Conditions Effecting the Gastrointestinal System and Pharmacotherapy Part Two: Hepatobiliary System A&P & DX Lehne’s 11th Ch 83 (p.981) Lehne's 10th Ch 80 (p.994) Huether & McCance Ch 38 (p.896-906) Ch 37 Anatomy NURS 282/432 – Pathophysiology & Pharmacology II 1 Material is intellectual property, developed solely for use by respective course students. Not to be shared or posted to any platform without faculty consent and permission. Learning Objectives • Liver A&P • Cirrhosis • Hepatitis • Vaccinations for Hep A & B • Tx for Hep B & C • Post-Exposure prophylaxis • Gallbladder A&P • Cholelithiasis • Bile acids • Pancreas A&P • Pancreatitis • Pancreatic enzyme deficiency • Pancrealipase 2 Hepatobiliary System 3 Liver A&P 4 Case Study Martin is a 46YM PMSH: chronic alcoholism, IV drug use, unprotected sex with multiple partners, alcoholic cirrhosis & appendectomy requiring blood transfusions 30 years ago. He was admitted to the hospital from the outpatient clinic with abdominal swelling and confusion. He has unintentionally gained 15 lbs during the past four weeks. According to his wife: “My husband’s very confused and he has been acting strangely. This morning, he couldn’t answer my questions and seemed not to recognize me. I think that his stomach has been swelling up again, too. He is still drinking, at least a 6 pack of beer per day. And I recently found out he’s been seeing other women.” 5 Case Study cont’d • PE: • • • • • • Abd: Distended, firm, and slightly tender (+) prominent veins observed around umbilicus (+) hepatosplenomegaly Skin: slightly jaundiced Labs on admission: • Leukocytes 15,000 per microliter • Ammonia 250 ug/dL • Bilirubin 2.4 mg/dL • AST 107 IU/L • ALT 86 IU/L • Alk Phos 224 IU/L • Anti-HCV (+) • HCV RNA (+) • Albumin 2.7 g/dL (normal 3.5-5 g/dL) • Prothrombin time 16s (normal 10-13s) 6 1. Based on the labs, why has Martin’s cirrhosis shown a sudden & unexpected progression? 2. Identify what risk factors that may have contributed to Martin’s condition? 3. Explain the weight gain and the patho behind it 4. Which lab test strongly suggests Martin has developed hepatic encephalopathy? And what medication would you expect to administer? 7 Liver A&P • Locations • Upper right quadrant (URQ) of the abdomen, under the diaphragm • Structure • Large fibrous capsule that is divided by the falciform ligament into the right and left lobes • Ducts • Has right and left hepatic ducts and a common hepatic duct; drains bile • Functional Unit • Hepatocytes = liver cells; arranged in lobules, can regenerate, up to a point • Liver blood supply • Hepatic artery • Oxygenated blood from general circulation liver • 300 mL/min • Supplies 25% of blood • Hepatic Portal vein • Deoxygenated blood from stomach, pancreas, spleen, small & large intestines liver • 1,000 mL/min • Carries absorbed nutrients to the liver • Supplies approximately 75% of blood flow to the liver. • Hepatic vein • Empties into the inferior cava 8 Liver A&P cont. • Bile • Produced by hepatocytes • 600-1200 ml/day • Exits from liver via hepatic duct system • Gallbladder ~ storage • CBD Duodenum • When small intestine empty, bile backs up through ductal system GB • After consuming fat, GB ejects bile into ducts duodenum • Yellowish liquid, containing • H2O • Bile salts • Dissolves fats • Conjugated bilirubin by the liver • Cholesterol • Electrolytes ~ HCO3 • Neutralizes acidic gastric contents • Promotes actions of intestinal & pancreatic enzymes • Bile salts/acids • Formed from cholesterol • Emulsification of fats for digestion, facilitates absorption via small intestine • Fats • Fat-soluble vitamins ~ A, D, E, K 9 Primary Roles of the Liver Storage, excretion, metabolism, 1st pass, glucose regulation, detoxification • Stores blood (~ 450mL), Fe, fat-soluble vitamins (A, D, E,K), B12, glycogen. • Filtration/detox of blood • Phagocytic cells, Kupffer cells, remove bacteria • Degrades hemoglobin into globin and amino acids to be re-used in the synthesis of more hemoglobin • Metabolism of CHO, protein, fat, drugs • Synthesis of clotting factors (prothrombin) and albumin • Provides a source of heat since most metabolism takes place here • Conjugates bilirubin when RBC breakdown in blood • Ammonia (NH3), which is a by-product of protein metabolism urea. • Lipoprotein synthesis -LDL, HDL 10 Common Labs of Hepatic Function • Liver enzymes (Liver function tests, LFTs) • AST (aspartate aminotransferase) & ALT (alanine aminotransferase) • Involved in metabolic reactions, present mainly in liver cells • Released into circulation in liver disease, hepatocellular injury, necrosis • ALP (alkaline phosphatase) • Mainly in bile ducts • Increases with biliary obstruction • Markers of injury, elevated in liver disease, biliary obstruction, liver injury • In liver disease, liver cells release AST/ALT into the circulation • When biliary tree obstructed, bile duct cells release ALP • Alk phos = obstruction • ALT/AST may rise as well, but these 2 liver enzymes are elevated to greater extent in liver disease • Bilirubin • Component of bile • Breakdown of RBCs • Measure of liver’s ability to perform enzymatic/metabolic functions • Elevated in liver disease 11 Common Labs of Hepatic Function • Albumin • Serum protein synthesized by liver • Measure liver’s capacity for protein synthesis • Decreased in liver disease • Prothrombin time • Measures function of clotting cascade • Liver synthesizes most coagulation factors • Deficient clotting & elevated prothrombin time • Blood Urea Nitrogen (BUN) • Urea is made in the liver • Decreased BUN (ammonia not being converted to urea) • Ammonia • By-product of protein metabolism • Most is absorbed into portal circulation & converted to urea • Elevated in liver disease 12 13 DX of the Liver: Hepatitis 14 Hepatitis Overview • Inflammation of the liver • Can be acute or chronic • Treatable/Manageable with drugs, self-limiting • Causes & types • Infections, contagious • Often viral - 5 types • A, B, C, D, E, • A, B, C most common • Can recover in time but advanced age & comorbidities - ↑’d risk of liver failure, liver ca, cirrhosis • Non-viral, non-contagious • EtOH • Meds ~ APAP, antiseizure meds, ABX • Autoimmune DX • Usually recover • May develop liver failure, liver cancer, or cirrhosis • Both types can result in liver cell destruction, necrosis, autolysis, hyperplasia & scarring • Forms • Acute • Proceeds through phases – prodromal/pre-icteric, icteric, recovery • Chronic • Cont’d disease lasting > 6 months • Only types B, C, D - Primarily B & C • Severity & disease progression depends on extent of liver damage • Can live with it for years, but health deteriorates as liver function declines fibrosis, obstruction, cirrhosis, failure, liver ca 15 • Fulminant ~ liver failure Patho of Hepatitis Viral Hepatitis • Virus targets the hepatocytes • Hepatocyte damage • Virus attacks the hepatocytes • Cell-mediated immune responses to the virus • Cytotoxic cytokines and natural killer cells lyse infected hepatocytes • Injury inflammation • Pathologic lesions of chronic hepatitis: necrosis, scarring, Kupfer cell hyperplasia, phagocyte infiltration • Swelling and necrosis in the liver cells. • Swelling and severe inflammation of the liver can produce biliary stasis • Recovery possible from but can remain as carriers (people with previous chronic low-grade infection or no history of active disease). Carriers can still spread hepatitis even if they are asymptomatic. • Hepatitis double punches hepatocytes • Hepatocytes get attacked (virus) AND lysed (by body’s defense mechanisms). 