[CIS PIDD] [cis-pidd] Patient with a gain of function mutation in CARD11 (Benta disease) and acute liver failure despite liver transplantation

[CIS-PIDD]

Dear Simon,

  You have not told us a great deal about the liver histology. Could she be getting something equivalent to the giant cell hepatitis + histiocytes that can occur in children, sometimes associated with autoimmune hemolytic anemia? Those patients seem to respond only to rituximab or large doses of iv pushed steroids.

Best, Anthony

From: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] On Behalf Of CIS-PIDD
Sent: Friday, October 20, 2017 12:47 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Subject: [cis-pidd] Patient with a gain of function mutation in CARD11 (Benta disease) and acute liver failure despite liver transplantation

Dear Colleagues,

Advice and ideas that might help with the following case would be highly appreciated:

A 30 year old woman with a gain of function mutation in Card11 (Benta disease) had a increased frequency of upper respiratory infections but was until recently otherwise well. She had a greatly increased number of naive B cells (1547 cells/µl), reduced switched memory B cells, reduced IgG and IgA with normal IgM and normal vaccine responses. She had mild thrombocytopenia, a slightly increased spleen and and ALT was mildly increased (55 U/l). About 1 1/2 years ago she was started on monthly Ivig replacement therapy and tolerated it well and she delivered a healthy child last December.  About  8 weeks ago her transaminases started to rise, went into the high thousands and within 2 weeks she developed liver failure. The cause of the original liver disease is still unclear. She was negative for hepatitis A-E, CMV, EBV, HSV, and the result of a biopsy were not very helpful: compatible with autoimmunhepatitis or virus hepatitis with a mixed infiltrate of B cells, T cells (both without clonality, and no dominance of B cells) and histiocytes – EBV in the biopsy was negative. She had taken no other medication besides the pill and immunoglobulins and the pathologist said the picture would not fit to a toxic liver damage. Under the hypothesis of an autoimmunhepatitis she was treated with steroids and in the end for a short time with the combination of MMF and steroids but did not improve under this therapy.

She was HU listed and got liver transplanted. She was immunosuppressed with the standard protocol of our center with steroids and Tacrolimus (an mTor-Inhibitor was discussed but due to concerns about wound healing dismissed) . In the first days after transplantation the transaminases and INR recovered but on day 6 within hours went sky high again. The transplant team claimed that there was no vascular reason for the destruction of the transplant. A biopsy revealed again no clear answer to the cause of the organ destruction and the pathologist suggested reperfusion injury - which the transplant team due to the time course thought was highly unlikely. Within a couple of days she lost the transplant - was relisted and got a second organ 7 days ago. This time the transplant team was more worried about immunactivation/rejection so she was treated with rituximab, several times with ATG, got plasmaphareses 6 times and her Immunglobulin–levels were monitored more closely and with ivig treatment the level held constantly above 8 g/l.  She is covered with antibiotics and antifungals and again received Tacrolimus. Now after a period of recovery the transaminases start to rise again and the team is afraid to also loose the next organ.

Now we have a patient that is already highly immunosuppressed - might have an infection (PCT was high in the last days but decreased slowly) and/or again an autoimmune reaction to her transplanted organ.

Has anybody else experienced liver disease in a patient with Card11 mutations? Or other NF-Kb activating diseases?  What do you think could be done for this patient?

An mTor inhibitor? High dose ivIG? An NFK-b Inhibitor (Bortezomib?)…. Any suggestions?

BR

Simon

Prof. Dr. Simon Rothenfusser
Immundefekt-Ambulanz für Erwachsene („AIDA“)
Medizinische Klinik IV
Klinikum der Ludwigs-Maximilian Universität
Pettenkoferstraße 8a, 80336 München

E-mail: Simon.rothenfusser at med.uni-muenchen.de<mailto:Simon.rothenfusser at med.uni-muenchen.de>



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