Hepatitis E, usually an acute hepatitis in the immunocompetent, has a chronic form described in immunocompromised hosts. We report the clinical course and outcome of an adult liver transplant recipient whose posttransplant period was complicated by chronic hepatitis E, Epstein-Barr virus infection, and cellular rejection of the graft.
Hepatitis E virus (HEV) infection is known to be transmissible via various routes. A chronic form of persistent HEV has been described in immunocompromised hosts, especially in transplant recipients who are on immunosuppression. We describe an adult liver transplant (LT) recipient whose post-LT course was complicated by chronic HEV, Epstein-Barr viremia (EBV), and acute cellular graft rejection resulting in management dilemmas and ultimately graft failure and mortality.
Mr. X was a 48-year-old Chinese male with chronic hepatitis B virus infection and multifocal hepatocellular carcinoma that was beyond standard criteria, precluding LT. In early November 2009, he approached a center in another country as a transplant tourist and received a deceased liver graft. Postoperatively, he was discharged with tacrolimus 1mg bid, mycophenolate mofetil 750 mg bid, and prednisolone 20 mg od.
He returned to us 3 weeks later to continue post-LT care at our center. He was noticed to be deeply jaundiced with a mixed cholestatic-hepatitic picture on his liver tests (see Table
Serial liver tests for patient Mr. X.
Date | Oct-09 | 24 Nov-09 | 28 Nov-09 | 4 Dec-09 | 12 Dec-09 |
---|---|---|---|---|---|
Event | pre-OLT | OLT 3 Nov-09 | ERCP 26 Nov-09 | Liver biopsy | Liver biopsy 11 Dec-10 |
Bilirubin | 14 | 246 | 298 | 453 | 458 |
(Normal: 3–24 umol/L) | |||||
Alkaline phosphatase | 224 | 319 | 244 | 251 | 138 |
(Normal 32–103 U/L) | |||||
Alanine transaminase | 22 | 129 | 151 | 285 | 169 |
(Normal: 7–36 U/L) | |||||
Aspartate transaminase | 43 | 138 | 172 | 407 | 164 |
(Normal: 15–33 U/L) | |||||
— | 192 | 126 | 100 | 77 | |
(Normal: 11–63 U/L) |
Date | 17 Dec-09 | Feb-10 | Mar-10 | Apr-10 |
---|---|---|---|---|
Event | ERCP 14 Dec-10 | Liver biopsy | ERCP stent change | 2 weeks prior to demise |
Bilirubin | 471 | 438 | 457 | 662 |
(Normal: 3–24 umol/L) | ||||
Alkaline phosphatase | 128 | 277 | 372 | 951 |
(Normal 32–103 U/L) | ||||
Alanine transaminase | 163 | 257 | 121 | 168 |
(Normal: 7–36 U/L) | ||||
Aspartate transaminase | 137 | 207 | 128 | 264 |
(Normal: 15–33 U/L) | ||||
67 | 227 | 207 | 180 | |
(Normal: 11–63 U/L) |
Serial liver tests for patient Mr. X. Bilirubin (Normal: 3–24 umol/L), ALP: Alkaline phosphatase (Normal: 32–103 U/L), ALT: alanine transaminase (Normal: 7–36 U/L), AST: aspartate transaminase (Normal: 15–33 U/L), GGT:
Serology and blood polymerase chain reaction (PCR) were positive for Epstein-Barr virus (EBV) and hepatitis E virus (HEV) genotype 3. Liver tissue was also positive for EBV by PCR. Serology and blood PCR were negative for cytomegalovirus, herpes simplex virus, hepatitis B virus, hepatitis C virus, parvovirus, and human herpes virus 6. Liver tissue was negative for viral inclusions. He was treated with acyclovir for EBV infection with demonstrable reduction in serum EBV viral load by PCR.
