Hepato & Panc Patho 10.21.21 Professor's Notes PDF

**I. [Overview of Major Diseases of the Hepatobiliary System & Pancreas]** ***A. [Categories of Pathology]*** - Liver Failure - Sequelae of Liver Disease - Hepatitis - Cirrhosis - Miscellaneous Liver Disease - Hepatic Tumors - Cholelithiasis - Pancreatic Pathology ***B. [Ba...

**I. [Overview of Major Diseases of the Hepatobiliary System & Pancreas]** ***A. [Categories of Pathology]*** - Liver Failure - Sequelae of Liver Disease - Hepatitis - Cirrhosis - Miscellaneous Liver Disease - Hepatic Tumors - Cholelithiasis - Pancreatic Pathology ***B. [Basics of Hepatobiliary and Pancreatic Pathology]*** 1\. ***[The liver is connected to the digestive tract via the portal veins and the bile ducts]*** - The portal circulation is separated from the systemic circulation - If blood flow through the liver is obstructed, the increased pressure will open normally minute connections between the portal and systemic circulations - This allow blood to bypass the liver - This results in toxic metabolites to reach systemic circulation - This also prevents the systemic circulation from acquiring needed substances made in the liver - This increased flow from portal to systemic circulations is called portal hypertension 2\. ***[Bilirubin released from hemoglobin is taken up, processed, and excreted by the liver]*** 3\. ***[All serum proteins, except immunoglobulins, are made in the liver]*** - These serum proteins are the major factor regulating plasma oncotic pressure - Lack of these proteins from liver disease induces edema formation - Lack of clotting proteins made by the liver results in bleeding problems 4\. ***[Damage to the liver can be identified by enzymes released into the blood]*** - Aspartate transaminase (AST) and alanine transaminase (ALT) can be measured to diagnose or monitor liver dysfunction 5\. ***[The liver is the body's metabolic factory]*** - Functions of the liver include the removal from circulation, metabolism, detoxification, and modification of drugs, hormones, cytokines, and other metabolites 6\. ***[Infections of the liver may be part of a generalized infection or may be due to hepatotropic pathogens]*** - EX: hepatitis viruses A, B, C, D, E 7\. ***[Liver cells are facultatively mitotic; i.e., they may regenerate if portions]*** ***[of the liver are injured irreparably]*** 8\. ***[The most common tumors found in the liver are metastatic]*** 9\. ***[Bile salts may precipitate, forming stones]*** 10\. ***[Pancreatic enzymes are secreted in the inactive, proenzyme form. They are activated in the intestinal lumen]*** 11\. ***[Damage to the pancreas may be identified by enzymes released into the blood]*** - Amylase is elevated with pancreatic injury 12\. ***[The pancreas has endocrine and exocrine functions]*** - Endocrine -- main hormone is insulin, also glucagon and somatostatin - Exocrine -- 20 digestive enzymes, plus bicarbonate are excreted by the exocrine portion of the pancreas **II. [Liver Failure]** ***A. [Because it receives direct venous drainage from the stomach and ]*** + ***[intestines, the liver is subject to substantial threat]*** - Threats may be due to... - Absorbed microorganisms, their products - Toxic chemicals or drugs absorbed from the intestines - Defenses of the liver include.. - 1\) Enormous reserve capacity - The liver normally utilizes only \~10% of its cells to meet daily requirements - 2\) Highly developed regenerative capacity - The liver can replace large amounts of injured or lost cells - These advantages may be offset by the fact that significant quantity of liver tissue may be destroyed by the time clinically significant signs and symptoms occur - Many liver diseases involve diffuse damage - Result is often chronic or severe disease - Longstanding liver disease may overwhelm the liver's reserve and + regenerative capacities - Etiology & Pathogenesis of Liver Disease is caused by... - Toxins -- alcohol & drug related - Infections -- viruses, bacteria, parasites - Disturbances of vascularity or of bile excretion - Tumors -- primary or metastatic - These causes result in 4 main clinical entities - Acute hepatitis - Chronic hepatitis - Fibrosis - Cirrhosis - Acute liver failure develops when major damage to hepatocytes occurs - Causes - Following diffuse damage, e.g. extensive hepatonecrosis - Following systemic shock, multiorgan involvement, such as with ARDS - Following chronic liver disease reaching a critical threshold - Acute liver failure results in jaundice, coma and bleeding tendencies - 80% mortality **III. [Sequelae of Liver Disease ]** The effects of liver disease may produce include jaundice, malabsorption (covered in GI lectures), and disordered hepatic metabolism ***A. [Jaundice is caused by abnormalities of