- Email: [email protected]
Liver Pathology
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Preface Liver Pathology
Jay H. Lefkowitch, MD Editor
This issue of Gastroenterology Clinics of North America is devoted to liver pathology. It has been a pleasure to serve as guest editor and to assemble an esteemed roster of experts from the United States, Europe, and South Africa to provide their insights (and striking photomicrographs) on a spectrum of “of the moment” topics in hepatology. Over the past decade, IgG4-related disease (IgG4-RD) has entered the differential diagnostic lists of many organ systems. For the liver, the major representation of IgG4RD is either as a biliary tract disease resembling primary sclerosing cholangitis (IgG4sclerosing cholangitis or IgG4-SC) or as a mass obstructing the large bile ducts, resembling cholangiocarcinoma. Drs Chen and Deshpande make an important point about IgG4-RD involving the hepatobiliary system: although it may be an isolated condition, it is usually associated with other organ manifestations (eg, pancreatitis, tubulointerstitial nephritis). The useful photomicrographs and rich characterization of the pathogenesis and epidemiology of this unusual disorder are a helpful diagnostic resource. Pediatric liver disease is represented by articles on nonalcoholic fatty liver disease and interpretation of the pediatric liver biopsy. Drs Fleet and Lavine cover the breadth of current knowledge on the demographics, histopathologic correlates (including the lesion referred to as type 2 nonalcoholic steatohepatitis [type 2 NASH], which involves portal and periportal regions, in contrast to the centrilobular involvement seen in adults with type 1 NASH). The pathogenesis of pediatric NASH is related to multiple hits, and the authors discuss roles for reactive oxygen species, overexpression of cytochrome p450 2E1, activation of hepatic stellate cells, and the adiponectin-leptin axis. Interpretation of pediatric liver biopsies is a unique subspecialty within liver pathology that requires a different set of eyes from adult liver biopsies. As Dr Deborah Schady and Dr Milton Finegold concisely describe in their article, the diseases of neonates and children differ from adult conditions and include extrahepatic biliary atresia, metabolic disorders, mutations of bile salt transporter proteins, and others that may require different diagnostic techniques (transmission electron microscopy, genomic
Gastroenterol Clin N Am - (2017) -–http://dx.doi.org/10.1016/j.gtc.2017.03.001 0889-8553/17/ª 2017 Published by Elsevier Inc.
gastro.theclinics.com
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Preface
analysis, immunohistochemistry) to reach the correct diagnosis. They provide updates on the pathogenesis of biliary atresia (eg, maternal chimeric CD81 T cells as the initial “hit”) and two additional forms of progressive familial intrahepatic cholestasis: types 4 and 5. Their article serves as an excellent “primer” on the spectrum of pediatric liver disease. The issue includes several articles on liver tumors, including hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). The astounding progress made during the last two decades in understanding the pathogenesis of HCAs is highlighted by Paulette Bioulac-Sage and Charles Balabaud. The four recognized types of HCAs are now genomically correlated with their primary pathologic features and include steatotic, atypical, inflammatory, and unclassified types. The subtleties required for the pathologist handling these neoplasms are fully discussed and illustrated in their update. Practitioners who enjoy and/or want to learn more about the morphologic aspects of the liver will appreciate the comprehensive coverage of HCC in all its subtypes in Dr Michael Torbenson’s article. Dr Torbenson subdivides each of the subtypes into categories regarding morphology, clinical findings, molecular correlates, and prognostic elements. Twelve major subtypes, including steatohepatitic, clear cell, cirrhotomimetic, fibrolamellar, and others (including several proposed new candidate subtypes), are discussed at length and are accompanied by outstanding photomicrographs. Further amplification on the immunohistochemical menu available for confirming the presence of HCC (or differentiating it from metastatic neoplasms) is presented in the article by Drs Choi and Kakar. There are multiple articles on medical liver diseases (including posttransplantation issues such as antibody-mediated rejection, or AMR). Dr David Kleiner carefully outlines a pathway for the pathologist to pursue in order to optimize recognition of drug-induced liver injury (DILI). DILI may have a varied histologic spectrum, including cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis. Key images help