Doppler imaging of the graft confirmed patent graft vessels. Magnetic resonance imaging was suggestive of an anastomotic biliary stricture, and this led to successful endoscopic deployment of a biliary stent across the stricture. However, despite regular stent changes per 3 months with good bile outflow, his liver tests did not improve and he remained deeply jaundiced. A liver biopsy was performed in December 2009 that demonstrated moderate acute cellular rejection (rejection activity index score 5) (Figure
Histomicrograph of liver biopsy in December 2009.
Marked portal inflammation with bile duct damage, endothelialitis, and mixed lymphoplasmacytic infiltrate
Biopsy 2 weeks after steroid pulse therapy showing marked improvement with only minimal portal inflammation and mild residual bile duct damage
Histomicrograph of liver biopsy in February 2010.
Mild portal, periportal inflammation
Lobular inflammation with cholestasis
Preserved bile duct within a portal tract; lymphocytic inflammation
His graft function continued to deteriorate with HEV RNA detectable up to 6 months after LT. He was admitted in April 2010 with jaundice, ascites, peripheral oedema, and constitutional symptoms. Graft failure with disseminated bacterial and fungal infection led to his demise soon after (6 months post-LT).
HEV is an RNA virus, transmissible by the fecal-oral route, usually through contaminated food and water. However, it is now recognized that in the viremic phase, HEV transmission may be blood borne as well [
Although previously assumed to manifest only as an acute hepatitis with spontaneous resolution, recent data and literature now suggest that HEV infection does have a chronic form, more commonly seen in the immunocompromised host. Most reports of chronic HEV have been in transplant recipients on immunosuppression. CD4+ IFN
The diagnosis of HEV infection is usually made on the basis of positive serology in the immunocompetent host. However, in the context of immunosuppression, antibody testing has been reported to be repeatedly negative despite detectable HEV RNA in the blood [
Our case report is interesting for the following reasons.
Firstly, our patient returned from the overseas centre 3 weeks after transplant with a persistent, progressive liver dysfunction which did not improve despite successful biliary stenting and treatment for graft rejection. HEV serology was positive within 5 weeks post-LT. To our knowledge, our patient is one of the earliest to be diagnosed with HEV infection so soon after LT. As HEV genotype 3 is of the swine variety, it is possible that the patient had acquired it from ingestion of contaminated pork. However, it could also have been the result of implantation of an organ from a cadaveric donor who previously had HEV infection, resulting in reactivation with immunosuppression. HEV serology was not tested in our patient prior to LT as there had been no clinical indication to do so. How our patient would have acquired HEV and if transplant tourism increased the risk for this, we are unable to prove in this recipient. HEV is not endemic in our country. However, the implications of transplant tourism include having broad differentials for the cause of graft hepatitis. In light of the scarcity of available organs and the rising costs of healthcare, transplant clinicians should be mindful to consider unusual/uncommon infections from their patients returning from other centers.
Secondly, our patient also had concurrent EBV infection as demonstrated by serology and detectable DNA in the blood and liver tissue. EBV infections are commonly observed in patients after liver transplantation, and serologic evidence of active infection is demonstrable in close to 25% of cases [
Thirdly, as inferred from the pathogenesis of chronic HEV above, reducing immunosuppression that targets T cells may be a possible therapeutic option [
Transplant recipients should be cautioned against consuming meat from partially cooked animal sources which may harbor the HEV. Although a recent large, phase 3 study has demonstrated efficacy of an HEV recombinant vaccine [
Transplant tourism may be an enticing option for the deteriorating LT candidate waiting at length for a suitable graft. Even some global medical insurance programs are promoting this option [
The transplant tourist presents a unique set of potential complications and problems not usually encountered in one’s own center. The physician is required to consider a wide list of differentials and to think “out-of-the-box” when managing such recipients, especially in the first year after transplant.
Hepatitis E virus
Epstein-Barr virus
Liver transplantation
Polymerase chain reaction
Post-transplant lymphoproliferative disorders