bilirubin metabolism]*** + - Bilirubin is the breakdown product of hemoglobin -- it occurs in several steps - 1\) RBC's which are aged or damaged are phagocytosed in liver & spleen - 2)Hemoglobin is degraded in the liver Kupffer cells and in the spleen - 3\) Hemoglobin is broken down by loss of iron from heme, becomes bilirubin - 4\) Bilirubin is released into the blood - 5\) It is bound to albumin - 6\) This unconjugated, non-water soluble bilirubin is conjugated in the liver - 7\) Water soluble, conjugated bilirubin becomes a component of bile, excreted into the intestines, aiding in digestion of fats - 8\) Excess bilirubin is reabsorbed in the intestines - 9\) This bilirubin is recycled to the liver to become a part of bile or excreted in urine - *Enteroheptatic circulation* of bilirubin - *Hyperbilirubinemia* is the condition in which bilirubin levels are elevated - Normal levels = 0.3-1 mg/dl total - Classifications of hyperbilirubinemia are biochemical - Conjugated - Unconjugated - Mixed conjugated & unconjugated - *Jaundice*, the yellow coloration of the skin and sclera, occurs when - Bilirubin \> 3mg/dl - *Icterus* is an older synonym for jaundice - Jaundice serves as an observable, clinical marker for liver dysfunction from a number of etiologies - Jaundice may be classified as - Prehepatic or hemolytic jaundice \-- is unconjugated hyperbili - Hepatic jaundice -- is mixed, conjugated & unconjugated hyperbili - Posthepatic or obstructive jaundice -- conjugated hyperbili Prehepatic jaundice -- unconjugated hyperbilirubinemia + ======================================================== - Excessive bilirubin formation is usually due to erythrocyte lysis - Called hemolytic jaundice - Rupture of RBC's is followed by the sequence I mentioned above - Etiology \-- Hemolysis may result from... - Abnormal hemoglobins -- sickle, thalassemia, etc - Immune-mediated -- blood mismatches - Drug induced hemolysis - Hypersplenism - Resolution of large bruises -- especially in newborns - Genetic lack of conjugating enzymes - i.e., *Gilbert's syndrome* - Autosomal dominant defect in bilirubin uptake - Mild jaundice, not clinically a problem - Regardless of the etiology, hemolysis overwhelms the liver's capacity to conjugate and excrete bilirubin - Bilirubin levels in the blood rise, tissue deposit followsjaundice Hepatocellular jaundice -- mixed hyperbilirubinemia + ===================================================== - Failure of the liver to take up, conjugate, and / or excrete bilirubin is the most common type of jaundice clinically seen - Failure to conjugate and excrete are more common than failure of uptake - Hyperbilirubinemia may be predominantly unconjugated or conjugated, depending on the pathology - Etiology -- variety of diseases - Damage to liver cells by infection, tumors, drugs or chemicals - Most commonly seen with viral hepatitis - Other causes drugs, alcoholic cirrhosis, metabolic disease - Newborn infants -- neonatal jaundice - Due to immaturity of liver, more easily overwhelmed by normal bilirubin load in first 2-3 weeks of life in addition to sluggish bile flow (functional obstruction) - Predominantly unconjugated **Post-hepatic, Obstructive jaundice -- conjugated hyperbilirubinemia** + - The third mechanism that can cause jaundice is obstruction of the bile duct system - Disturbance in the excretion of bile that has already been conjugated by the liver - Normal draining of bile into the duodenum is substantially reduced or completed blocked = *cholestasis* - Bilirubin and bile salts accumulate, first in the liver, then spill into the blood - Bile salts cause pruritus = itching - Bile flow to the intestines is reduced - Decreased color = *acholic* (tan colored) stools - Steatorrhea and its consequences occur - Etiology - May be due to intrahepatic or extrahepatic abnormalities - Intrahepatic causes - Viral or other infections, drugs damage the liver - Swelling follows - Fine intrahepatic ducts are compressed - Congenital biliary atresia - Deficient quantity of bile ducts, inadequate to drain liver - Extrahepatic causes - Usually obstruction of common bile duct due to... - Externally compressing tumor or inflammation of bile ducts, pancreas, duodenum - Gallstones - ***[Clinical Picture]*** - Bilirubin, whether conjugated or unconjugated, binds to tissues, staining them yellow - Early elevation of bilirubin can be detected in the sclera first - Later skin and mucous membranes yellow - Pruritus due to bile salts in the bloodtissues - Unconjugated, also called *indirect bilirubin*, is albumin bound and + cannot cross the blood-brain barrier or appear in urine - Conjugated or *direct bilirubin*, is water-soluble and hence, crosses into the brain and urine - This crossing into the brain occurs in newborns