Review Article JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

Post-Transplant Immunosuppression in Autoimmune

Liver Disease
Claire Kelly , Yoh Zen, Michael A. Heneghan
Institute of Liver Studies, Kings College Hospital, London, UK

Autoimmune liver diseases (AILDs) are a group of conditions where immune-mediated liver damage can lead to
the need for transplantation. Collectively, they account for almost a quarter of all liver transplants. Outcomes in
terms of graft and patient survival for all liver transplants have improved markedly over decades with improve-
ments in patient selection, surgical techniques and longer-term care and this is also seen in patients with AILDs.
The current five- and ten-year survival rates post-transplant in autoimmune disease are excellent, at 88% and
78%, respectively. A key factor in maintaining good outcomes post liver transplant for these autoimmune con-
ditions is the immunosuppression strategy. These patients have increased the rates of rejection, and autoim-
mune conditions can all recur in the graft ranging from 12 to 60% depending on the population studied.
Immunosuppressive regimens are centred on calcineurin inhibitors, often combined with low dose corticoste-
roids, with or without the addition of antimetabolite therapy. There is no clear evidence-based immunosuppres-
sive regimen for these conditions, and a tailored approach balancing the individuals’ immunological profile
against the risks of immunosuppression is often used. There are disease-specific considerations to optimised
graft function including the role of ursodeoxycholic acid in both primary biliary cholangitis and primary scle-
rosing cholangitis and the role and timing of colectomy in primary sclerosing cholangitis in inflammatory
bowel disease patients. However, unmet needs still exist in the management of AILDs post liver transplantation
Autoimmune Liver Disease

particularly in building the evidence base for optimal immunosuppression as well as mitigating the risk of
recurrent disease. ( J CLIN EXP HEPATOL 2023;13:350–359)

A
utoimmune liver disease (AILD) describes a range
of conditions, predominantly autoimmune hepati-
tis (AIH), primary biliary cholangitis (PBC) and
primary sclerosing cholangitis (PSC). In these AILDs, im-
mune-mediated liver damage can result in the need for
liver transplantation (LT). Indications for LT in patients
with AILDs are similar to those in other chronic liver dis-
eases that result in liver failure (decompensated cirrhosis
and hepatocellular carcinoma). However, other distinct
indications exist for each group (pruritis in PBC, cholan-
gitis in PSC and acute liver failure in AIH).1–3 Collectively,
these AILDs represent the third commonest indication
for LT in most liver transplant centres and account for
approximately 24% of all LTs3–6.
Keywords: autoimmune liver disease, immunosuppression, transplanta-
tion
Received: 6.4.2022; Received in revised form: 10.6.2022; Accepted: 4.7.2022;
Available online 12 July 2022
Address for correspondence: Claire Kelly, Institute of Liver Studies, Kings
College Hospital, London, UK.
E-mail: clairekelly4@nhs.net
Abbreviations: AIH: Autoimmune hepatitis; AILD: Autoimmune liver dis-
ease; CNI: Calcineurin inhibitors; IBD: Inflammatory bowel disease; LT:
Liver transplantation; PBC: Primary biliary cholangitis; PSC: Primary scle-
rosing cholangitis; rAIH: Recurrent autoimmune hepatitis; rPBC: Recur-
rent primary biliary cholangitis; rPSC: Recurrent primary sclerosing
cholangitis
https://doi.org/10.1016/j.jceh.2022.07.002
Improvement in surgical techniques, patient selection,
perioperative care and immunosuppressive regimens have
helped increase post-LT patient and graft survival in
AILD.7,8 Outcomes after LT for AILD are good, with
the European Liver Transplant Registry showing survival
rates of approximately 88% and 78%, at five- and ten-
years, respectively, in donation after brainstem death
(DBD) donors from 1998 to 2017.9 This registry also an-
alysed survival in living donor liver transplantation
(LDLT) in AILD (n = 705) finding 85% and 74% alive after
one- and ten-years. However, all AILD can recur post-LT
with the potential for graft loss and need for re-transplan-
tation.4,10–16 Recurrent disease in AILD is common, and
the prevalence increases with time following LT,
ranging from 17 to 42% in AIH, 12 to 30% in PBC and
12 to 60% in PSC.4,5,17,18 The variability in rates of recur-
rent disease in likely related to whether protocol or clin-
ically indicated liver biopsies post-LT are performed. It is
known that recurrent disease negatively impacts quality
of life as well as graft and overall survival.1,19 There is,
therefore, a need to risk stratify patients to tailor post-
transplant care and immunosuppressive strategy to opti-
mise patient outcomes.
AUTOIMMUNE HEPATITIS
AIH is a complex immune-mediated necroinflammatory
condition where liver damage occurs through a combination

