Hepatitis C Information Central

Hepatology, July 1999, p. 338-339, Vol. 30, No. 1
HEPATOLOGY Elsewhere

PREDNISONE WITHDRAWAL ADVOCATES: BEWARE OF RECURRENT AUTOIMMUNE HEPATITIS

Prados E, Cuervas-Mons V, de la Mata M, Fraga E, Rimola A, Prieto M, Clemente G, Vicente E, Casanovas T, Fabrega E. Outcome of autoimmune hepatitis after liver transplantation. Transplantation 1998;66:1645-1650. [ Link previously at www.ncbi.nlm.nih.gov ]. Reprinted with permission.

ABSTRACT

Background. Recurrence of autoimmune hepatitis after liver transplantation is not rare, but there is little information about its time of onset, risk factors, response to treatment and prognosis. The aim of this study was to evaluate the rate of recurrence and outcome of autoimmune hepatitis after transplantation.

Methods.The records of patients transplanted in eight centers in our country between 1984 and 1996 were retrospectively analyzed.

Results. Forty-three of the 2331 (1.8%) recipients fulfilled diagnostic criteria of autoimmune hepatitis at the time of transplantation. Sixteen patients were excluded from evaluation. Nine (33%) of the 27 patients evaluated fulfilled criteria for recurrence of autoimmune hepatitis, with a mean time of recurrence after orthotopic liver transplantation of 2.6 ± 1.5 years. Patients with recurrence had a longer follow-up time after transplantation (5.1 vs. 2.5 years, P = 0.0012) and were receiving less immunosuppressive treatment. The estimated risk of recurrence of autoimmune hepatitis in the graft increased over time: 8% over the first year and 68% 5 years after transplantation. None of the seven patients with liver-kidney microsomal-positive antibodies recurred (P = 0.059). Fifty percent of the patients failed to respond or responded only partially to therapy, although none of the patients have deteriorated clinically after 2.4 ± 1.06 years of follow-up after recurrence.

Conclusions. Recurrence of autoimmune hepatitis in the graft is a common event with an incidence that increases over time as immunosuppression is reduced. Although response to treatment is poor, patient and graft survival do not appear to be decreased.

Ratziu V, Samuel D, Sebagh M, Farges O, Saliba F, Ichai P, Farahmand H, Gigou M, Feray C, Reynes M, Bismuth H. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol 1999;30:131-141. [ Link previously at www.ncbi.nlm.nih.gov ]. Reprinted with permission.

ABSTRACT

Background/Aims: After liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown. Methods: In this retrospective study we reviewed the clinical course of 25 patients transplanted or autoimmune hepatitis and followed for a mean of 5.3 years(2-8.5 years).

Results: The actuarial 5-year patient and graft survival rates were 91% (±6%) and 83% (±8%). The actuarial 1-yearrate of acute rejection was 50% (±10.2%), which was comparable to that of patients transplanted for primary biliary cirrhosisand primary sclerosing cholangitis. Autoantibodies persisted in 77% of patients, at a lower titer than before liver transplantation. Ten patients were excluded from the study of autoimmune hepatitis recurrence, one because of an early postoperative death and nine because of Hepatitis C virus infection acquired before or after liver transplantation. In the remaining 15 patients, who were free of Hepatitis C virus infection, 5-year patient and graft survivals were 100% and 87%, respectively. Despite triple immunosuppressive therapy, three patients (20%) developed chronic hepatitis with histological and serological features of autoimmune hepatitis in the absence of any other identifiable cause. The disease was severe in two patients, leading to graft failure and asymptomatic in another, despite marked histological abnormalities. In one of these three patients, autoimmune hepatitis recurred on the second liver graft as well.

Conclusions: Patients undergoing liver transplantation for autoimmune hepatitis have an excellent surviva rate although severe primary disease may recur, suggesting the need for stronger post-operative immunosuppressive therapy.

COMMENTS

Whether or not autoimmune hepatitis (AIH) recurs after orthotopic liver transplantation (OLT) has been controversial for manyyears. In 1984, Neuberger et al.¹ described the first caseof recurrent AIH after OLT in which the recurrence of disease,based on elevated liver enzyme levels and liver biopsy findingscompatible with AIH, coincided with a significant reduction incorticosteroid dosage as part of the immunosuppressive regimen.In this patient an increase in immunosuppressive therapy led tonormalization of liver tests. Subsequently at the University ofPittsburgh, Wright et al.² documented histological recurrenceof AIH after liver transplantation in 11 of 43 (25.6%) cases.However, in the same year, investigators from the Mayo Clinicreported that none of 24 patients who underwent OLT for AIH hadevidence of recurrent disease after transplantation.³

The importance of the studies by Prados et al. from Spain, and Ratziu et al. from France, is that they identified reasonablylarge cohorts of patients with AIH undergoing OLT, documenteddisease by strict exclusion criteria, and found that post-transplantthese patients develop recurrent disease. Patients were thoroughlyinvestigated to exclude the possibility of simultaneous infectionwith the Hepatitis C virus (HCV) based on negative HCV RNA bypolymerase chain reaction. All patients also had negative serologicalmarkers for Hepatitis B virus and no evidence for alcohol abuseor exposure to hepatotoxic drugs. Liver biopsy specimens showedfindings compatible with AIH, and the presence of at least oneof the antibodies associated with AIH, such as antinuclear antibody,smooth muscle antibody, or liver-kidney microsomal antibody, wasalso required for the diagnosis of recurrentAIH.

