Hepatobiliary System





Viral Hepatitis


Clinical Features


Hepatitis A Virus





  • Single-stranded RNA (ssRNA) virus (picornavirus)



  • Transmission route: fecal-oral



  • Incubation: 2 to 6 weeks



  • Self-limited



  • Not associated with chronic carrier state, chronic hepatitis, or hepatocellular carcinoma (HCC)



Hepatitis B Virus





  • Partially circular double-stranded DNA virus (hepadnavirus)



  • Transmission route: perinatal, sexual, and parenteral



  • Incubation: 6 to 8 weeks



  • Chronic infection (10%): persistent serum hepatitis B surface antigen (HBsAg) more than 6 months after diagnosis



  • Associated with chronic hepatitis, fulminant hepatitis, cirrhosis, and HCC



  • Anti-HBsAg confers long-term immunity



Hepatitis C Virus





  • ssRNA virus (flavivirus-like)



  • Transmission route: parenteral



  • Incubation: 6 to 12 weeks



  • Highest rate of chronic hepatitis (60% to 80%) and persistent infection



  • Associated with cirrhosis and HCC



  • Anti-hepatitis C virus (HCV) does not confer immunity



  • Serum transaminases: fluctuating



Hepatitis D (Delta Agent) Virus





  • Defective RNA virus requiring HBsAg (envelope protein) for infectivity



  • Transmission route: parenteral



  • Associated with more severe course of HBV infection, cirrhosis, and HCC



Hepatitis E Virus





  • ssRNA virus



  • Water-borne infection



  • Incubation: 6 weeks



  • Virion shed in stools



  • Usually self-limited



  • High mortality rate among pregnant women



Hepatitis G Virus





  • Nonpathogenic



Gross Pathology





  • Noncontributory



Histopathology


Acute Viral Hepatitis


Injury is predominantly hepatocellular in the acini (zone 3)




  • General features




    • Predominantly lymphocytic infiltrate, usually conspicuous in zone 3



    • Swollen hepatocytes with rarefied and granular cytoplasm



    • Apoptotic hepatocytes showing pyknotic nuclear remnants, shrunken and dense cytoplasm



    • Liver cell dropout with replacement by small groups of lymphocytes and macrophages




  • Specific features




    • Hepatitis A virus (HAV): perivenular cholestasis; hepatitis with periportal inflammation (interface hepatitis) and dense portal infiltrate, including abundant plasma cells



    • HBV: ground-glass hepatocytes (indicating abundant HBsAg in the hepatocytes—evidence of viral infection) ( Figure 7.1A )




      Figure 7.1


      A, Ground-glass hepatocytes in hepatitis B. B, Chronic hepatitis C. Classic lymphoid aggregates with focal mild interface hepatitis.




Chronic Viral Hepatitis





  • Persistent liver injury with positive viral serology and/or nucleic acid test, and abnormally high serum aminotransferase of greater than 6 months’ duration



  • Injury is accentuated in the portal and periportal regions



  • General features




    • Portal inflammatory infiltrate predominantly composed of lymphocytes with or without interface hepatitis of varying severity (see Figure 7.1B )



    • Spotty or confluent necrosis with or without bridging necrosis



    • Portal fibrous expansion, periportal fibrosis, bridging fibrosis to cirrhosis (stages 1 to 4)




  • Specific features




    • HBV: ground-glass hepatocytes



    • HCV: lymphoid aggregates or follicles with or without germinal centers, focal mild macrovesicular steatosis, damaged interlobular bile ducts




Special Stains and Immunohistochemistry





  • Immunohistochemistry for hepatitis B core antigen (HBcAg), HBsAg, and hepatitis B e antigen (HBeAg)



Other Techniques for Diagnosis





  • Electron microscopy: HBsAg in hepatocyte cytoplasm (22-nm spheres and rods)



Differential Diagnosis





  • Serologic markers and virologic assays of viral infection are virtually essential to establish or exclude the diagnosis



Alcoholic Hepatitis





  • Clinical history is important



  • Fatty change is typical but not always present



  • Many ballooned hepatocytes and Mallory-Denk bodies are usually seen



  • Megamitochondria may be seen



  • Lobular inflammatory foci (usually rich in neutrophils)



  • Perivenular and pericellular fibrosis (chicken-wire pattern)



Nonalcoholic Steatohepatitis





  • Significant steatosis is present, predominantly macrovesicular



  • Zone 3 injury with lobular inflammatory foci pattern in adults



  • Zone 1 injury with portal inflammatory dominant pattern in children



  • Ballooned hepatocytes and Mallory-Denk bodies are typical findings



  • Megamitochondria may be seen



  • Perivenular and pericellular fibrosis (chicken-wire pattern) in adults



  • Fibrosis initiates in portal tracts in children



Autoimmune Hepatitis





  • Serologic markers important (positive antinuclear antibody [ANA], anti–smooth muscle antibody [ASMA], or liver-kidney microsomal antibody [LKM])



  • Coexistent autoimmune diseases are common



  • Prominent plasma cells in the portal and periportal region or deep within the parenchyma



  • Marked interface hepatitis and parenchymal activity



  • Bridging necrosis is common and may form hepatitis rosettes



Epstein-Barr Virus Hepatitis





  • Seen more often after transplantation



  • Marked sinusoidal lymphoplasmacytic inflammatory infiltrate characteristically in single-file arrangement