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 JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
HLA DR3 recipient
Need for re-do LT for AIH
Chronic AIH presentations
Abnormal liver enzymes at the time of LT
Discontinuation of steroid therapy
Moderate or severe inflammation of the explanted liver
High IgG pre-LT
MMF use
Figure 1 Factors associated with AIH recurrence post-LT. AIH, autoim-
mune hepatitis; LT, liver transplantation.
of immunological, genetic and environmental factors. The
prevalence of AIH varies, ranging from 4 (Singapore) to
42.9 (Alaska) cases per 100,000 persons, but it is clear that
disease prevalence is increasing worldwide.20–22
The clinical presentation of AIH is variable, with acute,
chronic or acute-on-chronic manifestations.23 Patients
with AIH who require LT can have any phenotype of
disease and those with chronic disease can present with
their index presentation of liver disease or following
treatment with immunosuppressants.24,25 Moreover, of
all the AILD's, AIH is unique in presenting with acute
liver failure.
Factors associated with a lack of response to the stan-
dard treatment include younger age and model for end-
stage liver disease score >12 at diagnosis as well as acute
presentations, high bilirubin and HLA DRB1*03.24 Lack
of response to standard immunosuppression regimens is
predictive for LT, particularly after six months of treat-
ment.26
AIH accounts for 5% of the indications for LT per-
formed in the United States and 7% of those performed
in the United Kingdom.1,27 Outcomes post-LT for patients
with AIH are good, with five- and ten-year patient survival
rates of 81% and 77%, respectively.4,28–31 However, a long-
term analysis of mortality suggested a reduced one-year
survival post-LT for patients with AIH compared to other
indications for LT.32
The European Liver Transplant Registry reported on
long-term outcomes post-LT in AILD, comparing LDLT
and DBD grafts. Patients with AIH had the highest rate
of LDLT (P < 0.001) but this was likely related to a high
proportion of children in this AIH cohort.9
Despite the overall good outcomes, managing these pa-
tients post-LT can pose distinct challenges. There is a
higher risk of late acute rejection (9%), chronic rejection
(16%) and disease recurrence (36–68% at five years) than
other LT indications.2,6,11,31,33,34 This immunological risk
needs to be taken into account with the choice of immuno-
suppressive strategy.
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Immunosuppressive Therapy
A key factor in the post-LT management of AIH is mainte-
nance immunosuppressive strategy. Successful post-LT
management strikes a balance between the complications
of drug therapy and the optimisation of patient and graft
survival. However, despite published data on post-LT out-
comes in patients with AIH, there is no evidence-based
optimal regimen available.6,35 Thus, many patients have a
tailored strategy to balance their perceived individual risks
and benefits.
Treatment with CNI therapy is the mainstay of post-LT
immunosuppression.33,36 In many centres, the CNI is com-
bined with steroid therapy (dual immunosuppressive strat-
egy) either alone or in conjunction with an antimetabolite
as a triple immunosuppressive strategy.33,36,37 In our
centre, first-line therapy is with tacrolimus and long-term
low-dose steroid therapy. There are reports of dual immu-
nosuppressive strategies (steroid and CNI) having a higher
risk of AIH recurrence than triple immunosuppression
with the addition of an antimetabolite (OR 1.47; P =
0.018).38 However, other reports suggest the rates of recur-
rent AIH (rAIH) are similar in those on triple immunosup-
pression to those not on this strategy.39 Type of CNI
Autoimmune Liver Disease
(ciclosporin versus tacrolimus) has not been associated
with a significant difference in recurrence rates.40–42
Interestingly, recent publication of the largest dataset
reporting over 700 patients transplanted for AIH
highlights MMF use as a risk factor for recurrence.43
Maintenance Steroid Therapy
The role of steroid maintenance therapy is controversial.
Many transplant centres use long-term low-dose steroid ther-
apy as part of their maintenance immunosuppressive strat-
egy in AILD, as this has been reported to minimise rAIH.44
However, concerns remain about the side-effect profile of
these drugs. Steroid withdrawal in non-AILDs improves
metabolic profile (hypertension, hyperlipidaemia and dia-
betes mellitus) without increasing the risk to the graft. How-
ever, there is concern that steroid withdrawal increases the
recurrence of AIH in the graft post-LT.6,11 In our centre,
low-dose steroids (prednisolone 5 mg) are continued long-
term in post-LT AIH patients. It has been suggested that
this approach provides a good balance, reducing the inci-
dence of rAIH without increasing the risk of osteoporosis
and infection.35,42 Other studies have conflicting results,
with steroid withdrawal not increasing the risk of rAIH, acute
cellular rejection, graft loss or death.45,46 However, there are
also reports that steroids do not present an increased side-
effect profile (infections and metabolic parameters).47 The
American Association for the Study of Liver Diseases sug-
gests that a gradual withdrawal of steroids should be consid-
ered in AIH patients’ post-LT as this approach has benefits
without increasing risk.33 One must take into consideration
351
 POST-TRANSPLANT IMMUNOSUPPRESSION KELLY ET AL

