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Autoimmune Hepatitis: Surviving Crises of Doubt and Elimination

2020; Lippincott Williams & Wilkins; Volume: 15; Issue: S1 Linguagem: Inglês

10.1002/cld.917

2046-2484

Albert J. Czaja,

Hepatitis B Virus Studies

Watch a video presentation of this article Autoimmune hepatitis (AIH) has survived doubts about its existence1-4 and clinical and pathological definitions that have overly restricted its clinical phenotype.5-10 AIH was originally considered to be a disease predominantly of young women associated with hypergammaglobulinemia1, 6-8 and defined by one or the other of its major pathological configurations ("chronic persistent hepatitis" versus "chronic active hepatitis").9, 10 AIH has also survived proposals in favor of putative causative agents that have threatened its validity,11-18 the continuing lack of a signature marker to define its identity,19-22 and reduced investigational and funding priorities because of its rarity.23 The emergence of AIH from its origins as "lupoid hepatitis,"24, 25 "chronic active liver disease" (CALD),26, 27 and "hepatitis B surface antigen (HBsAg)-negative chronic active hepatitis"13, 28 has constituted a learning process that has overcome hurdles of preconceptions, misunderstandings, skepticisms, and biases (Fig. 1), and it has exemplified a maturation process that has involved an international cadre of investigators. Ironically, the attempt that was made by an eminent group of European pathologists—nicknamed by Dame Sheila Sherlock "The Gnomes of Zurich"29—to codify the confusing nomenclature of emerging chronic inflammatory liver conditions actually introduced its own set of confusing terms whose meanings were often not self-explanatory. Perhaps this outcome was to be expected from a "Tower of Babel" cohort comprising Gnomes from Belgium (2), Germany (2), Austria (2), Denmark (1), Switzerland (2), and a single Brit, who spoke the Queen's finest English but whose native language was German. Figure 2 shows a gathering of latter-day Gnomes on a grassy knoll in Belgium. Demonstration of the lupus erythematosus (LE) cell phenomenon in patients with chronic hepatitis was the first clue that this liver disease was different from others with similar manifestations24 (Fig. 1). The preconception had been that the LE cell phenomenon was unique to systemic lupus erythematosus (SLE), and hence there followed the misunderstanding that LE cell-positive liver disease was part of SLE (or would evolve into SLE).1, 30, 31 Hypergammaglobulinemia and a positive response to glucocorticoid therapy supported the possibility that the liver disease was immune mediated,32 but lupoid hepatitis never satisfied criteria for SLE2-4 nor the extant criteria for autoimmunity.33, 34 Ian Mackay (Fig. 3) did not coin the term "lupoid hepatitis" to imply that AIH was part of SLE,30 because even then the two disorders were known to be quite discrete. The objective was to show that the LE cell phenomenon had a broader significance than originally suggested. As a corollary to the foregoing, it should be noted that although liver disease is not uncommon in patients with SLE, AIH occurs only occasionally and is not more prevalent in SLE than in the general population.35 The early treatment trials for AIH were based on management strategies developed for SLE. One regimen, which has been promulgated since 1972,36, 37 was developed after consultation with rheumatologists, but at a time when the critical drug actions and the pathogenic mechanisms of the disease were unclear. The effectiveness of glucocorticoid treatment in the clinical trial spearheaded by Dr. William H.J. Summerskill (Fig. 4) was evident after less than 30 patients had been enrolled in the placebo arm,36 and the results of this trial and other studies38, 39 supported the glucocorticoid-based management regimens that are still used today. The findings of these studies also helped foster the precedent of "diagnosis by treatment response," that is, the diagnostic therapeutic trial, which has yet to be completely eliminated from diagnostic criteria.40 The finding of smooth muscle (SMAs)41 and antinuclear antibodies (ANAs)42 helped solidify the diagnosis, and the demonstration of γ-globulin deposits43, 44 and "piecemeal necrosis" (now called interface hepatitis)45 constituted a distinctive, albeit not pathognomonic, pathological phenotype characterized by "nibbling" destruction of individual