distinguish among these and other lesions such as eosinophilia and/or granulomas. The clinical and (sometimes) pathologic conundrum of so-called overlap syndromes (autoimmune hepatitis-primary biliary cholangitis and autoimmune hepatitis-primary sclerosing cholangitis) reflects a mismatch of serologic test results and morphologic findings that do not sit happily together. This contentious topic is covered by longtime experts, Drs Czaja and Carpenter, with superb tables that provide enormous clarification. Czaja and Carpenter provide very specific details on approaches to medication that should be most helpful for guiding therapy in these atypical cases. Dr Helen Wainwright and Dr Mark Sonderup provide a masterful and global look at how HIV and its treatment with antiretroviral medications impact the liver. The statistic that 37 million people worldwide are currently living with HIV is astonishing, and for those with concomitant chronic hepatitis B or C, there has been a well-recognized negative prognostic impact. Questions regarding potential DILI from antiretrovirals come up frequently in clinical practice, and their article is extremely helpful in distilling the liver pathology according to each of six classes of antiretroviral drugs (nucleoside reverse transcriptase inhibitors; nonnucleoside reverse transcriptase inhibitors; protease inhibitors; integrase inhibitors; fusion inhibitors; and chemokine receptor antagonists). This is a “must-read” article for pathologists, gastroenterologists, and hepatologists who take care of individuals with HIV. Individuals with acute or chronic heart failure may have serious hepatic complications that come to be further evaluated by liver biopsy, particularly if a heart transplant is contemplated and a possible heart-liver transplantation is on the horizon. In an article from my own medical center with Dr Anne Koehne de Gonzalez, we discuss
Preface
and illustrate the spectrum of morphologic changes in cardiac hepatopathy, from centrilobular congestion to cirrhosis, and rarely, to HCC. Cardiologists increasingly call on the pathologist to stage the degree of fibrosis in order to evaluate the need for combined heart-liver transplantation. In their update on hepatic progenitor cells (HPCs), Drs Matthias Van Haele and Tania Roskams review the role of these fascinating cells in liver disease, their prime location (the canal of Hering between the terminal segment of the bile duct epithelium and hepatocytes), and several of the immunohistochemical stains that are used in their identification, including EpCAM, NCAM, SOX9, CK7, and CK19, among others (Epithelial Cell Adhesion Molecule, Neural Cell Adhesion Molecule/CD56, sex-determining region Y-box 9, cytokeratin 7, and cytokeratin 19, respectively). The authors cite the multiple studies that corroborate that the ductular reaction is derived from activated HPCs, including their own work, which clarified that 50% of liver parenchyma must be lost before HPCs become activated. Senescence of hepatocytes as a driving factor is emphasized. There remains controversy on how regenerative activity and replacement of effete hepatocytes are accomplished, with the authors pointing out that the Zajicek concept of the “streaming liver” (the proceeding of new progeny hepatocytes in a “streaming” gradient from periportal HPCs downward toward the central veins) is at odds with other studies showing the possibility of more local replacement at lobular sites of cell loss, such as a self-renewing centrilobular population of hepatocytes. Although the histopathology of acute cellular rejection following liver transplantation is widely known, the topic of AMR is currently a contentious one, with many unanswered questions (particularly for the hepatic pathologist). What is the best method for demonstrating C4d: immunofluorescence or immunohistochemistry? Dr Michael Lee’s pragmatic approach is to review the described light microscopic features and anticipated C4d staining (all well illustrated) in the context of other diagnostic criteria, including the presence of donor-specific antibodies. I am indebted to all the contributors to this issue who provided such superbly detailed articles and helpful illustrations. I greatly appreciate the invitation to serve as guest editor from the series consulting editor, Dr Norman Gitlin, and Kerry Holland, editor of Gastroenterology Clinics of North America. This issue points up the inextricable interrelationship between clinical hepatology and liver pathology, a link that has existed since the founding days of modern hepatology in the 1950s and continues unchanged into the future. Jay H. Lefkowitch, MD Department of Pathology and Cell Biology Columbia University Medical Center 630 West 168th Street PH 15 West, Room 1574 New York, NY, 10032, USA E-mail address: [email protected]