the previous duration of steroid therapy pre-LT and the risk
of adrenal suppression.
Disease Recurrence
AIH can recur post-LT, and this is associated with a higher
risk of graft loss, with overall survival reported at 76% at
five years in rAIH.48 However, it can be challenging to diag-
nose rAIH, as it can be difficult to distinguish from graft
rejection.33 Establishing an accurate frequency of
rAIH has been challenging as the diagnostic criteria for
rAIH have not been standardised, with the international
AIH group report and simplified score not validated
post-LT.49,50
AIH is reported to recur in 8%–68% of transplanted pa-
tients. The frequency is reported to increase over time,
from 8 to 12% at 1 year and 36–68% at 5 years.4,10,51 Risk
factors implicated in recurrence include the susceptibility
alleles HLA-DRB1*0301 or DRB1*0401 in the transplant
recipient and HLA-DR locus mismatching.52 Control of
disease activity prior to LT for patients with AIH is associ-
ated with a lower risk of rAIH.4 However, immunosuppres-
sion escalation to achieve this outcome needs to be
balanced against the increased risk of perioperative infec-
Autoimmune Liver Disease
patients.60,61 The indications for LT in PBC are those seen
in other end-stage liver diseases, with intractable pruritus a
disease-specific indication.62–64
Although PBC is considered a relatively rare disease, up
to 10% of the patients listed for LT in North America and
Europe have this diagnosis.5,65 However, this need for LT
has been reducing, which may be related to earlier treat-
ment with ursodeoxycholic acid (UDCA) and the develop-
ment of new therapies for UDCA non-responsive disease.66
PBC has excellent outcomes post-LT, with five-year
overall survival of 90%.67 Despite this, PBC can recur in
the graft and a small proportion of patients will require
re-transplantation as a result.
Immunosuppressive Therapy
CNI therapy is also the corner stone of post-LT immuno-
suppressive maintenance therapy for patients with PBC.
Two meta-analyses reported on the risk of recurrent PBC
(rPBC) by immunosuppression type. Whilst one did not
find an association, the other reported recurrent disease
in 29% of their cohort and an increased rPBC risk with ta-
crolimus.68,69 In the largest cohort reported thus far, the
Global PBC Study Group have shown that tacrolimus in-

