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Regression of human cirrhosis: an update, 18 years after the pioneering article by Wanless et al.

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Abstract

Cirrhosis has been traditionally viewed as an irreversible, end-stage condition. Eighteen years ago, Wanless, Nakashima, and Sherman published a study that was based on the concept that hepatic architecture is under constant remodeling in the course of chronic liver diseases, even during their most advanced stages; depending on the balance between injury and repair, the histologic changes might be progressing or regressing. These authors described in detail the morphologic features of regressing cirrhosis, identified a set of histologic features of regression that they called the “hepatic repair complex,” and provided convincing morphologic evidence that incomplete septal cirrhosis represents regressed cirrhosis. In the years that followed publication of this pioneering article, a number of clinical studies with performance of pre- and post-treatment liver biopsies provided abundant evidence that cirrhosis can regress after successful therapy of chronic hepatitis B, chronic hepatitis C, autoimmune hepatitis, and genetic hemochromatosis. Evidence for other chronic liver diseases may also be provided in the future, pending ongoing studies. Successful therapy allows resorption of fibrous septa, which can be followed by loss of nodularity and architectural improvement; however, many vascular lesions of cirrhotic livers are not thought to regress. Cases of cirrhosis that are considered more likely to improve than others include those of recent onset, with relatively thin fibrous septa and mild vascular changes. Histologic examination of liver biopsy specimens from patients with chronic liver diseases provides the opportunity to appreciate the features of the hepatic repair complex on a routine diagnostic basis; however, interpretation is often difficult, and can be aided by immunohistochemical stains. Clinicopathologic correlation is essential for a meaningful assessment of such cases. For many patients, cirrhosis is not an end-stage condition anymore; therefore, use of the term “cirrhosis” has been challenged, almost 200 years after its invention. However, regression of cirrhosis does not imply regression of molecular changes involved in hepatocarcinogenesis; therefore, surveillance for hepatocellular carcinoma should be continued in these patients.

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References

  1. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH (1977) The morphology of cirrhosis: definition, nomenclature, and classification. Bull World Health Organ 55:521–540

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M (2010) Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis. Hepatology 51:1445–1449

    Article  PubMed  PubMed Central  Google Scholar 

  3. Laennec RTH (1819) De l’auscultation mediate. Vol. 1. Brosson et Claude, Paris, pp 368–369

    Google Scholar 

  4. Wanless IR, Nakashima E, Sherman M (2000) Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 124:1599–1607

    PubMed  CAS  Google Scholar 

  5. Pérez-Tamayo R (1979) Cirrhosis of the liver: a reversible disease? Pathol Annu 14(Pt 2):183–213

    PubMed  Google Scholar 

  6. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19:1513–1520

    Article  PubMed  CAS  Google Scholar 

  7. Friedman SL (1999) Hepatic fibrosis. In: Schiff ER, Sorrell MF, Maddrey WC (eds) Schiff's diseases of the liver, 8th edn. Lippincott-Raven, Philadelphia, p 371

    Google Scholar 

  8. Sciot R, Staessen D, Van Damme B, Van Steenbergen W, Fevery J, De Groote J, Desmet VJ (1988) Incomplete septal cirrhosis: histopathological aspects. Histopathology 13:593–603

    Article  PubMed  CAS  Google Scholar 

  9. Chejfec G (2000) Controversies in pathology: is cirrhosis of the liver a reversible disease? Arch Pathol Lab Med 124:1585–1586

    PubMed  CAS  Google Scholar 

  10. Geller SA (2000) Coming or going? What is cirrhosis? Arch Pathol Lab Med 124:1587–1588

    PubMed  CAS  Google Scholar 

  11. Ray MB (2000) Regression of cirrhosis: a timely topic. Arch Pathol Lab Med 124:1589–1590

    PubMed  CAS  Google Scholar 

  12. Chedid A (2000) Regression of human cirrhosis. Arch Pathol Lab Med 124:1591–1592

    PubMed  CAS  Google Scholar 

  13. Wanless IR (2000) In reply. Arch Pathol Lab Med 124:1592–1593

    Google Scholar 

  14. Kutami R, Girgrah N, Wanless IR, Sniderman K, Wong F, Sherman M (2000) The Laennec grading system for assessment of hepatic fibrosis: validation by correlation with wedged hepatic vein pressure and clinical features. Hepatology 32:407A

