-antitrypsin def * A1-AT levels

Other: Hepatic vascular thrombus *doppler U/S, Shock liver *hx of low BP, acute cholelithiasis *Hx and U/S.