with high conjugated bilirubin levels, may damage developing brain - Not a significant problem in adults---barrier more resistant - Conjugated bilirubin is passed in urine, appears brown ***B. [When hepatocytes are damaged, their numerous metabolic functions may be disrupted, causing disordered hepatic metabolism]*** + Damage may affect a few cells or be diffuse =========================================== - Systemic effects occur when significant numbers of hepatocytes are injured - EX: Chronic depression of hepatic metabolism causes generalized weakness and weight loss - Specific effects occur when a particular hepatic function is affected - EX: depression of protein synthesis causes hypoalbuminemia, results in edema - As fluid accumulates in the tissue spaces, finger pressure on the skin creates a pit -- called *pitting edema* - Signs and symptoms - Series of neurologic abnormalities due to failure liver, causing altered protein metabolism - Amino acids by products accumulate, cannot be cleared by liver - AA accumulate as ammonia - Ammonia has toxic CNS effects - These by products produce disruptive neurotransmitter effects - Other effects are not clearly understood - ***[Clinical Picture]*** - Mild -- transient sluggishness or lethargy - Severe -- disorientation, coma, tremor Injury that prevents hepatic lipoprotein synthesis leads to altered lipid + metabolism - This injury disrupts the normal exchange of fat and lipoprotein between the liver and stored fat in adipose tissue - Fat accumulates in the liver cells - Fatty liver is reversible, but if the insult is prolonged or severe, the hepatocytes may not survive Other effects of altered hepatic metabolism + ============================================= - Depression of detoxification function - Drugs are not metabolized efficiently, levels build up in the blood - The side effects of a given drug are then exaggerated - Therapeutic drug doses must be adjusted - Because less is inactivated by the damaged liver, greater effects are produced with smaller than normal doses - Hormones are not regulated - Higher than normal hormone levels may - EX: male alcoholics, liver damage interferes with inactivation of small amount of estrogen normally produced by the adrenals - Estrogen levels accumulate, causing *feminization*, - Gynecomastia (breast enlargement) - Testicular atrophy **Renal failure may follow hepatic failure** + - *Hepatorenal syndrome* usually late in course of hepatic disease - Poor prognostic sign when kidneys become involved - Pathogenesis - Thought that circulating vasoconstrictors, normally destroyed in the liver, damage the kidneys by interfering with adequate blood flow - This is functional impairment, not structural - Normal function can be restored if blood flow re-established - If not, renal failure is progressive Now that we have looked at typical sequelae of liver damage as our foundation, we can now consider the principal patterns of pathogenesis that produce them **IV. [Hepatitis]** ***A. [General]*** - - May be acute or chronic - Etiology - Viral infections - Toxic drug reactions - Alcohol abuse - Autoimmune disorders - Pathology -- regardless of etiology, the pathology on biopsy is similar + - Liver is swollen, usually darker due to retained bile - Histology -- these changes may be mild, moderate, or severe - Hepatocellular changes - Cytoplasmic only -- reversible - Cytoplasmic + nuclear \-- irreversible - Inflammation - No PMN's - Macrophages and Kupffer cells proliferate to clear necrotic cells - Regeneration of hepatocytes - Hepatocytes are facultatively mitotic - Under stressful conditions, they may regenerate - :-, necrotic liver cells replaced - Various hepatic functions will be sufficiently depressed to produce abnormal lab diagnostic tests - Outcomes - Most recover, but small percentage have progressive, massive hepatic necrosis - Called *fulminant hepatitis* - Hepatic encephalopathy occurs - Death may follow ***B. [Acute viral hepatitis is the most common liver disease in the world]*** + - Etiology \-- Most are caused by one of several *hepatotrophic viruses* - Hepatitis virus **A**, **B**, **C**, **D**, **E** - Old terms were A, B, and the others were grouped as non-A, non-B until the specific pathogen was identified - Hepatitis may occur as a part of systemic disease also, not due to a hepatotrophic virus - These so-called non-specific forms of hepatitis best illustrated by Epstein-Barr virus which causes infectious mononucleosis with hepatitis as a part of the clinical picture - May also be a part of illnesses such as measles, chicken pox - Pathogenesis - [All except HBV are RNA viruses] - Each virus has a specific pattern for... - Duration of viremia - Mode of transmission - Duration of incubation - Clinical symptoms - Chronic