The group from Spain found that 9 of 27 (33%) patients met the criteria for recurrent AIH after OLT. This represents a greaterpercentage of recurrent AIH than encountered by the group fromFrance in which only 3 of 15 patients (20%) experienced recurrenceof disease. The average time to the diagnosis of recurrent AIHwas 5.3 years after OLT. Although all three patients in the Frenchstudy were receiving triple immunosuppressive therapy with corticosteroids,azathioprine and cyclosporine at the time of recurrent AIH, noneof the 9 patients in the Spanish study were receiving azathioprineat the time of recurrence and all had undergone tapering of corticosteroidsseveral months before. Actuarial patient and graft survival rateswere similar in the recurrence and nonrecurrence groups in bothstudies.

The French study reported a total of 15 HCV-negative patients who were transplanted for AIH. Among these patients, 9 (60%)experienced at least one episode of acute allograft rejectionconfirmed by liver biopsy. This is slightly less than the 79%rate of acute rejection (26 of 33 patients) reported after OLTfor AIH from Stanford University.⁴ In our series, we also noteda lower incidence of acute allograft rejection in patients withAIH who received tacrolimus-based immunosuppressive therapy comparedwith those who received cyclosporine. However, patients with AIHhad a higher incidence of acute rejection than a control groupof patients with alcohol-induced cirrhosis, regardless of theimmunosuppressionregimen.

In the Spanish study, HLA data were obtained from 4 of the 9 patients who experienced recurrent AIH, and showed that all 4 patients were HLA DR3⁺. These findings are consistent with those at the University ofPittsburgh,² where 9 of 11 patients (81%) with recurrent AIHafter OLT were HLA DR3⁺ recipients of HLA DR3-negative grafts. One possible explanationfor this phenomenon is that the HLA DR3 phenotype is associatedwith an increased humoral immune response. The French study didnot identify any correlation between HLA status and recurrenceofAIH.

The finding that all patients with recurrence of AIH after OLT in the Spanish study had undergone tapering of corticosteroidsand were not receiving azathioprine, raises the possibility thatpatients with AIH should be maintained on higher doses of immunosuppressivetherapy for longer periods of time. This is in diametric oppositionto the popular recent practice of rapid reduction and withdrawalof corticosteroids after OLT. In 1991, Pedrosa et al.⁵ reportedconversion to alternate-day prednisone therapy on an average 36 weeks after OLT; in their experience, only 1 of 28 patients developedacute allograft rejection while receiving the alternate-day prednisoneregimen. McDiarmid at al.⁶ from the University of CaliforniaLos Angeles reported in 1995 that only 2 of 33 patients receivingcyclosporine therapy who underwent steroid withdrawal experiencedbiopsy-proven rejection. At the University of Colorado, Stegallet al.⁷ prospectively withdrew prednisone in 28 adult OLT patients.Two patients experienced biopsy-proven rejection and 2 othersexperienced elevation of liver tests but were not biopsied. Inthis study, 3 of 5 insulin-dependent diabetic patients discontinuedinsulin use, 4 of 14 hypertensive patients discontinued antihypertensivemedications, and 9 of 13 patients with hypercholesterolemia experienceda significant decrease in serum cholesterol levels after prednisonewithdrawal. No patient with similar conditions in a control groupof 24 patients maintained on prednisone therapy experienced anyimprovement of these associated medical conditions. The Japanesegroup of Abe et al.⁸ reported that 1 of 12 pediatric OLT patientsexperienced acute rejection after prednisone withdrawal, althoughthe liver disease leading to OLT was notreported.

Based on the results of these two studies reporting the outcome of AIH after OLT, it would appear reasonable to not submitAIH patients to corticosteroid withdrawal after OLT and maintainadequate tacrolimus or cyclosporine blood levels. In addition,patients with AIH should be followed long-term, with liver biopsywhen appropriate, to identify and treat the 20% to 30% of patientswho may develop recurrentAIH.

Rene Davila, M.D. Emmet B. Keeffe, M.D. Department of Medicine Stanford University Palo Alto, CA

REFERENCES

1.	Neuberger J, Portmann B, Calne R, Williams R. Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting. Transplantation 1984;37:363-365.
2.	Wright HL, Bou-Abboud CF, Hassanein T, Block GD, Demetris AJ, Starzl TE, Van Thiel DH. Disease recurrence and rejection following liver transplantation for autoimmune chronic active liver disease. Transplantation 1992;53:136-139.
3.	Sanchez-Urdazpal L, Czaja AJ, Van Hoek B, From RAF, Wiesner RH. Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis. HEPATOLOGY 1992;15:215-221.
4.	Hayashi M, Keeffe EB, Krams SM, Martinez OM, Ojogho ON, So SKS, Garcia G, et al. Allograft rejection after liver transplantation for autoimmune liver diseases. Liver Transpl Surg 1998;4:208-214.
5.	Pedrosa MC, Rohrer RM, Kaplan MM. Alternate-day prednisone therapy after orthotopic liver transplantation (letter). N Engl J Med 1991;325:1658-1659.
6.	McDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR, Simmons F, et al. A randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation 1995;60:1443-1450.
7.	Stegall MD, Everson GT, Schroter G, Karrer F, Bilir B, Sternberg T, Shrestha R, et al. Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension, and hypercholesterolemia without causing graft loss. HEPATOLOGY 1997;25:173-177.
8.	Abe M, Fuchinoue S, Koike T, Sato S, Uchida Y, Murakami T, Sageshima J, et al. Transplant Proc 1998;30:1441-1442.

JACQUELYN MAHER, EDITOR San Francisco General Hospital Building 40, Room 4102 1001 Potrero Avenue San Francisco, CA 94110

ADVISORY COMMITTEE Laurie DeLeve, Los Angeles, CA David Crabb, Indianapolis, IN Adrian DiBisceglie, St. Louis, MO Emmet Keeffe, Palo Alto, CA Joel Lavine, San Diego, CA Michael Nathanson, New Haven, CT Don Rockey, Durham, NC