Pharmacologic agents
A positive response to immunosuppressive therapy can strengthen the diagnosis of snAIH. 11,12,32,35,37 However, a lack of response to therapy does not exclude the diagnosis of snAIH or spAIH. 7,34 Three-month treatment trials with corticosteroids should be considered in all patients regardless of the serological findings to further confirm diagnosis in patients with a positive response. 7,9 Given that spAIH and snAIH are similar in most respects apart from their serology, theoretically, the treatment for both should be the same, including steroid use with or without the addition of azathioprine. However, the literature provides variations in dosing and duration of both induction and maintenance periods.
Reported treatment regimens vary greatly, which limits comparison of responses to immunosuppression across studies. Treatment regimens initially developed for AIH, and later studied in snAIH, included two phases, an induction phase consisting of 30 mg of prednisone daily and azathioprine 50 mg daily, or prednisone 60 mg daily; and a maintenance phase including prednisone 10 mg daily and azathioprine 50 mg daily, or prednisone 20 mg daily. 9 If there is uncertainty of the diagnosis, treatment should be administered for 3 months with the higher dose of prednisone, given that azathioprine requires some time to reach effective levels. 9 Although never formally studied, the combination of budesonide and azathioprine may be useful for treatment in patients prone to side effects from prednisone, including patients with hypertension, diabetes, obesity, or osteoporosis.
Gassert et al. 11 conducted a retrospective review over a 5-year period and found no significant differences between patients with spAIH and those with snAIH with respect to age, sex, serum ALT levels, and AIH pretreatment diagnostic scores. Twenty of the 30 spAIH patients underwent pretreatment liver biopsies, and eight more had post-treatment liver biopsies. A total of six snAIH patients were included following a liver history confirmation. Studies have shown that clinical presentation alone does not increase probability of diagnosing snAIH and that histological variations help to support the diagnosis of snAIH. 9,19 Of the snAIH patients, 83.3% had moderate to severe interface hepatitis vs. 85% in the spAIH group), 83.3% had advanced fibrosis vs. 40% in the pAIH group, and 17% had plasma cells vs. 60% in the spAIH group. Treatment was standardized among spAIH and snAIH patients, with administration of prednisone 20 mg daily. The mean time to remission was recorded when ALT levels normalized, and was similar in in spAIH and snAIH patients (2.6 vs. 2.7 months, respectively). Within 3 months, 88.9% of spAIH patients and 66.7% of snAIH were in remission. One year later, one of the six snAIH patients had an increase in serum aminotransferase levels, indicating possible relapse or misdiagnosis. Strengths of the study include testing of all patients for atypical antibodies, including SLA. There was standardization in the treatment regimen with prednisone 20 mg daily, which was tapered over several months. However, there was some variation in the initiation of azathioprine 50 mg daily beginning sometime within the first 2 months of steroid therapy in patients who had a decline in serum ALT levels. A major limitation includes the small sample size of only 30 patients with spAIH and six with snAIH. That greatly reduced the power of the findings.
Heringlake et al. 12 approached treatment in a different way by using responsiveness to treatment to support the diagnosis of snAIH. Among the initial 126 cryptogenic chronic liver disease patients, the IAIHG scoring system identified approximately one-third of the cohort to have snAIH and thought to benefit from treatment with immunosuppressants. Thirty-seven presumed snAIH patients were allocated to receive both prednisolone and azathioprine combination therapy or monotherapy prednisolone 1 mg/kg/day induction therapy followed by a stepwise reduction of steroids. Patients who had at least a probable-AIH score of 10–12 points before treatment and 12–14 points after treatment, had superior responses to corticosteroid therapy. 9,12,32,35,40 Although there were inconsistencies with the immunosuppressive regimen administered, a total of 34 of the 37 who received any immunosuppressive treatment responded favorably. Two of the nine patients with cryptogenic liver disease receiving immunosuppressive therapy responded positively with a p-value of <0.005. A positive treatment response was thus supportive of a snAIH diagnosis. 12
Kaymakoglu et al. 28 looked into possible regimens for relapsing snAIH and spAIH patients. Initially all patients received a treatment regimen of prednisone 30 mg daily and azathioprine 50-75 mg daily with a gradual reduction of steroids after a month. There were regular assessments with biochemical tests and physical exam at 3–6-month intervals. Response to therapy was assessed using the IAIHG scoring system. Follow-up for response assessment in cryptogenic hepatitis subjects was a median of 48 months, ranging between 36–60 months. Shorter follow-up times leaves room for the possibility of overestimation of responses to treatment. After 2 years, seven cryptogenic cases and one spAIH case were thought to have achieved complete remission, and thus treatment was stopped for these subjects. Out of the seven cryptogenic AIH subjects, six relapsed in 1 to 20 months after stopping treatment (71%). One AIH subject relapsed (100%). Combination therapy was restarted in patients with relapse after drug withdrawal, and they maintained complete remission thereafter. 28 Overall, responses to immunosuppressive therapy were similar in both the snAIH and spAIH groups. The study did not define complete remission, making it difficult to determine long term effects of treatment and to rule out over estimation bias.
Liver transplant
If immunotherapy does not result in improved outcomes, end-stage cases may be treated by liver transplant. AIH accounts for only 2.3% of all liver transplants. Early recognition of snAIH is often delayed as a result of the exhaustive workup required to make the diagnosis of snAIH. 11 The 5-year survival of patients and their grafts in AIH ranged from 73% to 92%, and the actuarial 10-year survival after transplant was >70%. 9 Patients with acute liver failure who had an underlying diagnosis of snAIH were at an increased risk of developing graft hepatitis following transplant. 2 Patients with Model for End-stage Liver Disease (MELD) scores greater than 35 did particularly poorly in transplant outcomes. 3 Improved rates of spontaneous survival were associated with steroid use in patients with initial significant aminotransferase levels greater than 30 times normal, but more prominent if subject had illness of less than 2 weeks duration.
Wigg et al. 41 studied 110 consecutive cases of seronegative acute liver failure requiring liver transplants over a course of 12 years. The study endpoint was short-term mortality of less than 2 months rather than all-cause mortality. Thirty-one deaths occurred in the seronegative group, of which 20 (67%) occurred in less than 2 months. Two patients with short-term mortality died from graft ischemia and one died from primary graft non-function. In those with late mortality, chronic rejection occurred in two patients and primary graft non-function following a regraft occurred in one patient. Adjusting for pretransplant risk factors of early mortality, it was found that survival following transplantation for snAIH was 83%, 81%, 73% at 2, 12, and 60 months, respectively. The most common cause of early death was sepsis or multiorgan dysfunction. Factors contributing to risk of early death included high donor body mass index, recipient age of more than 50 years, and non-Caucasian recipient ethnicity. Interestingly, pretransplant renal function was not identified as an important predictive variable for post-transplant outcomes, as seen in non-seronegative causes of acute liver failure. It was inferred that the donor liver quality rather than the recipient comorbidities held more importance in determining early death risk. 41