hepatitis caused by... - HBV, HCV, HDV - Neoplastic transformation occurs in... - HBV and HCV - Vaccines are used for - HAV and HBV Clinical and Biochemical Features of Acute Hepatitis + ====================================================== - Symptoms - May vary in timing, intensity and duration, but generally similar symptoms in all forms of hepatitis - Nausea, anorexia, fever, malaise, +/- weight loss - Signs - Enlarged liver, tender - Jaundice \~1 week after constitutional symptoms - Signs and symptoms generally recover over 3-8 weeks - Biochemical tests - Bilirubin elevation -- mostly conjugated (direct) - Elevated ALT, AST (liver enzymes) - Reflecting liver cell necrosis, release of cell enzymes - Levels fall with general clinical improvement ***C. [Acute hepatitis A is usually mild]*** - Etiology & Pathogenesis - Due to infection with hepatotrophic **hepatitis A virus (RNA virus)** - Once viruses replicate in the liver, they are passed into the intestines, subsequently into the feces - Hence, [transmission] is by fecal-oral route - i.e., contaminated food and drinks from improper hygiene - Shellfish may be contaminated by sewage - Often involved in epidemic outbreaks in closed populations - i.e., military bases, college campuses, ships, etc - Lay term is *infectious hepatitis* (all viral hepatitis is infectious) - ***[Clinical Picture]*** - Mild disease, may even be asymptomatic follows a [short incubation] [period] - Illness confers lifelong immunity from further infection - Prognosis: favorable recovery ***D. [Hepatitis B infection is a more serious infection, generally, than hepatitis A]*** - Etiology & Pathogenesis - Infection with hepatitis B virus (only DNA hepatotrophic virus) - [Transmission ] - Blood-borne - i.e., by blood or blood products - Blood now screened, so transmission via blood transfusions is uncommon - Spread by shared needles of addicts - Spread vertically from mother to child - i.e., from mother's blood to fetus via placenta - Also spread by body fluids - Semen, saliva - And by close physical contact, inoculating through breaks in the skin and mucous membranes - :-, can be sexually transmitted - Since blood-borne, also known as *serum hepatitis* Clinical Patterns ----------------- - HBV infections cause several patterns of illness - Acute hepatitis \-- self-limited, full recovery---range from mild-moderate - Fulminant hepatitis -- rare, but results in massive liver necrosis - Chronic hepatitis -- patient continue to shed viruses and is infectious; may last for many months to years \-- HBV & HCV - *Chronic persistent hepatitis* - Long period of symptoms, but limited hepatic necrosis - Symptoms may be mild or clinically asymptomatic - *Chronic active hepatitis* - More serious as liver necrosis progresses over long period of time - Scarring and cirrhosis evolve - At high risk for hepatocellular carcinoma - Therefore, chronic hepatitis is graded according to the degree of liver cell necrosis - Lab findings - Intact HBV virus is also called a *Dane particle* - Consists of coat -- **HBsAg** (hepatitis B surface antigen) - Core -- **HBcAg** (hepatitis B core antigen) - e antigen -- **HBeAg** (hepatitis B e antigen - HBcAg is not detectable in the blood, but [antibodies] to this antigen appear in serum---i.e., "anti-HbcAg---as evidence of its presence - HBsAg and HBeAg [antigens] are detectable in the blood at various stages of the viremia - Presence of these antigens in the blood implies active viral infection and :-, infectivity - If they fail to clear over time or if anti-HbcAg persists, chronic infectivity results ***E. [A subset of HBV sufferers become carriers]*** - Some HBV infected patients are unable to completely eliminate HBV particles - Due to inability to mount an adequate immune response - Infection persists - Some patients still have ongoing minimal signs of liver dysfunction - Some patients have no liver abnormality - Carrier state presents a constant hazard - Asymptomatic patients remain actively infected with virus - Capable of spreading infection, sometimes for years - Identifying carriers is somewhat difficult since some patients may have had a milder illness initially which went clinically undiagnosed as HBV - Without the knowledge of their being infected, the person is unaware he/she is infectious - Carrier states... - Do not exist for hepatitis A - Do exist for hepatitis B & C - High among homosexuals and intravenous drug users ***F. [NANB (non-A, non-B) viruses include C, D, E]*** ### Hepatitis C + ============= - First of the NANB viruses to be identified - Etiology - Accounted for most of post-transfusion hepatitis before screening developed specifically for HCV - May also be involved in sporadic epidemics, non-transfusion related - May be sexually