Open Journal of Gastroenterology, 2013, 3, 307-310 OJGas Published Online November 2013 (
Post-transplant plasma cell hepatitis in a liver transplant
patient treated with pegylated interferon plus ribavirin
Miguel Jiménez-Pérez, Francisco Javier Rando-Muñoz, Rocío González-Grande,
Fernando González-Panizo Tamargo, Jesús de la Cruz Lombardo,
Juan Miguel Rodrigo López, Román Manteca González
Department of Gastroenterology and Hepatology, Liver Transplantation Unit, University Hospital Carlos Haya, Málaga, Spain
Received 18 August 2013; revised 25 September 2013; accepted 15 October 2013
Copyright © 2013 Miguel Jiménez-Pérez et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The recurrence of hepatitis C after a liver transplant
remains an important cause of graft loss and retrans-
plant. Antiviral therapy with peginterferon plus ri-
bavirin (PEG-INF/RBV) can achieve a sustained viral
response and histological improvement in a high per-
centage of cases. However, this treatment is not ex-
empt from important side effects or from the possi-
bility of precipitating rejection, with the resulting
graft loss. We report the case of a liver transplant
patient who received treatment with PEG-INF/RBV
and developed plasma cell hepatitis as the presenting
form of rejection.
Keywords: Liver Transplantation; C Hepatitis
Treatment; Plasmatic Cells; Allograft Rejection;
Autoinmune Response
Despite the fact that new triple therapy with the associa-
tion of proteasa inhibitor has achieved satisfactory re-
sponse rates for HCV-Genotype 1, even in liver trans-
plant patient, the treatment combination of peginterferon
plus ribavirin (PEG-INF/RBV) was the best treatment
available in our daily clinical practice in 2010 for relapse
of hepatitis C virus (HCV) in liver transplant patients.
However, its efficacy and tolerability are somewhat less
than in non-transplant patients, and special consideration
must be given to the frequency and severity of its side
effects, as they may cause important morbidity, which
can even lead to graft loss [1,2]. Acute or chronic rejec-
tion in association with this treatment is potentially se-
vere, though controversial complication, and rates vary
considerably between the different studies (0% - 25%)
[2-5]. Diagnosis of this complication is often difficult
because of its form of presentation and the existence of
histological features that are superimposed on other enti-
ties, such as recurrent hepatitis C or autoimmune hepati-
tis [3,6]. We report the case of a patient who developed
plasma cell hepatitis after treatment with PEG-INF/RBV,
which we believe was an unusual form of presentation of
acute rejection leading to graft loss and the death of the
A 61-year-old man underwent liver transplantation in
January 2010 due to hepatic cirrhosis associated with
HCV and hepatocarcinoma. When he was enlisted for
liver transplantation presented Child-Score of B-7 and
MELD-Score of 13, laboratory findings of hypertension
portal as well as splenomegaly and pancytopenia that
was decisive for not treating with antiviral therapy HCV
infection before liver transplantation. After transplanta-
tion, immunosuppression theraphy consisted of neoral
cycolosporine and steroids that were gradually tapered
during the first year. In the immediate post-transplanta-
tion liver (LT) period the pacient was keeping a good
liver function until the 30th day post-transplantation
when laboratory findings reported the result of HCV-
RNA 9,290,000 copies per mililiter. Eventually, there
was a progressive biochemical and virological worsening
which was decisive to perform a liver biopsy in 21th
month post-LT, this reported the histological relapse. In
that moment, laboratory findings included AST (ami-
notransferase) 239 IU/L (15 - 35); ALT (alanine ami-
notransferase) 427 IU/L (30 - 65); Ɣ-GT (gamma-glu-
tamiltransferase) 185 IU/L (15 - 85); AP (alkaline phos-
fatase) 208 IU/L (50 - 135); and HCV RNA, 16,353,000
copies per milliliter (Figure 1). Histologically, a mild
interfase hepatitis was reported with focal apoptotic bodies
and portal-portal linkage distorsion with periportal fibrosis,
M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310
Figure 1. Clinical and analitical secuence after liver trasplantation.
but not cirrhosis (Grade 2 Metavir stage II) (Figure 2).
Treatment was started with subcutaneous PEG-INF
α2a at a dose of 180 µg per week and ribavirin, 1200 mg
per day. Initial side effects were asthenia and hemolytic
anemia, necessitating reduction of the dose of ribavirin.
