Pathology of The Liver-Medicine And Pathophysiology-Lecture Notes, Study notes of Pathophysiology

Download Pathology of The Liver-Medicine And Pathophysiology-Lecture Notes and more Study notes Pathophysiology in PDF only on Docsity! Gastrointestinal Pathophysiology Notes: Dr. Glickman NON-INFECTIOUS HEPATOCELLULAR DAMAGE 1. Alcohol: The prototype of hepatotoxins a. Alcoholic Steatosis (Fatty Liver): Occurs within a few days of alcohol consumption, and is completely reversible with cessation of alcohol intake. Usually macrovesicular. Grossly, the liver becomes enlarged with a soft greasy yellow cut surface. b. alcoholic hepatitis: Although potentially reversible, this lesion may smolder on long after cessation of alcohol intake. Mostly neutrophils, with admixed lymphocytes, macrophages. c. liver cell necrosis, often with Mallory bodies, which appear as coarse eosinophilic skeins of protein, typically found in ballooned hepatocytes. d. Fibrosis and Cirrhosis: Predominant fibrosis is in zone 3 (centrilobular), often with a component of sinusoidal fibrosis. Resulting cirrhosis is usually micronodular (nodules less than 3 mm). Bile stasis may lend a yellow-green hue to the parenchymal nodules. 2. Drug-related Injury: Adverse drug reactions induce an astonishing array of hepatic changes that virtually recapitulate all types of hepatic disease, summarized elsewhere in this lecture. Therefore, adverse drug reactions should be considered in the differential diagnosis of all forms of hepatic disease. Many drugs cause more than one pattern of injury. a. Pathogenesis of drug-related injury: see Dr. Chung’s lecture. b. Major hepatic drug reactions and some implicated agents: A complete listing of hepatic drug reactions is beyond the scope of this lecture and is covered elsewhere in the course. However, a few classic examples will be mentioned. Microvesicular fat: tetracycline, salicylates. Cholestasis (with or without hepatocellular injury): chlorpromazine, sex steroids, including oral contraceptives Centrilobular necrosis: acetaminophen, carbon tetrachoride Hepatitis, acute to chronic: isoniazid, alpha-methyldopa, nitrofurantoin, phenytoin Fibrosis-cirrhosis: ethanol, methotrexate, amiodarone, cinchophen Granuloma formation: sulfonamides, alpha-methyldopa, quinidine, phenylbutazone, hydralazine, allopurinol, isoniazid, nitrofurantoin, penicillin Veno-occlusive disease: cytotoxic drugs, pyrrolidine alkaloids Hepatic or venous thrombosis: estrogens, including oral contraceptives Peliosis hepatis: anabolic steroids, thorotrast 3. Reye's Syndrome: Clinical: An acute postviral illness, largely of children, characterized by progressive hepatic failure and encephalopathy. Pathogenesis poorly understood, but may be related to hyperammonemia, elevated serum free fatty acids, and salicylate toxicity and/or synergism. While fatality is 10-40% in reported series, recovery is usually complete. Pathology: Microvesicular fatty change of the liver (first 3- 5 days of illness); Concomitant disruption of mitochondrial ultrastructure with pleomorphic enlargement, distortion of cristae, formation of electron-lucent matrices. Similar changes in skeletal muscle, kidneys and heart. docsity.com we . Notes: Dr. Glict 4. Liver Disease in Pregnancy: In any pregnant woman with evidence of hepatic compromise (e.g., hypoalbuminemia, jaundice, elevated serum liver enzymes), these three lesions must be ruled out: a. Acute fatty liver of pregnancy: Accumulation of microvesicular fat in hepatocytes, associated with potentially rapid onset of liver failure and death. Etiology is unclear. Treatment: termination of pregnancy. Diagnosis is usually made on an emergency basis, using frozen sections stained for fat. b. Recurrent cholestasis of preganancy: A benign disease, with pure cholestasis, probably on the basis of steroid-induced hepatocellular damage. While not life-threatening, the pruritus can drive a woman to distraction. Treatment: termination of pregnancy. c. Eclampsia: Disseminated intravascular coagulation causing necrosis of hepatic parenchyma. Potentially fatal if untreated secondary to hemorrhage and circulatory collapse. |-VIRAL INFECTIONS OF THE LIVER - NON. 1. Liver Abscesses: a. Developing countries: Common; most represent parasitic infections, e.g., amebic, echinococcal, and (less commonly) other protozoal or helminthic organisms. b. Developed countries: Uncommon; usually bacterial or in origin, typically is a complication of infection elsewhere. c. Mechanism of spread: Organisms reach the liver via the portal vein (e.g., intra-abdominal infection), arterial supply (systemic infection), biliary tree (e.g., ascending cholangitis), or direct invasion from adjacent structures, or by a penetrating injury. d. Histologic features: Usually non-specific, although parasitic fragments may be identifiable in tissue sections. 