16 Strains of Hepatitis Virus HAV HBV HCV HDV HEV Onset Abrupt Insidious Insidious Abrupt Abrupt Transmission Fecal-oral, Parenteral, Sexual Blood & body fluids Sexual, Perinatal Blood & body fluids, Sexual Blood & body fluids, Sexual Fecal-oral, Perinatal Sources Contaminated food, water, utensils, feces, unsanitary conditions (sex uncommon) IV drug use Transfusions Sex IV drug use Transfusions Sex Incubation 30 days 60-180 days 35-72 days Chronic No Yes, 5-10% Yes, 80% IV drug use Transfusions Sex 30-180 days, dependent on HBV for multiplication Yes, 5% as coinfection with Hep B Here is a trick to their mode of transmission: Contaminated food, water, utensils, feces Hepatitis A = Anal for mouth-fecal route 15-60 days Hepatitis B = Blood and body fluids Rare Carrier State No Yes Yes Yes, 80% as superinfection with chronic Hep B Yes Severity Mild Mild Severe Severe Severe in pregnancy Cancer Risk No Severe; may be prolonged or chronic Yes, 25-40% Yes, 25-30% Yes, no > than Hep B Unknown, unlikely Cirrhosis Risk No 40% 30% Yes, w/ superinfection Unknown, unlikely No Hepatitis C = Circulation, for blood and IV use Hepatitis A and E = Vowels and bowels for fecal route 17 Clinical Presentation of Hepatitis Stage Manifestations Explanation Preicteric (prodromal) Fatigue, malaise, anorexia, nausea, general muscle aching, fever, headache, a distaste for cigarettes, mild upper right quadrant discomfort Jaundice, light-colored stools, dark urine, pruritic skin, tender and enlarged liver, mild aching pain, clotting problems •Hepatocytes are infected • Chronic active hepatitis by the virus, causing pain • Persistence of clinical sx & liver inflammation after in liver (right upper acute stages of HBV, HBV/HDV coinfection, HCV quadrant) as well as liver inflammation and swelling. • LFTs remain elevated x 6 months Icteric Posticteric/Recovery Manifestations fade, may take several weeks (8-16 • HBsAg persists •Hepatocytes malfunction, • Chronic, active HBV or HCV predisposes to cirrhosis, altering bilirubin hepatocellular carcinoma metabolism, which causes an increase in serum • Constitutes carrier states bilirubin (jaundice) and dark urine. •Hepatocytes malfunction • Fulminant hepatitis and inflammation occurs, • Uncommon, rapidly progressing form blocking bile production, • Complications w/in 3 weeks causing light-colored • Liver failure stools. •Hepatocytes malfunction • Hepatic encephalopathy and decrease the • Death synthesis of blood clotting factors. •Liver inflammation and swelling leads to biliary obstruction. •Hepatocytes recover. 18 DX of Hepatitis Virus HAV Antibodies anti-HAV Immunity IgM anti-HAV Active disease IgG • Past infection • Vaccinated • Protections against repeated infection Antigens HBV anti-HBs Hepatitis B surface Antibody Immunity post vaccine or infection, provides protections anti-HBc • Hepatitis B core antibody • Past or current infection • Appears at onset of sx • NO PROTECTION • IgM • Ig M anti-HBc •Recent infection • <6 mos •Acute infection HBsAg Infected Surface antigen • https://www.hepb.org/prevention-anddiagnosis/diagnosis/hbv-blood-tests/ HCV anti-HCV Infection Not definitive of acute, chronic or resolved infection F/U w/ HCV RNA test (quantifies viral load) HDV anti-HDV Immunity Not easily detectable titers HEV anti-HEV Immunity HDAg Acute infection https://www.cdc.gov/hepatitis/hbv/pdfs/serologicc hartv8.pdf 19 Pharmacotherapy for Prevention of Hep A & Hep B 20 Prevention of Hepatitis • Hep A • Vaccination • • • • • • • All children @ 1yo Non-domestic traveling MSM IV abusers Long-term liver disease Frequent blood transfusions, hemophilia Exposure, living w/ someone who is hep A (+) • Hygiene & precautions • Hep C • No vaccine • Screening of blood donors • Hep D • No specific vaccine • Hep B vaccine, only if not already Hep B (+) • Hep E • Hep B • Vaccination • All infants @ birth • Older children not previously vaccinated • Adults @ risk • No vaccine • Ensure safe drinking water • Healthcare workers • Sexual activity • IV abusers 21 Pharmacotherapy for Chronic Hep B & Hep C 22 TX for Hepatitis B&C • • • • • Interferon Alpha Ribavirin Protease inhibitors NS5A inhibitors Nucleoside Analogs 23 Post-Exposure Pharmacotherapy for Hepatitis 24 Management of Post-Exposure to Hepatitis • Hep A • Immune globulin • Used to prevent after exposure • Concentrated Abs pooled from human plasma • HAV vaccine • Hep D • Immune globulin • Hep E • None • Hep B • HBIG • HBV vaccine • Hep C • None 25 DX of the Liver: Cirrhosis 26 Overview of Cirrhosis • Late-stage liver irreversible disease in which the liver becomes scarred • Liver and hepatocytes swell and