  • Marked hepatocellular regeneration



  • EBV encoded RNA in situ hybridization may be helpful



Primary Biliary Cholangitis





  • Bile ductular reaction



  • Florid duct lesion with granuloma



  • Damage and loss of interlobular bile duct



  • Positive antimitochondrial antibody (AMA)



  • Cholestatic picture



Primary Sclerosing Cirrhosis





  • Bile ductular reaction



  • Periductal fibrosis and loss of interlobular bile duct



  • Association with ulcerative colitis is common



  • Characteristic beading on endoscopic retrograde cholangiopancreatography (ERCP)



Drug-Induced Liver Injury





  • Clinical history is important (time course of drug use)



  • Negative serologic markers of viral infection



Pearls





  • Serologic markers (viral and autoimmune), virologic assays, as well as the pattern of hepatic enzyme elevations are most important in distinguishing the many causes of hepatitis.





Selected References




  • Batts K.P., Ludwig J.: Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995; 19: pp. 1409-1417.



  • Gerber M.A., Thung S.N.: The diagnostic value of immunohistochemical demonstration of hepatitis viral antigens in the liver. Hum Pathol 1987; 18: pp. 771-774.



  • Goodman Z.D., Ishak K.G.: Histopathology of hepatitis C infection. Semin Liver Dis 1995; 15: pp. 70-81.



  • Ishak K.G.: Chronic hepatitis: morphology and nomenclature. Mod Pathol 1994; 7: pp. 690-713.



  • Sciot R., Van Damme B., Desmet V.J.: Cholestatic features in hepatitis A. J Hepatol 1986; 3: pp. 172-181.


Nonviral Infections


Clinical Features





  • High mortality rate



  • Patients often have fever and right upper quadrant tenderness



  • Surgical drainage is often required



  • Bacterial abscesses are caused by portal spread of extrahepatic infection with Staphylococcus aureus, Salmonella typhi, and Treponema pallidum (syphilis)



  • Parasitic abscesses are caused by Entamoeba histolytica, Echinococcus species, malaria, Leishmania species, Ascaris lumbricoides , and liver flukes (e.g., Clonorchis sinensis, Fasciola hepatica , and Opisthorchis viverrini )



Gross Pathology





  • Bacteremic spread through arterial or portal system: multiple, soft, grossly necrotic lesions



  • Bacteremic spread by direct extension or trauma: solitary, large, soft, grossly necrotic lesions



Syphilis





  • Single or multiple soft well-circumscribed lesions (gummas) that eventually scar, resulting in hepar lobatum, which grossly resembles cirrhosis



Entamebiasis





  • Well-circumscribed lesion containing thick, dark material



Echinococcal (Hydatid) Cyst





  • Space-occupying cystic lesion with internal daughter cysts



  • Granular cyst contents (hydatid sand) composed of scolices and hooklets



Ascariasis





  • Numerous foul-smelling cavities



Malaria and Leishmaniasis





  • Hepatomegaly (secondary Kupffer cell hyperplasia)



Histopathology


Bacterial





  • Marked neutrophilic infiltrate with hepatocyte destruction ( Figure 7.2A )




    Figure 7.2


    A, Bacterial abscess. Low-power view shows liver parenchyma with marked necrosis. B, Amebic abscess. Liver tissue showing necrotic debris with trophozoites at the center of the photomicrograph.



Syphilis





  • Congenital: neonatal hepatitis



  • Tertiary: gummas (granulomatous abscesses), which heal as dense scars



Entamebiasis





  • Necrotic debris with trophozoites at the periphery (see Figure 7.2B )



Echinococcal Infection





  • Outer laminated nonnuclear layer, inner nucleated germinal layer with attached capsules containing numerous scolices that are released into the cyst cavity and give rise to daughter cysts



  • Secondary cholangitis results from obstruction of intrahepatic bile ducts



Ascariasis





  • Necrotic debris with granulomatous and eosinophilic response to degenerated parasites



Liver Flukes





  • Biliary epithelial hyperplasia, cholangitis, and periductal fibrosis



Malaria





  • Kupffer cell hyperplasia and phagocytosis of ruptured erythrocytes



Leishmaniasis





  • Kupffer cell hyperplasia and phagocytosis of organisms (Donovan bodies)



Special Stains and Immunohistochemistry





  • Gram stain: helps highlight bacteria



  • Warthin-Starry, Dieterle stain, or T. pallidum immunohistochemistry: syphilis



  • Giemsa stain to identify amastigotes: leishmaniasis



  • Direct examination for Echinococcus species scolices and liver flukes



Other Techniques for Diagnosis





  • Culture or nucleic acid tests may help identify organism



Differential Diagnosis





  • See earlier discussion for specific infection characteristics



Pearls





  • Amebic abscesses are more likely to spread into the thoracic cavity.



  • Echinococcal cysts should be removed intact, due to risk of severe allergic reactions with disruption .





Selected References




  • Bissada A.A., Bateman J.: Pyogenic liver abscesses: a 7-year experience in a large community hospital. Hepatogastroenterology 1991; 38: pp. 17-20.



  • Koneman E.W.Allen S.D.Woods G.L. et. al.Color Atlas and Textbook of Diagnostic Microbiology.2005.Lippincott Williams & WilkinsPhiladelphia:pp. 1244-1326.


