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• W1520228078 abstract "Hepatitis C virus—autoimmune hepatitis (HCV-AIH) overlap syndrome has been described in the literature since the early 1990s with numerous case reports and proposed guidelines of management.1-5 However, definitive diagnosis and appropriate therapy for the syndrome remain controversial and there are still no formalized treatment strategies. Azhar and associates describe the case of a 40-year-old woman with HCV-AIH who was treated initially with steroids and immunosuppression and subsequently with consensus interferon (Infergen; interferon alfacon-1, Three Rivers Pharmaceuticals) and ribavirin with success.6 This case raises a number of important and interesting points concerning the diagnosis, management, and potential pitfalls of treatment.The diagnosis of true HCV-AIH is often challenging, as the concurrent presence of serologic markers typically found in AIH and serologic evidence of HCV infection is well documented.7,8 EIA-3, the third-generation enzyme-linked immunosorbent assay anti-HCV screening test, which is currently used in many institutions, appears to have increased sensitivity in the high-prevalence setting9 and more than 99% specificity in the blood donor population.10 However, autoantibodies such as antinuclear antibody (ANA), antismooth muscle antibody, or anti—liver and kidney microsomal 1 antibody have been reported in 9-38%, 5-91%, and 0-10%, respectively, of patients with chronic HCV infection.4 Therefore, in order to definitively diagnose HCV-AIH overlap syndrome as a distinct entity, the existence of both diseases must be confirmed independently. The diagnosis of HCV is relatively straightforward, as evidenced by positive antibody +/- viremia, though a modest proportion (up to 19%) of patients with AIH do demonstrate HCV RNA in their serum.5 The International Autoimmune Hepatitis Group (IAIHG) has defined 3 categories for diagnosing AIH: not AIH, probable AIH, and definite AIH.11 Prospective validation of these cohorts has suggested a sensitivity of 97-100% for the diagnosis of AIH.12,13 These criteria were subsequently revised in 1999.14 More recently,15 the IAIHG has streamlined the diagnostic criteria, with a sharper focus on the clinical diagnosis of AIH, with the aim of making the criteria more readily usable. According to the 1999 criteria, the patient reported by Azhar and colleagues at most meets criteria for probable AIH, as positive viral markers and biliary changes on histology decrease the overall score significantly. According to the simplified criteria, using the patient's provided laboratory values yields an overall score of 5, whereas a score of 6 or greater is required to make a diagnosis of probable AIH. Furthermore, as it has been pointed out,16 and as evidenced by the scoring systems, a higher titer of ANA confers a higher likelihood of definite AIH. In this case, the ANA titer, though positive, was only 1:80 in the presence of HCV and thus not typical of true HCV-AIH overlap syndrome.Histologic diagnosis of the overlap syndrome is another important consideration. Although no single histologic feature is pathognomonic of either HCV or AIH, distinct composite histologic patterns have been described for each entity. In general, patients with AIH are more likely to have severe lobular necrosis and inflammation, piecemeal necrosis, multinucleated hepatocytes, and broad areas of parenchymal collapse, whereas patients with HCV are more likely to have bile duct damage, bile duct loss, steatosis, and lymphoid cell follicles within portal tracts. The combination of portal lymphoid aggregates and steatosis was found to have 91% specificity for HCV, whereas the pattern of lymphoplasmacytic portal, interface, and acinar hepatitis had 81% specificity for AIH.17 The most common histologic pattern in liver biopsies of patients with HCV-AIH overlap syndrome is consistent with AIH, though the HCV pattern and a mixture of both AIH and HCV patterns can also be present. In addition, the AIH histologic pattern is associated with higher serum levels of γ-globulins and a higher frequency of cirrhosis, compared to the HCV pattern.18 In the current case, although necroinflammatory changes are more consistent with AIH, they can also be seen in HCV; bile duct damage and steatohepatitis together significantly favor a diagnosis of HCV. Thus, the biopsy is more suggestive of HCV with autoimmune features.Another important consideration is the type of treatment once a diagnosis of HCV-AIH overlap syndrome is made. The discordant forms of treatment for HCV infection and AIH have made medical management of this overlap syndrome difficult. Administration of interferon to patients with HCV infection complicated by autoimmune features has led to an exacerbation of the underlying AIH.19,20 In fact, it has been recently shown that a de novo