Book on hepatitis from page 356 to 363

Book on hepatitis from page 356 to 363

356  Hepatology 2012
parameter) without a downward trend, rising lactate, and hypoglycemic episodes.
PNFG is a critical situation and requires immediate retransplantation.
Death within the first year after LT is often associated with bacterial infections.
Management of infections due to multidrug-resistant gram-positive pathogens
represent a major therapeutic challenge in the transplant setting (Radunz 2011).
Overall incidence of fungal infections in LT recipients has declined due to early
identification and treatment of high-risk patients. However, overall mortality rate
for invasive candidiasis and aspergillosis remains high (Liu 2011).
The clinical symptoms of acute cellular rejection are non-specific, may not be
apparent or may manifest as fever, right upper quadrant pain, and malaise. A liver
biopsy is indispensable for confirming the diagnosis of acute rejection. High dose
corticosteroids (3 days of 500-1000 mg methylprednisolone) are the first-line
treatment for acute rejection.
Long-term complications after liver
transplantation
Management issues for the long term include opportunistic infections, chronic
ductopenic rejection, side effects due to immunosuppression including
cardiovascular complications and renal dysfunction, de novo malignancies, biliary
complications, osteoporosis and disease recurrence.
Opportunistic infections
Opportunistic infections in the medium and long term after LT are primarily viral
and fungal in origin. Opportunistic bacterial infections are uncommon after 6
months in patients receiving stable and reduced maintenance doses of
immunosuppression with good graft function.
Cytomegalovirus (CMV) infection plays an important role in the LT setting
(Andrews 2011) (Figure 3). Current guidelines recommend antiviral prophylaxis
over pre-emptive therapy in preventing CMV disease in high-risk LT recipients
(CMV-seronegative recipients of organs from CMV-seropositive donors [D+/R-]).
Delayed-onset CMV disease occurs in 15-38% of CMV D+/R- LT patients with
prophylactic treatment over 3 months (Eid 2010). A controlled clinical trial
demonstrated that valganciclovir, an oral prodrug of ganciclovir, is as effective and
safe as intravenouos (IV) ganciclovir for the prophylaxis of CMV disease in solid
organ (including liver) transplant recipients (Paya 2004). In the kidney transplant
setting, the Impact study demonstrated a marked reduction in the incidence of CMV
disease extending valganciclovir prophylaxis from 100 to 200 days (Humar 2010).
However, side effects and financial burden of this prolonged approach need to be
considered. In cases of ganciclovir-resistant CMV disease, alternative therapeutic
options include CMV hyperimmune globulins, or in rare cases, antiviral medication
(foscarnet, cidofovir or leflunomide) (Eid 2010).
Occurrence of post-transplant lymphoproliferative disease (PTLD) in the first
year after solid-organ transplantation is typically related to Epstein-Barr virus
(EBV) infection. EBV-seronegativity of the recipient before infection, high EB viral
load, intensity of immunosuppression and young age have been reported as risk
factors for PTLD (Smets 2002). Outcomes have improved since rituximab has been
incorporated into treatment regimens (Kamdar 2011). Therapeutic management
Update in Transplant Hepatology  357
options include reduction of immunosuppression, rituximab, combination
chemotherapy, and adoptive immunotherapy.
Oral reactivation of human herpes simplex virus-1 (HSV-1) after LT is common.
Development of varicella-zoster virus (HHV-3) after LT is typically related to
intense immunosuppressive therapy and its therapy does not differ from the non-transplant setting. There is a potential role of human herpes virus (HHV)-6 and
HHV-7 as copathogens in the direct and indirect illnesses caused by CMV. To what
extent HHV-6 and HHV-7 may be directly causing symptomatic disease is not clear
(Razonable 2009).
Figure 3. Cytomegalovirus (CMV) infection of the upper gastrointestinal tract. A. Liver-transplanted patient complaining of dysphagia and epigastric discomfort with multiple
longitudinal esophageal ulcers seen at upper endoscopy. B. Endoscopic findings of deep
esophageal ulcerations with fibrinoid necrosis in another immunocompromised patient. In both
cases, lesions were caused by CMV infection. Diagnosis depends on a positive mucosal
biopsy, which should include specimens from the ulcer margins and ulcer base. Hematoxylin
and eosin staining typically reveals "owl's-eye" cytoplasmic and intranuclear inclusion bodies.