transmitted - Pathology & Prognosis - Although initial clinical illness may be milder than HBV, it progresses to chronic hepatitis in 50% of those infected - At risk for... - Many of these chronic hepatitis patients may develop cirrhosis - Incidence of hepatocellular carcinoma is higher than other forms of hepatitis Hepatitis D + ============= - Hepatitis D cannot infect alone, but only in concert with HBV - Hepatitis D is a viroid, an incomplete RNA virus that cannot infect on its own - Requires HBV, i.e., HDV infects in concert with HBV - Co-infection occurs simultaneously with HBV - Superinfection occurs superimposed on an established HBV infection **Hepatitis E** + - Not common in US ###### FUN ***G. [Drug and chemical hepatitis are due to hepatoxic agents]*** - Some drugs or chemical exposures are known to cause risk of liver dysfunction and induce a chemical hepatitis - Some drugs cause an idiosyncratic reaction---i.e., an unexpected and unpredictable hepatoxicity - Some drugs only induced problems at higher doses (i.e., dose dependent hepatitis) or in combination with other agents, such as alcohol - Most of the hepatitis caused by drugs will resolve when the causative agent is removed **V. [Cirrhosis of the Liver]** ***A. [Cirrhosis of the liver is a nonspecific, end-stage toward which numerous pathogenic sequences converge]*** - Definition - Chronic destruction of liver parenchyma (structure), fibrosis, and resultant scarring that progressively impair hepatic function - Progressive, no cure, irreversible - Slowly progressive destruction of hepatocytes occurs unnoticed until it reaches the point at which adequate function can't be sustained - Etiology - Any cause of liver necrosis which is long-term - Infection, drug, chemical, alcohol, extrahepatic obstruction - Genetic metabolic diseases, autoimmune - Insult induced necrosis overwhelm the liver's regenerative capacity - Pathology & Pathogenesis - Diffusely distributed areas of fibrosis between areas of hepatocytes that retain regenerative capabilities - Hence, the term *nodular* - The condition of nodularity and fibrosis is called cirrhosis - Scarring causes contraction of the normal volume of the liver - Cirrhotic livers are, :-, smaller than normal livers - This pattern takes 10-20 of chronic insult to induce mature changes - Cirrhosis may result from - Primary liver insults - Obstruction of the biliary tree inducing secondary cirrhosis - Chronic bile stasis causes leakage of bile into liver due to backup pressure - This destroys liver cells - Histology - Normal structure is destroyed - Nodules of regenerating cells separated by bands of fibrous tissue - Accumulation of fat in hepatocytes - ***[Clinical Picture]*** - Variable reflecting differing degrees of functional loss at given point in progression - Typically involves - Jaundice - Wasting - Coagulation disorders - Plasma protein deficiencies, especially hypoalbuminemia - When threshold of liver deficiencies reached, continued necrosis depletes reserves and liver failure ensues rapidly - Other clinical symptoms - Cardiopulmonary failure/pulmonary edema - Renal failure due to hypoperfusion - Endocrinopathies due to altered liver metabolism #### Cirrhosis has principal consequences seen clinically---liver failure and portal hypertension ***B. [Increased pressure in the portal vein is the result of restricted blood flow through the cirrhotic liver]*** + - Definition - The hepatic vein drains the spleen, stomach, intestines and pancreas, channeling the blood through the liver for detoxification - When the liver scars, it restricts the passage of blood flow through the liver, raising the pressure in the portal venous system - This is called *portal hypertension* - ##### Major consequences of portal hypertension + Hepatic shunting ================ - If blood flow through the liver is reduced, functional hepatocytes have reduced access to blood - Impairs their detoxification activities - Toxins concentrate in the blood, inducing systemic damage - Most serious accumulation is ammonia - Normally incorporated into urea in the liver, then excreted as urea in the urine - Instead ammonia builds up in the serum, causing hepatic encephalopathy - Ongoing hepatic necrosis is exacerbated by the insufficient blood flow Pressure Effects ================ - Increased pressure in the portal system causes a backup pressure that diverts blood to a lower resistance collateral circulation - Links the portal vessels to other venous channels - Normally, these vessels are small, but can enlarge to carry increased blood flow when additional volume is shunted through them - This blood is delivered to the inferior vena cava - Allows blood to by-pass high resistance liver circulation - Location of these collateral vessels - Abdominal