Case 8 Goal: Students will understand the role of bile and pancreatic enzymes in the digestion of food Learning Objectives

Contents 1 Normal 2 Signs and symptoms 3 Differentials 4 Pancreatitis 5 Gallstones 6 Medications 7 Session Notes

[edit] Normal

1. Draw a diagram of the extra-hepatic biliary system.

2. Describe the synthesis, transport and storage of bile.

• Bile made in liver, transported to gallbladder where it is stored until stimulated for release by CCK or ACh
• Bile is breakdown product of heme; heme converted to unconjugated bilirubin in macrophages of spleen & bone marrow → bound to albumin & sent to liver where it is conjugated (more water soluble)
  • 3 ways to go:
    • out with feces w/o bacterial mod
    • out w/ urine after bacterial mod → reabsorption → renal excretion
    • put back into bile after bact mod → reabsorption → travel in plasma until hepatocytes conjugate it and package it in bile

3. List the constituents of bile and describe the functions of these constituents.

• Phospholipids, cholesterol, bilirubin, protein & bile pigments
• Phospholipids gives it amphipathic nature
• Cholesterol gives it hydrophobic qualities
• Bilirbubin provides pigment

4. Describe the mechanism of bile stone formation.

• Cholesterol
  • Due to cholesterol supersaturation (not enough bile acids unable to solubilize it all) & nucleating factors i.e. plasma Ca, gallstone hypomotility, mucus hypersecretion
• Pigment stone
  • Unconjugated bilirubin + Ca
    • Intravascular hemolysis causes increased hepatic production of conjugated bilirubin

5. List the major etiologies of acute pancreatitis.

• Gallstones – w/ EtOH account for >80% of cases
• EtOH
• Trauma inc. medical procedures i.e. ERCP
• Meds i.e AIDS drugs, diuretics, chemotherapeutic agents, & estrogens
• Mumps
• Autoimmune pancreatitis
• Hypercalcemia, hypertriglyceridemia,

6. Describe the mechanisms by which acute pancreatitis develops.

• Early enzyme activation causes destruction of pancreatic tissue (by means listed above). Immunologic response destroys affected host tissue. Lipases cause fat necrosis (triglycerides→FAs). Elastases cause increased vascular fragility & hemorrhage. Proteases cause cell necrosis.

7. Identify the mediators that are involved in the pathogenesis of the inflammatory process.

• Lipase i.e. phospholipase A
• Elastase
• Trypsin, chymotrypsin

8. Describe the clinical appearance of a person with acute pancreatitis.

• Severe abdominal pain
• Tachycardia
• Upper ab tenderness (w/ guarding)
• Decreased bowel sounds
• Gray Turner sign = ecchymosis in flanks
• Cullen sign = periumbilical ecchymosis

9. List blood tests that are markers for pancreatitis.

• Triglycerides
• Amylase
  • Lipase is better

• Review the extrahepatic biliary system
  • Structure
  • Function
  • What causes dilation of the common bile duct?
  • Pancreas
    • Structure
      • Average adult pancreas about 12-15 cm in length and weighs 60-140g.
      • Covered by thin areolar connective tissue capsule which gives rise to the connective tissue septa dividing the organ into lobules. (Blood vessels, nerves, lymphatics, and ducts transverse these septa)
      • Each lobule is supplied by a principal small artery.
      • Majority of organ consists of exocrine acini containing isolated aggregations of endocrine cells (islets of Langerhans).
    • Function
      • Mixed exocrine and endocrine gland
      • Exocrine part consists of numerous acini segregated into lobules that secrete many enzymes needed in digestion
      • Exocrine secretions include inactive proenzymes to hydrolyze proteins (trypsin, chymotrypsin, carboxypeptidase, elastase), lipids (lipases - already active, phospholipases), carbohydrates (amylase - already active), and nucleic acids (ribonuclease, deoxyribonuclease). Enterokinase converts trypsinogen to trypsin which then activates other enzymes.
      • Acinar secretions are stimulated by CCK and acetylcholine. Insulin also stimulates exocrine secretions wherase glucagon inhibits.
      • Endocrine part (neuroendocrine) consists of the islets of Langerhans, which secrete hormones such as insulin, glucagon, and somatostatin.
      • Alpha cells secrete glucagon which works to increase blood glucose.
      • Beta cells secrete insulin which works to decrease blood glucose.
      • Delta cells secrete somatostatin which inhibits both insulin and glucagon secretion.
  • Gall bladder
    • Structure
      • The gall bladder is a pear-shaped organ (~10cm by ~4cm) attached posteriorly to the right lobe of the liver. The wall measures up to 2mm thick.
      • It is composed of a blind-ending fundus, a central body, and a narrow neck
      • Has 3 layers: mucosa, muscularis externa, and adventitia/serosa
      • Does NOT have a muscularis mucosa or a submucosa
    • Function
      • Stores up to 30-50mL of bile
      • Approximately 1000 mL of bile flows daily from the liver, posibbly into and out of the gallbladder