tion. A summary of the factors that have been linked to

creases the risk of rPBC (HR 2.06, P < 0.0001) and sup-
recurrent disease are shown in Figure 1.4,10,11,53,54
ported the use of ciclosporin in post-LT PBC.70 However,
Inadequate maintenance immunosuppression, espe-
it should be remembered that patients with PBC have
cially discontinuation of steroid therapy, has been reported
both an increased frequency of acute cellular rejection
to play a role in disease recurrence.11 However, rAIH has
and late onset acute rejection and thus optimal immuno-
also been reported to those on an immunosuppression
suppression is also important.44,71–73 Acute cellular
regimen that should be adequate to prevent rejection.55
rejection post-LT in PBC ranges from 21.7% to 83.3%.74–76
Generally, asymptomatic rAIH with minimal histologi-
This can decrease patient and graft survival and play a
cal changes may be suppressed by optimising immunosup-
role in disease recurrence.74,77 In our centre, tacrolimus is
pression.10,56 However, more significant changes are more
used initially, with a consideration of switch to ciclosporin
likely to require higher doses of corticosteroids alone or in
after three months, particularly in higher-risk individuals.
conjunction with additional immunosuppressive agents.
This switch is instituted on a tailored basis and depends
Re-transplantation may be required for those who develop
on whether there have been episodes of rejection.
graft cirrhosis despite the optimisation of immunosup-
pressive treatment, with graft loss reported in 13–50%
with rAIH among adults.11,53 UDCA
The administration of prophylactic UDCA post-LT for
PBC PBC is associated with reduced rPBC, graft loss, liver-
related death and all-cause mortality.70 Furthermore, a
PBC is a chronic liver disease, with immune-mediated
combination of ciclosporin and UDCA was associated
injury to biliary epithelial cells and represents an interac-
with an even lower risk of both rPBC and mortality.70
tion between genetic and environmental factors.57 The
This has been confirmed by other researchers, showing
prevalence ranges from 19.1 (Australia) to 40.2 (USA) cases
UDCA prophylaxis significantly decreased the rate of
per million persons. The mean age at diagnosis is 60 years
rPBC.70,78 Therefore, prophylactic UDCA should be
and there is a female preponderance, with a female to male
administered (10–15 mg/kg/day) after LT to prevent
ratio of 4:1.58 PBC tends to be more aggressive in men, with
rPBC and improve graft and patient survival.70,79 The
higher rates of both transplantation and mortality re-
role of second-line therapies in post-LT PBC patients re-
ported.59
mains uncertain, although is probably appropriate for in-
While approximately half of patients are asymptomatic
dividuals who are either non-responsive to UDCA or who
at diagnosis, PBC can progress to symptomatic disease,
have symptoms relating to rPBC despite appropriate
including intractable pruritus, fatigue and decompensated
weight-based UDCA dosing. In our institution, all patients
cirrhosis resulting in the need for LT in up to one-third of