fibrose, causing the liver to enlarge • As fibrosis spreads from infiltration of WBCs & inflamm process, the liver shrinks, and its functionality is affected. • When this happens, the lobules of the liver are covered with fibrous connective tissue and get filled with fat obstructed biliary channels & blood flow jaundice and portal htn • Causes • Alcohol abuse • Gallstones that obstruct bile flow in the gallbladder • Cystic fibrosis, which causes mucous plugs to form in the bile duct • Chronic hepatitis, particularly HCV • Long-term exposure to toxic material • Storage disorders, such as hemochromatosis, which is a buildup of iron in the body 27 Pathogenesis and Complications of Cirrhosis 28 Abdominal distension caused by gross ascites. Ascites • Fluid accumulation in peritoneal cavity • Portal HTN pushes fluid back abdominal cavity • Liver unable to produce sufficient albumin • Albumin needed for maintaining colloidal pressure & fluid balance 29 Clinical Manifestations of Cirrhosis 30 DX & Management of Cirrhosis • • • • • • • • • • • • Liver biopsy if clinical sx not evident ✓ liver enzymes, bilirubin, albumin, PT Rest Encourage cessation of etoh, drugs Avoid hepatoxic meds Implanted shunt for portal htn Fluid restrictions Low sodium diet Eliminating source of protein breakdown Paracentesis Diuretics Liver transplant 31 • • • • • Pharmacological Treatment Vitamins (esp Vitamin K) Corticosteroids GI prophylaxis Ferrous sulfate, folic acid Bile-acid sequestering agents – aid in bile excretion (colesevelam, cholestyramine, colestipol) • Non-selective Betablocker • TX for encephalopathy • Lactulose ~ rid ammonia via fecal excretion • Lowers the pH of colon, which inhibits the diffusion of ammonia from colon blood, thereby ↓ blood ammonia levels • Ammonia levels will decrease by 25-50% • Pt will have 2-3 soft BMs/day • May repeat doses hourly • Desired outcome: clearing of confusion & improved mental status • ABX ~ suppress intestinal flora to ↓ ammonia production 32 Gall bladder A&P 33 Gallbladder • Small, pear-shaped saclike organ • Under-surface of the liver • Functions • Bile Reservoir (bile digests fat) • Receives from liver via cystic duct • Bile concentration • Maintenance via H2O removal • Release of bile • Chyme in small intestine from eating • Triggers contraction of gallbladder • Bile duct system small intestine 34 DX of the Gallbladder: Cholelithiasis 35 Disorders of the Gallbladder • Gallstones • • • • Form when concentration of all components necessary for bile synthesis are not in equilibrium Cause obstruction of the biliary system and inflammation or infection of the gallbladder. Small, hard crystalline mass formed from bile pigments, cholesterol, and calcium salts Risks • • • • • • • • • Obesity (causes increased cholesterol secretion in bile) Middle age Female Oral contraceptive use/pregnancy • Hormonal changes of GB fxn & cholesterol levels • Increased cholesterol saturation Rapid weight loss/bariatric surg/sleeve Native American ancestry Genetic predisposition/fam hx Gallbladder, pancreas, or ileal disease High cholesterol intake (allows for supersaturation of bile) • Symptoms • Often asymptomatic or vague • Epigastric and right hypochondrium pain • Intolerance to fatty foods Disorders of the Gallbladder • Gallstones • Formed from impaired metabolism of cholesterol, bilirubin, and bile acids • 2 main components: cholesterol & pigment from bilirubin breakdown • Excess cholesterol comes from the 5Fs scenario • Excessive stasis in gallbladder • Type depends on chemical composition • Cholesterol • Formed from bile supersaturated with cholesterol produced by the liver • Most common • Pigmented brown, yellow, green, or yellowish-green in color • Occurs secondary to hemolysis (SCA) • Bacterial metabolism in biliary infection • If gallstones are in the gallbladder, the condition is known as cholelithiasis. • If gallstones are in the cystic duct, the condition is known as cholecystitis (inflammation of the gallbladder and cystic duct), and it can be acute or chronic. • If gallstones are in the common