CT, Ross

• • • Bile
      • How is bile made?
        • Bile is an exocrine secretion of the liver
        • It is carried from the parenchyma of the liver by bile ducts that fuse to form the hepatic duct; the cystic duct then carries the bile into the gallbladder where it is concentrated
        • Bile is returned via the cystic duct to the common bile duct, which delivers bile from the liver and gallbladder to the duodenum

• • • • Components
        • Water
        • Phosphlipids (i.e., lecithin) and cholesterol
        • Bile salts (also called bile acids): primary (secreted by liver: cholic acid, chenodeoxycholic acid; secondary (converted by bacterial flora in the intestine): deoxycholic acid, lithocholic acid
        • Bile pigments, principally the glucuronide of the bilirubin roduced in the spleen, bone marrow, and liver by the breakdown of hemoglobin
        • Electrolytes: sodium, potassium, calcum, magnesium, chloride and bicarbonate

• • • • Function

• • • • • Water – serves as solute in which other components are carried
        • Phospholipids and cholesterol – are metabolic substrates for other cells in the body; act as precursors of membrane components and steroids; largely reabsorbed in the gut and recycled
        • Bile salts – act as emulsifying agents that aid in the digestion and absorption of lipids from the gut and help to keep the cholesterol and phospholipids of the bile in solution, largely recycled, going back and forth between the liver and gut
        • Bile pigments – detoxify bilirubin, the end product of hemoglobin degradation and carry it to the gut for disposal
        • Electrolytes – establish and maintain bile as an isotonic fluid; also largely reabsorbed in the gut

Emi Bays, Ross Histology

[edit] Signs and symptoms

• Doubled over in pain (severe abdominal pain)
• Throwing up bile and retching
  • What is the difference?
• Fast heart rate
• Moderately tender abdomen with guarding
• Why are bowel sounds decreased?
• Define scaphoid
• Labs
  • High alkaline phosphatase
  • High triglycerides
  • High amylase
  • High lipase
  • How do they measure pancreatic enzymes?
  • What are AST and ALT?
  • What is included in a stat lab?

[edit] Differentials

• Food poisoning (signs and symptoms)
• Perforated viscus – esp peptic ulcer
• Acute cholecystitis and biliary colic ( may also have elevated serum amylase)
  • Sonography and radionuclide scanning are helpful in establishing the diagnosis of cholelithiasis and cholecystitis
• Acute intestinal obstruction
  • Can be differentiated by history of colicky pain, findings on abdominal examination, and x-rays of the abdomen showing changes characteristic of mechanical obstruction
• Mesenteric vascular occlusion
• Renal colic
• Myocardial infarction
• Dissecting aortic aneurysm
• Connective tissue disorders with vasculitis (inflamed blood vessels)
• Pneumonia
• Diabetic ketoacidosis b/c it is often accompanied by abdominal pain and elevated total serum amylase levels; however, serum lipase and pancreatic isoamylase levels are not elevated in DK

Emi Bays, access medicine

[edit] Pancreatitis

• What is it?
  • Inflammation of the pancreas
  • Clinical manifestations can range in severity from mild, self-limited to a life-threatening acute inflammatory process. Duration can range from a transient attack to an irreversible loss of function.
• Difference between acute and chronic
  • Acute pancreatitis is a group of reversible lesions ranging in severity from edema and fat necrosis to parenchymal necrosis with severe hemorrhage. Can return to normal if the underlying cause is removed. Gallstones are present in 35% to 60% of cases of acute pancreatitis, and about 5% of patients with gallstones develop pancreatitis.
  • Chronic is characterized by the presence of irreversible destruction of exocrine pancreatic parenchyma, fibrosis, and in late stages, the destruction of endocrine parenchyma.
• How does it disrupt normal digestion?
• Causes
  • Acute Pancreatitis:
    • Approximately 80% of cases in Western countries are associated with either biliary tract disease or alcoholism.
    • Less common causes include:
      • obstruction of the pancreatic duct system
      • medications, including thiazide diuretics, azathioprine, estrogens, sulfonamides, furosemide, methyldopa, pentamindine, and procainamide
      • infections with mumps, coxsackieviruses and mycoplasma pneumoniae
      • metabolic disorders
      • acute ischemia induced by vascular thrombosis, embolism, vasculitis, and shock
      • trauma
      • inherited alterations in genes encoding enzymes and their inhibitors
  • Chronic Pancreatitis:
    • Most common cause is long-term alcohol abuse (patients usually middle-aged males)
    • Less common causes include:
      • long-standing pancreatic duct obstruction
      • tropical pancreatitis, a poorly characterized disease seen in Africa and Asia (attributed to malnutrition)
      • hereditary pancreatitis (mutations in PRSS1 and SPINK1)
      • idiopathic chronic pancreatitis