2. Diffuse parenchymal infection, non-viral: Often in Kupffer cells. Formation of granulomas is common. a. Fungi: Histoplasmosis, Candida b. Protozoa: Toxoplasmosis, leishmaniasis &e Malaria and the liver: deposition of malarial pigment (hemozoin) in Kupffer cells, or sinusoidal lymphocytosis with impairment of sinusoidal blood flow (Tropical Splenomegaly Syndrome). 3. Parasites: Hepatic disease other than abscess formation includes: a. Schistosomiasis:Deposition of ova within hepatic parenchyma, inducing a brisk eosinophilic inflammatory response, granuloma formation, and progressive portal-based fibrosis, which causes obliteration of branches of the portal vein, resulting in non- cirrhotic portal hypertension. b. Clonorchiasis, Fascioliasis:Liver flukes migrate up the biliary tree and inhabit the major intrahepatic bile ducts. ci Other reported parasites: Ascariasis, toxocariasis, capillariasis. docsity.com Gastrointestinal Pathophysiol Jotes: Dr. Glicl There are also many non-viral causes of chronic hepatitis, including drugs, metabolic disorders such as Wilson’s disease, autoimmune hepatitis, and primary biliary cirrhosis, Distinguishing histologic features among these possibilities are for the most part absent. An increased proportion of eosinophils and neutrophils is suggestive of a drug reaction. Massive Necrosis (Fulminant Hepatitis): Defined as hepatic insufficiency progressing from onset to death (or hepatic transplantation) within 2-3 weeks. Viral hepatitis accounts for 50-65% of cases, but may also result from drugs, poisoning (e.g., Amanita phalloides), and many other causes. Pathology: The entire liver may be involved or only portions. Microscopically, entire lobules or portions thereof may be necrotic, with liquefaction of hepatocytes and collapse of the reticulin framework, with surprisingly little inflammatory reaction. If the patient survives for more than a week, secondary changes develop, including marked regenera- tion of hepatocytes, which take on the appearance of proliferating ductules, and hyper- trophy and hyperplasia of surviving Kupffer cells, which become laden with lipofuscin and cellular debris. CIRCULATORY DISORDERS 1. Impairment of vascular inflow Infraction is rare, due to the double blood supply of the liver. Nevertheless, significant vascular impairment may occur. a. Liver infarcts: Thrombosis or compression of an intrahepatic branch of the hepatic artery by polyarteritis nodosa, embolism, neoplasia, or sepsis may result in a localized infarction. Portal vein obstruction and thrombosis: Extrahepatic causes include malignancy in abdominal organs, peritoneal sepsis with portal vein pylephlebitis (this may also occur with hepatic abscess), pancreatitis with splenic vein thrombosis propogating into the portal system, and postsurgical thrombosis. Intrahepatic causes are most frequently cirrhosis (see below). Low-flow states with Shock or Left Ventricular Failure: Ischemic necrosis of zone 3 hepatocytes (those furthest from the blood supply), also termed centrilobular necrosis. Sinusoidal occlusion: Sickle Cell Disease and may cause direct occlusion of sinusoidal channels by sickled erythrocytes and fibrin thrombi, respectively. Impairment of Vascular Outflow: Common histologic features: Acute: centrilobular congestion, may result in hemorrhagic necrosis Chronic: Atrophy of centrilobular hepatocytes, and pericentral fibrosis. a. Acute and Chronic Passive Congestion and Central Hemorrhagic Necrosis: Usually cardiac (particularly right-sided) failure (this is commonplace at autopsy, the result of preterminal circulatory failure). Macroscopically, the congestion and subtle depression of the centrilobular areas have been termed nutmeg liver. docsity.com intestinal Pathophysiol Jotes: Dr. Glick b. Hepatic Vein Thrombosis (Budd-Chiari Syndrome): systemic thrombotic _ disorders. c. Hepatic