A control blood test during treatment week 16 showed
hemoglobin 10.5 g/dL (12 - 16), platelets 101,000/µL
(140,000 - 350,000), leukocytes 3400/µL (4000 - 11,000
/µL), AST 577 IU/L (15 - 35) , ALT 523 IUL/(30 - 65)
Ɣ-GT 449 IU/L (15 - 85), AP 538 IU/L (50 - 135), TB
(total bilirrubin) 7 mg/dL (0.3 - 1.5), DB (direct bilir-
rubin) 5 mg/dL (0.1 - 0.5), INR 1.97, prothrombin time
37.8% (70% - 130%), associated with a poor general
state, intense asthenia, fever, reduced consciousness,
renal impairment and jaundice. During the treatment
viral load decreased but never became negative and ci-
closporine levels (CsA) remained the whole time within
therapeutic range (levels C2: 500 ng/ml +/ 120) (Figure
The patient was admitted to hospital and antiviral ther-
apy was withdrawn. He was diagnosed with extrahospital
pneumonia caused by Streptococcus pneumoniae that
was treated with amoxicillin-clavulanic acid during 14
days with good response, as well as an urinary tract in-
fection cause by Echerichia coli which initially re-
sponded well to ciprofloxacin therapy. However, the liver
profile still showed marked cytolysis and a progressive
increase in bilirubin, which reached 30 mg/dL. Abdomi-
nal-pelvic ultrasound and computed tomography ruled
out the presence of vascular or biliary alterations and
other pathological findings. Antigen assays and poly-
merase chain reaction for CMV were also negative. Viral
markers for HAV-IgM and HBV, as well as ANA, AMA,
ASMA and antiKLM antibodies, were all negative. Gam-
ma-globulin/IgG levels were normal.
A liver biopsy revealed a severe portal and periportal
lymphoplasmocytic infiltrate (interphase hepatitis), hepa-
tocyte necrosis and periportal fibrosis with no data in-
dicative of rejection, thus suggesting an autoimmune or
toxic hepatitis (Figure 3).
Finally, the patient experienced progressive worsening
of liver function with no response to extracorporeal
cleansing techniques (MARS) and died.
Acute rejection is a potentially serious adverse effect in
patients with a recurrence of hepatitis C after liver trans-
plantation and who are receiving treatment with inter-
feron (interferon or peginterferon, with or without ri-
bavirin), and which can even lead to graft loss [1,2]. Al-
though the association between interferon therapy and
acute rejection in liver transplantation is not as well-
documented as it is for kidney transplantation, the im-
munomodulatory and immunostimulatory effects of in-
terferon have been suggested as possible mechanisms
leading to acute rejection in liver-transplant patients [1,
In our case, and given the initial suspicion of acute re-
jection, we performed a liver biopsy, which only showed
the presence of a severe portal and periportal lym-
phoplasmocytic infiltrate (interphase hepatitis), with no
Copyright © 2013 SciRes. OPEN ACCESS
M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310 309
Figure 2. Septal fibrosis and disarranged lobular
Figure 3. Lynphoplasmocitic interfase hepatitis.
other relevant histological findings.
The differentiation between acute cellular rejection,
recurrence of HCV or autoimmune hepatitis can often be
difficult, due to the superimposition of the histologic
findings [3]. The absence of findings suggestive of acute
or chronic cellular rejection (no eosinophils, bile duct
lesions or endothelialitis), together with the exclusion of
other causes of graft dysfunction, suggests a de novo
autoimmune process. Liver graft dysfunction in trans-
plant patients treated with PEG-INF/RBV who develop
similar autoimmune phenomena to a de novo acute auto-
immune hepatitis (AIH) has been described in various
recent reports [7,8]. The patient histologically presented
an interfase hepatitis, with no biliary lesions or granu-
loma, as well as no genetic liver disease (normal values
of alpha 1-anti-trypsin, serum ceruloplasmine, iron and
ferritin levels). Biochemically, there was a predominant
serum aminotransferase abnormality (AST 557 IU/L ALT
523 IU/L). Additionally, no toxic or alcohol injury was
reported. But, on the other hand, he lacked the rest of the
criteria necessary for de novo AIH, such as the absence
of autoantibodies (ANA, SMA, anti-LKM1, AMA) and
normal levels of globulin, gamma-globulin or immu-
noglobulin G [9]. Considering all of these and the pres-
ence of HCV, we believe that it concerned an unusual
form of presentation of rejection, triggered by the treat-
ment with PEG-INF/RBV, that mimics AIH. Fiel et al.
[10] recently published a series of cases of liver trans-
plant patients with HCV who had a severe plasma cell
infiltrate simulating AIH and which they called post-
transplant plasma cell hepatitis. The authors related the
entity to subtherapeutic levels of immunosuppression
and considered it to be a variant of acute rejection. Al-
though these authors did not associate the situation with
the use of interferon, the known association between this
drug and autoimmune phenomena suggests the need for
further study to define the role of PEG-INF in the devel-
opment of plasma cell hepatitis and to establish its rela-
tion with rejection or AIH [11].