Drug-Induced Liver Injury


Clinical Features





  • Clinical history important (e.g., ingesting an agent known to cause liver disease)



  • An appropriate time interval between exposure and onset of disease



  • A histologic lesion known to be associated with the suspect drug



  • Resolution of the lesion after withdrawal



  • Can be acute or chronic



  • Correlation with laboratory testing (e.g., acetaminophen level) may be helpful



  • Drug-specific clinical presentations and literature references are available from LiverTox ( livertox.nlm.nih.gov.easyaccess1.lib.cuhk.edu.hk/ )



Histopathology





  • Different agents may result in different liver injury patterns, such as the following:




    • Zone 3 hepatocellular necrosis: acetaminophen



    • Mimicking acute viral hepatitis: antituberculous drugs, anesthetics, herbal medicine, nonsteroidal antiinflammatory drugs



    • Cholestasis with duct damage and duct loss: amoxicillin and clavulanic acid (Augmentin)



    • Vanishing bile duct: chlorpromazine, amoxicillin and flucloxacillin, haloperidol, temozolomide



    • Microvesicular steatosis: valproic acid, tetracycline, nucleoside analogues, salicylate (Reye syndrome)



    • Hypertrophic hepatic stellate cells and perivenular and pericellular fibrosis: hypervitaminosis A



    • Sinusoidal obstruction syndrome/veno-occlusive disease: pyrrolizidine alkaloids or chemotherapeutic agents associated with bone marrow transplantation



    • Steatohepatitis-like: amiodarone, tamoxifen, methotrexate



    • Hepatitis with features of autoimmune hepatitis: anti-TNFα immunomodulators, immune checkpoint inhibitors




  • Drug toxicity should always enter the differential diagnosis when abundant eosinophils or epithelioid granulomas are present or when hepatitis and cholestasis are both present



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Viral Hepatitis





  • Positive serologic markers or viral nucleic acid tests



  • Immunohistochemistry may help to detect viral antigens (e.g., HBV, cytomegalovirus [CMV], herpes simplex virus [HSV], EBV)



Autoimmune Hepatitis





  • Positive ANA, ASMA, and anti-LKM



  • Prominent plasma cells



  • Responds to corticosteroids



Biliary Obstruction





  • Imaging studies may help



Primary Biliary Cholangitis





  • Positive AMA



  • Florid duct lesion



Pearls





  • Careful correlation of past and present history is essential, including use of herbal remedies and over-the-counter medications .



  • Rule out other liver diseases .





Selected References




  • Geller S.A., Petrovic L.M.: Effects of drugs and toxins on the liver.Geller S.A.Petrovic L.M.Biopsy Interpretation of the Liver.2004.Lippincott Williams & WilkinsPhiladelphia:pp. 111-124.



  • Kleiner D.E.: Drugs and toxins.Burt A.D.Ferrell L.D.Hubscher S.G.MacSween’s Pathology of the Liver.2018.Churchill LivingstoneLondon:pp. 673-753.



  • Kleiner D.E.: Recent advances in the histopathology of drug-induced liver injury. Surg Pathol Clin 2018; 11: pp. 297-311.



  • Zen Y., Yeh M.M.: Checkpoint inhibitor-induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol 2019; 36: pp. 434-440.



  • Zimmerman H.J.: Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver.2nd ed.1999.Lippincott Williams & WilkinsPhiladelphia


Alcoholic Liver Disease and Alcoholic Steatohepatitis


Clinical Features





  • Nonspecific symptoms including malaise, anorexia, weight loss, and tender hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase



  • About 20% to 25% of heavy drinkers develop alcoholic steatohepatitis



Gross Pathology





  • Early: large, soft, greasy, yellow liver



  • Late: shrunken, mottled, red-brown liver with bile staining



  • End-stage: cirrhosis



Histopathology





  • Steatosis



  • Zone 3 injury pattern



  • Ballooning degeneration ( Figure 7.3A )




    Figure 7.3


    Steatohepatitis.

    A, Macrovesicular fat with ballooned hepatocyte and lobular inflammatory infiltrate. B, Mallory-Denk bodies are present in the ballooned hepatocytes with associated inflammatory foci. C, Pericellular and perisinusoidal fibrosis (chicken-wire pattern).



  • Lobular inflammatory infiltrates, especially rich in neutrophils



  • Mallory-Denk bodies and megamitochondria (see Figure 7.3B )



  • Perivenular and pericellular fibrosis (see Figure 7.3C )



  • Bile ductular reaction



  • Sclerosing hyaline necrosis



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Clinical history is essential



Chronic Viral Hepatitis





  • Positive serologic and/or virologic markers of viral infection



  • Hepatocellular injury and initiation of fibrosis are more marked in the periportal areas, as opposed to alcoholic steatohepatitis (perivenular and pericellular fibrosis and hepatocellular injury predominantly in zone 3 region)



  • Mallory-Denk bodies are more common in steatohepatitis



Fatty Liver of Pregnancy





  • Typically occurs in third trimester of pregnancy



  • Steatosis is microvesicular



Nonalcoholic Steatohepatitis





  • Steatosis is essential



  • Neutrophilic aggregates (satellitosis) are not common



  • Glycogenated nuclei are more common



  • Sclerosing hyaline necrosis or veno-occlusive lesion are not present



Pearls





  • Major pathologic effects of alcohol are caused by interference with lipid metabolism, mitochondrial damage, and cytoskeletal injury .



