BMS150_PAT5-08_LiverPath2_Win2023 (1).pdf

Liver Pathology Part II Resources: Robbin’s and Cotran’s Pathologic Basis of Disease BMS 150 Chapter 18 Week 14 Harrison’s Principles of Internal Medicine Chapters 339, 342, 343, 346  Hepatitis Overview Hepatitis A Hepatitis B...

Liver Pathology Part II Resources: Robbin’s and Cotran’s Pathologic Basis of Disease BMS 150 Chapter 18 Week 14 Harrison’s Principles of Internal Medicine Chapters 339, 342, 343, 346  Hepatitis Overview Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Genome ssRNA dsDNA ssRNA ssRNA ssRNA Route of Fecal-oral Parenteral, Parenteral Parenteral Fecal-oral transmission (contaminated sexual food/water) transmission Incubation 2-6 weeks 2-26 weeks 4-26 weeks Same as HBV 4-5 weeks period Chronic liver Never 5 – 10% > 80% Ranges – 10 – Only in disease? 90% (90% with immuno- superinfection) compromised Diagnosis Serum IgM Hep B HCV RNA HDV RNA or HEV RNA or against HAV antigens – antibodies antibodies surface or against HDV against HEV core Syndromes of Hepatitis Infection Asymptomatic with recovery Acute symptomatic with recovery 1. incubation period 2. symptomatic preicteric phase 3. symptomatic icteric phase Icterus = jaundice 4. convalescence Chronic hepatitis ▪ Carrier state or low-grade symptoms Fulminant hepatic failure (rare) Long-term untreated HBV or HCV can progress to cirrhosis or hepatocellular carcinoma ▪ More common with HCV  Hepatitis A Common, especially in areas with poorer hygeine ▪ 30 – 50,000 new cases/year in US Transmission: Fecal-oral route Almost always self-limited and never enters a chronic carrier state, but very rarely can cause fulminant hepatic failure Clinical Features ▪ Usually fatigue, nausea, jaundice ▪ Often asymptomatic Hepatitis B Most prevalent form worldwide Transmission: through blood or sexual contact ▪ Most people worldwide living with hep B acquired at childbirth Clinical course can include: ▪ Acute hepatitis with recovery and clearance of the virus ▪ Nonprogressive chronic hepatitis ▪ Progressive chronic disease ending in cirrhosis Which can then progress to hepatocellular carcinoma ▪ Fulminant hepatitis with massive liver necrosis ▪ An asymptomatic carrier state Relatively low prevalence of chronic hepatitis in NA ( less than 2%) but can be very high in other regions of the world (>8%) Age is the best predictor of chronicity: children have almost 90% rate of chronicity while the number drops to about 5% in adults  Hepatitis B Clinical features of acute HBV: Nonspecific constitutional symptoms such as anorexia, fever Jaundice, upper right quadrant pain – 30% of acute hepatitis No symptoms (about 70%) Very rarely hepatic failure Hepatitis B: Serological Response Acute HBV that resolves – typical findings on blood labs (left) Chronic HBV – typical findings on blood labs (right) Viral Hepatitis: Hepatitis C 1.6% of the population, have chronic HCV infection Transmission: blood-blood Risk factors: IV drug use, blood transfusions Persistent infection and chronic hepatitis are the hallmarks of HCV infection (80 – 85%) ▪ Generally asymptomatic nature of the acute illness Viral Hepatitis: Hepatitis C Progression to chronic disease occurs in the majority of HCV-infected individuals In the past, cirrhosis eventually occured in 20% to 30% of individuals with chronic HCV infection ▪ Newer treatments have resulted in much better outcomes for those with chronic infection, however – chronic hepatitis C can now be cured Antiviral regimens are matched to genotype of HCV – most common genotype is 1a or 1b in North America ▪ Still most common indication for liver transplantation Hepatitis C: Serological Response Acute HCV that resolves (less common) – typical findings on blood labs (left) Chronic HCV that does not resolve (more common) – typical findings on blood labs (right) Viral Hepatitis: Hepatitis D & E Hepatitis D: Needs coinfection with hepatitis B for its life cycle ▪ Hepatitis B + D simultaneously can result in acute severe hepatitis ▪ In those with chronic hepatitis B infection, additional infection (superinfection) with