wall - Converge at the umbilical vein - Dilate, visible on surface of abdomen - Called caput medusae - Anorectal - Engorgement of the anorectal veins by increased shunting causes portal hypertension hemorrhoids - Esophagus - Engorgement of the thin-walled veins of the lower esophagus result in esophageal varices - Subject to rupture and bleeding - Hematemesis may be massive---remember clotting dysfunction is a part of cirrhosis Splenomegaly ============ - Portal hypertension also causes enlargement of the spleen - Backup pressure congests splenic veins - Spleen can enlarge up to seven times normal weight - Secondary hypersplenism develops - Anemia, leukopenia, thrombocytopenia **Ascites** - Etiology - Portal hypertension -- transudation of plasma due to pressure - Serosal surface of intestines, liver - Hypoalbuminemia - Low serum protein cause reduced vascular oncotic pressure - Hypovolemia - As serum leaks out, low blood volume triggers aldosterone - This causes water and sodium retention - This adds to ascites fluid - Complications - Ascites may become infected, resulting in peritonitis - Ascites may be of sufficient magnitude to increase abdominal pressure - This may result in diaphragmatic pressure and respiratory compromise ***C. [About ½ of all cirrhosis involves alcohol abuse]*** + - Definition - High alcohol intake == one pint of spirits (brandy, gin, vodka, rum) per day - Alcohol abuse may cause fatty liver, acute hepatitis or cirrhosis - Etiology & Pathogenesis - Alcohol excess causes production of high levels of metabolites that have damaging effects on hepatocytes - Asymptomatic fatty degeneration precedes irreversible alcoholic liver damage - Liver may initially enlarge due to excess fat accumulation - As scarring develops, liver decreases in size - Slow decline in liver function occurs, exacerbated during "binges" - Binges may induce acute alcoholic hepatitis - Prognosis - Death usually occurs within 5 years of liver failure **VI. [Miscellaneous Liver Diseases]** Genetic Metabolic Diseases ========================== - Gilbert's (discussed previously) - Autosomal dominant disorder - Lack of conjugating enzymes for bilirubin - Wilson's Disease - Autosomal recessive disorder of copper metabolism - Copper accumulates in plasma, deposited in tissues - Deposition in liver causes cirrhosis - Alpha~1~-antitrypsin Deficiency - Autosomal recessive - Causes liver disease and emphysema **Other Diseases** - Primary Biliary Cirrhosis - Idiopathic (unknown etiology) - Progressive destruction of intrahepatic bile ducts - May be immune-mediated - Primary Sclerosing Cholangitis - Idiopathic - Destruction of intra and extrahepatic bile ducts - May be immune-mediated - Often associated with Crohn's and UC **VII. [Hepatic Tumors]** - Vast majority of tumors are metastatic - Primary is usually in colon, breast, stomach, or lung - Tumor "emboli" establish multiple foci in the liver - The most significant primary tumor is hepatocellular carcinoma or hepatoma - Most originate in cirrhotic livers - Associated with HBV, HCV infection - Childhood primary tumor is hepatoblastoma - ***[Clinical Picture]*** - Signs of liver dysfunction - Jaundice, ascites, hepatosplenomegaly - Liver pain - Diagnosis - CT, MRI - Biopsy - Prognosis - When liver metastases present from primary site, most die within a few months **VIII. [Cholelithiasis]** ***A. [Cholelithiasis (gallstones) are the most common cause of disease]*** + ***[affecting the biliary tree]*** - Stones usually are formed inside the gallbladder, hence called gallstones - Common occurrence, at autopsy \~15-20% of adults - Stones formed from chemicals in bile that precipitate - Stones called gallstones or *choleliths* - Process of stone formation called *cholelithiasis* - Etiology & Pathogenesis - Risk factors -- the Four F's---I learned Five F's + - Female, fat, forty, fertile, flatulent - Flatulence is due to fat malabsorption from stones blocking bile excretion - :-, more common in females - Other risk factors + - High calorie diets - Genetic factors - Cholesterol lowering drugs cause excess cholesterol to be excreted in bile - Pathogenesis of cholelithiasis is imbalance in composition of bile Types of Gallstones + ===================== - Cholesterol Stones - Majority of stones --75% - Formation - Major constituents of normal bile - Water - Various inorganic ions - Bile salts - Lecithin AND - Conjugated bilirubin - Cholesterol - Since cholesterol is a lipid, low water solubility - Bile salts needed to suspend cholesterol - When cholesterol or other bile component is in excess OR bile salts deficient, it prompts bile to become *lithogenic* - i.e., stone forming - Form when bile becomes supersaturated with cholesterol - Insufficient bile to keep cholesterol in solution - Crystals induce precipitation - Cholesterol crystals allow a site for layered stone formation--- - Other causes - Beyond excess or deficiency of bile components, a further component is required - Due to imbalance, bile irritates the gall bladder mucosal wall - Causes irritated surface to act as a site for tiny points of precipitation - Such as focus is called a *nidus* - Once formed at the nidus, further precipitation is favored - Like a grain of sand induces pearl formation - Pigment Stones + - Less common than cholesterol stones - Formed by same mechanism, but the cause is calcium bilirubinate - Excess of bilirubin in bile for whatever reason, causes stones - Excess bili due to hemolysis, such as with sickle cell anemia, etc - Pathology - Cholesterol stones - Yellow, round, firm, large - Pigment stones - Black, faceted, soft, small/multiple ***B. [The most common condition associated with stone formation is]*** + ***[inflammation of the gall bladder \-- cholecystitis]*** - Etiology & Pathogenesis - Mucosal irritation from stones which obstruct outlet of the gallbladder - Obstruction may be intermittent, partial or complete - At foci of irritated mucosal, enteric bacteria invade - Sets up acute inflammation - Following inflammation and repair... - Bile-concentrating ability is reduced - Inflammation may be acute, acute recurrent or evolve to chronic inflammation - Pathology - Obstruction of cystic duct emptying from gallbladder - Due to stones - Due to edema from inflammation - Due to scarring from healing - Usually a combination - Obstruction results in... - Interference with bile flow into and out of gallbladder - Bile still can flow directly from liver to intestines - However, if stones excreted from gallbladder, they may obstruct common bile duct - Obstructive jaundice---conjugated hyperbilirubinemia - ***[Clinical Picture]*** + - In many cases, presence of stones causes no symptoms - Many discovered on plain abdominal x-rays for other investigation or at autopsy - If present, symptoms may include - Intermittent colicky pain in RUQ - Due to obstruction of cystic duct from stone - Sharp pain that has abrupt onset, then fades - Pain is from smooth muscle contraction of cystic duct with its outlet blocked - Called *biliary colic* - Usually occurs after eating---when gallbladder is stimulated to contract in response to a meal - If acute inflammation is present - Fever - Rupture/peritonitis a possibility - Chronic inflammation usually present with a history of chronic, intermittent dull pain, occasional sharp pains - Diagnosis - Typical history, risk factors - Plain abdominal x-ray - Ultrasound - Treatment - Surgical - Removal of the gallbladder and stones - Old laparotomy VS - New laparoscopic - Lithotripsy - Fragment stones with ultrasound, allowing small pieces to pass through ducts - Chemical dissolution - Especially in high risk individuals (elderly, clotting dysfunction,etc) - Administration of bile acids to restore balance to bile and allow dissolving of cholesterol stones ***C. [Biliary tree carcinomas are not common]*** - Carcinoma of the gallbladder - Etiology & Pathogeneis - Older patients, mostly female - Risk factor is prevalence of stones - Pathology - Grows into liver, extrahepatic ducts, duodenum - Few clinical symptoms until late disease - Early metastases - :-, poor prognosis **IX. [Pancreatic Pathophysiology -- *we will study diabetes with endocrine*]** ***A. [General]*** - Two main diseases - Inflammation AND - Neoplasia - Problems with the pancreas are uncommon, but significant when they occur - A&P - Structure - Head in curve of duodenum - Tail lying against hilum of the spleen - Body centrally located between these two areas - Predominately exocrine tissue - Excretes \~20 digestive enzymes - Duct system - Pancreatic duct terminates by joining the common bile duct, sharing the common entry into the duodenum at the *Ampulla of Vater* - Entry of pancreatic juices and bile are controlled at the junction of the Ampulla of Vater and duodenum - This sphincter is called the *sphincter of Oddi* - Pancreatic juices contain - Bicarbonate - Neutralizes incoming gastric acid - Resultant combination pH (very low from gastric, very high from pancreas) is optimal for activation of pancreatic proenzymes - Enzymes in their pro-enzyme / inactive form ***B. [Pancreatitis may present as an acute form, which is life-threatening or a chronic form, which involves recurring acute episodes]*** + - - Acute Pancreatitits + ===================== - Etiology & Pathogenesis - Three key factors - 1\) Potent proteolytic and lipolytic enzymes are normally sequestered in inactive forms within the cytoplasm, ER and Golgi of the pancreas until secretion - 2\) Digestion of pancreatic tissue and blood vessels by the