There are more than 2000 OLT done with "domino livers". The not so good experience is now sufficient to abandon the "domino livers". In the University Hospital of Coimbra, Portugal, they a lot of data about this topic.

Your initial question to me about this topic is what got me to post the question on Research Gate.  There are now several studies looking at medical therapies to prevent or treat FAP complications.  For example, a 2013 study published in JAMA by Berk et al, showed that among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life.  Perhaps these strategies should be considered in recipients of FAP domino livers and a trial be constructed as part of the Amyloid LTX registry.

I think that is a good suggestion John. Additionally I think patients in an urgent situation also might benefit from a domino liver.

I sent the following request to Bo Goran Ericzon at the Karolinska, who heads the FAP Liver Transplant Registry:

"Bo Goran,

Do you know of any effort to prophylax the recipient of a domino FAP liver with diflunisal, a NSAID? It seems to me that with the reports of de novo FAP now becoming problematic symptom wise after more than 5 years in a growing number of patients, that this approach of prophylaxis may reduce the incidence and severity of this problem. If not, would this be a study that the Registry might want to promote as the next phase of its existence?"

 Bo Goran's response was:

John,

Yes, Diflunisal has been discussed as profylaxis for development of disease symptoms in Domino recipients. We have started this in one patient 7-8 years after ltx with a domino graft and having initial symptoms of FAP.

In Europe Tafamidis (pfizer) is registered and presently the only drug that can be used for FAP patients with early symptoms. Very expensiv drug (170-200.000 USD per year lifelong) and with, in my eyes, limited effect. Diflunisal, previously used as NSAID in Sweden but registration was dropped and can presently only be used in a clinical trial. There are efforts to have it reg again for this new indication. As you saw in the article diflunisal seems to be at least as efficient as the reg Tafamidis but to a fraction of its cost. Since Tafamidis is not registered for post livertx treament it may be possible to treat domino recipients with this drug in spite of the fact that Tafamidis exists on the market. (European pharma rules).

We have a very small fraction of our domino patients showing FAP symptoms so far (50% passed 8 y f.o) it may however increase with time. Portugal have a larger fraction with symptoms. We said so far that prophylaxis for so many years for all patients may cause more problems with side-effcts of the diflunisal treatment, rather than just wait for symptoms and treat early when needed which is our present policy.

We have discussed with Pfizer to start a study in domino recipients but they changed from being quite positive to not being very interested. At AASLD we (by Arie Stangou) for FAPWTR suggested a multicenter study in domino recipients and we are presently looking into how this could be done. We are talking to our collegues in Portugal who have most patients at risk. I can comeback to you if get more centers interested.

If I have a domino recipient with inital FAP symptoms I would defenitely try Diflunisal. Typical symptoms are needed and diabetes, alcohol etc other causes excluded. All domino recipients will have some deposits on histology, not necessarily indicating that FAP is the cause of peripheral neuropathy.

Best Regards

Dec 11, 2014, 11:51

I then responded to Bo Goran with the question and proposal:

"Thanks for the update. With the registry, do you know if those with de novo symptoms, i.e. Portugal, are associated with a particular TTR mutation? If so, perhaps those patients should receive diflunisal prophylaxis, versus those, like the Swedish phenotype, that have a milder course and where it can be started with onset of symptoms.

I agree that it is impractical from a cost standpoint to look at Tafamidis for treatment in these patients. Not only has it not been proven to be effective in transplant patients, but the cost and safety needs to be assessed. .

I think you have an opportunity of getting centers in the US to participate. I spoke with the Lahey group on Monday and they are interested as are we."

I would be interested if other groups would like to come together with a proposal for a global protocol.

We would be interested as well and could probably organize the whole Nordic Liver group to participate

Let me start to work on a concept proposal to distribute to some key groups - perhaps we can get funding from NIDDK

Would be interesting to organize a symposium on this subject.

How to Liver Domino?

That would be a good idea, but we need to think of who we would like to see participate and the goal of the meeting.  Clearly the FAP registry group, groups from Japan, Nordic countries, Portugal and Boston.  Given the prevalence of FAP in Portugal, it makes sense to have someone there be the organizer.  Maybe we can discuss this at the HPB meeting in Porto in February - are you going?

I am not poing to Oporto, but if you want to stay for one day in Lisbon we can arrange a meeting, I am not right now in the OLT setting but I can talk and network my colleagues

Rui, I am leaving Oporto through Lisbon on Sunday, but cannot stay to Monday.  

can anybody share with me articles that studies various TTR mutations in cell lines and animal models. Thanks