Hepatobiliary study notes Intro - metabolic lobule (acinus) is centered on the portal areas, whereas the classic lobule is centered on the central vein; zone 1 is the hepatocytes near the portal areas, zone 2 is the hepatocytes midway between the portal areas and central veins, and zone 3 is the hepatocytes around the central veins - liver's ability to regenerate is legendary - if individual hepatocytes are destroyed but the architecture of the lobule is not, the remaining hepatocytes will totally regenerate the liver parenchyma - if whole lobules are destroyed, the remaining lobules will expand, the bile may or may not drain as well - increased bilirubin in the bloodstream is jaundice - because of too much bilirubin being produced, the liver fails to take up and/or conjugate bilirubin, or the liver doesn't send bilirubin to the right place - in all but hemolytic jaundice, bile production is diminishedl stools may become light-colored, and intestinal absorption of fat and fat-soluble vitamins is diminished - obstructive jaundice presents the familiar bile plugs, which begin as dilatations of the caniculi and end up forming bile lakes when the caniculi rupture When the liver fails - jaundice is usual - hyperbilirubinemia is mostly the conjugated sort - hypoalbuminemia is usual - without albumin, ascites and edema develops; hypocholesterolemia is also usual becasue the liver is not making LDL's - coagulopathy of liver disease results from dominished hepatic synthesis of factors II, V, VII, IX, and X - detoxification of nasty compounds fails and hyperammonemia and fetor hepaticus (distinctive odor of the breath) - hepatorenal syndrome - poorly understood syndrome of liver failure because--> 1) typically follows aggressive diuresis to relieve edema in a cirrhotic; 2) circulating volume in liver failure is low to begin with; 3) urine sodium is near-zero in hepatorenal syndrome; it's not reasonable to think that at least part of the problem is prerenal azotemia - hepatic encephalopathy - probably results from a combination of factors - when the liver finally gives up completely, refractory hypotension supervenes, probably from total-body arteriolar relaxation Circulatory problems - congestion of the liver requires excessive attention - if death has been preceded by a few hours of inadequate circulation, count on seeing some hepatocyte necrosis in the centers of lobules - cardiac sclerosis may supervene if hepatic congestion and underperfusion have been extreme and longstanding ; this is substantial fibrosis in the central areas of the lobule - liver infarcts - difficult to have an arterial infarct because of the dual blood supply to the liver - when a branch of the portal vein is compromised, the worst that usually happens is atrophy of hepatocytes in a region (Zahn's infarct) - hepatic vein thrombosis - Budd-Chirari - most common cause is polycythemia vera - another important cause is invasion of the hepatic veins by hepatocellular carcinoma - portal vein thrombosis - results from hypercoagulable blood, invasion by hepatocellular carinoma, pancreatitis, or cirrhosis - major problems are acsites and venous infarction - necrosis of the liver - infections can produce tiny to massive - poisons tend to cause damage to disinct portions of the lobule - central necrosis - ischemia, carbon tetrachloride, chloroform, acetaminophen - mid-zonal necrosis - yellow fever - peripheral necrosis - phosphorus, eclampsia - peliosis hepatis - non-endothelialized lakes of blood among the hepatocytes - usual cause is anabolic steroid use by bodybuilders - a blow to the liver may cause these to rupture Infections - viral hepatitis: genreal considerations - can get each of these infections only once - most people shake most of these viruses most of the time - infectivity peaks just before symptoms appear - in acute, the liver swells and becomes tender, jaundice often appears, and pt passes brown urine - serum transaminases go sky-high - acute viral hepatitis - widespread liver cell injury, with cell sweling - sinusoids close (lobular disarray) - lysis of liver cells - apoptosis of individual liver cells as eosinophilic councilman bodies - hypertrophy / hyperplasia of Kuppfer cells - massive necrosis may supervene on any kind of acute hepatitis, often kills the patient in short order - sub-massive necrosis is a little less striking histologically and lasts a little longer, killing the patient in a few months - chronic persistent hepatitis - will see a dense, mostly lymphocytic inflammatory infiltrate in the portal areas, without spill-over into the parenchyma - chronic active hepatitis - indicates a downward course to cirrhosis - a heavy inflammatory infiltrate of lymphocytes, spilling from the portal areas into the parenchyma - piecemeal necrosis - apoptosis of cells as the edge of the inflammatory infiltrate - bridging necrosis - confluent-lytic areas in which all hepatocytes have died, leaving behind only collapsed reticulin stroma - fibrosis - radiating outward from the portal areas - cirrhosis - an irreversible scarring of the whole liver sufficient to permanently interfere with circulation of blood to the hepatocytes - will see disruption of the normal liver architecture by fibrous scars and nodules of regenerative liver cells - micronodular cirrhosis - fibrous scar bands are relatively thin; think alcoholism, hemochromatosis, primary-autoimmine biliary cirrhosis, or biliray obstruction/infection - macronodular cirrhosis - fibrous scar bands are relatively thin - greater than 0.3 cm; think chronic active hepatitis progressed to cirrhosis; Wilson's disease, galactosemia, and alpha-1-protease inhibitor deficiency may produce either pattern - post-necrotic cirrhosis - end-stage liver; macronodular cirrhosis with really big, thick fibrous-scar bands; usually from either sub-massive necrosis, or progression of another type of cirrhosis to the end stage - hepatitis A - usually self-limited disease caused by a tiny RNA enterovirus; by fecal-oral route - IgM anti-HAV - appears in blood when symptoms begin, then disappears within 12 months - IgG anti-HAV - appears in blood during the symptomatic period, usually stays around for life, rendering the pt immune - Hepatitis B - serum hepatits - world's most serious DNA-related health problem - routes include transfusion, needles, hospital mishaps, sex, and mother to child - HBsAg - surface antigen; envelope protein - HBcAg - core antigen, nucleocaspid - HBeAg - means virus is being replicated - incubation is usually 1-4 months - HBsAg appears in blood shortly before symptoms begin - HBeAg - remains in blood during acute viral replication; disappears only if replication stops - Anti-HBeAg - appears soon after viral replication stops - Anti-HBcAg - appears in blood typically before symptoms begin - Anti-HBsAg generally appears when infection is pretty much over, and is a sure sign of recovery - symptoms begin only when T-cells become angry with HBsAg and HBcAg and start killing the hepatocytes that produce them - the acute disease may be subclinical, or can cause weeks of jaundice and misery, or can cause fulminant hepatitis and death, or sub-massive hepatic necrosis with resolution or cirrhosis - people who become carriers are those who mount a poor immune response; men are at greater risk than women - anyone who has the virus for a long time risks developing hepatocellular carcinoma - people who continue to harbor the virus are those who are not good at making interferon - alpha-interferon is the mainstay treatment for hepatitis B - hepatits D - an incomplete RNA virus which can replicate only while the synthesis of HBsAg is also taking place - it may co-infect or superinfect someone with HBV - hard to transmit, primarily a gay guy's and IV drug abuser's disease - hepatits C - transmitted by the same routes as hepatitis C, but probably not as catching - vertical transmission from mother to child is common - incubation period is a week to 6 months - the acute infection is more likely to be subclinical - about a third of hepatitis C virus carriers have chronic active hepatitis or cirrhosis - alpha interferon is the mainstay treatment - as with HBV, carrying HCV is an important cause of cryoglobulimemia - anti-HCV usually indicates the persistent presence of hepatitis C virus in the body - hepatitis E - an important, water-borne epidemic calcivirus infection in poor nations; rarely is chronic - yellow fever - councilman bodies, necrosis especially in the mid-zone of the lobule, and a suprising lack of inflammatory response Not infections, but similar histology - autoimmune hepatitis - chronic active hepatitis progressing to cirrhosis, without chronic virus infection but with evidence of immune injury - current thinking is that something first damages the liver and patients then get sensitized to their livers and start destroying them over the long haul - primary biliary cirrhosis - autoimmune disease caused by antibodies against pyruvate dehydrogenase - bile ducts attacked by immune system, resulting in severe obstructive jaundice - drugs and poisons - especially rough on the liver - acetaminophen, amanita phalloides toadstools, carbon tetrachloride and chloroform, isoniazid, methyldopa, and phosphorus - all can produce massive necrosis - acetaminophen overdose is very common - ordinarily, we only use the safe pathway to metabolize this, but when that is overloaded, the drug gets shunted into a pathway that produces free radicals Cholangitis - cholangitis is supparation involving bile ducts - the underlying cause is