CT, Robbins and Cotran

• Acute onset of symptoms
  • What does it mean that he is throwing up bile?
    • How does this trigger vomiting
• Risk factors
• Diagnostic criteria
  • Why do the increased enzymes indicate pancreatitis?
• Social History
  • Smoking
  • Alcohol
  • How do they affect pancreatitis
• Complications
• Treatment

[edit] Gallstones

• Types
  • Pigment stones
  • Cholesterol stones
• Causes
  • Cholesterol Stone formation involves four simultaneous defects:
    • Supersatureation of bile with cholesterol as a result of hepatocellular hypersecretion of cholesterol
    • Gallbladder hypomotility promotes nucleation
    • Cholesterol crystal nucleation in bile becomes accelerated
    • mucus hypersecretion in the gallbladder traps the crystals causing aggregation into stones
  • Pigment stone formation is caused by infection of the biliary tract, which leads to release of microbial beta-glucuronidases that hydrolyze bilirubin glucuronides. This unconjugated bilirubin along with inorganic calcium salts comprise pigment gallstones.

CT, Robbins and Cotran

• How do gallstones contribute to pancreatitis
• Complications
• Treatment
• Ultrasound
  • Interpret/explain what we are looking at

[edit] Medications

• Hydrochlorothiazide
  • Is this contributing to his problems

[edit] Session Notes

Case 8

Learning Objectives

• Normal
  • Review the extrahepatic biliary system
    • Structure
    • Function
      • Get bile to the duodenum
        • When bile is produced by the liver, it is transported and stored in the gall bladder
        • In response to CCK, the gall bladder contracts and the sphincter of Oddi relaxes, allowing bile to flow through into the common bile duct to the duodenum
        • A sphincter at the main pancreatic duct and a pressure gradient keep bile from flowing into the pancreas
      • What causes dilation of the common bile duct?
        • Obstruction/restriction
        • But early in an obstruction it may not be dilated, so no dilation does not mean no obstruction
  • Pancreas
    • Structure
      • Acinar and ductal cells
        • Acini secrete enzymes (stimulated mainly by CCK)
        • Duct cells secrete bicarb to neutralize gastric acid (stimulated mainly by secretin)
        • Intercalated (aka intralobular) ducts drain the acini and secrete bicarb and water
        • Interlobular are the larger ducts between lobules and are stimulated by secretin and may also secrete bicarb (see Berne and Levy)
    • Function
      • Exocrine (98%)
        • During cephalic and gastric phases, small volume of juices are released with high concentration of enzyme
        • During intestinal stage, a large volume of juice is released with a lower concentration of enzymes
        • Enzymes are amylolases, lipases, and proteases (which need to be activated by trypsin)
      • Endocrine (2%)
        • Islets of Langerhans
        • Secrete hormones: insulin, glucagon, somatostatin, pancreatic polypeptide
        • Secretions have an effect on exocrine secretions: insulin stimulates, glucagon and somatostatin inhibits, somatostatin also inhibits insulin and glucagon, and inhibits G cells; PP inhibits exocrine secretion, GB contraction, and stimulates GI motility
  • Gall bladder
    • Structure
      • Storage of bile (30-50 mL)
      • Concentration of bile by reabsorption of water and electrolytes (Na+ and bicarb) by epithelial cells
    • Function
  • Bile
    • How is bile made?
      • Bile acids are made from cholesterol (hydroxylation reactions)
      • Conjugated form of bile acid is bile salt – this happens in hepatocytes
      • Bile salts are unconjugated in the intestine and predominantly reabsorbed in the terminal ileum
      • 1 L is released by the liver a day, but 10-20% of this is made in a day (the rest is recycled)
    • Components
      • Cholesterol forms a steoid nucleus and primary and secondary acids attach to this
      • Primary acids are cholic acid and chenodeoxycholic acid (this is a treatment for gall stones)
      • Secondary acids are created by bacteria in the intestine
      • Water
      • Phospholipids
      • Electrolytes
      • Pigments (bilirubin)
    • Function
      • Interact with fats to disrupt lipid aggregations and increase the surface area available for lipases to digest
  • Signs and symptoms
    • Doubled over in pain (severe abdominal pain)
    • Throwing up bile and retching
      • What is the difference?
    • Fast heart rate
    • Moderately tender abdomen with guarding
    • Why are bowel sounds decreased?
    • Define scaphoid
  • Labs
    • High alkaline phosphatase
    • High triglycerides
    • High amylase
    • High lipase
    • How do they measure pancreatic enzymes?
    • What are AST and ALT?