Veno-occlusive Disease (VOD): Associated with hepatotoxic alkaloids found in herbal teas (Jamaican "bush tea"), antineoplastic drugs, immunosuppressants, and hepatic irradiation, VOD is of primary concern in patients post-bone marrow transplant with hepatic dysfunction. The terminal hepatic vein exhibits focal subendothclial deposition of a delicate collagen network, with ultimate obliteration of the smaller veins of the liver. Thrombosis may propogate into the major veins, mimicking Budd-Chiari syndrome. JAUNDICE AND CHOLESTASIS Jaundice (also termed icterus) is the clinical indicator of hyperbilirubinemia. Cholestasis refers to cessation of bile flow with accumulation of biliary substances in blood, including bile salts, bilirubin and biliary proteins (e.g., alkaline phosphatase). Morphologically, cholestasis is evident as accumulation of pigmented material in tissue sections: -ballooned hepatocytes with wispy cytoplasm ("feathery degeneration -dilated canaliculi with green-brown plugs of bile ("canalicular cholestasis"), typically around terminal hepatic vein. Bile may rupture into the extravascular space and be phagocytosed by Kupffer cells, or may for bile lakes in the parenchyma. A. Extrahepatic biliary obstruction. (e.g., gallstones, tumor, extrinsic compression) Specific histologic features in the portal tracts include: -Portal tract edema and bile duct distension, and periductular inflammation ("cholangiolitis"), particularly neutrophils. -Proliferation of bile ductular structures in the portal tract and at the junction of the portal tract and hepatic parenchyma. -Superimposed bacterial infection of the biliary tree results in neutrophils entering the bile ductular lumen in great numbers ("cholangitis"). Cholestatic drug reactions (see above). . Primary biliary tract diseases There is a specific set of diseases that involve direct destruction of bile ducts, each with a characteristic morphology. Unfortunately, characteristic features are not always present, and so differentiating these diseases from one another and from secondary biliary obstruction and chronic active hepatitis is frequently problematical. on 1. Primary Biliary Cirrhosis (PBC): Thought to be an autoimmune disorder focused on inter- lobular bile ducts and cholangioles, this disease causes chronic inflammation of intrahepatic bile ducts leading to their destruction and, in time, cirrhosis. Primarily affects women (F:M ratio 9:1), with average age of clinical onset 50-55 years (range 20-80 years). a. Pathology: Histological damage is irregular and may vary in severity within a given liver. Assessment of disease progression by biopsy is thus somewhat unreliable. Nevertheless, four histological stages have been described which are helpful in monitoring disease status. 1. Stage I: Florid Duct Lesion: dense portal infiltrate of lymphocytes, plasma cells and scattered other inflammatory cells, granulomas around bile ducts with lymphocytic infiltration of bile ductular. Parenchymal cholestasis may be present. 2. Stage II: Ductular Proliferation: The portal inflammation remains, and may spill over into docsity.com Gastrointestinal Pathophysiol Jotes: Dr. Glict the parenchyma, resembling chronic active viral hepatitis. 3. Stage III: Fibrosis: Fibrous septa may interconnect portal areas and create nodules. Bile ducts are markedly reduced, inflammation is less marked, granulomas are infrequent, and cholestasis may be prominent. 4. Stage IV: Cirrhosis: Fibrous septa subdivide the liver into overt micronodules. 2. Primary Sclerosing Cholangitis (PSC): An uncommon cholestatic condition with hyperbilirubinemia and elevated serum alkaline phosphatase, and frequently associated with chronic ulcerative colitis. Pathology: Segmental, random and uneven chronic fibrosing inflammatory reaction involving single or multiple combinations of intra- and extrahepatic bile ducts, leading to focal fibrous stricture or obliteration of the biliary tree. A milder variant (pericholangitis) with mild periductular inflammation without sclerosis is seen in many patients with ulcerative colitis undergoing liver biopsy. 