hepatocytes along the edges of the portal tracts associated with a lymphocytic infiltrate in the periportal regions (Fig. 5). The clinical phenotype of AIH was also biased by the early clinical descriptions of the disease in young women with cirrhosis, who were sometimes referred to as "Kunkel's girls,"5-8 after the prestigious Rockefeller University, Lasker Awardee immunologist Henry George Kunkel25 (Fig. 6), and by the dictum that chronic hepatitis required 6 months of continuous disease activity to exclude a self-limited acute hepatitis.9, 10 Reports of patients outside this clinical phenotype were rare (or not accepted for publication), and the acceptance of acute or acute severe (fulminant) hepatitis as a presenting manifestation of the disease was slow.46 The early pathological concept that "chronic persistent hepatitis" (portal hepatitis) was nonaggressive9, 47 shaped early management strategies that sought improvement of "chronic active hepatitis" (interface hepatitis) (Fig. 5) to at least "chronic persistent hepatitis."36, 48 Furthermore, the dictum that cirrhosis was irreversible stymied explanations of longevity in treated patients with cirrhosis49, 50 and interpretation of reduced or absent fibrosis in previously cirrhotic tissue samples.51-53 Regression rather than reversal of cirrhosis was gradually accepted as a pathological outcome,54-57 and the application of the Ishak scoring system for fibrosis allowed estimations of this regression.58 The concepts that "chronic persistent hepatitis" could progress to cirrhosis,48 that normal liver tissue was a better treatment result than near-normal liver tissue,28 and advanced hepatic fibrosis could improve with glucocorticoid therapy without invoking sampling error by needle biopsy51-53, 59 were difficult lessons to learn. Discovery of the Australia antigen,60 that is, hepatitis B virus (HBV), and descriptions of drug-induced liver injuries that resembled classical AIH,11, 12, 14 as seen with minocycline, nitrofurantoin, and other medications,61 suggested possible causes of AIH, but these insights mainly refined the diagnostic criteria without eliminating AIH as a distinct and separate diagnosis.40 Notwithstanding, "drug-induced AIH" is sometimes indistinguishable from idiopathic AIH and appears to respond similarly to glucocorticoids.61, 62 Once remission is achieved, however, the challenge is to determine whether glucocorticoids can be stopped permanently (implying a drug-induced etiology) or whether the hepatitis will relapse and indicate idiopathic AIH.61, 62 Discovery of the hepatitis C virus (HCV)63 was the most serious challenge to the existence of AIH,15, 16 and it required retesting and reinterpretation of the early clinical experiences.18 The exclusion of HCV as a causative agent became the strongest validation of AIH.17, 64 An engaging debate arose in the 1990s between Italy and the United Kingdom concerning the role of HCV in the pathogenesis of the infrequently occurring subtype designated type 2 AIH. Unlike the current political wrangling between the European Union and the United Kingdom, the HCV-AIH dispute was resolved easily and amicably by analyses of sera exchanged between the Italian and British laboratories. It emerged that HCV rarely caused bona fide AIH.65-67 Furthermore, anti–liver/kidney microsome type 1 antibody (anti-LKM1) in patients with type 2 AIH reacted against a 13-amino acid sequence in cytochrome P450 2D6 (CYP2D6) that was different from the amino acid sequences recognized by anti-LKM1 in some patients with chronic hepatitis C.68 The findings supported the concept that the LKM1 antibodies were generated in different diseases responding to different epitopes.68 Diagnostic criteria have now been codified,40, 69-71 diagnostic scoring systems have been developed to support clinical judgment,40, 64, 72 autoantibody profiles have been expanded,69, 73, 74 patient subgroups have been defined by serological markers,75 treatment endpoints have been refined,69, 76 and new first-line (budesonide and azathioprine)77 and second-line (mycophenolate mofetil, 6-mercaptopurine, tacrolimus, cyclosporine)78-82 treatment regimens have been introduced (Figs. 1 and 7). Genetic predispositions, which had been described since the 1970s,83, 84 have been confirmed and expanded by high-resolution techniques85-87 and genome-wide associations.88-90 The shortfall of risk based on associations with human leukocyte antigens and genetic