Chronic ductopenic rejection
Advances in immunosuppressive regimens have greatly reduced the incidence of
chronic ductopenic rejection and allograft failure. Chronic rejection begins within
weeks to months or years after LT and affects about 4% to 8% of patients
(Neuberger 1999). The most widely recognized manifestation of chronic rejection is
obliterative arteriopathy and damage or loss of small ducts (Demetris 1997).
Chronic rejection may appear indolently and might only become apparent as liver
test injury abnomalities (GGT, AP, bilirubin, transaminases). The diagnosis needs to
be confirmed by histopathologic examination. Switching the baseline
immunosuppression from cyclosporine A (CSA) to tacrolimus (TAC) and initiating
mycophenolate mofetil (MMF) rescue therapy represents a treatment option in these
patients (Daly 2002).
358  Hepatology 2012
CNI-induced nephrotoxicity and alternative
immunosuppressive protocols
Despite the introduction of new immunosuppressive agents (Table 4), calcineurin
inhibitors (CNI) remain the key drugs of most immunosuppressive regimens. Both
CSA and TAC inhibit the calcineurin-calmodulin complex and therefore IL-2
production. Renal failure, mainly due to CNI nephrotoxicity, is the most common
complication following orthotopic LT. The incidence of chronic renal dysfunction
has been reported in up to 70% of patients in the long term after LT (Afonso 2008,
Ziolkowski 2003). End stage renal disease has been described to occur in 18% of
patients during a post-transplant follow-up of 13 years (Gonwa 2001).
In LT patients with CNI-induced nephrotoxicity, a complete replacement of CNI
with conversion to MMF has shown conflicting results with respect to occurence of
rejection ranging between 0% and 60% (Creput 2007, Moreno 2003, Schmeding
2011, Moreno 2004). MMF inhibits inosine monophosphate dehydrogenase, a
critical enzyme in the de novo pathway of purine synthesis. Results from previous
studies with immunosuppressive regimens including MMF and minimal CNI
treatment suggest a significant improvement in renal function in this patient group
(Beckebaum 2011, Cicinnati 2007a, Beckebaum 2004a, Cantarovich 2003, Garcia
2003, Raimondo 2003).
De novo immunosuppression with MMF combined with induction therapy and
delayed CNI introduction is another approach to reduce CNI-related nephrotoxicity
especially in patients with higher MELD score or significant renal dysfunction. In a
randomized clinical trial, a daclizumab/MMF/delayed low-dose TAC-based
regimen was compared with a standard TAC/MMF regimen (Yoshida 2005). In
both study arms, corticosteroids were tapered over time. Statistically significant
higher median GFR were found in the delayed CNI group, although acute rejection
episodes were not statistically significant different in either group. Similar results
have been found in two retrospective studies in LT patients receiving thymoglobulin
induction therapy and delayed initiation of CNI (Bajjoka 2008, Soliman 2007). The
group from Regensburg initiated a single arm pilot study to determine the safety and
efficacy of a CNI-free combination therapy (basiliximab induction/MPA and
delayed [10 days post-transplant] sirolimus [SRL]) in patients with impaired renal
function (GFR <50 ml/min and/or serum creatinine >1.5 mg/dL) at LT
(Schnitzbauer 2010a). The study design stipulates that if at least 8 of the 9 patients
do not present with steroid-resistant acute rejection within 30 days after LT, an
additional 20 patients will be included. Results from this “bottom-up”
immunosuppressive strategy need to be awaited to determine if this strategy works
to prevent or avoid further renal dysfunction during follow-up after LT. Moreover, a
flaw of combined MMF and mTOR inhibitors therapy are agonistic side effects
such as bone marrow suppression, which may limit their combined use in a
substantial proportion of patients.
Another approach to maintain renal preservation is replacement of CNI by mTOR
inhibitors such as SRL or everolimus (EVL) (Sanchez 2005, Harper 2011, Saliba
2011, Kawahara 2011). Reported side effects of mTOR inhibitors include increased
incidence of wound infection and dehiscence, hepatic artery thrombosis,
hyperlipidemia, thrombocytopenia, leucopenia, and anemia. The antifibrotic effect
of mTOR inhibitors may provide an explanation for impaired wound healing
(Watson 1999).
