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Treatment of specific disorders in porphyria

Transplantation & Immunosuppression in Patients with Acute Porphyria

Introduction​​

Occasionally the need for transplantation arises in patients with the acute porphyrias, namely acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP). In some cases the need for transplantation results directly from the presence of porphyria itself. Thus patients with AIP are predisposed to end-stage chronic renal failure, while, very rarely, the symptoms of AIP or VP may be so severe as to suggest the use of liver transplantation as a form of gene replacement therapy. In other cases, the need for transplantation is not directly related to the presence of porphyria but arises from some unrelated disease.

A major consideration when determining the suitability for transplantation of patients with AIP, VP or HCP is the potential for these patients to develop life-threatening acute attacks (progressing from abdominal pain and autonomic dysfunction to severe motor neuropathy with quadriparesis) in response to a wide range of commonly prescribed medications. Of particular concern are:

  1. The need for prolonged immunosuppressive therapy. In everyday practice, where patients with acute porphyrias require treatment, drugs are often needed for short periods only ore are readily substitutable with alternative drugs known to be safe in porphyria. However, following transplantation, the limited range of immunosuppressive agents and the need for prolonged if not lifelong therapy constitutes something of a bottleneck. In the worst case, the choice may fall between precipitating a fatal acute attack, or discontinuing the agent, resulting in severe organ rejection. There is less risk to life in renal transplantation, since the patient can always fall back on chronic dialysis if immunosuppression cannot be maintained and the kidney is rejected. Unfortunately there is no such fall-back position with cardiac or liver transplantation.
  2. The need for adjunctive therapy of various forms, e.g. antibiotics and antifungals for infections arising from immunosuppression and antihypertensives for hypertension and renal dysfunction associated with immunosuppressive agents. Many transplant patients will require a significant number of different medications, with considerable risk of eventually requiring of a single agents or combinations of agents which might prove porphyrinogenic.

Note that erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP) are not acute porphyrias, i.e. patients with EPP or CEP are not drug-sensitive and the concerns with the safety of immunosuppression described below do not apply to these patients. Liver transplantation is well described in EPP since these patients may develop liver failure secondary to a severe hepatic accumulation of protoporphyrin, while bone marrow transplantation is described in both as a form of gene replacement therapy.

Published Experience​​

Published experience with transplantation in the acute porphyrias is limited to a few case reports. Interestingly, none has developed acute attacks in response to immunosuppression with varying combinations of all the drugs listed above. We must stress however that such reassuring preliminary evidence does not necessarily imply that further patients will tolerate the immunosuppression. There is marked inter-individual variation in drug sensitivity, and reported safety in one case is not necessarily mean that it will be tolerated in another; nor does an adverse experience mean that other patients will not tolerate the same drug.

Furthermore, experience in liver transplantation should be removed from this body of evidence: these porphyric patients have effectively received enzyme replacement therapy (in the form of a new liver with its associated haem synthetic enzymes) and experience in these patients is irrelevant in determining the acceptability of specific drugs in patients with porphyria.

Choice of Immunosuppression​

Safest agents

A combination of pharmacological and clinical evidence suggests that the safest agents are prednisone, azathioprine and mycophenolate mofetil (MMF). Mycophenolate does not significantly interact with the cytochrome P450 system (which is haem requiring, and therefore is frequently associated with induction of porphyria), but is rather metabolized by a glucuronyl transferase pathway. It safe use in a patient with AIP who received in renal transplant has been published. Azathioprine is not metabolized by the cytochrome P450, but is listed in many older drug lists as potentially unsafe: this may be based on older data involving overly sensitive animal models. More recent references suggest it is safe, and it has been used in most patients with the acute porphyrias who have received transplants.

Theoretically less safe agents

Ciclosporin, tacrolimus and sirolimus all interact extensively with the cytochrome P450 system. This mandates extreme caution in their use, however, uneventful use of ciclosporin has been described in two transplant patients, and of tacrolimus and sirolimus in single patients.

Drawing Conclusions​​

Currently the situation is that there is no clinical evidence to suggest that transplantation should not be undertaken, and a combination of prednisone, azathioprine and ciclosporin, tacrolimus or sirolimus, and mycophenolate if necessary, is not actively contraindicated. Against this must be placed the fact that the metabolism of ciclosporin, tacrolimus and sirolimus predicts that these drugs may, in some patients, prove porphyrinogenic. Currently the most appropriate conclusion, given our inadequate state of knowledge, is that transplantation must be considered risky: a successful outcome is definitely possible but cannot be guaranteed.

Minimizing Risk​​

As a general principle in porphyria, combinations of potentially porphyrinogenic triggers may well precipitate the acute attack in patients who would otherwise tolerate any specific trigger presented on its own. It is absolutely essential therefore that any patient receiving and tolerating immunosuppression is not exposed to any other dangerous medication (such as antibiotics or antihypertensives): any adjunctive therapy must be carefully chosen to minimize the risk of aggravating porphyria.

Pre-transplant Trial of Immunosuppression​

In one case report, a patient in whom transplantation was contemplated was given a trial of ciclosporin, which was tolerated, before transplantation was undertaken. This is an interesting approach but one which is not been validated in practice; as described above, the propensity to acute attacks is subject to marked intra- and inter-individual variation, and the outcome in the trial phase need not necessarily predict the outcome in the actual treatment phase.

However, in an environment where resources are constrained, a trial of immunosuppressive therapy before the decision to transplant is taken may be sensible. If the trial is successful, this does not necessarily mean that no problems will arise after transplantation. If however, the patient react adversely to the immunosuppressive trial, then this is very useful information which may militate against transplantation.