  • Genetically determined susceptibility is thought to account for the fact that only 20% to 25% of heavy drinkers develop alcoholic steatohepatitis, whereas individuals with minimal to no alcohol intake may develop histologically identical nonalcoholic steatohepatitis .





Selected References




  • Brunt E.M.: Alcoholic and nonalcoholic steatohepatitis. Clin Liver Dis 2002; 6: pp. 399-420.



  • Geller S.A., Petrovic L.M.: Alcoholic liver disease.Geller S.A.Petrovic L.M.Biopsy Interpretation of the Liver.2004.Lippincott Williams & WilkinsPhiladelphia:pp. 134-149.



  • Scheuer P.J., Lefkowitch J.H.: Fatty liver and lesions in the alcoholic.Scheuer P.J.Lefkowitch J.H.Liver Biopsy Interpretation.2000.WB SaundersLondon:pp. 111-133.


Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis


Clinical Features





  • A manifestation of the metabolic (insulin resistance) syndrome



  • Risk factors: central obesity, hyperglycemia, type II diabetes, arterial hypertension, and hypertriglyceridemia



  • Nonalcoholic steatohepatitis (NASH) is the progressive lesion of nonalcoholic fatty liver disease (NAFLD), which may progress to cirrhosis and liver failure



  • Histologically, NASH is almost identical to alcoholic steatohepatitis but occurs in individuals who do not have significant alcohol history



Gross Pathology





  • Early: large, soft, greasy, yellow liver



  • Late: shrunken, mottled, red-brown liver with bile staining



  • End-stage: cirrhosis



Histopathology





  • Nonspecific steatosis in NAFLD



  • Predominantly macrovesicular fatty change



  • Typically starts in a zone 3 centrilobular pattern



Nonalcoholic Steatohepatitis





  • In adults, begins as a zone 3 injury pattern consisting predominantly of macrovesicular steatosis, ballooned hepatocytes, and lobular inflammation



  • In children, begins as a zone 1 injury pattern with steatosis and inflammation accentuated in periportal regions, and initiation of fibrosis in portal tracts



  • Pigmented macrophages and acidophile bodies can be seen



  • Cytoplasmic Mallory-Denk bodies (fibrillary eosinophilic material composed of intermediate cytokeratin filaments associated with ubiquitin)



  • Zone 3 perivenular and pericellular fibrosis (chicken-wire pattern), which progresses to central-portal bridging



  • Cirrhosis (end-stage disease)



  • A NAFLD activity scoring (NAS) system designed and validated by the NASH Clinical Research Network including assessment of steatosis, lobular inflammation, hepatocellular ballooning, and a separate staging scheme for fibrosis can be used after establishing the diagnosis of NASH for the evaluation of disease activity and stage before and after mitigation of NASH



Special Stains and Immunohistochemistry





  • Immunohistochemical stains for ubiquitin and p62 have been developed to identify Mallory-Denk bodies.



  • Rearrangement of the intermediate filament cytoskeleton in ballooned hepatocytes can be demonstrated by the loss of cytoplasmic keratin 8/18 immunostaining and may be evaluated as a marker for the more objective detection of hepatocellular ballooning in NASH.



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Clinical history is essential



Chronic Viral Hepatitis





  • Positive serologic/virologic markers of viral infection



  • Inflammation is more accentuated in the portal and periportal areas



  • Fibrosis initiates in portal regions



  • Mallory-Denk bodies are more common in steatohepatitis



Fatty Liver of Pregnancy





  • Typically occurs in third trimester of pregnancy



  • Steatosis is microvesicular



Biliary Obstruction (Especially PBC)





  • Mallory-Denk bodies may be present and would most likely be seen in periportal as opposed to pericentral areas.



Wilson Disease





  • Mallory-Denk bodies may be present and would most likely be seen in periportal as opposed to pericentral areas



  • Marked copper overload



Indian Childhood Cirrhosis





  • Occurs almost exclusively in India



  • Mallory-Denk bodies are often present



  • Steatosis conspicuously absent



  • Marked copper overload



Pearls





  • Presence of Mallory-Denk bodies associated with lobular inflammatory infiltrates and steatosis (predominantly macrovesicular) in a zone 3 injury pattern suggests alcoholic or nonalcoholic steatohepatitis .



  • Mallory-Denk bodies may be present in other pathologic processes, including chronic cholestatic disease, Wilson disease, Indian childhood cirrhosis, and even HCCs (about 10%) .





Selected References




  • Brunt E.M.: Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001; 21: pp. 3-16.



  • Brunt E.M.: Nonalcoholic steatohepatitis: pathologic features and differential diagnosis. Semin Diagn Pathol 2005; 22: pp. 330-338.



  • Guy C.D., Suzuki A., Burchette J.L., Brunt E.M., et. al.: Nonalcoholic steatohepatitis clinical research network. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocytes injury in nonalcoholic fatty liver disease. Hum Pathol 2012; 43: pp. 790-800.



  • Kleiner D.E., Brunt E.M., Van Natta M., et. al.: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: pp. 1313-1321.