    Google Scholar 

  15. Kim MY, Cho MY, Baik SK, Park HJ, Jeon HK, Im CK, Won CS, Kim JW, Kim HS, Kwon SO, Eom MS, Cha SH, Kim YJ, Chang SJ, Lee SS (2011) Histological subclassification of cirrhosis using the Laennec fibrosis scoring system correlates with clinical stage and grade of portal hypertension. J Hepatol 55:1004–1009

    Article  PubMed  Google Scholar 

  16. Kim SU, Oh HJ, Wanless IR, Lee S, Han KH, Park YN (2012) The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis. J Hepatol 57:556–563

    Article  PubMed  Google Scholar 

  17. Dienstag JL, Goldin RD, Heathcote EJ, Hann HWL, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER (2003) Histological outcome during long-term lamivudine therapy. Gastroenterology 124:105–117

    Article  PubMed  CAS  Google Scholar 

  18. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J, Brosgart CL, Borroto-Esoda K, Arterburn S, Chuck SL, Adefovir Dipivoxil 438 Study Group (2006) Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 131:1743–1751

    Article  PubMed  CAS  Google Scholar 

  19. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z, Chi YC, Zhang H, Hindes R, Iloeje U, Beebe S, Kreter B (2010) Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52:886–893

    Article  PubMed  CAS  Google Scholar 

  20. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ (2013) Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381(9865):468–475

    Article  PubMed  CAS  Google Scholar 

  21. Papachrysos N, Hytiroglou P, Papalavrentios L, Sinakos E, Kouvelis I, Akriviadis E (2015) Antiviral therapy leads to histological improvement of HBeAg-negative chronic hepatitis B patients. Ann Gastroenterol 28:374–378

    PubMed  PubMed Central  Google Scholar 

  22. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling M–H, Albrecht J (2002) Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 122:1303–1313

    Article  PubMed  CAS  Google Scholar 

  23. Everson GT, Balart L, Lee SS et al (2008) Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis. Aliment Pharmacol Ther 27:542–551

    Article  PubMed  CAS  Google Scholar 

  24. D'Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, Paradis V, Colombo M, Bedossa P (2012) A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56:532–543

    Article  PubMed  Google Scholar 

  25. Dufour JF, DeLellis R, Kaplan MM (1997) Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 127:981–985

    Article  PubMed  CAS  Google Scholar 

  26. Czaja AJ, Carpenter HA (2004) Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 40:646–652

    Article  PubMed  CAS  Google Scholar 

  27. Serpaggi J, Carnot F, Nalpas B, Canioni D, Guéchot J, Lebray P (2006) Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol 37:1519–1526

    Article  PubMed  Google Scholar 

  28. Falize L, Guillygomarc'h A, Perrin M, Lainé F, Guyader D, Brissot P, Turlin B, Deugnier Y (2006) Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 44:472–477

    Article  PubMed  Google Scholar 

  29. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M (2015) Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149:367–378

    Article  PubMed  Google Scholar 

  30. Friedman SL, Ratziu V, Harrison SA et al (2017) A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology

  31. Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E (1983) Conversion of micronodular cirrhosis into macronodular cirrhosis. Hepatology 3:928–931

    Article  PubMed  CAS  Google Scholar 

  32. Quaglia A, Alves VA, Balabaud C, Bhathal PS, Bioulac-Sage P, Crawford JM, et al, International Liver Pathology Study Group (2016) Role of aetiology in the progression, regression, and parenchymal remodelling of liver disease: implications for liver biopsy interpretation. Histopathology 68:953–967

    Article  PubMed  Google Scholar 

  33. Kaplan MM, DeLellis RA, Wolfe HJ (1997) Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 126:682–688

    Article  PubMed  CAS  Google Scholar 

  34. Grand RJ, Vawter GF (1975) Juvenile Wilson disease: histologic and functional studies during penicillamine therapy. J Pediatr 87:1161–1170