pancreas' own enzymes is the underlying cause of necrosis and hemorrhage - 3\) Most acute pancreatitis is seen in patients with - Alcohol abuse OR... - Cholelithiasis - Trauma to the abdomen - Therefore, anything that limits normal pancreatic duct drainage may favor extravasation (escape)of the enzymes into pancreatic tissue -- categories... - Obstruction of the main pancreatic duct - Due to stones, adjacent tumor, or edema from alcohol abuse - Mechanical disruption - Blunt abdominal trauma, sharp trauma (GSW, knives) - Excess stimulation of pancreatic exocrine function - Alcohol abuse - Drugs - Excessively fatty foods - Some cases are idiopathic - Pathology - Regardless of origin, acute pancreatitis is based on the effects of enzyme release and tissue / vessel destruction - Proteolysis due to trypsinogen activation - Lysis of elastic tissue in vessels due to elastase - Fat necrosis inside and adjacent to the pancreas due to lipase activation - Pancreatic liquefactive necrosis due to autodigestion - Extensive inflammatory exudate formation - Gross appearance - Pancreas is edematous, hemorrhagic and irregular (necrotic areas) - Chemical peritonitis -- surface of nearby organs appear inflamed - Later, pseudocysts form in the pancreas - Liquefactive necrosis resolves, leaving fluid fill spaces called *pseudocysts* - ***[Clinical Picture]*** + - Nausea / vomiting - Mid-epigastric or back pain - Fever due to inflammatory response, usually not due to infection - Mild course, without necrosis -- also called *acute edematous* *pancreatitis* - Few symptoms, quick resolution - More severe course, with necrosis -- also called *acute hemorrhagic* *pancreatitis* -- it can cause... - Intense radiating pain, extensive local hemorrhage & necrosis - Vascular shock - Renal failure - ARDS - i.e., life-threatening Chronic Pancreatitis + ====================== - Etiology & Pathogenesis - Most chronic pancreatitits occurs in chronic alcohol abusers - Alcohol abuse is more common than chronic pancreatitis - i.e., not all chronic alcohol abusers will develop chronic pancreatitis - Successive episodes of acute pancreatitis result in a progressive loss of functional pancreatic parenchyma - Progressive scarring (fibrosis) results in loss of exocrine and endocrine function - ***[Clinical Picture]*** + - Pain \-- Scarring can entrap nerves or cause stenosis of duodenum - Exocrine insufficiency - Lack of digestive enzymes results in malabsorption - Steatorrhea - Protein deficiency - Fat soluble vitamin deficiencies develop - Night blindness (vit A) - Bleeding (vit K) - Endocrine insufficiency - Late in course, diabetes evolves - Treatment - Symptomatic - Cannot restore pancreatic function, but can treat diabetes, vit deficiencies, etc - Patient must cease drinking alcohol!! Benign tumors of the pancreas are rare. We will discuss endocrine functions of the pancreas with the Endocrine System Pathology section. ***C. [Adenocarcinoma of the pancreas is increasing in incidence]*** - Etiology & Pathogenesis - Fourth leading cause of death from cancer - Usually occurs after age 40 - For unknown reasons, this adenocarcinoma is increasing in frequency in Western populations - Risk factors - Firmly associated with smoking - Chronic pancreatitis - Dietary factors questionable, no proof - Pathology - Epithelial malignancy of ducts of the pancreas -- adenocarcinoma - Primary tumors arise with different frequencies according to location - Head -- 60% why this predominance? - Bulk of the pancreas is in the head - :-, Contains most of the ducts - Body -- 10% - Tail -- 5% - Diffuse -- 25% - Histology - Most are moderately differentiated with prominent fibrosis - ***[Clinical Picture]*** - Early metastases - Most are widely spread at the time of symptoms / diagnosis - Due to location of pancreas... - Elaborate venous and lymphatic drainage makes these tumors readily and early accessible to metastasis - Main routes - Local -- causes obstructive jaundice (conjugated bili) - Lymphatic -- spreads to regional lymph nodes - Hematogenous -- first spreads to liver - Clinical presentation syndromes -- symptoms may vary according to lactation of mass effect - 1\) Weight loss, anorexia, chronic persistent epigastric pain, radiating to the back (celiac plexus) - 2\) Obstructive jaundice with painless palpable enlargement of the gallbladder - Called *Courvoisier's sign* - 3\) Migratory thrombophlebitis in deep leg veins - Other symptoms and signs - Ascites - Splenomegaly - Intestinal obstruction - Prognosis - Due to aggressive growth and early metastases, overall prognosis is very grim - Survival past 2 years is unusual -- only 5% survive 5 years compared to colorectal ( 50 %) or Hodgkin's ( 70 %) - Most (90%) die within 6-12 months of diagnosis - - - - - ll ***Fine'***