type of AIH can develop after liver transplantation secondary to interferon treatment for HCV.21,22 In contrast, an improvement of serum aminotransferase levels in patients with chronic HCV infection has been observed with corticosteroid administration; however, complete normalization of liver chemistry tests (LCT) rarely occurs in these patients.23 In addition, these biochemical improvements are frequently accompanied by increased levels of viremia.24 As noted by the authors, according to most experts, the approach to the management of patients with HCV-AIH overlap syndrome must start with the determination of the predominant entity to allow for the selection of the most appropriate form of therapy.25 In cases where one disease does not appear to predominate, a possible approach may be to target the more treatable disease first, such as HCV genotype 2 or 3.Given these general considerations, there are a number of important management questions that pertain to this case. Due to the potential challenges and concerns that treatment of one disease could exacerbate the other, clinicians may be reluctant to commence any treatment at all and employ a watch-and-wait approach. In our experience, and as demonstrated by this case, the longterm benefits of treatment usually outweigh the risks. As noted above, the most pressing question is often which entity to tackle first. In this case, given the apparent predominance of HCV, as well as the favorable genotype, the use of interferon initially may have been more prudent. Another question is the choice of treatment for the AIH component. The authors initially used prednisone and azathioprine and then changed to mycophenolate mofetil (Cellcept, Roche Palo) due to a suboptimal response. Patients with true AIH demonstrate a rather rapid response to steroid treatment; therefore, the lack of complete response after 4 months of treatment may have been an indication that the HCV component was the main contributor to the persistently elevated LCT. Additionally, although the investigators increased the dose of azathioprine to 1.5 mg/kg/day, the literature appears to support maximizing the dose of azathioprine in nonresponsive patients to 2 mg/kg/day.3 Furthermore, although mycophenolate mofetil is now well-accepted as second line treatment for AIH, much data indicate that it is not more efficacious for patients who do not respond to first line therapy and should mainly be reserved for those who are unable to tolerate the side effects of azathioprine.26 Finally, clinicians should be aware that azathioprine itself can cause an increase in LCT during therapy.Another important consideration is when to discontinue treatment of one disease entity and when to consider treating the other. The authors continued treatment of AIH for approximately 9 months prior to starting the HCV treatment because of an insufficient biochemical response. One may argue that, when possible, a second liver biopsy should be performed to gauge any interval disease change after therapy. Furthermore, a biopsy may elucidate whether the patient should be converted to the second form of treatment completely or whether the initial therapy should be continued in some form, as the authors chose to do with mycophenolate mofetil. This is particularly important given the considerable hematologic side-effect profile of this medication, which may further complicate HCV treatment. We agree with the choice of consensus interferon, rather than the pegylated form, given the concern for possible flares of AIH during HCV treatment and to allow better control of the side effects of the interferon. In addition, there are emerging data showing that pegylated interferon itself may induce autoimmune antibodies and other phenomena.27,28Despite many case reports and much data on the overlap of HCV and AIH, this syndrome remains poorly elucidated. Although there are some recommendations in the literature, methods to secure a definitive diagnosis and treatment strategy continue to be controversial. Recent trends indicate that the best approach may be to determine the more predominant and easily treated entity and then to employ sequential therapy based upon this information. Nevertheless, these decisions remain extremely challenging, and clinicians must use their clinical knowledge and cautiously treat each patient on an individual basis. We applaud the investigators for their success, though we may have made slightly different choices. However, it is clear that, in most cases, offering treatment of one disease, using the above approach, though riddled with anxiety, will likely be beneficial to the patient." @default.
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• W1520228078 title "A new approach for treatment of hepatitis C in hepatitis C-autoimmune hepatitis overlap syndrome." @default.
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