    Article  PubMed  CAS  Google Scholar 

  35. Lee YA, Wallace MC, Friedman SL (2015) Pathobiology of liver fibrosis: a translational success story. Gut 64:830–841

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, Theise ND (2003) Regeneration of hepatocyte “buds” in cirrhosis from intrabiliary stem cells. J Hepatol 39:357–364

    Article  PubMed  CAS  Google Scholar 

  37. Crawford JM, Bioulac-Sage P, Hytiroglou P (2018) Structure, function, and responses to injury. In: Burt AD, Ferrell LD, Huebscher SG (eds) MacSween’s pathology of the liver, 7th edn. Elsevier, Philadelphia, pp 1–87

    Google Scholar 

  38. Bedossa P, Hytiroglou P, Yeh MM (2018) Vascular disorders. In: Burt AD, Ferrell LD, Huebscher SG (eds) MacSween’s pathology of the liver, 7th edn. Elsevier, Philadelphia, pp 636–672

    Chapter  Google Scholar 

  39. Wanless IR, Liu JJ, Butany J (1995) Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 21:1232–1237

    PubMed  CAS  Google Scholar 

  40. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G (1995) Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 21:1238–1247

    PubMed  CAS  Google Scholar 

  41. Caldwell S, Intagliata N (2012) Dismantling the myth of “autocoagulation” in cirrhosis: an old dogma dies hard. Hepatology 55:1634–1637

    Article  PubMed  Google Scholar 

  42. Intagliata NM, Northup PG (2015) Anticoagulant therapy in patients with cirrhosis. Semin Thromb Hemost 41:514–519

    Article  PubMed  CAS  Google Scholar 

  43. van der Meer AJ, Berenguer M (2016) Reversion of disease manifestations after HCV eradication. J Hepatol 65(1 Suppl):S95–S108

    Article  PubMed  Google Scholar 

  44. Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P (2015) Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 62:956–967

    Article  PubMed  Google Scholar 

  45. Theise ND (1996) Cirrhosis and hepatocellular neoplasia: more like cousins than like parent and child. Gastroenterology 1996(111):526–528

    Article  Google Scholar 

  46. Theise ND, Park YN, Kojiro M (2002) Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis 6:497–512

    Article  PubMed  Google Scholar 

  47. Hytiroglou P, Park YN, Krinsky G, Theise ND (2007) Hepatic precancerous lesions and small hepatocellular carcinoma. Gastroenterol Clin N Am 36:867–887 vii

    Article  Google Scholar 

  48. Sun Y, Zhou J, Wang L, Wu X, Chen Y, Piao H, Lu L, Jiang W, Xu Y, Feng B, Nan Y, Xie W, Chen G, Zheng H, Li H, Ding H, Liu H, Lv F, Shao C, Wang T, Ou X, Wang B, Chen S, Wee A, Theise ND, You H, Jia J (2017) New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment. Hepatology 65:1438–1450

    Article  PubMed  CAS  Google Scholar 

  49. Hytiroglou P, Snover DC, Alves V, Balabaud C, Bhathal PS, Bioulac-Sage P, Crawford JM, Dhillon AP, Ferrell L, Guido M, Nakanuma Y, Paradis V, Quaglia A, Theise ND, Thung SN, Tsui WMS, van Leeuwen DJ (2012) Beyond "cirrhosis": a proposal from the international liver pathology study group. Am J Clin Pathol 137:5–9

    Article  PubMed  Google Scholar 

  50. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K (2015) Changing nomenclature for PBC: from 'cirrhosis' to 'cholangitis'. Hepatology 62:1620–1622

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Aristotle University Medical School, 54006, Thessaloniki, Greece

    Prodromos Hytiroglou

  2. Department of Pathology, New York University School of Medicine, 550 First Avenue, TH415, New York, NY, 10016, USA

    Neil D. Theise

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  1. Prodromos Hytiroglou
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This is part of a topical collection entitled "Vascular liver lesions: contemporary views on long-recognized entities"

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Hytiroglou, P., Theise, N.D. Regression of human cirrhosis: an update, 18 years after the pioneering article by Wanless et al.. Virchows Arch 473, 15–22 (2018). https://doi.org/10.1007/s00428-018-2340-2

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