  • Yeh M.M., Brunt E.M.: Pathologic features of fatty liver disease. Gastroenterology 2014; 147: pp. 754-764.


Acute Fatty Liver of Pregnancy


Clinical Features





  • Onset typically occurs during third trimester of pregnancy



  • Bleeding, nausea and vomiting, jaundice, and occasionally coma



  • Usually resolves after delivery



Gross Pathology





  • Greasy, small, pale-yellow liver



Histopathology





  • Microvesicular steatosis ( Figure 7.4 )




    Figure 7.4


    Acute fatty liver of pregnancy.

    Marked microvesicular transformation of hepatocytes.



  • Canalicular and intrahepatocytic cholestasis may occur



  • Portal tract inflammation may be prominent



Special Stains and Immunohistochemistry





  • Oil red O (on frozen-section slide) demonstrates microvesicular fat droplets.



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Clinical history is essential



Drug-Induced Liver Injury





  • May show similar histologic features (e.g., tetracycline, valproic acid, nucleoside analogues), which are all associated with microvesicular fatty change



  • Clinical history is required for definitive distinction



Reye Syndrome





  • Also shows microvesicular steatosis



  • History of aspirin use



  • Associated with encephalopathy



Hepatitis C Virus





  • Typically shows macrovesicular steatosis



  • Shows lobular hepatitis and portal lymphoid aggregates



Alcoholic Steatohepatitis





  • Mallory-Denk bodies are typically prominent and often associated with a neutrophilic infiltrate



Pearls





  • Onset during pregnancy, usually third trimester



  • Pathogenesis: defective intramitochondrial fatty acid oxidation





Selected References




  • Kaplan M.M.: Acute fatty liver of pregnancy. N Engl J Med 1985; 313: pp. 367-370.



  • Liu J., Ghaziani T.T., Wolf J.L.: Acute fatty liver disease of pregnancy: updates in pathogenesis, diagnosis, and management. Am J Gastroenterol 2017; 112: pp. 838-846.



  • Riely C.A.: Acute fatty liver of pregnancy. Semin Liver Dis 1987; 7: pp. 47-54.



  • Rolfes D.B., Ishak K.G.: Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. Hepatology 1985; 5: pp. 1149-1158.


Hemochromatosis


Clinical Features





  • Abnormal accumulation of iron in liver, pancreas, myocardium, and other organs



  • Hereditary: homozygous recessive, loss of function in the HFE gene



  • Acquired: multiple transfusions, Bantu hemosiderosis (alcoholic beverages brewed in iron drums in sub-Saharan Africa)



  • Most often presents in men older than 40 years



  • Liver is the most severely affected organ



  • Classic triad: cirrhosis, skin pigmentation, and diabetes mellitus (not as common now owing to early diagnosis and treatment)



  • Patients may also have abdominal pain, cardiac dysfunction, and atypical arthritis



  • Laboratory studies show increased serum iron and ferritin



  • Increased risk for developing HCC



Gross Pathology





  • Enlarged liver with dark-brown pigmentation



  • Ultimately leads to cirrhosis with persistent dark-brown pigmentation



Histopathology





  • Early: hemosiderin granules in cytoplasm of periportal hepatocytes



  • Middle:




    • Progressive iron deposition in lobules and eventually bile duct epithelium and Kupffer cells, resulting in hepatocyte necrosis, portal inflammation, and portal and bridging fibrosis ( Figure 7.5A )




      Figure 7.5


      Hemochromatosis.

      A, Hepatocytes containing a large amount of iron. B, Prussian blue stain is strongly positive, highlighting the massive iron deposits.



    • Lobular inflammation typically absent




  • Late: fibrous septa develop over years with progression to cirrhosis with intense hemosiderin pigmentation



Special Stains and Immunohistochemistry





  • Prussian blue stain for iron highlights increased iron deposition (see Figure 7.5B )



Other Techniques for Diagnosis





  • Hepatic iron index (HII): biochemical quantitation of hepatic iron in fresh tissue or paraffin block calculated as micromoles of iron per gram dry weight divided by patient’s age




    • Homozygotes: HII greater than 2 (may be greater than 40)



    • Heterozygotes: less than 2



    • Normal individuals: less than 1




  • Nucleic acid testing for germline loss-of-function variants in the HFE gene, most commonly C282Y and/or H63D



Differential Diagnosis


Hemosiderosis





  • Patients typically have a cause for secondary iron overload (e.g., multiple transfusions, porphyria cutanea tarda, or chronic dietary iron overload as in Bantu siderosis).



Cirrhosis of Nonbiliary Etiology





  • Common to have iron overload in cirrhosis due to nonbiliary etiology (e.g., HCV, alcohol, NASH)



Pearls





  • Iron is directly hepatotoxic; no inflammatory mediators released .



  • Women are less commonly affected and present later as a result of physiologic blood loss during menstruation and pregnancy .



  • Treatment is reduction of iron overload by phlebotomy .





Selected References




  • Bacon B.R., Britton R.S.: The pathology of hepatic iron overload: a free radical-mediated process. Hepatology 1990; 11: pp. 127-137.



  • Brunt E.M.: Pathology of hepatic iron overload. Semin Liver Dis 2005; 25: pp. 392-401.