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Preface Liver Pathology
Jay H. Lefkowitch, MD Editor
This issue of Gastroenterology Clinics of North America is devoted to liver pathology. It has been a pleasure to serve as guest editor and to assemble an esteemed roster of experts from the United States, Europe, and South Africa to provide their insights (and striking photomicrographs) on a spectrum of “of the moment” topics in hepatology. Over the past decade, IgG4-related disease (IgG4-RD) has entered the differential diagnostic lists of many organ systems. For the liver, the major representation of IgG4RD is either as a biliary tract disease resembling primary sclerosing cholangitis (IgG4sclerosing cholangitis or IgG4-SC) or as a mass obstructing the large bile ducts, resembling cholangiocarcinoma. Drs Chen and Deshpande make an important point about IgG4-RD involving the hepatobiliary system: although it may be an isolated condition, it is usually associated with other organ manifestations (eg, pancreatitis, tubulointerstitial nephritis). The useful photomicrographs and rich characterization of the pathogenesis and epidemiology of this unusual disorder are a helpful diagnostic resource. Pediatric liver disease is represented by articles on nonalcoholic fatty liver disease and interpretation of the pediatric liver biopsy. Drs Fleet and Lavine cover the breadth of current knowledge on the demographics, histopathologic correlates (including the lesion referred to as type 2 nonalcoholic steatohepatitis [type 2 NASH], which involves portal and periportal regions, in contrast to the centrilobular involvement seen in adults with type 1 NASH). The pathogenesis of pediatric NASH is related to multiple hits, and the authors discuss roles for reactive oxygen species, overexpression of cytochrome p450 2E1, activation of hepatic stellate cells, and the adiponectin-leptin axis. Interpretation of pediatric liver biopsies is a unique subspecialty within liver pathology that requires a different set of eyes from adult liver biopsies. As Dr Deborah Schady and Dr Milton Finegold concisely describe in their article, the diseases of neonates and children differ from adult conditions and include extrahepatic biliary atresia, metabolic disorders, mutations of bile salt transporter proteins, and others that may require different diagnostic techniques (transmission electron microscopy, genomic
Gastroenterol Clin N Am - (2017) -–http://dx.doi.org/10.1016/j.gtc.2017.03.001 0889-8553/17/ª 2017 Published by Elsevier Inc.
gastro.theclinics.com
ii
Preface
analysis, immunohistochemistry) to reach the correct diagnosis. They provide updates on the pathogenesis of biliary atresia (eg, maternal chimeric CD81 T cells as the initial “hit”) and two additional forms of progressive familial intrahepatic cholestasis: types 4 and 5. Their article serves as an excellent “primer” on the spectrum of pediatric liver disease. The issue includes several articles on liver tumors, including hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). The astounding progress made during the last two decades in understanding the pathogenesis of HCAs is highlighted by Paulette Bioulac-Sage and Charles Balabaud. The four recognized types of HCAs are now genomically correlated with their primary pathologic features and include steatotic, atypical, inflammatory, and unclassified types. The subtleties required for the pathologist handling these neoplasms are fully discussed and illustrated in their update. Practitioners who enjoy and/or want to learn more about the morphologic aspects of the liver will appreciate the comprehensive coverage of HCC in all its subtypes in Dr Michael Torbenson’s article. Dr Torbenson subdivides each of the subtypes into categories regarding morphology, clinical findings, molecular correlates, and prognostic elements. Twelve major subtypes, including steatohepatitic, clear cell, cirrhotomimetic, fibrolamellar, and others (including several proposed new candidate subtypes), are discussed at length and are accompanied by outstanding photomicrographs. Further amplification on the immunohistochemical menu available for confirming the presence of HCC (or differentiating it from metastatic neoplasms) is presented in the article by Drs Choi and Kakar. There are multiple articles on medical liver diseases (including posttransplantation issues such as antibody-mediated rejection, or AMR). Dr David Kleiner carefully outlines a pathway for the pathologist to pursue in order to optimize recognition of drug-induced liver injury (DILI). DILI may have a varied histologic spectrum, including cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis. Key images help distinguish among these and other lesions such as