3. Graft-versus-Host Disease (GVHD): A serious complication of allogeneic bone marrow transplantation. Hepatic involvement with this disease reflects attack of the donor immune system on antigens expressed on the biliary epithelium Pathology: Portal tracts show lymphocytic infiltration and necrosis of bile ducts. Cholestasis is prominent. Particularly characteristic is endothelialitis, in which lymphocytes attach to and infil- trate the endothelium of the terminal hepatic vein and/or portal vein, lifting the endothelium off the basement membrane. Over time bile ducts decrease in number, and fibrosis may develop around the portal tract. 4. Paucity of Bile Duct Syndromes: Diminished or absent intrahepatic bile ducts, ranging from inflammatory to syndromatic conditions. Of primary concern is Biliary Atresia, which is inflammatory loss of bile ducts in the weeks following birth, requiring surgical intervention for survival. CIRRHOSIS Cirrhosis has been mentioned several times above (see the discussions of alcohol, viral hepatitis, and biliary tract diseases), but merits separate emphasis. Cirrhosis is the generic term for hepatic disease of varied etiology having the following characteristics: 1) Interconnecting fibrous scars formed in response to hepatocytic injury and loss which obliterate the normal hepatic architecture. 2) Nodules of regenerative hepatocytes, varying from micronodules (less than 3 mm in diameter) to macronodules (3 mm to several centimeters in diameter). 3) Abnormal arteriovenous interconnections. Once cirrhosis is established, determining the etiology may be quite difficult. Such features as loss of bile ducts, accumulation of iron or copper (see below), or ground glass cells may permit identification of the underlying disease process. - Alcoholic Cirrhosis (60-70% of cirrhotic livers in the Western World): Typically micronodular; only with long-standing regeneration do larger macronodules develop. Fibrous bands are usually central-portal. docsity.com Gastrointestinal Pathophysiology Notes: Dr, Glickman ranging from several cm to up to 30 cm in size. Sheets and cords of cells resembling normal hepato- cytes or with more variation in cell and nuclear size. Typically marked by abnormally arrayed blood vessels with no portal tracts or bile ducts evident. Strongly associated with use of oral contraceptives, also with pregnancy and use of anabolic steroids. MALIGNANT TUMORS 1. Hepatocellular Carcinoma (HCC; unfortunately, also called "hepatoma"): Accounts for 90% of primary liver cancers, arising typically in the mid-to-late decades of life with a male:female ratio of 3-4:1. Accounts for 40% of all cancers in high-incidence locales (Africa, Southeast Asia). In U.S. and Western Europe, HCC represents 2-3% of all cancers. a. Etiology: Strongly associated with protracted HBV infection, particularly when acquired early in life;cirrhosis from other causes (alcoholism, primary hemochromatosis, Tyrosinemia); environmental carcinogens (aflatoxin B, from Aspergillus flavus); and iatrogenic carcinogens (Thorotrast). b. Gross: unifocal, usually large mass; as multifocal nodules; or diffusely infiltrative c. Microscopic: may range from well-differentiated to highly anaplastic undifferentiated lesions. In well-differentiated tumors, tumor cells resemble hepatocytes and are arranged in trabecular (sinusoidal) or acinar (tubular or pseudoglandular) patterns. Features helpful in determining hepatocellular origin are bile formation in canaliculi (by light microscopy; uncommon in poorly differentiated tumors), cytoplasmic inclusions resembling Mallory bodies, and im- munoperoxidase staining for alpha-fetoprotein. d. Prognosis: Usually grave, but dependent upon tumor stage and coexisting cirrhosis. Fibrolamellar variant of HCC: Arising in the absence of identifiable risk factors or underlying liver disease in children, adolescents and young adults, it is more often resectable, with 60% survival at 5 years. Usually a single, sometimes encapsulated multinodular mass, this variant contains prominent fibrous bands separating trabeculae of large, eosinophilic polygonal hepatocytes. Hyalin globules and PAS-positive inclusions may be present in the cytoplasm of tumor cells. 2. Cholangiocarcinoma: Arising from elements of the intrahepatic biliary tree. a .Etiology: Thorotrast, protracted infection of the biliary tree with clinorchis, other parasites. 5. Gross: unifocal large mass, multifocal, or diffusely infiltrative. c. Microscopic: neoplastic glands and tubules, and may closely resemble adenocarcinomas elsewhere. Dense fibrous stroma, vascular invasion common. d. Prognosis: Dismal, as these tumors are rarely resectable at the time of detection. 