  • Deugnier Y.M., Loreal O., Turlin B., et. al.: Liver pathology in genetic hemochromatosis: a review of 135 cases and their bioclinical correlations. Gastroenterology 1992; 104: pp. 228-234.



  • Deugnier Y.M., Turlin B., Powell L.W., et. al.: Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histologic hepatic iron index: a study of 192 cases. Hepatology 1993; 17: pp. 30-34.


Wilson Disease


Clinical Features





  • Abnormal accumulation of copper in liver, brain, eyes, and other organs



  • Variable age of onset



  • Autosomal recessive, mutations in the ATP7B gene encoding a copper transporter



  • Laboratory findings include decreased serum ceruloplasmin, increased hepatic copper, increased urinary excretion of copper



  • Serum copper levels not helpful



  • Most commonly presents with acute or chronic liver disease



  • Neuropsychiatric symptoms are also frequent at presentation secondary to involvement of basal ganglia



  • Kayser-Fleischer rings are diagnostic (green-brown deposits of copper in Descemet membrane in limbus of cornea)



Gross Pathology





  • Liver eventually becomes cirrhotic



Histopathology





  • Excessive copper granules in hepatocytes can only be seen with special stain ( Figure 7.6 )




    Figure 7.6


    Wilson disease.

    High-power view shows liver cells containing cytoplasmic copper pigment.



  • Mild to moderate fatty change



  • Focal hepatocyte necrosis



  • Glycogen vacuoles in hepatocyte nuclei



  • Mallory-Denk bodies in periportal hepatocytes



  • Acute and chronic hepatitis



  • Cirrhosis following chronic hepatitis



  • Rarely, massive liver necrosis



Special Stains and Immunohistochemistry





  • Rhodanine stain for copper positive



  • Orcein stain for copper-associated protein positive



Other Techniques for Diagnosis





  • Quantitation of hepatic copper in fresh tissue or paraffin block (more than 250 μg copper/1 g dry liver), typically with mass spectrometry



  • Sequencing of ATP7B gene



Differential Diagnosis


Viral Hepatitis





  • Serologic/virologic markers are positive



  • No accumulation of copper



Chronic Obstructive Cholestasis





  • Lesser degree of copper accumulation



Pearls





  • Normally free copper is absorbed in the stomach and duodenum, weakly bound to albumin, transferred to hepatocytes, and incorporated into α 2 -globulin to form ceruloplasmin, which is re-secreted into plasma; senescent ceruloplasmin is taken up by hepatocytes, degraded by lysosomes, and copper excreted into bile .



  • Wilson disease gene is ATP7B on chromosome 13 and encodes a transmembrane copper-transporting adenosine triphosphatase (ATPase) located on canalicular membrane of hepatocytes .



  • Treatment is copper chelation with D-penicillamine .





Selected References




  • Ludwig J., Moyer T.P., Rakela J.: The liver biopsy diagnosis of Wilson’s disease: methods in pathology. Am J Clin Pathol 1994; 102: pp. 443-446.



  • Sternlieb I.: Perspectives on Wilson’s disease. Hepatology 1990; 12: pp. 1234-1239.



  • Stremmel W., Meyerrose K.W., Niederau C., et. al.: Wilson disease: clinical presentation, treatment and survival. Ann Intern Med 1991; 115: pp. 720-726.



  • Stromeyer F.W., Ishak K.G.: Histology of the liver in Wilson’s disease: a study of 34 cases. Am J Clin Pathol 1980; 73: pp. 12-24.


α 1 -Antitrypsin Deficiency


Clinical Features





  • Variable age of onset



  • Autosomal recessive disease caused by mutations of the SERPINA1 gene on chromosome 14



  • Absent or decreased α 1 -antitrypsin activity results in unchecked activity of neutrophilic elastase leading to pulmonary emphysema (destruction of elastic fibers supporting alveolar spaces)



  • The most common variant protein (E366K) associated with liver disease is abnormally folded, resulting in impaired transport to the Golgi and accumulation in the endoplasmic reticulum of hepatocytes



  • In some patients, there is liver disease without pulmonary emphysema owing to functional mutant forms that inhibit neutrophil elastase but that are not appropriately degraded in hepatocytes



  • Clinical hepatic presentations range from:




    • Neonatal hepatitis with cholestatic jaundice



    • Young adults with recurrent attacks of hepatitis that either resolve or lead to chronic hepatitis and cirrhosis



    • Middle-aged to older adults with cirrhosis after a clinically silent course




  • Increased risk for HCC, especially in homozygous patients



  • Successful liver transplantation is curative



  • Augmentation therapy with intravenous α 1 -antitrypsin delays the natural course of lung disease, but does not impact liver disease



Gross Pathology





  • Noncontributory



Histopathology





  • Round to oval, variably sized eosinophilic globules most concentrated in periportal hepatocytes



  • Otherwise variable histologic features




    • Neonatal hepatitis with or without cholestasis



    • Chronic hepatitic picture



    • Cirrhosis




Special Stains and Immunohistochemistry





  • Eosinophilic globules are positive for periodic acid–Schiff (PAS) and resistant to diastase digestion ( Figure 7.7 )




    Figure 7.7


    α 1 -Antitrypsin deficiency.

    Hepatocytes containing intracytoplasmic eosinophilic globules (periodic acid–Schiff stain with diastase).



