Autoimmune hepatitis (AIH) remains a disease without a diagnostic marker, and one that is as much an art to manage as is scientific discipline. As a broadly presenting clinical entity, AIH is a chronic and relapsing disease that nestles amongst a family of autoimmune liver diseases that likely share varying genetic risk, but have differing environmental triggers . In spite of the best efforts of Hepatologists to understand this apparently mixed group of hepatitic processes better, patients still undergo a series of investigations designed to exclude alternate better diagnoses, at which point, in the absence of a viral, metabolic or toxic insult, immunosuppression is initiated .
Immune serology represents an area of laboratory testing which has the potential to introduce some disease specificity into clinical practice. The best example of this is of course the presence of anti-mitochondrial antibodies, which albeit not infallible, do indicate a high probability of diagnosing primary biliary cirrhosis when tested and documented in the correct clinical context [3, 4]. Highly disease specific antinuclear antibody profiles are also seen in PBC, which have been reported to not only aid diagnosis when anti-mitochondrial antibodies are absent, but which also appear to have prognostic utility, and which segregate associated HLA risk [5, 6]. Autoimmune hepatitis as a whole has a less notable direct association with autoantibodies, with most patients (AIH-1) having serological profiles, antinuclear antibody or smooth muscle antibody, that are not immediately within the apparent disease pathway, and which may not always be present when making a diagnosis, nor which have a direct therapeutic relationship. Type 2 autoimmune hepatitis is much less common, especially in North American practice, but does differ from type 1 disease, by its clinical presentation and tighter serologic specificity: although the AIH-1-specific ANA and SMA targets are clearly in need of better definition, those of anti-LKM1 (autoantibodies against liver and kidney microsomal antigens) and anti-LC1 (liver cytosol type 1 antigen) in AIH-2 have been refined. Their refinement means ironically that the immunological science behind AIH-2 is much clearer, and is presently driving concepts of AIH disease pathogenesis and future treatments .
Although most patients with AIH do well if compliant with appropriately administered treatment (and dramatically so if one recalls the now unseen natural history of untreated disease), there are recognized risk factors for poor outcomes based on clinical parameters. Patients who fail therapy clinically are younger, with higher levels of bilirubin and MELD scores, and more often have an acute presentation [8, 9]. There is also a higher frequency of carriage of HLA DRB1*03 in patients failing therapy. The HLA remains the only genetic association with AIH that is robustly defined, with other risk loci still awaiting to be reliably confirmed, as cohorts of robustly defined AIH are slowly assembled for genome wide, immunochip and sequencing evaluation .
A third group of AIH was initially proposed with the discovery of antisoluble liver antigen (SLA) autoantibodies . Although it is now clear that anti-SLA seropositive patients do not define a subgroup of AIH, but rather belong to the AIH-1 group, this marker, unlike ANA and SMA may be of clinical utility not just for the seronegative patients with AIH-1 for whom treatment is as effective if promptly begun, but also in predicting disease severity [12-15]. Antibodies to SLA [reactive against a transfer ribonucleoprotein involved in the transport of selenocysteine ] have been associated with marked hepatitis, a need for more intense treatment and relapse.
The family affair that is autoimmunity has further pointed clinicians in a direction of evaluating other autoantibodies from alternate autoimmune diseases in patients with AIH. In our local unpublished clinic practice we observed that 37% had co-existing autoimmune disease (the leading three diseases being hypothyroidism, systemic lupus and inflammatory bowel disease) whereas 26% gave a family history of autoimmune disease. Confirmed overlap with PSC was seen less commonly in 6% of patients whereas confirmed overlap with PBC in only 3%. Although it is not frequent that AIH overlaps with primary Sjögrens (in one study eight out of 475 patients with Sjögrens had AIH ), antibodies to Ro/SSA have been recognized in AIH for some time , and Liaskos et al.  first reported in abstract form that antibodies to ribonucleoprotein/Sjögren's syndrome A antigen (anti-Ro/SSA) were found in 98% of patients with anti-SLA, and the presence of both anti-Ro52 and anti- SLA in three quarters of European individuals with AIH and anti-SLA was confirmed by a French multicentre study reported in Liver International . The study by Liaskos et al.  reported co-existence of SLA and Ro-52 autoantibodies in patients with AIH from three different centres, including, it should be noted, cases from the Mayo group, and in addition showed the lack of cross-reactivity between these antibodies. Antibodies to Ro/SSA target two distinct antigens, Ro52 and Ro60, and antibodies to Ro52 (anti-Ro52) and Ro60 (anti-Ro60) are independent markers, not cross-reactive, but like anti-SLA, are associated with HLA DRB1*03 .