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 JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
with PBC are started on UDCA post-LT unless intolerant
of it previously.
rPBC
The recurrence of immune features, such as high IgM, anti-
mitochondrial antibody and aberrant mitochondrial pro-
tein expression in biliary epithelium, has been recorded
in approximately 70% of patients with PBC post-LT. How-
ever, histological disease characteristic of PBC is only
found in a subset.80 The frequency for rPBC has been re-
ported to range from 17% to 46% after LT, with differences
impacted by differing practices over the use of protocol or
clinically indicated graft biopsies.5,60,81,82 Data suggests
rPBC can negatively affect patient and graft survival.83
The median time from transplantation to diagnosis of
rPBC is approximately five years. Rates of rPBC increase
with time, with 30% prevalence ten years after LT.75,84,85
However, PBC may recur earlier, even as early as nine
months post-LT86.
Many factors have been linked with rPBC, including
young donor age, older recipient, long cold ischaemia
time and immunosuppression regimen (see Figure 2).75,87
Increased ALT and ALP within the first year after LT and
initial immunosuppression with tacrolimus were both
associated with a higher risk of rPBC.79 Patients receiving
tacrolimus have earlier onset and more severe rPBC,
whereas, the use of ciclosporin is protective.5,88,89 Of
note, rPBC has been reported to occur with weaning of ci-
closporin and disease resolution reported with the reintro-
duction of ciclosporin and prednisone.90
PSC
PSC is a chronic, immune-mediated cholestatic liver dis-
ease affecting intrahepatic and extrahepatic bile ducts,
causing progressive inflammation and obliterative
fibrosis.2,91–93 It has a strong association with
inflammatory bowel disease (IBD) particularly in men
with up to 75% of these IBD cases ulcerative colitis.94,95
This association with ulcerative colitis increases the risk
of liver disease progression when compared to Crohn's dis-
ease.96,97
PSC is a rare disease, seen more commonly in Northern
European countries with a prevalence of 23.99 per 100,000
Younger age at diagnosis (<40 years) and LT
Use of tacrolimus post-LT
Gender mismatch between recipient and donor
High IgM
ALT >50 at 6 months post-LT
Cholestatic liver function tests in the first 6 months post-LT
Figure 2 Factors associated with PBC recurrence post-LT. LT, liver
transplantation; PBC, primary biliary cholangitis.
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Presence of IBD
Colon in situ
Cholangiocarcinoma prior to LT
Any acute cellular rejection or >2
episodes of rejection
Increased donor age
Male gender
Younger recipient age
Figure 3 Factors associated with PSC recurrence post-LT. LT, liver
transplantation; PSC, primary sclerosing cholangitis.
persons in the USA.98 It is more prevalent in men with a
mean age at diagnosis of 37 years.96
Clinical presentation is variable, with many patients
diagnosed when asymptomatic on the basis of abnormal
liver function tests.93,99 Symptomatic patients present
most commonly with fatigue, abdominal pain and pruri-
tus.98 A more aggressive presentation can occur, character-
ised by recurrent biliary obstruction and cholangitis that
may progress to cirrhosis, liver failure or hepatobiliary ma-
lignancies.62,92 However, in general, patients with PSC have
Autoimmune Liver Disease
a poor prognosis and require a LT within 10–15 years of
diagnosis as a result of the complications of cirrhosis.100
Patients with PSC can also be listed for recurrent cholangi-
tis, but these patients are often low priority due to low
model for end-stage liver disease or equivalent scores.101
In the USA, they often require exception points and in
the UK may need to be listed for LT as a ‘variant’. There
are no therapeutic options currently available to prevent
disease progression in patients with PSC.102
LT is the only proven treatment to improve survival for
patients with PSC and end-stage liver disease, with 36.7% of
patients progressing to LT or death during a median
follow-up of 14.5 years.96,103 Based on the United Network
for Organ Sharing (UNOS) database, PSC has been the
most frequent cause of end-stage liver disease requiring
LT among AILDs, accounting for 48% of total liver trans-
plants for this patient group and 4.5% of LT indications
overall.7 Furthermore, the need for LT in PSC has increased
over recent years. Post-LT outcomes are favourable, with
five-year graft and patient survival of 85.4% and 85.5%,
respectively.104
Post-LT, the main complications are acute cellular rejec-
tion, chronic rejection, hepatic artery thrombosis, biliary
strictures and disease recurrence.105 PSC is now the most
common disease to recur after LT.93 Recurrence occurs in
up to 20% of LT recipients within five years and increases
the risk of graft failure and mortality.106
An additional factor to be considered in the post-LT
PSC patient is the higher risk of gastrointestinal malig-
nancy, and the need to ensure any IBD is managed expedi-
ently. Attention to these factors helps improve post LT
outcomes for these patients.
353
 POST-TRANSPLANT IMMUNOSUPPRESSION
Immunosuppressive Therapy
The immunosuppression regimen after LT in patients with
PSC consists of a CNI, mainly tacrolimus, either with corti-
costeroids as dual therapy or with the addition of an anti-
metabolite as a triple regimen. Like with other
autoimmune indications, the regimen intends to prevent
disease recurrence and improve graft survival. In our centre,
tacrolimus is the first-line therapeutic agent used with the
addition of a second agent based on individual patient risk.
Data regarding the impact of the type of immunosup-
pression used on PSC recurrence rate is inconclusive.
Two studies reviewing the influence of CNI type on rPSC
after LT, did not find a statistically significant link between
tacrolimus use and rPSC, with one suggesting a non-
significant trend towards increased rPSC with ciclospor-
in.107,108However, others have reported an increased risk
of rPSC with tacrolimus.109 A meta-analysis described ci-
closporin as decreasing the risk of rPSC after LT, whereas
tacrolimus did not.68 Despite this, our practice is to use ta-
crolimus-based regimens.
One factor that may influence immunosuppression
choice is underlying IBD activity. Data have shown that
both tacrolimus and a dual immunosuppressive regimen
Autoimmune Liver Disease
with mycophenolate mofetil increase the risk of IBD
relapse post-LT.110 Further studies are required to confirm
which immunosuppressive regimen is more beneficial in
patients with PSC after LT.
Role of Colectomy on Post-LT Outcomes
The presence of active ulcerative colitis post-LT increases
the risk of disease recurrence, therefore the control of coli-
tis should be prioritised.111 Colectomy has been shown to
decreases the risk of recurrence of PSC.68,109,112 The timing
of colectomy, whether before, at the time of LT or after re-
mains uncertain. However, a lower threshold for colectomy
should be considered in patients with PSC-IBD who need
transplantation, and this would also reduce colonic cancer
risk.68,112 In our institution, colectomy is considered at the
time of transplant for those who have active IBD despite
medical therapy.
rPSC
The diagnosis of rPSC can be challenging because biliary
strictures can occur post-LT for other reasons. Criteria
for establishing a diagnosis of rPSC include evidence of
biliary strictures more than ninety days after LT.105 Howev-
er, there is a need to exclude other potential contributory
factors for biliary disease, including hepatic artery throm-
bosis, ductopenic rejection, non-anastomotic strictures
less than 90 days after LT and donation after cardiac death
related complications. Liver biopsy can be helpful in estab-
lishing the diagnosis.105
Recurrent PSC is estimated to occur in approximately
one quarter of patients (20–25%) over a 10-year period
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KELLY ET AL
post-LT.14,105,113 Over one-third (36%) of patients develop
biliary strictures over 8 years follow up, and rPSC was rec-
ognised in 20%, with a mean time to diagnosis of 4.6 years
post-LT.108
A variety of risk factors have been identified for the
development of rPSC (see Figure 3). Recipient factors
include a younger or older age at the time of LT, male
gender and the presence of cholangiocarcinoma.15,18,114
Donor factors include gender mismatch, CMV mismatch
and the use of living related donor, mainly with the use
of grafts from parents.115,116 It is uncertain whether the
increased biliary complications with living donor LT is a
trigger for rPSC or whether genetics given donors are often
first-degree relatives are key.117,118 Steroid-resistant acute
cellular rejection and late onset acute rejection have both
been linked with rPSC.32,44 Patients with cholestasis at
three months post-LT have a higher probability of devel-
oping rPSC.119
A key factor in rPSC is the co-existence of IBD, particu-
larly if the IBD is active.120 Additionally, the presence of
IBD following LT is associated with a reduction in patient
survival.121 The use of tacrolimus has been shown to be
associated with an increased risk of developing de novo
IBD after LT.121,122 The exacerbation of pre-existent IBD
may be observed post-LT for PSC, and IBD tends to be
more severe post-LT.123
Disease recurrence in PSC is associated with a decreased
graft survival, and this is compounded by the lack of treat-
ment options before pre- and post-LT.48,92 Of those with
rPSC, nearly half (46%) progressed to graft failure with
an associated increased risk of death.107
Some centres continue to use 13–15 mg/kg UDCA for
rPSC, as it improves liver biochemistry. However, it is un-
known if this has any impact on overall outcomes.124,125
Recently, increased mortality in patients having LDLT
compared to DBD LT (hazard ratio 1.95, P < 0.001) was
described that was not seen in AIH (P = 0.787), PBC (P =
0.0.314) or a non-AILD cohort with alcohol-related disor-
ders (P = 0.49).9 When data were adjusted to include the
10 centers with the greatest LDLT volume, this association
with mortality was comparable (PSC P = 0.033; AIH, PBC,
control group P = NS). The risk of death from graft failure
and non-liver causes in patients with PSC undergoing
LDLT remained significant when compared to DBD grafts
(P = 0.02) but this was not seen in other AILDs.9
Further analysis of predictors of mortality in PSC LDLT
found no relationship with recipient sex, blood group
mismatch, ischaemic time and donor-recipient sex match-
ing. However, multivariate analysis did find recipient age of
28 years or older, a donor of 50 years or older and donation
from a male were associated with an increased risk of death
(P = 0.013, P = 0.008, P = 0.025, respectively).9 There was no
significant link with donor sex and mortality in the PSC
DBD group (P = 0.637). Risk for requiring redo-LT was
similar in LDLT and DBD grafts.9 Additionally, death
 JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