Update in Transplant Hepatology  359
In a recently published randomized controlled study, patients were treated with
CSA for the first 10 days, then randomized to receive EVL plus CSA up to day 30,
and then either continued on EVL monotherapy (EVL group) or maintained on CSA
with or without MMF (control group) (Masetti 2010). One-year results showed that
MDRD was significantly better in the EVL monotherapy group as compared to the
control group. Results from two multicenter, randomized, Phase III studies
(ClinicalTrials.gov Identifiers: NCT00378014 & NCT00622869) comparing EVL-based regimen versus CNI-based regimen in de novo LT recipients will add further
information with respect to the role of mTOR inhibitors for renal preservation after
LT.
Table 4. Clinically used immunosuppressive agents in liver transplantation.
Immunosuppressant Class  Immunosuppressive Agent
Corticosteroids  Prednisone, prednisolone, methylprednisolone
Calcineurin inhibitors  Cyclosporin A, tacrolimus
Antimetabolites  Mycophenolate mofetil, azathioprine
mTOR Inhibitors  Sirolimus, everolimus
Polyclonal antibodies  Antithymocyte globulin (ATG)
Monoclonal anti-CD3 antibodies  Muromonab-CD3 (OKT3)
Chimeric monoclonal antibodies  Anti-IL-2 inhibitors (basiliximab)
Monoclonal anti-CD52 antibodies  Alemtuzumab (campath-1H)
Other side effects of CNI
Beside potential nephrotoxicity, CNI therapy is associated with side effects that
include cardiovascular complications, tremor, headache, electrolyte abnormalities,
hyperuricemia, hepatotoxicity, and gastrointestinal symptoms. Neurotoxicity,
including tremor, paresthesia, muscle weakness, and seizures, more often occurs in
TAC-treated patients; whereas gingival hyperplasia, as a rare event, and hirsutism
are associated with CSA treatment.
Cardiovascular side effects due to CNI and steroids include hyperlipidemia,
arterial hypertension, and diabetes (Beckebaum 2004b).
The prevalence of new-onset diabetes mellitus after LT has been reported to occur
in 9-21% of patients (John 2002, Konrad 2000). The prevalence of post-transplant
diabetes is even higher if cofactors such as hepatitis C are present. In various
studies, the diabetogenic potential has been reported to be higher in patients
receiving TAC than in those receiving CSA. In contrast, CSA has a more
pronounced effect on lipid levels. CSA can act by modulating the activity of the
LDL receptor or by inhibiting the bile acid 26-hydroxylase that induces bile acid
synthesis from cholesterol.
Corticosteroid minimization/avoidance protocols
There is ongoing discussion of steroid avoidance due to dyslipidemia, osteoporosis,
development of cataracts, weight gain, hypertension, and a deleterious impact on
glucose control. A recently published literature review (Lerut 2009) analysed the
actual status of corticosteroid minimization protocols in LT based on a detailed
analysis of 51 peer- and 6 non-peer-reviewed studies. Results from the majority of
360  Hepatology 2012
studies showed that these protocols have clearly metabolic benefits and are safe
with respect to graft and patient survival. Other research groups have reported
encouraging findings with steroid-free protocols including basiliximab induction
therapy (Filipponi 2004, Llado 2008, Becker 2008). A steroid-free alemtuzumab
induction regimen resulted in less hypertension and rejection but with more
infectious complications. So far, the overall benefit of alemtuzumab induction in LT
recipients remains questionnable (Levitsky 2011).
Figure 4. Non-melanoma skin scancers and liver transplantation (LT). Organ transplant
recipients have an increased risk of development of non-melanoma skin cancers as compared
to the non-transplant setting. Premalignant lesions such as actinic keratoses [A] are
predominantly located on sun-exposed areas. Squamous cell carcinoma [B,C] is the most
frequent skin cancer after LT followed by basal cell carcinoma [D] (Photographs kindly provided
by PD Dr. Hillen, Transplant Dermatology Outpatient Unit, Department of Dermatology,
University Hospital Essen, Germany).
De novo malignancies
Incidence of malignancies is higher in transplant patients and depends on the length
of follow-up, characteristics of the transplant population,  choice of
immunosuppression and era in which the LT was performed (Buell 2005, Fung
2001). A cumulative risk has been reported of 10%, 24%, 32% and 42% at 5, 10, 15
and 20 years, respectively, for development of de  novo  cancers after LT
(Finkenstedt 2009). The highest risks in the transplant setting are nonmelanoma skin
cancers, mainly squamous cell carcinoma and basal cell carcinoma (Figure 4).