In our patient, an increase in immunosuppression and
treatment with steroids may have been indicated [12].
However, this was impeded by the concurrence of severe
acute infectious processes, extrahospital pneumonia and
urinary tract infection, so that we could not therefore
evaluate any possible response to this.
In conclusion, treatment with interferon in liver trans-
plant patients who experience a relapse of HCV may
trigger autoimmune phenomena which can, unusually,
lead to potentially severe side effects, including graft loss.
This, together with the difficulty differentiating between
rejection, recurrence of HCV and AIH, necessitates ade-
quate evaluation of the treatment requirements in patients
with recurrent HCV.
Withdrawal of therapy and the possible use of steroids
should be considered as the first line of therapy.
[1] Berenguer, M. (2008) Systematic review of the treatment
of established recurrent hepatitis C with pegylated inter-
feron in combination with ribavirin. Journal of Hepatol-
ogy, 49, 274-287.
[2] Rubín, A., Aguilera, V. and Berenguer, M. (2011) Liver
transplantation and hepatitis C. Clinics and Research in
Hepatology and Gastroenterology, 35, 805-812.
[3] Hassan, Q., Roche, B., Buffet, C., Bessede, T., Samuel,
D., Charpentier, B. and Durrbach, A. (2012) Liver-kidney
recipients with chronic viral hepatitis C treated with in-
terferon-alpha. Transplant International, 25, 941-947.
[4] Burra, P., Targhetta, S., Pevere, S., Boninsegna, S.,
Guido, M., Canova, D., Brolese, A., et al. (2006) Antivi-
ral therapy for hepatitis C virus recurrence following liver
transplantation: Long-term results from a single center
experience. Transplantation Proceedings, 38, 1127-1130.
[5] Levitsky, J., Fiel, M.I., Norvell, J.P., Wang, E., Watt,
K.D., Curry, M.P., Tewani, S., et al. (2012) Risk for im-
mune-mediated graft dysfunction in liver transplant re-
cipients with recurrent HCV infection treated with pegy-
Copyright © 2013 SciRes. OPEN ACCESS
M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310
Copyright © 2013 SciRes.
lated interferon. Gastroenterology, 142, 1132-1139.
[6] Belli, L.S., Volpes, R., Graziadei, I., Fagiouli, S., Starkel,
P., Burra, P., Alberti, A.B., et al. (2012) Antiviral therapy
and fibrosis progression in patients with mild-moderate
hepatitis C recurrence after liver transplantation. A ran-
domized controlled study. Digestive and Liver Disease,
44, 603-609.
[7] Berardi, S., Lodato, F., Gramenzi, A., D’Errico, A., Lenzi,
M., Bontadini, A., Morelli, M.C., et al. (2007) High inci-
dence of allograft dysfunction in liver transplanted pa-
tients treated with pegylated-interferon alpha-2b and ri-
bavirin for hepatitis C recurrence: Posible de novo auto-
inmune hepatitis? Gut, 56, 237-242.
[8] Fiel, M.I. and Schiano, T.D. (2012) Plasma cell hepatitis
(de-novo autoinmune hepatitis) developing post liver
transplantation. Current Opinion in Organ Transplanta-
tion, 17, 287-292.
[9] Czaja, A. (2008) Performance parameters of the diagnos-
tic scoring systems for autoimmune hepatitis. Hepatology,
48, 1540-1548.
[10] Fiel, M.I., Agarwal, K., Stanca, C., Elhajj, N., Kontorinis,
N., Thung, S.N., Schiano, T.D., et al. (2008) Posttrans-
plant plasma cell hepatitis (de novo autoinmune hepatitis)
is a variant of rejection and may lead to a negative out-
come in patients with hepatitis C virus. Liver Transplan-
tation, 14, 861-871.
[11] Demetris, A.J. and Sebagh, M. (2008) Plasma cell hepati-
tis in liver allografts: Variant of rejection or autoimmune
hepatitis? Liver Transplantation, 14, 750-755.
[12] Czaja, A.J. (2012) Diagnosis, pathogenesis, and treatment
of autoinmune hepatitis after liver transplantation. Diges-
tive Diseases and Sciences, 57, 2248-2266.
PEG-INF: pegylated interferon;
RBV: ribavirin;
CMV: cytomegalovirus;
HCV: hepatitis C virus;
HAV: hepatitis A virus;
HBV: hepatitis B virus;
ANA: antinuclear antibody;
AMA: antimitocondrial antibody;
ASMA: anti-smooth muscle antibody;
antiKLM: anti-liver/kidney microsomal antibody.