In this month's journal, Montano-Loza and colleagues  further investigated the implications of anti-Ro/SSA alone and in conjunction with anti-SLA, in a well characterized cohort of patients with type 1 AIH, from their large North American referral centre. One-hundred and seventy patients were included (predominantly because serum was available, from a larger repeatedly analysed cohort of 318 patients; this pragmatism of course underlies the bias of most clinical papers, where if the design is not prospective there always remains a residual risk of selection/referral bias). Sixty-eight patients (40%) had concurrent immune diseases, including twelve patients with multiple diseases. Autoantibodies were evaluated by commercially available ELISAs, with there being 65 patients (38%) with antibodies to Ro52; 11 patients (6%) with antibodies to Ro60; and 27 patients with antibodies to SLA (16%). Twenty-six patients with antibodies to Ro52 had antibodies to SLA (40%), and 26 patients with antibodies to SLA had antibodies to Ro52 (96%). Patients with antibodies to Ro52 and antibodies to SLA had a higher frequency of HLA DRB1*03 (78 vs. 50%, P = 0.05; where HLA data were available) and lower occurrence of HLA DRB1*04 (22 vs. 57%, P = 0.01) than patients with antibodies to Ro52 alone. Antibodies to Ro52 alone [HR 2.90; 95% CI 1.18–7.14, P = 0.02] and antibodies to Ro52 in conjunction with antibodies to SLA [HR, 2.98; 95% CI, 1.07–8.43, P = 0.04] were independently associated with the development of cirrhosis and hepatic death or liver transplantation.
The wide confidence intervals for the hazard ratios of course underlie the relative rareness of significant events in such a well-treated cohort, and the difficulty in immediately translating these observations to the clinic patient in front of you. Yet, it does remain necessary to go forward from this study and cast the net wider both in terms of clinic populations studied, and serologic patterns tested for, in search of better tools to risk stratify patients with AIH. Thus, this study albeit with the caveats of its retrospective nature, and need for external validation in the non-Mayo setting, does suggest that anti-Ro52 alone and anti-Ro52 in conjunction with anti-SLA, are independently associated with the development of cirrhosis and the occurrence of hepatic death or need for transplantation; whether this is true for all populations is not clear, and given the experience that clinical presentation is influenced by heritage, this remains something particularly important to pursue. Antibodies to Ro52 are present in 96% of patients with anti-SLA, and this close association appears not to be explained by concurrent rheumatic diseases, suggesting that the association of HLA DRB1*03 with the dual expression of anti-Ro52 and anti-SLA, may in part relate to genetic risk for severe disease.
Montano-Lopez et al. therefore confirm prior published  and presented studies , of what is clearly an interesting observation of almost complete concurrence of anti- SLA with anti-Ro52 in AIH, and associate this with carriage of HLA DRB1*03, and disease severity. Looking ahead, therapy for AIH is hopefully likely to become more immune specific, and mirror that of inflammatory bowel disease or rheumatoid arthritis. Therefore, better identification of prognostically deleterious serum markers (including through novel proteomic approaches) may be of help in triaging patients to early use of potent immunomodulatory agents. Combining serologic approaches with genetic dissection of disease risk will provide a multidimensional approach to disease diagnosis, management and stratification, which should ultimately have the potential to become dynamic longitudinal tools, guiding personalized healthcare.