Premaligant lesions such as actinic keratoses are mostly located on sun-exposed
areas. Squamous cell carcinoma and basal cell carcinoma are increased by factors of
~65-200 and ~10, respectively, in organ transplant recipients as compared to the
immunocompetent population (Ulrich 2008). An annual routine dermatological
Update in Transplant Hepatology  361
follow-up exam, limitation of sun exposure and protective measures including
sunscreens are highly recommended for transplant patients.
A higher incidence of colon cancer in patients with inflammatory bowel disease
who are transplanted for PSC has been reported in the literature (Hanouneh 2011). It
is therefore necessary to maintain an adequate colonoscopic surveillance in these
patients even in the absence of bowel  symptoms or active disease at regular
intervals (Fevery 2011). A trend has been recently reported toward an increased
incidence of advanced colon polyps and colon carcinoma in patients transplanted for
other diseases than PSC after LT. However, larger studies are needed to determine
whether post-transplant colon cancer surveillance should be performed more
frequently than in the non-transplant setting (Rudraraju 2008).
Recent studies reported a significantly higher incidence of aerodigestive cancer
including lung cancer among patients who underwent LT for alcohol-related liver
disease (Vallejo 2005, Jimenez 2005). A Spanish transplant group recommended
annual screening for oropharyngeal tumors in patients with a history of alcohol
overconsumption (Benlloch 2004).  SRL exerts antiangiogenic activities that are
linked to a decrease in production of vascular endothelial growth factor (VEGF) and
to a markedly inhibited response of vascular endothelial cells to stimulation by
vascular endothelial growth factor (VEGF) (Guba 2002). Furthermore, the ability of
SRL to increase the expression of E-cadherin suggests a mechanism for blocking
regional tumor growth and for inhibiting metastatic progression. Therefore, we give
special consideration for mTOR inhibitor-based immunosuppressive regimens not
only patients transplanted for HCC but also those with de novo malignancies after
LT.
Biliary complications
Biliary leaks generally occur as an early post-transplant complication. In patients
with biliary stones, endoscopic sphincterotomy and stone extraction are the
treatment of choice.
Biliary strictures are one of the most common complications after LT, with a
reported incidence of 5.8-34% (Graziadei 2006). Early anastomotic strictures (AS)
usually have a technical origin; while strictures appearing later have a multifactorial
origin. Nonanastomotic strictures (NAS) without underlying hepatic artery
thrombosis are commonly referred to as ischemic-type biliary lesions (ITBL).
Risk factors for ITBL include preservation-induced injury, prolonged cold and
warm ischemia times, altered bile composition, ABO blood incompatibility and
immunological injury (Verdonk 2007, Buis 2009).
Endoscopic  retrograde cholangiography (ERC) or percutaneous transhepatic
cholangiography (PTC) have typically been used as the primary approach, leaving
surgical intervention for those who are nonresponsive to endoscopic interventions or
who have diffuse intrahepatic bile duct damage. Novel radiological methods such as
magnetic resonance cholangiopancreaticography (MRCP) have been introduced as
an additional diagnostic tool for biliary complications.
The long-term efficacy and safety of endoscopic techniques have been evaluated
in various transplant centers (Qin 2006, Zoepf 2006, Pascher 2005).
Nonanastomotic strictures are commonly associated with a less favourable response
to interventional endoscopic therapy in comparison to anastomosis stenosis (Figure
5). An Austrian group found anastomotic strictures in 12.6% of patients transplanted
362  Hepatology 2012
between October 1992 and December 2003 and nonanastomic strictures in 3.7%
during a mean follow-up of 53.7 months after LT (Graziadei 2006). Interventional
endoscopic procedures were effective in 77% of patients with anastomosis stenosis;
whereas treatment of nonanastomotic strictures showed long-term effectiveness in
63% of patients. A surgical approach was required in 7.4% of transplant recipients.
Figure 5. Biliary tract complications after liver transplantation. A. Endoscopic retrograde
cholangiography (ERC) showing post-transplant short filiform anastomotic biliary stricture in a
46-year-old patient transplanted for HCV and alcohol-related cirrhosis 6 months earlier.
Therapy sessions include dilatation and an increasing number of bile duct endoprostheses at
short intervals of every 2-3 months. Prior to endoscopic therapy an endoscopic spinkterotomy is
performed. B. ERC of a 41-year-old patient transplanted for HCV diagnosed with ischemic-type
biliary lesions (type 3) with long nonanastomotic stricture extending proximally from the site of
the anastomosis and strictures throughout the entire liver.