associated with PSC recurrence was higher in the LDLT
than DBD groups (P = 0.044). Biliary complications were
also higher in patients with LDLT PSC (P = 0.031).9
OVERLAP SYNDROMES
Although there are no strict definitions, overlap syndromes
represent the combined features of AIH and PBC or
PSC.126,127 Patients with overlap syndromes have an earlier
onset and an increased frequency of recurrence when
compared to their counterparts receiving LT for AIH,
PBC or PSC.35,128 Taken together, the data suggest that
overlap syndromes represent more severe end of the spec-
trum of AILDs that are more likely to manifest in the
graft. Whether increased immunosuppression with or
continued corticosteroid use would be of benefit remains
uncertain.
PLASMA CELL RICH REJECTION
As outcomes post-LT in AILD improve, late graft dysfunc-
tion becomes more prominent and can be challenging to
manage. As well as recurrent disease and late cellular rejec-
and is not only seen more frequently in paediatric liver
transplant recipients (up to 5%) but can also be found in
adults (1–2%).129–132 It was not only mainly seen in
children transplanted for biliary atresia but is also more
frequently in PBC.133,134
The aetiology is unclear; however, it is associated with
several risk factors, including the number of acute rejection
episodes, steroid dependence, HLA DR3 and pegylated
interferon use which was formerly used in the treatment
of recurrent hepatitis C infection.135–138 Grafts from
older women have been reported as being associated with
increased risk, although this has not been universally
acknowledged.134,135 It is characterised by a plasma cell
rich interface hepatitis, with centrilobular necroinflamma-
tion with plasma cell infiltration also described (see
Figure 4).139 IgG4 positive plasma cells are over-
represented, and donor specific antibodies are positive in
over half of cases with portal microvascular C4d stain-
ing.140 Serum IgG levels are increased and there can be pos-
itive autoantibodies with elevated liver enzymes.133 The
features of plasma cell rich rejection are summarised in
Figure 5.
Treatment differs from that used in rejection, with the