almost always obstruction; E. coli is most common - liver abscesses in the U.S. are usually of bacterial origin, spreading either up the bile ducts (ascending cholangitis) or via the portal vein (appendicitis, diverticulitis), or from septic emboli (bacterial endocarditis), or following a dirty wound Portal Hypertension - increased pressure in the portal venous system, for whatever reason - can be pre-hepatic, intra-hepatic, or post-hepatic - it is very troublesome - pts get ascites, mechanisms of formation include: 1) increase in hydrostatic pressure in the venules 2) the increase (most mechanisms) in hydrostatic pressure within the hepatic sinusoids themselves 3) diminished circulatory volume due to low serum albumin, with a tendency of the kidneys to retain sodium and water (do not give a diuretic because of likelyhood of shock, kidney failure, or hepatorenal syndrome) - porto-systemic shunting results when blood from the guts finds other routes back to the right side of the heart - this results in esophageal varices, hemorrhoids, and caput medusae around the belly button; hepatic encephalopathy is likely - fibrocongestive splenomegaly produces big, firm spleens that often produce clinically significant hypersplenism - can be treated with a porto-caval shunt Alcoholic liver disease - alcoholic steatosis - review - the drunken hepatocytes make too much fatty acid, make it into excess triglyceride instead of burning it, then can't complex the triglyceride to apolipoproteins, and can't export the lipoporteins they do make - fatty liver by itself it totally reversible once the drinker sobers up, the same applies to fatty liver from other causes - microvesicular steatosis is typical of Reye's syndrome, problem pregnancies, mitochondrial problems, and toxicity from outdated-tetracycline poisoning - alcoholic hepatitis - liver cells are dying, worst in centrilobular regions - surviving cells often bear Mallory's alcoholic hyaline (masses of altered prekeratin fibers plus stress proteins); free Mallory's hyaline is chemotactic for neutrophils - also look for giant mitochondria - cholestasis is usual because of bile caniculi with bile lakes and bile plugs - look for fibrosis as liver cells die off, notably around the central veins - the heart drug amiodarone is infamous for producing the same histopathology, and post-ileal bypass hepatitis and Wilson's disease can be dead ringers - if you have alcoholic hepatitis, you may have jaundice, hepatic encephalopathy, and all the signs and symptoms of portal hypertension - alcoholic cirrhosis - in order to get this, one need at least 15 pint years; 2/3 of drinkers die without cirrhosis - at first, the liver is big because of widespread hepatocyte overgrowth and fatty change from ongoing drinking; later, the liver becomes small from scarring and sobriety - you will see nodules and fibrosis instead of the normal architecture and proliferated bile ducts in the scar tissue (good sign of alcoholism) - early Laennec's cirrhosis has fine bands and a micronodular pattern; later the pattern is post-necrotic; when scar tissue obstructs flow, clinicians see jaundice Iron overload - healthy adult has total body iron content of around 4 gm; red cell contains close to 3 gm - 10 gm Fe/day is normal with a healthy diet - heme iron is absorbed much more readily than non-heme iron - dietay iron deficiency can be expected in a young girl who has been menstruating for a year with a bad diet - ferrous iron is complexed to apoferritin as it traverses the cell - iron absorbtion in the gut by the gut also increases when there is increased normoblastic activity - absorption is mildly increased in hemolytic anemias or after hemorrhage; it is more markedly increased in ineffective erythropoiesis - stroage iron exists in two principle forms: 1) ferritin is a bit of iron as the center of a protein micelle; the protein shell explains the negative Prssian blue stain; this is the short-term storage form 2) hemosiderin is aggregates of ferritin with much of the protein gone; this is Prussian blue positive form; it is a less labile strorage form that accumulates when there is excess ferritin - hemosiderin is the yellow pigment surrounding a bruise - the fetus gets priority when the mother becomes iron deficient - iron does harm to cells by generating free radicals - hemosiderosis - increased total body iron; most of the excess is in the reticluoendothelial cells; spill over into the parenchymal cells can cause trouble - primary hemosiderosis - 13% of people carry an autosomal gene for excessive iron absorption via the gut - secondary hemosiderosis can be caused by a variety of illnesses - hemochromatosis is hemosiderosis which has damaged parenchymal cells; total body iron sores in excess of 10 gm are very dangerous - primary hemochromatosis - the problem is greatly increased absorption from the gut - secondary hemochromatosis most often occurs in thalassemia major and in severe sideroblastic anemias - the classic hemochromatosis triad is liver trouble, diabetes mellitus, and skin discoloration - liver disease is the most serious problem in the majority of diagnosed hemochromatosis patients - hepatocyte lysosymes and mitochondria are packed, and liver iron stores are often more than 100x normal - micronodular cirrhosis is usually present - this cirrhosis is less severe than alcoholic cirrhosis - around 50% of pts have enough damage to their beta cells to develop symptomatic glucose tolerance - cardiac injury is caused by iron overload - endocrine injury is another problem -> loss of libido, loss of secondary sexual characteristics, testicular atrophy (secondary to pituitary failure with deposition in anterior lobe and leydig cells) - joint injury from iron deposition in synovium; results in synovial hyperplasia and erosion of bone and cartilage - skin pigmentation in hemochromatosis is primarily due to increased melanin - sepsis -> vibrio vulnificans, pasteurella pseudotuberculosis, and yersinia enterocolitica are much more pathogenic in the presence of iron overload (even E. coli) - secondary hemochromatosis and secondary hemosiderosis tend to not be as severe or result in cirrhosis (except for the ones associated with thalassemia major or sideroblastic anemia) - most of the iron is in the Kuppfer cells, not the hepatocytes - hemosiderosis due to chronic alcohol abuse results from increased absorption of iron through the gut - hemosiderosis due to increased or ineffective erythropoeisis is usual because of increased absorption of iron through the gut Wilson's Disease - untreated it is lethal, treated it is harmless - an autosomal recessive problem in which the liver is unable to dispose of excess dietary copper via the bile - ceruloplasmin is low; serum copper spills copiously into the urine - eventually the copper accumulates damaging liver, joints, brain, proximal tubules, and red cells, and making the distinctive keyser-Fleischer corneal ring - the liver passes from fatty change to chronic active hepatitis to micronodular cirrhosis to post-necrotic cirrhosis Liver Poisons - inflammation may mimic acute, chronic-persistent, or chronic-active hepatitis of viral etiology - acetaminophen - massive hepatic necrosis - allopurinol - granulomas - alpha-methyldopa - inflammation, granulomas, massive necrosis - amiodarone - inflammation, alcoholic hepatitis mimic, cirrhosis - anabolic steroids - cholestasis - chlorpromazine - cholestasis - estrogens - cholestasis, thrombosis - ethanol - fatty change, alcoholic hepatitis, cirrhosis - halothane - massive hepatic necrosis - isoniazid - inflammation - methotrexate - inflammation, cirrhosis - oxyphenisatin - inflammation - tetracycline - microvesicular fatty change Reye's syndrome - an acute illness which follows another viral illness, usually flu or chicken pox, usually in a child or young teen - cytotoxic cerebral edema, microvesicular fatty change to the liver, subtle damage to the mitochondria throughout the body, and extreme elevations in serum ammonia - increased intracranial pressure produces vomiting - later, in severe cases, the liver enzymes rise, and the liver itself fails - several inborn errors of metabolism produce crisis similar to Reye's - the link to salicylates was made epidemiologically Pediatric liver disease - biliary atresia - EHBA - a tragic birth defect in which the common bile duct and/or hepatic ducts and/or many larger intrahepatic ducts are without lumens along some or all of their length; these children suffer severe neonatal hyperbilirubinemia; need surgery or liver failure - neonatal hepatitis - giant cell hepatitis - ongoing liver cell destruction in a baby - look for the lobular disarray, focal cell necrosis, cholestasis, and Kupffer cell hyperplasia you'd see in any kind of hepatitis - the infant's liver regenerates well producing prominent giant hepatocytes with many nuclei - the prognosis is much more favorable than in biliary atresia Benign liver masses - hamartomas - cavernous hamartomas are little birthmarks, seen in maybe 1% of livers - focal nodular hyperplasia - looks like a chunk of cirrhotic liver grafted onto a healthy one; usually a central star-shaped large scar - cysts are bounded by biliary epithelium; in Caroli's disease, some of the bile ducts are dilated; polycystic liver may occur with either mendelian polycystic kidney disease - liver cell adenomas may occur sporadically, but most are common in women on BCPs and men on anabolic steroids; present as soft masses that usually cause no problems; seldom turn malignant Primary Cancers of