HDV usually results in chronic infection with both Hepatitis E: ▪ Zoonosis that results in self-limited acute hepatitis ▪ Associated with a very high mortality in pregnant women (up to 20%) Other Hepatic Infections - FYI Bacterial – staph aureus, typhoid fever, syphilis ▪ Mild inflammation & cholestasis tend to occur Protozoal infestations can cause appearance of abscesses in liver (amebic, other protozoons) ▪ Abscesses are associated with fever and, in many instances, right upper quadrant pain and tender hepatomegaly ▪ Poor prognosis Alcoholic Liver Disease Three distinct but overlapping forms of alcoholic liver injury: 1) Hepatitis: Hepatocyte swelling and necrosis Mallory bodies Neutrophilic reaction 2) Hepatic steatosis Reversible 3) Steatofibrosis including cirrhosis Irreversible, looks just like cirrhosis from viral causes Only 10-15% of alcoholics develop cirrhosis Alcoholic Liver Disease: Major Pathologic Patterns Alcoholic Liver Disease: The Cellular Effects of Alcohol Causing Hepatitis Alcohol promotes movement of bacterial endotoxin from the gut into the portal circulation → liver inflammation Stimulates the release of endothelins from sinusoidal endothelial cells → vasoconstriction as well as contraction of activated stellate cells ▪ Endothelins are potent vasoconstrictors released from capillary endothelial cells ▪ leads to a decrease in hepatic sinusoidal perfusion Alcohol is metabolized to acetaldehyde (alcohol dehydrogenase, catalase, and microsomal activity) ▪ Acetaldehyde is toxic and can cause lipid peroxidation if concentrations rise too high ▪ More pathways next slide →  Metabolism of alcohol → decreased NAD+ NAD+ is necessary for fatty acid oxidation… therefore fat accumulation in the liver Metabolism of alcohol by CYP2E1 → free radical production Cirrhosis Typical micronodular cirrhosis of alcoholic liver disease Blue-staining fibrous tissue “traps” nodules of poorly-functioning heptatic tissue Alcoholic hepatitis – cellular findings Alcoholic steatohepatitis Hepatocytes “ballooned” by accumulation of fat in fat vacuoles (arrowheads) Red oval shows immune cells surrounding dead/dying hepatocytes ▪ Clusters of blue nuclei Inset shows an “empty” hepatocyte ▪ Brown staining is for particular keratins that are important components of the cytoskeleton ▪ Some hepatocytes prematurely ubiquinate keratin → collapse of the cytoskeleton Alcoholic Liver Disease Clinical Features: ▪ Non-specific symptoms are common: Malaise, anorexia, weight loss, upper abdominal discomfort, tender hepatomegaly ▪ Alcoholic hepatitis attends to appear acutely following bouts of heavy drinking ▪ Alcoholic steatosis usually does not have many symptoms and is usually reversible upon cessation of alcohol use Prognosis: ▪ 5-year survival approaches 90% in those who are free of jaundice, ascites, or hematemesis and abstain from alcohol ▪ Drops to 50%-60% in those who continue to drink Non-Alcoholic Fatty Liver Disease (NAFLD) Steatosis in the absence of significant alcohol consumption ▪ Most common cause of liver disease in US Forms include: ▪ Non-alcoholic steatohepatitis (NASH) Progresses to cirrhosis in 10 – 20% of cases In those that progress to cirrhosis, the incidence of liver cancer can be as high as 1-2% per year ▪ Simple hepatic steatosis and steatosis complicated by inflammation These show fewer long-term complications unless they progress to NASH Non-Alcoholic Fatty Liver Disease (NAFLD) Non-Alcoholic Steatohepatitis (NASH) Pathologic findings: ▪ Initially hepatocyte ballooning, lobular inflammation, and steatosis (fat accumulation in hepatocytes) ▪ With progressive disease there is steadily more fibrosis, eventually leading to cirrhosis ▪ Strongly associated with obesity and the metabolic syndrome Pathophysiology: ▪ “two-hit” model, involving 1) hepatic fat accumulation and 2) increased oxidative stress Free radicals cause lipid peroxidation of the accumulated intracellular fat ▪ Obesity seems to be associated with reduced intestinal barrier function → increased inflammation in the liver Movement of microbes from