  • Immunohistochemistry for α 1 -antitrypsin highlights eosinophilic globules



Other Techniques for Diagnosis





  • Serum α 1 -antitrypsin quantitation (<85 mg/dL is highly predictive)



  • Serum protein electrophoresis with reduction in alpha-1 band (not specific)



  • Identification of common variant proteins by mass spectrometry, or genetic variants by allele-specific PCR or sequencing of SERPINA1



  • Identification of mutant proteins by isoelectric focusing




    • About 75 variants identified and named alphabetically according to migration on isoelectric gel




  • Normal genotype is PiMM



  • PiZZ is the most clinically significant genotype and shows the highest association with carcinoma



  • Patients with PiMZ genotype have 50% normal α 1 -antitrypsin and 50% mutant form



  • Other mutant alleles include S (reduced levels of α 1 -antitrypsin but no clinical disease unless inherited in combination with another mutation) and null (no detectable protein)



Differential Diagnosis





  • Other types of chronic hepatitis include viral, drug, and autoimmune hepatitis, but they do not demonstrate the PAS-positive and diastase-resistant globules that are characteristic of α 1 -antitrypsin deficiency



Pearls





  • α 1 -Antitrypsin deficiency is one of the few liver diseases that can still be diagnosed in an end-stage liver explant because of the PAS-positive and diastase-resistant globules that remain in the hepatocyte cytoplasm.



  • This is a multifactorial disease in which there are heterogeneous genetic mutations, resulting in highly variable clinical presentations even among members of individual families .





Selected References




  • Clark V.C., Marek G., Collinsworth A., et. al.: Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol 2018; 69: pp. 1357-1364.



  • Cohen C., Derose P.B.: Liver cell dysplasia in alpha 1-antitrypsin deficiency. Mod Pathol 1994; 7: pp. 31-36.



  • Deutsch J., Becker H., Aubock L.: Histopathological features of liver disease in alpha-1-antitrypsin deficiency. Acta Paediatr 1994; 393: pp. 8-12.



  • Lomas D.A., Evans D.L., Finch J.T., et. al.: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992; 57: pp. 605-607.



  • Propst T., Propst A., Dietze O., et. al.: Alpha-1-antitrypsin deficiency and liver disease. Dig Dis 1994; 12: pp. 139-149.


Autoimmune Hepatitis


Clinical Features





  • Young and middle-aged women (female-to-male ratio of 7:3)



  • Often associated with extrahepatic autoimmune disorders such as rheumatoid arthritis, thyroiditis, Sjögren syndrome



  • Hyperglobulinemia



  • Characterized by serum autoantibodies, classically ANA, ASMA, soluble liver antigen (SLA), and anti-LKM1



  • Negative viral serologic/virologic markers



  • Responsive to immunosuppressive therapy



Gross Pathology





  • Noncontributory



Histopathology





  • Significant portal and periportal inflammatory infiltrate with lymphocytes and plasma cells (prominent plasma cells are the hallmark) ( Figure 7.8 )




    Figure 7.8


    Autoimmune hepatitis.

    A, Low-power magnification shows marked interface hepatitis and lobular inflammation. B, Prominent portal and periportal infiltrate of plasma cells.



  • Marked lobular inflammatory infiltrate with prominent plasma cells deep in the parenchyma



  • Increased lobular acidophil/apoptotic bodies



  • Prominent interface hepatitis



  • Bridging/confluent necrosis is common



  • Severe hepatocellular injury with hepatitic rosette formation and syncytial giant hepatocytes



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Drug-Induced Liver Injury





  • Clinical correlation and medication history including over-the-counter drugs is important in the differential diagnosis of this disease.



Chronic Viral Hepatitis





  • Positive virologic and serologic markers



  • Plasma cells less prominent



  • Milder lobular hepatitis and interface hepatitis (especially in HCV)



Pearls





  • Most frequent in young women and associated with hyperglobulinemia and various serologic markers of autoimmune disease



  • Rosette formation, although not specific, is highly suggestive of autoimmune hepatitis



  • This is one of the few forms of chronic hepatitis that responds well to immunosuppressive therapy





Selected References




  • Bach N., Thung S.N., Schaffner F.: The histologic changes of chronic hepatitis C and autoimmune hepatitis: a comparative study. Hepatology 1992; 15: pp. 572-577.



  • Czaja A.J.: Autoimmune hepatitis: evolving concepts and treatment strategies. Dig Dis Sci 1995; 40: pp. 435-456.



  • Johnson P.J., McFarlane I.G.: Meeting report. International autoimmune hepatitis group. Hepatology 1993; 18: pp. 998-1005.



  • Tiniakos D.G., Brain J.G., Bury Y.A.: Role of histopathology in autoimmune hepatitis. Dig Dis 2015; 33: pp. 53-64.



  • Washington M.K.: Autoimmune liver disease: overlap and outliers. Mod Pathol 2007; 20: pp. S15-S30.