eosinophilia and/or granulomas. The clinical and (sometimes) pathologic conundrum of so-called overlap syndromes (autoimmune hepatitis-primary biliary cholangitis and autoimmune hepatitis-primary sclerosing cholangitis) reflects a mismatch of serologic test results and morphologic findings that do not sit happily together. This contentious topic is covered by longtime experts, Drs Czaja and Carpenter, with superb tables that provide enormous clarification. Czaja and Carpenter provide very specific details on approaches to medication that should be most helpful for guiding therapy in these atypical cases. Dr Helen Wainwright and Dr Mark Sonderup provide a masterful and global look at how HIV and its treatment with antiretroviral medications impact the liver. The statistic that 37 million people worldwide are currently living with HIV is astonishing, and for those with concomitant chronic hepatitis B or C, there has been a well-recognized negative prognostic impact. Questions regarding potential DILI from antiretrovirals come up frequently in clinical practice, and their article is extremely helpful in distilling the liver pathology according to each of six classes of antiretroviral drugs (nucleoside reverse transcriptase inhibitors; nonnucleoside reverse transcriptase inhibitors; protease inhibitors; integrase inhibitors; fusion inhibitors; and chemokine receptor antagonists). This is a “must-read” article for pathologists, gastroenterologists, and hepatologists who take care of individuals with HIV. Individuals with acute or chronic heart failure may have serious hepatic complications that come to be further evaluated by liver biopsy, particularly if a heart transplant is contemplated and a possible heart-liver transplantation is on the horizon. In an article from my own medical center with Dr Anne Koehne de Gonzalez, we discuss
Preface
and illustrate the spectrum of morphologic changes in cardiac hepatopathy, from centrilobular congestion to cirrhosis, and rarely, to HCC. Cardiologists increasingly call on the pathologist to stage the degree of fibrosis in order to evaluate the need for combined heart-liver transplantation. In their update on hepatic progenitor cells (HPCs), Drs Matthias Van Haele and Tania Roskams review the role of these fascinating cells in liver disease, their prime location (the canal of Hering between the terminal segment of the bile duct epithelium and hepatocytes), and several of the immunohistochemical stains that are used in their identification, including EpCAM, NCAM, SOX9, CK7, and CK19, among others (Epithelial Cell Adhesion Molecule, Neural Cell Adhesion Molecule/CD56, sex-determining region Y-box 9, cytokeratin 7, and cytokeratin 19, respectively). The authors cite the multiple studies that corroborate that the ductular reaction is derived from activated HPCs, including their own work, which clarified that 50% of liver parenchyma must be lost before HPCs become activated. Senescence of hepatocytes as a driving factor is emphasized. There remains controversy on how regenerative activity and replacement of effete hepatocytes are accomplished, with the authors pointing out that the Zajicek concept of the “streaming liver” (the proceeding of new progeny hepatocytes in a “streaming” gradient from periportal HPCs downward toward the central veins) is at odds with other studies showing the possibility of more local replacement at lobular sites of cell loss, such as a self-renewing centrilobular population of hepatocytes. Although the histopathology of acute cellular rejection following liver transplantation is widely known, the topic of AMR is currently a contentious one, with many unanswered questions (particularly for the hepatic pathologist). What is the best method for demonstrating C4d: immunofluorescence or immunohistochemistry? Dr Michael Lee’s pragmatic approach is to review the described light microscopic features and anticipated C4d staining (all well illustrated) in the context of other diagnostic criteria, including the presence of donor-specific antibodies. I am indebted to all the contributors to this issue who provided such superbly detailed articles and helpful illustrations. I greatly appreciate the invitation to serve as guest editor from the series consulting editor, Dr Norman Gitlin, and Kerry Holland, editor of Gastroenterology Clinics of North America. This issue points up the inextricable interrelationship between clinical hepatology and liver pathology, a link that has existed since the founding days of modern hepatology in the 1950s and continues unchanged into the future. Jay H. Lefkowitch, MD Department of Pathology and Cell Biology Columbia University Medical Center 630 West 168th Street PH 15 West, Room 1574 New York, NY, 10032, USA E-mail address: [email protected]
iii