the gut into the portal circulation Non-Alcoholic Steatohepatitis (NASH) Non-Alcoholic Steatohepatitis (NASH) Clinical features: ▪ Usually asymptomatic until overt hepatic failure – clinical findings are due to atherosclerotic disease/diabetes that accompany NASH Cardiovascular disease is a frequent cause of death in those with NASH ▪ Fatigue and right-sided abdominal pain can occur in some, though ▪ Increases risk of hepatocellular carcinoma Diagnosis: ▪ Liver enzymes alone are poorly-reliable ▪ Scores calculated from age, BMI, fasting glucose, AST, ALT are helpful for gauging degree of inflammation and fibrosis ▪ Detection of fibrosis via imaging or biopsy for definitive diagnosis Drug and Toxin-Induced Liver Disease Most common cause of fulminant hepatitis ▪ But a wide range of pathological patterns and clinical presentations can result Insidious onset or rapid Hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction Hepatitis looks very similar histologically to viral hepatitis Toxins can: ▪ Be directly toxic ▪ Be converted by the liver into an active toxin ▪ Elicit an immune responses by acting as a hapten Most drugs or toxins affecting the liver can be classified as: ▪ Predictable hepatotoxins Dose-dependent, occur in most individuals ▪ Unpredictable or idiosyncratic hepatotoxins Independent of dose, rare Drug and Toxin-Induced Liver Disease Most common hepatotoxin causing acute liver failure is acetaminophen ▪ Main cause of acute liver failure necessitating liver transplant in the US ▪ So is Tylenol bad??? Not really – those with a long history of regular acetaminophen use, AS PER DIRECTED (i.e. not exceeding recommended dosages) very, very rarely have any significant hepatic damage Unfortunately it’s commonly used during suicide attempts and it’s in a lot of OTC medications, so unintentional overdose is surprisingly common Most common hepatotoxin causing chronic liver failure is alcohol Acetaminophen toxicity Low doses – conjugated and excreted in urine (95%) High doses – increased production of NAPQI ▪ If glutathione reserves are insufficient, then this reactive molecule damages hepatocytes FYI Autoimmune Hepatitis Etiology: ▪ unknown, though involves attack by cytotoxic T- lymphocytes ▪ Likely genetic, and can be triggered by certain medications (i.e. statins) or viral infections Epidemiology: ▪ Uncommon – 1-2/100,000/year m/c among white northern Europeans Most of those affected (78%) are female  Autoimmune Hepatitis Two types: ▪ Type 1 (most common): presence of ANA and anti- smooth muscle antibodies, HLA DR3 m/c in middle-aged to older individuals ANA = antinuclear antibodies (commonly found in autoimmune disorders such as lupus) ▪ Type 2 presence of anti-cytochrome antibodies (cytochrome p450) m/c in children and teenagers Autoimmune Hepatitis Prognosis: Many patients have relatively mild disease that can be treated conservatively with a “watch and wait” philosophy ▪ 10-year survival of all people with the disease is 80-90%, so a wide spectrum of severity Severe, untreated disease has a mortality of 40% ▪ Even with treatment, a large proportion go on to develop cirrhosis ▪ Recurs in up to 42% after liver transplant Portal Hypertension Caused by a combination of increased resistance to blood flow through the portal circulation, and a “hyperdynamic circulation” Causes include: ▪ Thrombosis and obstruction of the portal vein (prehepatic) ▪ Cirrhosis from any cause (intrahepatic) ▪ Severe right-sided congestive heart failure (post-hepatic) Blood accumulates in the hepatic veins → increased pressure in the portal system Typical complications: ▪ Ascites ▪ Formation of portosystemic venous shunts ▪ Congestive splenomegaly ▪ Hepatic encephalopathy Features of Portal Hypertension Hepatic encephalopathy Esophageal varices Splenomegaly Malnutrition Spider angiomas Caput medusae Ascites Hyperdynamic circulation → for reasons that are poorly understood, the overall blood flow through the intestines/stomach increases perhaps due to impaired liver clearance of vasodilatory substances Worsens pressures in the portal