Primary Biliary Cholangitis


Clinical Features





  • Most commonly occurs in middle-aged women



  • Serum AMA positive in more than 90% of cases



  • Insidious onset, with pruritus being the most common presenting symptom and jaundice developing later



  • Elevated serum alkaline phosphatase, with hyperbilirubinemia developing later



  • Chronic and progressive, with cirrhosis developing only after many years



Gross Pathology





  • Early: unremarkable



  • Late: finely granular capsule; bile-stained parenchyma



  • Ultimately liver becomes cirrhotic (biliary type cirrhosis)



Histopathology





  • Variability in stages of lesions (i.e., coexistence of different stages in single specimen)



  • Stage I (florid duct lesion) : focal destruction of small and medium-sized bile ducts by granulomatous inflammation; bile duct epithelium irregular and hyperplastic; dense portal tract infiltrate of lymphocytes, macrophages, plasma cells, and eosinophils ( Figure 7.9 )




    Figure 7.9


    Primary biliary cholangitis.

    A portal tract shows granulomatous inflammation, chronic inflammatory infiltrate, and paucity of bile ducts.



  • Stage II (ductular reaction) : disappearance of small bile ducts; scarring of medium-sized bile ducts; proliferation of bile ductules in portal tracts; inflammation and interface hepatitis of adjacent periportal hepatic parenchyma



  • Stage III (scarring) : small and medium-sized ducts scarce; little inflammation in fibrous septa or parenchyma; lymphoid aggregates with or without PASD-positive material representing residual basement membrane material in areas where ducts have been lost



  • Stage IV (cirrhosis) : cirrhosis, often with a jigsaw pattern



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Primary Sclerosing Cholangitis





  • Characterized by periductal fibrosis and typical ERCP findings



  • Lacks the florid duct lesion seen in PBC



  • Occurs in young men as opposed to middle-aged women



  • Negative AMA



  • Often associated with ulcerative colitis



Autoimmune Hepatitis–Primary Biliary Cholangitis Overlap Syndrome





  • AMA and ANA positive with histologic features of both PBC and autoimmune hepatitis (more than the usual degree of lobular hepatitis, interface hepatitis, and plasma cell infiltrate)



Autoimmune Cholangitis





  • Histologically identical to PBC



  • Patients are AMA negative and ANA positive



Graft-Versus-Host Disease and Liver Transplant Rejection





  • Clinical history important



  • Both can cause bile duct injury, lymphocytic cholangitis, and vanishing bile duct syndrome, which can resemble PBC



Pearls





  • AMAs are against E2 subunit of pyruvate dehydrogenase complex on interlobular bile ducts in PBC



  • Generally believed to be an autoimmune disease



  • Liver transplantation is definitive treatment





Selected References




  • Berk P.D.: Primary biliary cirrhosis, Parts I and II. Semin Liver Dis 1997; 17: pp. 1-250.



  • Lacerda M.A., Ludwig J., Dickson E.R., et. al.: Antimitochondrial antibody-negative primary biliary cirrhosis. Am J Gastroenterol 1995; 90: pp. 247-249.



  • Mahl T.C., Shockcor W., Boyer J.L.: Primary biliary cirrhosis: survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years. J Hepatol 1994; 20: pp. 707-713.



  • Sherlock S.: Primary biliary cirrhosis: clarifying the issues. Am J Med 1994; 96: pp. 27S-33S.


Primary Sclerosing Cholangitis


Clinical Features





  • More common in men in the third to fifth decades



  • Characteristic beaded appearance of intrahepatic biliary tree by contrast radiography (ERCP) due to irregular strictures and secondary dilations of affected bile ducts



  • About 70% of cases are associated with ulcerative colitis (conversely, only 4% of patients with ulcerative colitis have primary sclerosing cholangitis [PSC])



  • Elevated alkaline phosphatase and bilirubin; pANCA may be positive



  • Increased risk of cholangiocarcinoma (terminal event in about 10% of patients with PSC)



Gross Pathology





  • Early: unremarkable



  • Late: bile-stained, biliary-type cirrhosis



Histopathology





  • Characterized by fibroinflammatory stricture of the bile ducts anywhere from the ampulla of Vater to the interlobular bile ducts



  • Stage I (portal) : concentric periductal fibrosis and lymphocytic inflammation in portal tracts ( Figure 7.10A )




    Figure 7.10


    Primary sclerosing cholangitis.

    A, Histologic section of a portal field showing concentric periductal fibrosis. B, Histologic section of a portal field showing chronic inflammation and obliteration of the bile duct.



  • Stage II (periportal) : fibrosis extends into periportal parenchyma, interface hepatitis, and bile ductular reaction



  • Stage III (septal) : obliteration of bile ducts and bridging fibrosis (see Figure 7.10B )



  • Stage IV (cirrhotic) : biliary-type cirrhosis (jigsaw pattern)



  • Features of chronic cholestasis, especially pseudoxanthomatous changes, are commonly seen



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Well-Differentiated Cholangiocarcinoma





  • Heterogeneity of cells within individual glands



  • Perineural invasion often seen



  • Radiologic information is helpful



Primary Biliary Cholangitis





  • Occurs more commonly in middle-aged women



  • Typically positive for AMA



  • Florid duct lesions followed by absence of bile duct as opposed to the fibroinflammatory obliteration of ducts seen in PSC



Extrahepatic or Large Duct Intrahepatic Biliary Obstruction





  • Can give rise to a secondary sclerosing cholangitis similar to PSC



  • Features suggestive of secondary cholangitis include marked ductular reaction and severe cholestasis with inspissated bile, which is often green and laminated



  • Often see marked pseudoxanthomatous change and rapid onset (months) of biliary cirrhosis


Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hepatobiliary System
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