    • What is included in a stat lab?
  • Differentials
    • Food poisoning (signs and symptoms)
  • Pancreatitis
    • What is it?
      • Difference between acute and chronic
        • Chronic – permanent damage due to pancreatitis and eventually pancreatic insufficiency; classic triad is steatorrhea, DM, and calcifications (due to fat necrosis); primary symptom is pain
        • Acute – pancreatitis resolves with no permanent damage; this is immediately life-threatening; spectrum of disease from mild edematous to acute hemorrhagic
    • How does it disrupt normal digestion?
      • Causes
        • Early activation of enzymes
        • Sequestration of neutrophils (inflammation)
          • Cytokines and chemokines disrupt signaling pathway and exocytotic vesicles and lysosomes can fuse intracellulary, causing the release of hydrolase which activates the enzymes
        • Distant damage by enzymes
        • Certain medications, including thiazide diuretics, NSAIDs, opiates (constrict the sphincter of Oddi), estrogens, and others
        • Fat necrosis can exacerbate inflammation
        • 80% associated with biliary tract disease or alcoholism
          • Alcohol increases the permeability of pancreatic ducts so enzymes leak out; also precipitation of proteinaceous plugs clogs ducts and causes necrosis and inflammation; also causes fibrosis of the gland and leads to atrophy
  • Acute onset of symptoms
    • What does it mean that he is throwing up bile?
    • How does this trigger vomiting
  • Risk factors
  • Diagnostic criteria
    • Why do the increased enzymes indicate pancreatitis?
    • Cullen’s sign – periumbilical discoloration
    • Turner’s sign – discoloration of flanks
    • Ransom’s criteria
    • Amylase and lipase elevated
    • Alkaline phosphatase – elevated reflects biliary tract obstruction; chronic elevation leads to liver failure
    • CT scan if the patient does not improve in 24 hours to look for necrotic tissue
  • Social History
    • Smoking
    • Alcohol
    • How do they affect pancreatitis
  • Complications
    • 40% of patients who present with pancreatitis are deoxygenated due to the breakdown of pulmonary surfactants by phospholipase A
    • ARDS, hemorrhaging, pseudocyst formation, pancreatic abscess, systemic inflammatory response syndrome (SIRS)
  • Treatment
    • Analgesics for pain
    • Nasogastric suction
    • IV fluids and colloids to maintain volume, but no oral alimentation
    • Lifestyle changes: no alcohol or drugs, lower triglycerides
    • Surgery: cholecystectomy
    • ERCP (aimed at treatment of common duct)
• Gallstones
  • Types
    • Pigment stones
      • Calcifications of calcium and unconjugated bilirubin
    • Cholesterol stones
      • Supersaturation of bile causes precipitation of cholesterol, crystallization, aggregation, and formation of stones
  • Causes
    • Reduced motility of GB (can be enhanced by initial crystallization of cholesterol which is toxic to the gall bladder)
    • Mucus hyper-secretions trap crystals in GB and aid stone formation
    • Weight loss (increase in free fatty acids leads to increased bile production)
    • Increased hemolysis leads to increased hepatic secretion of bilirubin (for pigment stones)
  • How do gallstones contribute to pancreatitis
    • impaction of ampulla of Vater prevents pancreatic juices from moving through and if juices stay around long enough they become activated
    • blockage of other ducts (cystic ducts, common bile duct) can change the pressure in the extrahepatic ductal system
    • the smaller the stones, the more likely they are to cause pancreatitis because small stones are more likely travel into the duct system
  • Complications
    • Epyema (pus in pancreas)
    • Pancreatitis
    • Biliary colic
    • cholangitis
  • Treatment
    • Ursodeoxycholic acid (used prophylactically)
      • Increases concentration of this secondary bile acid to increase solubility
    • Endoscopy to remove stones
    • Cholecystectomy
• Ultrasound
  • Interpret/explain what we are looking at
• Medications
  • Hydrochlorothiazide
    • Is this contributing to his problems

Learning Objectives

1. Draw a diagram of the extrahepatic biliary system
2. Describe the synthesis, transport and storage of bile.
3. List the constituents of bile and describe the functions of these constituents.
4. Describe the mechanism of gall stone formation.
5. List the major etiologies of acute pancreatitis.
6. Describe the mechanisms by which acute pancreatitis develops.
7. Identify the mediators involved in the pathogenesis of the inflammatory process.
8. Describe the clinical appearance of a person with acute pancreatitis.
9. List blood tests that are markers for pancreatitis.