system Esophageal varices Portal hypertension results in the development of collateral channels at sites where the portal and caval systems communicate (i.e. distal esophagus) ▪ Collateral veins allow some drainage to occur, but result in enlarged, fragile, congested subepithelial and submucosal venous plexus within the distal esophagus (i.e. varices) develop in 90% of cirrhotic patients Cirrhosis and collateral circulation Why does cirrhosis result in portal hypertension and the development of varices? ▪ Think of the liver histology – blood flows from the portal triad (hepatic artery and portal vein) tributaries to the central vein ▪ If that pathway has increased resistance to flow, then pressures increase in the portal vein Cirrhosis causes necrosis and fibrotic “bridging” that interrupts the normal flow from triad to hepatic vein ▪ Anastomoses between the portal vein and the systemic circulation then get increased blood flow – it’s like blood is diverted from the liver to systemic veins nearby Look carefully at the diagram on the next slide Esophageal varices Esophageal varices How bad are they? ▪ May rupture causing massive hematemesis = medical emergency Inflammatory erosion of thinned overlying mucosa, increased tension in progressively dilated veins, and increased vascular hydrostatic pressure associated with vomiting contribute to it Treated by sclerotherapy (endoscopic injection of thrombotic agents); endoscopic balloon tamponade; or endoscopic rubber band ligation ▪ As many as half of patients die from the first bleeding episode Additional instances of hemorrhage occur in survivors in over 50% within 1 year - Each episode w/ similar rate of mortality Over half of deaths among individuals with advanced cirrhosis result from variceal rupture Intrahepatic biliary tract disease Affects the ducts and ductules within the liver ▪ Secondary biliary cirrhosis Secondary to uncorrected bile duct obstruction of the extrahepatic biliary tree (i.e. big bile ducts) ▪ Primary biliary cirrhosis (PBC) Autoimmune, non-supparative inflammation that destroys the intrahepatic bile ducts Portal inflammation leads to scarring and eventually cirrhosis ▪ Primary sclerosing cholangiitis (PSC) Intrahepatic and extrahepatic bile ducts become inflamed and the ducts become obliterated The unaffected areas dilate, leading to the appearance of ‘beads on a string’ PBC and PSC Primary biliary cirrhosis (PBC): Pruritus, fatigue, and abdominal discomfort are major initial presentations ▪ Eventually followed by skin pigmentation, xanthelasmas, steatorrhea, and vitamin D malabsorption ▪ osteomalacia and/or osteoporosis due to vitamin D malabsorption ▪ Cirrhosis, portal hypertension (+ variceal bleeding) and hepatic encephalopathy generally occur years - decades However, not all patients develop cirrhosis Pathogenesis is poorly understood ▪ Anti-mitochondrial antibodies against pyruvate dehydrogenase are usually found, as are T-cells that recognize this antigen Prevalence – 65/100,000 for women, 12/100,000 for men PBC and PSC Primary sclerosing cholangitis (PSC): Progressive fatigue, pruritus, and jaundice are major initial presentations ▪ Chronic liver disease → cirrhosis is the usual course weight loss, ascites, variceal bleeding, and encephalopathy Similar complications as PBC Median survival is ~ 12 years ▪ 7% develop cholangiocarcinoma ▪ Increased risk of colon cancer Pathophysiology is unclear but also likely autoimmune ▪ Associated with HLA-B8 and p-ANCA ▪ Thought that in those with ulcerative colitis, sensitized T-cells from the colon travel to the liver and cross-react with an as-yet unrecognized antigen Presents in early adulthood – middle-age ▪ 70% of patients are male, prevalence ~ 6/100,000 ▪ Greatly increased risk in those with ulcerative colitis General pathology of cholestasis - FYI In the parenchyma, cholestatic hepatocytes (1) are enlarged with dilated canalicular spaces (2). Apoptotic cells (3) may be seen, and Kupffer cells (4) frequently contain regurgitated bile pigments. In the portal tracts (triads) of obstructed liver there is also bile ductular proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation. Surrounding hepatocytes (7) are swollen and undergoing degeneration. 