Discussion:
Hepatic involvement in LCH is divided into two phases based on
histology. The early hepatitis phase is characterised by the active
infiltration of hepatic parenchyma by the Langerhans cells,
predominantly damaging hepatocytes and initiating fibrosis. The damage
is mediated by release of various proinflammatory cytokines released by
these cells leading to apoptosis and/or necrosis of
hepatocytes.4 The biopsy shows diffuse infiltration
with cells which are CD 207 and CD1a positive. The second phase which
may occur despite chemotherapy is a more chronic involvement, occurring
as a cholangiolar burnt-out disease.4 It is
characterised by hepatic parenchymal loss with progressive destruction
of biliary tree leading to sclerosing cholangitis.12This phase has minimal presence of histiocytes and is also observed
post-chemotherapy phase. In a large series from Argentina, sclerosing
cholangitis was seen in 18% patients with multisystem
LCH.18LT in LCH is mainly indicated for cirrhosis with
decompensation or portal hypertension due to LCH related secondary
sclerosing cholangitis. 18, 19
Among our cohort of 6 patients with LCH who underwent LT, the overall
graft and patient survival was 100% after a median follow up of 3
years. In a previous series on LCH related liver disease, 6 patients had
underwent LT, with a survival of 67% after a median period of 5.8
years.19 Two-thirds of their patients suffered from
post-transplant lymphoproliferative disorder (PTLD), and 50% required a
re-transplantation for acute refractory rejection within 3 months post
LT.
In a report from King’s College London on LCH, Of the 2 patients who
underwent LT with active disease, both had recurrence of LCH in the
allograft liver, 5 and 60 months after LT respectively despite
post-transplant chemotherapy using vinblastine, etoposide and
steroids.20 In a recent population based analysis of
60 patients undergoing LT for LCH, the overall 1-year survival was
79.4%.9 Also it was noted that more than 50%
patients had active extrahepatic disease at the time of LT and 8% had
disease recurrence in the graft over a mean follow up period of 2
years.9 50% of the patients had acute rejection and
10% had Post transplant lymphoproliferative disorder (PTLD). Similar
conclusions were drawn by the Whitington group, where 6 post-LT patients
had a 5-year survival of 67%, with 33% disease recurrence and
PTLD.19
None of our patients had recurrence of LCH or PTLD or T/B cell mediated
rejections in the post LT period. We start these patients on tacrolimus
based immunosupression, with periodic monitoring of trough levels as
mentioned before.
Vinblastine which is part of the first line regimen of the LCH IV
chemotherapy guidelines may worsen liver
dysfunction.21,22 It is also known to cause increased
systemic toxicity including peripheral neuropathy and bone marrow
suppression.23 Thus, in the category 2 subset of
patients, choosing the chemotherapeutic agents involves finding a fine
balance between disease remission and hepatotoxicity. We used a modified
chemotherapeutic protocol where vinblastine was replaced with
cytarabine.17 Two of our patients with decompensated
cirrhosis tolerated the drug well and completed the induction course.
There is also accumulating literature evidence in this regard. The
Japanese LCH 96 guidelines recommend cytarabine along with vincristine
and the group from Texas children hospital use a cytarabine based
chemotherapy (NCT02670707).24 Nonetheless, it is
noteworthy that there is no unified protocol for treating LCH with liver
disease. Many centres treat patients on case-to-case basis. In a recent
series from China, of 5 patients who underwent LT the pre-LT
chemotherapy regimen was different for each patient.25
The timing of LT in patients with LCH has been always a matter of
scientific debate. An LT done for a rapidly worsening liver without
achieving remission may lead to persistence of the disease post LT or a
disease recurrence. In patients with active disease and cirrhosis with
decompensation, a delay in LT may result in progressive liver
failure.20 The current available scientific evidence
is meagre to recommend a LT during active extrahepatic disease in
patients with LCH, and it is a general recommendation that active
extrahepatic malignancy is a contraindication for performing a LT. A
prior analysis has shown a good outcome when a LT is done following
disease remission in patients with LCH.25 Therefore,
it is imperative to confirm remission before offering LT. Two of our
patients who presented with active LCH and decompensated cirrhosis
underwent LT after successful induction chemotherapy cycles (after 1 and
3 cycles respectively) as the hepatic dysfunction was rapidly
progressing. Both these patients were confirmed to have disease
remission before undergoing LT.
The major limitation of our study is the small sample size. However,
this study throws light on the role and timing of LT in LCH. More
evidence is needed in suggesting specific agents like BRAF inhibitors
for the inducing remission of LCH in presence of an advanced liver
disease, whose disease is refractory to conventional and modified
chemotherapy.26 Based on our experience, we propose a
treatment algorithm for LCH patients with liver involvement (Figure 2).
Close monitoring by a multidisciplinary team though out the care with
timely interventions when needed could be the reasons for the excellent
results demonstrated in our series.