3. Mixed HCC-cholangiocarcinoma variants occur rarely. 4, Angiosarcoma: A highly aggressive neoplasm resembling those occuring elsewhere, associated with exposure to vinyl chloride, arsenic and Thorotrast - the latent period has ranged up to several decades. 5.Hepatoblastoma: A rare tumor of infancy recapitulating development of the liver in utero, capable of metastasis (and thus lethal) but sometimes resectable. May be either epithelial (small, compact dark embryonal or fetal hepatocytes) or mixed type (composed of the above cells mixed with those having greater differentiation, and interspersed with foci of mesenchymal differentiation). 6.Metastatic tumors: overwhelming majority of hepatic malignancies. Most commonly from carcinomas of the breast, lung and colon. Typically, multiple implants are present, with massive enlargement of the liver (up to several kg) in advanced cases. 12 docsity.com Gastictntesth . Dr. Glick REFERENCES Davies, S. E., J. Y. N. Lau, J. G. O'Grady, B. C. Portmann, G. J. M. Alexander, and R. Williams. 1992. Evidence that hepatitis D virus needs hepatitis B virus to cause hepatocellular damage. Am. J. Clin. Pathol. 98:554-558. Sherlock, S. 1993. Fulminant hepatic failure. Adv. Intern. Med. 38:245-267. Diener, T, O. 1993. Hepatitis delta virus-like agents: An overview. Prog. Clin. Biol, Res. 382:109-115. Martin, M. 1993. Primary sclerosing cholangitis. Annu. Rev. Med. 44:221-227. Purcell, R. H. 1993. The discovery of the hepatitis viruses. Gastroenterology 104:955-963. Krawezynski, K. 1993. Hepatitis E. Hepatology 17:932-941. Ma, C.K., R. J. Zarbo, H. F. Frierson,Jr., and M. W. Lee. 1993. Comparative immunohistochemical study of primary and metastatic carcinomas of the liver. Am. J. Clin. Pathol. 99:551-557. Scheuer, P. J., P. Ashrafzadeh, $. Sherlock, D. Brown, and G. M. Dusheiko. 1992. The pathology of hepatitis C. Hepatology 15:567-571. Batts, KP, Ludwig J. Chronic hepatitis- an update on terminology and reporting. Am J Surg Pathol 1995; 19:14089-1417. Bach, N., S. N. Thung, and F. Schaffner. 1992. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: A comparative analysis. Hepatology 15:572-577. Gerber, M. A. 1992. Chronic hepatitis C: The beginning of the end of a time- honored nomenclature. Hepatology 15:733-734. Desmet, V. J. 1992. What is congenital hepatic fibrosis. Histopathology 20:465-477. Colombo, M. 1992. Hepatocellular carcinoma. J. Hepatol. 15:225-236. Lissoos, T. W. and B. H. Davis. 1992. Pathogenesis of hepatic fibrosis and the role of cytokines. J. Clin. Gastroenterol. 15:63-67. Rockey, D, C. and S. L. Friedman. 1992. Cytoskeleton of liver perisinusoidal cells (lipocytes) in normal and pathological conditions. Cell Motil. Cytoskeleton 22:227-234. Annick Buendia, M. 1992. Hepatitis B viruses and hepatocellular carcinoma. Adv. Cancer Res. 59:167-226. Ishak KG. Chronic hepatitis: morphology and nomenclature. Hum Pathol 1994; 7:690-713. Soni P, Dusheiko GM, Harrison TJ, Dhillon AP. Genetic diversity of hepatitis C virus: Implications for pathogenesis, treatment, and prevention. Lancet 1995;345:562-566. Scheuer PJ. The nomenclature of chronic hepatitis: Time for a change. J Hepatol 1995;22:112-114. International Working Party. Terminology of chronic hepatitis. Am J Gastroenterol 1995;90:181-189. Teckman J, Perlmutter DH. Conceptual advances in the pathogenesis and treatment of childhood metabolic liver disease. Gastroenterology 1995;108:1263-1279. Bhandari BN, Wright TL. Hepatitis C: An overview. Annu Rev Med 1995;46:309-317. Pinzani M. Novel insights into the biology and physiology of the Ito cell. Pharmacol Ther 1995;66:387-412. Patel T, Gores GJ. Apoptosis and hepatobiliary disease. Hepatology 1995;21:1725-1741. Rubin EM, Martin AA, Thung SN, Gerber MA. Morphometric and immunohistochemical characterization of human liver regeneration. Am J Pathol 1995;147:397-404. Kaplan MM. Primary biliary cirrhosis, N. Engl. J. Med. 1996; 335: 1570-1580. Krawitt EL. Autoimmune hepatitis. N. Engl. J. Med 1996; 334:897-903. Knox TA and Olans LB. Liver disease in pregnancy. N. Engl. J. Med. 1996; 335:569-576. Lee Y M and Kaplan MM. Primary sclerosing cholangitis. N. Engl. J. Med. 1995; 332:924-933. Lee WM. Drug-induced hepatotoxicity. N. Engl. J. Med. 1995; 333: 1118-1127. 13 docsity.com