polymorphisms has stimulated interest in environmental factors, the intestinal microbiome, and epigenetic changes as pathogenic elements.91, 92 AIH has now established itself as an immune-mediated disease that must be recognized in all age groups,93, 94 genders,95 and ethnicities,96, 97 and in all forms of hepatitis before and after liver transplantation (LT)98-101 (Fig. 1). Its pathogenic mechanisms are still being clarified,102-105 and emerging pharmaceutical and molecular agents promise to target critical pathogenic pathways and individualize therapeutic regimens.106, 107 Biological therapies intended to disrupt key proinflammatory cytokine pathways (infliximab)108 and the activation, proliferation, and survival of B lymphocytes (rituximab and antibodies to B cell–activating factor [anti-BAFF])109, 110 herald the next investigational frontier (Fig. 7). The current clinical phenotype of AIH now includes acute-onset (<30 day) disease, acute severe hepatitis with liver failure (hepatic encephalopathy), asymptomatic progressive disease, autoantibody-negative ("cryptogenic") cirrhosis, variant syndromes with cholestatic features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and graft dysfunction after LT (recurrent and de novo AIH).19, 46, 111-114 The cadre of early pioneers who have described the phenotypes of AIH in adults and children, identified critical pathogenic mechanisms, and spearheaded the development of management strategies that are continuing to evolve are well represented by Ian Mackay,24, 30-32, 41, 83 Sheila Sherlock,8, 38, 42, 47 Roger Williams,39, 66, 85-87, 98 William H.J. Summerskill,2, 13, 26, 27, 36, 37, 53, 84 Ian McFarlane,66, 86 Diego Vergani,66, 68, 69 Giorgina Mieli-Vergani,68, 69 Karl-Hermann Meyer zum Buschenfelde,74 Michael Manns,10, 21, 23, 74, 75, 77 Ansgar Lohse,80 J.C. Homberg,73 Francesco Bianchi,40, 68 Edward Krawitt,64, 69 and Mikio Zeniya.64 The resources of single institutions have become insufficient to investigate the genetic predispositions, environmental and epigenetic factors, emerging biomarkers, and promising new therapies in AIH. National and international multicenter collaborations, exemplified by the International Autoimmune Hepatitis Group, Dutch Autoimmune Hepatitis Study Group, and various Japanese liver study groups, exemplify the research engines that will be necessary to establish new knowledge and direction. Treatment-naive AIH is a rare entity in tertiary referral centers, and this selection bias will appropriately direct investigational priority to second-line or rescue therapies and require large international collaborations to assess new first-line treatments. AIH has survived and flourished with promises still to keep, whereas its major liabilities are complacency with current management strategies and funding neglect. With absolute clarity, Albert Czaja (pronounced Chi-yah) has provided us with a sweeping yet detailed panorama of the evolution of our understanding of AIH. But this authoritative and lucid opus (or should that be lupoid opus?) is nothing less than we have come to expect from the first recipient of the AASLD Distinguished Clinician Educator/Mentor Award (2008) and from a 2016 Mayo Clinic Distinguished Alumnus Awardee, who by the way is a consummate gentleman. The scholarship embodied in this essay should come as no surprise because Albert has spent virtually his entire career (from fellowship at Mayo under his dear mentor Bill Summerskill) to retirement, investigating AIH in the clinic—actually Mayo Clinic—and the laboratory. His prodigious bibliography on the topic (which is evident in this essay) includes his authorship of most of the relevant clinical guidelines on this disease. His care for patients with AIH was always much sought after, from far and near, even since his retirement in 2007. Some aspects of AIH are puzzling, as exemplified in this essay. Although we now understand a great deal about the immunopathogenesis of AIH and its genetics, the precise cause is still somewhat illusory. Moreover, it is intriguing that, for the most part, successful management of AIH is still uncannily similar to the treatment established in clinical trials half a century ago. And yet, as Dr. Czaja points out, there is still opportunity in specialized centers to explore the most avant-garde etiologies, such as environmental factors, the intestinal microbiome, and epigenetic changes as pathogenic elements, and therapies arising therefrom.