Autoimmune Liver Disease

tion, an important cause of graft dysfunction includes inflammation more responsive to classical AIH therapy
plasma cell rich rejection (formerly known as de novo such as steroids and anti-metabolites.141,142 In our institu-
AIH, post-transplant allograft hepatitis and de novo im- tion, steroid therapy is considered a mandatory part of
mune hepatitis). It has overlapping features with AIH immunosuppressive therapy for these patients. With

Figure 4 Histopathology of plasma cell-rich rejection. (A): The portal tract is expanded with a dense inflammatory infiltrate and intense interface hep-
atitis (arrows) (x200). (B): The portal infiltrate contains many mature plasma cells (x400). (C): A focus of perivenular confluent necrosis is associated with
plasma cell infiltration (x200). (D): IgG4 immunostaining demonstrates many IgG4-positive plasma cells in the portal tract (x200).

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 POST-TRANSPLANT IMMUNOSUPPRESSION
De-novo autoantibody production
Elevated IgG
Co-existent T cell mediated or chronic rejection in 18-24%
IgG4 plasma cells are over-represented
Native or donor class II HLA haplotypes may predispose
Response to classical AIH therapy
Long term steroids required
Figure 5 Features of plasma cell rich rejection.
regard to immunosuppression type, patients maintained
on tacrolimus or mycophenolate mofetil have been re-
ported to be at a higher risk of developing plasma cell
rich rejection, whereas LT recipients treated with ciclo-
sporin have a reduced risk.134 It may be that patients
with LT on ciclosporin are more likely to be on corticoste-
roids, which could be protective.
Whilst outcomes for AILD patients post-LT are good,
these patients pose particular challenges. There are
increased immunological complications, particularly acute
cellular rejection and disease recurrence. This needs to be
Autoimmune Liver Disease
balanced against the complications of immunosuppressive
therapy. This is particularly true for patients having a re-do
LT for recurrent disease.
However, there is no clear evidence-based treatment
regimen for these patients, with often contradictory find-
ings in the literature. However, calcineurin inhibitors
remain the corner-stone of management. At present, the
management of patients with AILD requires not only a
tailored approach with the assessment of immunological
risk but that also takes into account disease specific modi-
fying treatment such as prophylactic UDCA in PBC.
There remains unmet needs in the post-LT care of AILD.
First, optimal immunosuppression regimen for the
increased risk of acute cellular rejection, taking into ac-
count disease type. Second, the prevention of disease recur-
rence post-LT is challenging. Currently, there is no clear
approach that is successful in mitigating the risk of disease
recurrence in all AILDs. As long-term outcomes continue
to improve, experience graft loss from disease recurrence
could become a more pressing concern for management
given the poor outcomes seen.48
CREDIT AUTHORSHIP STATEMENT
All authors contributed to (1) the conception and design of
the manuscript (2) drafting and revising the manuscript
critically for important intellectual content (3) final
approval of the submitted version.
CONFLICTS OF INTEREST
The authors have none to declare.
356 © 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
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KELLY ET AL
FUNDING INFORMATION
None.
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