42 Specific PSC and PBC pathologic findings PBC: ▪ Destruction of interlobular bile ducts due to lymphocytic inflammation +/- granuloma formation ▪ Patchy involvement, not all bile ducts affected to the same degree ▪ Severe cholestatic findings at the end-stages, accompanied by hepatomegaly Often end-stage cirrhosis → smaller, shrunken, scarred livers PSC: ▪ Large duct inflammation is similar to that seen in ulcerative colitis: acute, neutrophilic infiltration of the epithelium superimposed on a chronic inflammatory background; strictures can develop ▪ Smaller ducts often have little inflammation and show “onion skin” fibrosis around atrophic duct lumens ▪ Similar severe cholestatic findings at end-stage as PBC Acute cholecystitis One of the most common indications for abdominal surgery Acute inflammation of the gallbladder, precipitated 90% of the time by obstruction of the neck or cystic duct – It is the primary complication of gallstones and the most common reason for emergency cholecystectomy – Cholecystitis without gallstones = acalculous cholecystitis May occur in severely ill patients and accounts for about 10% of patients with cholecystitis Thought to be due to gallbladder ischemia Acute cholecystitis Results from chemical irritation and inflammation of the obstructed gallbladder ▪ Mucosal phospholipases hydrolyze luminal lecithins to toxic lysolecithins ▪ The normally protective mucus layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts ▪ Prostaglandins released and gallbladder distention cause inflammation, which results in gallbladder dysmotility ▪ Distention and increased intraluminal pressure compromise blood flow to the mucosa ▪ Bacterial contamination may occur later Acute cholecystitis Clinical Features Begins with progressive right upper quadrant or epigastric pain, frequently associated with mild fever, anorexia, tachycardia, sweating, nausea, and vomiting ▪ Most patients are free of jaundice; the presence of hyperbilirubinemia suggests obstruction of the common bile duct ▪ Rupture results in severe peritonitis as well as bleeding – the gallbladder can become gangrenous, which makes perforation worse Chronic cholecystitis Associated with cholelithiasis in >90% of cases Cause of chronic cholecystitis is obscure, in that it is not clear that gallstones play a direct role in the initiation of inflammation or development of pain – Supersaturation of bile predisposes to chronic inflammation – E. coli can be found in the bile in a significant minority (bile should be sterile) – Degree of inflammation found within the wall varies, from mild lymphocytic infiltration to more severe inflammation and fibrosis Chronic cholecystitis Clinical Features Recurrent attacks of either steady or colicky epigastric or right upper quadrant pain ▪ Nausea, vomiting, and intolerance for fatty foods are frequent accompaniments Complications include: ▪ Bacterial superinfection with cholangitis or sepsis ▪ Gallbladder perforation and local abscess formation or peritonitis ▪ Biliary enteric (cholecystoenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into the biliary tree, and potentially, gallstone-induced intestinal obstruction (ileus) ▪ Porcelain gallbladder = dystrophic calcification within the wall of the gall bladder, greatly increases risk of cancer Diseases of the extrahepatic ducts Cholangitis = bacterial infection of the bile ducts ▪ Cholangitis can result from any lesion that creates obstruction to bile flow, most commonly choledocholithiasis and biliary strictures ▪ Usually enteric gram-negative aerobes such as E. coli, Klebsiella, Enterococcus, or Enterobacter ▪ Acute onset of fever, chills, abdominal pain, and jaundice accompanied by acute inflammation of the wall of the bile ducts with entry of neutrophils into the luminal space ▪ Dangerous disorder that needs emergent referral Sepsis is the main concern – the patient can go into septic shock