the Liver - hepatocellular carcinomas - a deadly disease probably caused by longstanding infestation with hepatitis B and/or C viruses and/or iron overload - where HBV is endemic, hepatocellular carcinoma is the most common one in men, and secong only to cervical cancer in women - HBV and HCV are more likely to produce hepatocellular carcinoma when they cause rapid, prolonged cell turnover (i.e. Nowell's Law) - aflatoxin is probably responsible for the trademark p53 mutation required for epidemic African hepatocellular carcinomas - grossly, the tumor may be a single mass, or arise multicentrally - the more differentiated, the greener it gets (hepatocytes making bile) - have a great propensity to invade veins - look for -> bile production by tumor cells, mallory's hyaline, alpha-1-protease inhibitor inside cells, stainable hepatitis B virus proteins, stainable alpha-fetoprotein, and nearby livel cell dysplasia - when a cirrhotic deteriorates rapidly, it's common to find a hepatocellular carcinoma - death occurs through rupture, venous obstruction, liver failure, or lung metastases - cholangiosarcoma-type cancers can occur within the liver, or as a mix with hepatocellular - they are desmoplastic adenocarcinomas, often mucin producing - hepatoblastoma - a pediatric solid cancer; surgical resection is often curative - hepatic angiosarcoma - a rapidly lethal cancer; infamous for having been caused by exposure to industrial poisons and the radioactive contrast medium thorotrast - metastases to the liver - liver and lung are the two most common organs involved in fatal cancer - metastastic tumor in the liver tends to umbilicate (undergo central necrosis); hepatocellular carcinomas and cholangiosarcomas seldom do this - if it's cirrhotic liver, chances are it's hepatocellular carcinoma - untreatable liver metastases portend death within twelve months - necrosis zones in the liver 1) zone 1 (periportal) - hit hardest in phosphorus poisoning and eclampsia 2) zone 2 (mid-zonal) - hit hardest in yellow fever 3) zone 3 (centrilobular) - hit hardest in hypoxia and shock, in acetaminophen toxicity, and in CCl4 toxicity - keys to diagnosis - where is the hemosiderin? 1) in the hepatocytes --> primary hemochromatosis 2) in the Kuppfer cells --> hemolysis, transfusional hemochromatosis 3) in central hepatocytes --> longstanding congestion / repetitive ischemia - Mallory's hyaline in zone 3 plus fat and polys --> alcoholic hepatitis - random confluent-lytic necrosis --> unusual viral infections, in a baby or immunosuppresed - polys in the lumens of bile ducts --> ascending cholangitis - star-shaped portal-tract scar containing proliferating bile ducts filled with eosinophilic globs --> cystic fibrosis - star-shaped scar around central vein --> central hyaline sclerosis Biliary system - the liver produces a quart of bile a day - bile salts and lecithin keep cholesterol and unconjugated bilirubin-biliverdin solublized in the bile - birth defects - phrygian cap - an anomaly of the gallbladder in which the fundus is folded over on itself - gallstones - one adult in 10 has gallstones - usually asymptomatic, but can casue major problems - cholesterol stones may be pure or contaminated with calcium, oxalate, and/or bilirubin - 5 f's - fair-skinned, fat, female, fertile, flatulent, forty - bilirubin stones - are calcium bilirubinate; result from bile becoming super-saturated with unconjugated bilirubin - gallstones present problems when they --> obstruct the cystic duct, obstruct the common bile duct, erode through the wall of the gallbladder and the duodenum, or cause cancer of the gallbladder - acute cholecystitis - inflammation of the gallbladder, usually containing gallstones, usually with infection - the usual bugs are E.coli or enterococci - in the absence of gallstones, there's generally some systemic disease, and/or perhaps edema of a reister valve - the gallbladder is red, swollen, and tense - chronic cholecystitis - this just means fibrosis of the gallbladder, maybe from repeated bouts of mild or severe acute cholecystitis; there are almost always gallstones - look for hypertrophy and hyperplasia of the smooth muscle - Rokitansky-Aschoff sinuses, pseudo-diverticula where the mucosa has pooched into the muscularis propria - carcinoma of the gallbladder - adenocarcinomas are uncommon - usually associated with gallstones - cancer of the bile ducts - adenocarcinomas arising from these structures are uncommon; they produce obstructive jaundice - risk factors include ulcerative colitis and infestation of the liver with flukes or ascaris worms; men are at greater risk - most common site is the ampulla of Vater - the Klatskin tumor at the junction of the hepatic and common ducts is also common - cancer of the ampulla may be mucin-producing