Post-transplant plasma cell hepatitis in a liver transplant patient treated with pegylated interferon plus ribavirin

doi:10.4236/ojgas.2013.37053

Paper Menu >>

Journal Menu >>

Open Journal of Gastroenterology, 2013, 3, 307-310 OJGas

http://dx.doi.org/10.4236/ojgas.2013.37053 Published Online November 2013 (http://www.scirp.org/journal/ojgas/)

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

Email: mjimenezp@commalaga.com

Received 18 August 2013; revised 25 September 2013; accepted 15 October 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

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

1. INTRODUCTION

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

patient.

2. CASE REPORT

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,

OPEN ACCESS

M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310

308

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

1).

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.

3. DISCUSSION

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,

3].

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

M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310 309

Figure 2. Septal fibrosis and disarranged lobular

structure.

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.

REFERENCES

[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.

http://dx.doi.org/10.1016/j.jhep.2008.05.002

[2] Rubín, A., Aguilera, V. and Berenguer, M. (2011) Liver

transplantation and hepatitis C. Clinics and Research in

Hepatology and Gastroenterology, 35, 805-812.

http://dx.doi.org/10.1016/j.clinre.2011.04.009

[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.

http://dx.doi.org/10.1111/j.1432-2277.2012.01520.x

[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.

http://dx.doi.org/10.1016/j.transproceed.2006.02.135

[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-

M. Jiménez-Pérez et al. / Open Journal of Gastroenterology 3 (2013) 307-310

310

OPEN ACCESS

lated interferon. Gastroenterology, 142, 1132-1139.

http://dx.doi.org/10.1053/j.gastro.2012.01.030

[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. http://dx.doi.org/10.1016/j.dld.2012.01.017

[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.

http://dx.doi.org/10.1136/gut.2006.092064

[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.

http://dx.doi.org/10.1097/MOT.0b013e3283536622

[9] Czaja, A. (2008) Performance parameters of the diagnos-

tic scoring systems for autoimmune hepatitis. Hepatology,

48, 1540-1548. http://dx.doi.org/10.1002/hep.22513

[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. http://dx.doi.org/10.1002/lt.21447

[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.

http://dx.doi.org/10.1002/lt.21518

[12] Czaja, A.J. (2012) Diagnosis, pathogenesis, and treatment

of autoinmune hepatitis after liver transplantation. Diges-

tive Diseases and Sciences, 57, 2248-2266.

http://dx.doi.org/10.1007/s10620-012-2179-3

ABBREVIATIONS

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.