Zoepf et al. (2006) retrospectively analyzed results from 75 transplanted patients
undergoing ERC for suspected anastomic strictures. Balloon dilatation alone and
combined dilatation and endoprotheses placement was efficacious in 89% and 87%
of cases respectively, but recurrence occurred in 62% and 31% of cases
respectively. We therefore use dilatation plus stenting with endoscopic reassessment
in anstomotic strictures. Repeated ERC sessions are performed with increasing
endoprothesis diameter in trimonthly time intervals and double or triple parallel
stenting in selected cases. Up to 75% of patients are stent-free after 18 months of
endoscopic intervention (Tung 1999).
Medical treatment for bile duct strictures consists of UDCA and additional
antibiotic treatment in stricture-induced cholangitis. Complications related to
bilioenteric anastomosis require PTC or surgical intervention.
Metabolic bone disease
Liver cirrhosis and therapy with corticosteroids are risk factors for the development
of osteoporosis. Screening with bone densitometry should therefore begin prior to
LT (Wibaux 2011). A further increase in bone turnover has been described after LT
and may be associated with resolution of cholestasis, increased parathormone
secretion and/or CNI administration (Moreira Kulak 2010). Metabolic bone disease
Update in Transplant Hepatology  363
is therefore a common cause of morbidity after LT. Factors such as vitamin D
deficiency, hypogonadism, secondary hyperparathyroidism and adverse lifestyle
factors should be addressed and corrected. There are no specific therapies for post-transplant osteoporosis other than for nontransplanted patients. General
interventions to reduce fracture risk include adequate intake of calcium and vitamin
D. Bisphosphonates are currently the most effective agents for treatment of post-transplant osteoporosis (Moreira Kulak 2010) (www.dv-osteologie.org). A meta-analysis and systematic review of randomised controlled trials demonstrated that
bisphosphonate therapy within the first 12 months after LT is associated with
reduced accelerated bone loss and improved bone mineral density at the lumbar
spine (Kasturi 2010).
Recurrent diseases after liver transplantation
Disease recurrence may occur in patients transplanted for viral hepatitis, tumor
disease, autoimmune or cholestatic or alcohol-related liver diseases. With universal
recurrence of HCV in all replicative patients, hepatitis C continues to pose one of
the greatest challenges for preventing disease progression in the allograft.
Recurrence of hepatitis B in the allograft
Combined use of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogs has
emerged as treatment of choice in transplant HBV recipients (Figure 6) (Yan 2006,
Marzano 2005, Cai 2011) and its efficacy has been investigated extensively. HBV
recurrence using combined prophylactic regimens is less than 5%. However,
recurrence rates differ among various studies as most of them are small, with
varying proportions of patients with active viral replication at LT and varying
follow-up periods after LT. Furthermore there is a high variability (dose, duration
and method of HBIG administration) in the prophylactic protocols. According to the
German guidelines (Cornberg 2011) patients receive 10,000 IU HBIG intravenously
(IV) in the anhepatic phase followed by 2000 IU during the first postransplant week.
For long-term HBIG prophylaxis, trough anti-HBs levels at or above 100 IU/L
should be maintained. Subcutaneous (SC) HBIG application has various advantages
over intramuscular (IM) and IV administration (Beckebaum 2008b, Yahyazadeh
2011) and can be administered in stable and compliant patients after the early post-transplant period. It is well tolerated and patients can perform injections in a home
setting, thus reducing physician consultation time. Nucleos(t)ide analogs given prior
to LT should be continued indefinitely post-transplant.
Economic issues have led to a controversial discussion of whether indefinite
passive immunisation is necessary and if nucleos(t)ide analog therapy is sufficient
for antiviral prophylaxis (Naoumov 2001, Buti 2007, Gane 2007, Angus 2007, Neff
2007, Lo 2005, Wong 2007, Nath 2006, Yoshida 2007, Weber 2010, Karlas 2011).
Post-transplant studies have described unacceptable 2-4 year rejection rates of
approximately 25-50% with LAM monotherapy and with no initial phase of HBIG
therapy (Table 5) (see http://hepatologytextbook.com/link.php?id=9) (Marzano
2001, Jiao 2007, Zheng 2006).
A prospective, open-label, multicenter study was conducted on the safety and
efficacy of combined LAM/ADV therapy in HBsAg-positive LT recipients (Gane
2007) (Table 5) (see http://hepatologytextbook.com/link.php?id=9). Patients with