bile duct, the condition is known as choledocholithiasis. Causes of Gallstones • High concentration of cholesterol in the bile (most common): • Liver secretes high levels of cholesterol. • Bile cannot dissolve the excessive level of cholesterol. • Excessive cholesterol forms a mass or calculi. • High concentration of bilirubin: • Bilirubin is produced by the breakdown of red blood cells by the liver. • Conditions such as liver cirrhosis, blood disorders, and inflammation cause excess bilirubin production. • Excessive bilirubin contributes to gallstone formation. • Gallbladder does not empty completely: • Gallbladder empties infrequently or incompletely. • Stagnant bile becomes more concentrated. • Concentrated bile contributes to formation of gallstones. 38 Clinical Presentation of Cholelithiasis • Small calculi • Often asymptomatic • Excreted into bile • Larger calculi ~ obstruct bile flow manifestations • Biliary colic • Abdominal cramping & pain • Lodged gallstones in duct during GB ctx • Worsens after fatty meals • Abdominal pain • Especially right upper & middle upper quadrants • May radiate to back or right shoulder • Abdominal distension • Nausea and vomiting • Jaundice • Stone in CBD, impaired excretion of bilirubin • Clay-colored stools • obstructed flow of bile into the duodenum • Fever • inflammation of organ • Leukocytosis • inflammation and infection 39 DX & Management of Cholelithiasis • DX procedures • PMH • PE • LFTs • Pancreatic enzymes • Diagnostics • MRCP, ERCP • Goals of TX • Removal of calculi • Restoration of bile flow • PX reoccurrence • TX • Low-fat diet, increase fiber • Cholecystectomy • Laparoscopic removal of calculi or gallbladder • Choledochostomy • Surgical-induced opening for drainage • Meds • ABX, if infection (+) • Ursodiol (actigall) – GB stone dissolution and prevention • Decreases cholesterol content of bile/bile stones by suppressing chol synthesis & secretion from liver • Inhibits intestinal absorption of cholesterol 40 Pancreas A&P 41 Pancreas A&P • Exocrine functions • Enzymes, secreted into duodenum to facilitate food digestion • • • • • • Amylase – digestion of starch & glycogen Lipases – digestion of fats Proteases – digestion of proteins Trypsin Chymotrypsin Elastase • Electrolytes • bicarbonate ions – Neutralizes acid to protect enzymes from stomach acid & pepsin • The resulting pH elevation inactivates pepsin • Duct system • carries these substances to the duodenum to join the chyme • Endocrine functions • Hormone production • Insulin, glucagon • Maintenance of homeostasis • Blood glucose • H2O • Carries enzymes necessary for digestion 42 Pancreatitis 43 Pancreatitis Acute • Mild to life-threatening inflammation •Reversible •*Alcohol Abuse (chronic) •Stimulates increased secretion of pancreatic enzymes •Contracts the sphincter of Oddi, blocking flow •Severe Pain •*Gallstones and Biliary Tract Disease •Obstructs bile flow and pancreatic enzymes •Causes bile to reflux into the pancreatic ducts • Viral infections • Meds • Corticosteroids • Thiazide diuretics • Oral contraceptives • Sulfonamides • Non-steroidal anti-inflammatory drugs (NSAIDs) • Diagnostic complications • Hypertriglyceridemia • Renal failure •necrosis, abscess, gangrene, hemorrhage Chronic •Irreversible •Progressive, irreversible destruction Main risk factor is excessive alcohol consumption. •Scar tissue and fibrosis form in the organ as the pancreas is progressively destroyed. •This leads to strictures in the ducts and organ failure. Organ failure leads to a lack of pancreatic enzymes and fat malabsorption. •No alcohol allowed, especially with chronic pancreatitis •Scar tissue forms, irreversible, cysts form, walled off areas of necrosis, pancreatic juice, debris, blood •Other causes: •Gallstones •Tumor •Pseudocysts •Walled off collections of pancreatic secretions •Trauma •Cystic fibrosis 44 Pathophysiology of Acute Pancreatitis 45 Patho of Pancreatitis cont. • Prognosis for acute pancreatitis • Medical emergency • 15% mortality rate ~ ↑ with advancing age & comorbidity • Acute complications • Shock • Enzymes leak into general circulation • Triggered release of chemicals, immune mediators • inflammatory response, hemorrhage, vasodilation, fluid shifts from the vascular to the peritoneal cavity, and increased capillary permeability. • Infection • • • • Enzymes peritoneal cavity & destroys tissue Vulnerability to bacteria & infection Serious – require intensive tx Translocation of intestinal bacteria bloodstream, pneumonia • Malnutrition • ↓ pancreatic enzyme production • Pseudocyst, abscess • Accumulation of pancreatic fluids & necrotic debris • Rupturing hemorrhaging, infection, peritonitis • Chronic complications • DM • Damage to insulin-producing cells • Renal failure • Shock & RAAS activation • Decreased renal perfusion • Malnutrition • ↓ pancreatic enzyme production • Pancreatic cancer • Cellular mutations • Long-standing inflammation 46 Clinical Presentation of Pancreatitis • Acute manifestations • Sx vary and may be precipitated by a large meal or consuming a large quantity of alcohol. • Sudden & severe onset • Upper abdominal pain • Radiates to back • Worsens after eating • Minor relief by leaning forward or pulling the knees toward the chest • The pain radiates to the back and happens because of: • Inflammation • Pancreatic distention • Peritoneal irritation • Biliary tract obstruction • N/V • Mild jaundice • Low-grade fever • Blood pressure, pulse, RR △ • Chronic manifestations • Hyperglycemia • Insidious onset • Upper abdominal pain • • • • • • heavy, gnawing, or burning and cramp-like. Indigestion Unintentional wt loss Steatorrhea ~ oily, fatty, odorous Constipation Flatulence • Increased or decreased • Hyperglycemia • Transient 47 DX of Pancreatitis • PMH • PE • Serum amylase & lipase • Both will be elevated • Lipase is diagnostic • ALP – from bile ducts • Serum calcium • Hypocalcemia • malabsorption • • • • • Liver enzymes panel Serum bilirubin ABGs Stool analysis ~ lipid & trypsin Abdominal: X-ray, CT, MRI, ultrasound • Endoscopic retrograde cholangiopancreatography ERCP • CBC 48 Management of Pancreatitis • ICU monitoring • VS • Temp, HR, BP, RR • Intake & output • Strict measurement QH • Resting for the pancreas • Fasting • TPN clear liquids low-fat diet • Pancreatic enzyme supplements upon diet resuming • Hydration maintenance • IVF • Management of N/V • NGT w/ intermittent suction if persistent • Meds • Antiemetics, if N/V (+) • Antacids & acid-reducing agents • Raise pH • Decrease stimulation of pancreas by secretin • protect enzymes from inactivation • Anticholinergic agents • ↓ vagal stimulation, GI motility • Inhibit pancreatic enzyme secretion • Narcotics & analgesics • ABX, if infection (+) • Insulin, for hyperglycemia secondary to • Damage • TPN 49 Pancreatic Enzyme Deficiency & Pharmacotherapy 50 Approach to Deficiency of Pancreatic Enzymes • Pancrelipase (Creon) • ADEs • Mixture • Abdominal discomfort, • Lipases, amylases, proteases flatulence, • MOA/Use • HA, cough • Increased digestion of fats, carbs, & proteins • High-doses in GI tract • Diarrhea, nausea, • Contains pancreatic enzymatic activity cramping • Chronic pancreatitis, pancreatectomy, CF • Allergic reactions, occasionally • Delayed Release capsules • Efficacy • Dissolve in duodenum & upper jejunum • Measured with 24h fat excretion via stool • Taken with every meal & snack • Do not crush, chew, or retain in mouth – d/t risk • Improved nutritional status of irritating oral mucosa 51 Question 1 An analysis of most gallstones would reveal a high concentration of: A. phosphate B. bilirubin C. urate D. cholesterol 52 Question 2 A 31-year-old female is diagnosed with acute mild pancreatitis. Which of the following will be part of the initial treatment plan? (Select all that apply.) A. Narcotic analgesics B. Restriction of food intake C. Nasogastric suctioning D. Steroid therapy E. IV fluids 53 Question 3 • Tissue damage in pancreatitis is initially triggered by: A. insulin toxicity B. autoimmune destruction of the pancreas. C. backup of pancreatic enzymes. D. hydrochloric acid reflux into the pancreatic duct. 54
