LT was proposed 20 years ago to suppress the main source of mutant TTR, which is amyloidogenic, to prevent formation of amyloidosis and to stop progression of the disease [Holmgren et al. 1991
]. More than 2000 patients with FAP underwent LT worldwide [Wilczek et al. 2011
], half of them in Portugal and 200 in France. The results of the LT depend on the TTR gene mutation, the age of the patient and the stage of the disease.
The initial results concerned the biological effect, with 98% reduction of mutated TTR in the days following LT [Adams et al. 2000
; Holmgren et al. 1991
]. Afterwards, the effects of LT on neuropathy were evident since its progression was stopped in 70% of patients at mid term. This has been established for met30 TTR FAP according to the following objective parameters: clinical, functional, neurophysiological and histopathological, with a major reduction in axon loss [Adams et al. 2000
]. These findings were confirmed in the long term. LT does not allow either clinical or functional recovery [Adams et al. 2000
; Yamamoto et al. 2007
]; autonomic dysfunctions are unchanged.
Worsening of walking ability is possible after LT, seen in one-third of our cohort of patients after LT (personal data). Twenty percent required an aid for walking after LT (median delay of 11 years) (unpublished data). Independent risk factors for requiring aid for walking were major weight loss, previous walking difficulties and a late onset at LT. Worsening of walking ability may be explained by accumulation of wild type TTR in the nerve after LT [Liepnieks et al. 2010
]. For non-met30 TTR FAP, success of LT is less common. The benefit of LT on neuropathy is better when LT is performed at an early stage, before the onset of walking difficulties that require aid.
Effects on survival
Although LT doubles the median survival in early onset met30 TTR FAP, the impact of LT on survival for non-met30 TTR FAP is less obvious. The rate of survival at 5 years for patients with FAP after LT is 82% in met30 TTR FAP versus
59% in non-met30 TTR FAP according to the world register of LT in FAP [Wilczek et al. 2011
]. Independent risk factors of mortality in our center are severe autonomic dysfunction, late onset and non-met30 TTR mutation (unpublished data). Long-term follow up of early onset met30 TTR FAP shows a rate of survival of 100% in patients after LT versus
56.1% in those who did not have a transplant after 10 years [Yamashita et al. 2012
Effects on organ and ocular involvement
The effects of LT on cardiac involvement depend on the type of initial cardiopathy and the genotype, early or late onset, or TTR variant (met30 or non-met30). Progress of cardiopathy is possible after LT, marked by the following:
- Progressive thickening of the myocardium on echocardiogram after LT in late onset met30 TTR FAP in Sweden, explaining the possible development of congestive heart failure after LT [Olofsson et al. 2002].
- Development of conduction disorders requiring pacemaker implantation in 8% [Yamamoto et al. 2007] to 20% of cases after LT (personal communication, unpublished data).
Worsening of cardiopathy after LT can be explained by accumulation of wild type TTR in the myocardium [Yazaki et al. 2000
]. Periodic assessment of patients after LT is necessary due to the ongoing risk of progress of cardiopathy after LT, both on conduction disorders and restrictive cardiomyopathy.
Renal function is stable in most patients after LT, but cases of deterioration during the first quarter after LT requiring hemodialysis have been reported [Rocha et al. 2011
]. Chronic renal failure (34%), including 5% terminal end-stage disease after LT, is also possible [Ferreira et al. 2012
Combined heart and liver transplantation [Raichlin et al. 2011
] and kidney and liver transplantation must be discussed in cases of severe life-threatening cardiomyopathy or end-stage renal disease requiring dialysis.
Ocular manifestations are not influenced by LT, with a persisting risk of developing glaucoma or vitreous opacities in 8% and 12%, respectively due to the retinal source of mutated TTR [Sandgren et al. 2008
Morbidity and mortality
In our series of 200 patients who have had LT since 1993, 38% died, including 14% in the first year until 15 years after LT. Mortality during the first year is higher in patients with non-met30 TTR FAP versus
met30 TTR FAP. Deaths during the first year are due to cardiac causes (sudden death, cardiac insufficiency), infections or hepatic failure, as a direct result of surgery in 3.5% [Yamamoto et al. 2007
]. After the first year, patients died from progress of the amyloid disease (50%), affecting the heart or peripheral nervous system, or varied causes, including infection, stroke, suicide, hepatic causes.
Delay for LT varies from 6 to 12 months according to the rules fixed by the National Biomedical Agency. The waiting list for LT may vary from 6 to 18 months due to the shortage of donor organs (cadaveric donor) and a need to match donor and patient blood and body type. A patient with a very common blood type has less chance of quickly finding a suitable liver. Avoiding a long wait is possible if a patient has a living donor who is willing to donate part of their liver (living donor transplantation) via a partial hepatic graft. In such cases, the delay may be as short as 4 months. If the donor is a family member, they must not carry the TTR gene mutation.
Side effects of liver transplantation
LT is associated with the risks of surgery and acute liver rejection, which is usually controlled by pulses of methylprednisolone or modification of immunosuppressive drugs. LT is associated with an increased risk of infections, mainly during the first year after surgery, including septicemia which are usually favored by urinary incontinence [Adams et al. 2000
; Yamamoto et al. 2007
], and pulmonary infections which may be opportunistic in half of the cases (pneumocystosis, cytomegalovirus). Patients may develop acute renal failure (26%) after orthotopic LT [Ferreira et al. 2012
] or chronic renal failure (34%) which may lead to end-stage renal disease (5.1%). The risk of chronic renal insufficiency is associated with renal insufficiency before LT and onset of acute renal failure after LT (Ferreira et al. 2012
). pre-OLT is an independent risk factor [Ferreira et al. 2012
; Lobato and Rocha, 2012
]. Orthotopic LT may also be associated with cancer or lymphoproliferative syndrome (1% of cases) both favored by immunosuppressive drugs.
Immunosuppressants to use and their long-term risk/benefit ratio
The immunosuppressants we usually use are calcineurin inhibitors (CNI): ciclosporin or tacrolimus. The risk of acute rejection is about 20% with a loss of graft by chronic rejection below 5%. Liver transplant recipients are at high risk of developing acute and chronic renal failure as a consequence of the use of CNI. These two drugs have also a similar toxicity profile, which may compromise the long term benefits of liver transplantation (LT) and the quality of life after liver transplantation: at 10-year-post LT, the rate of chronic renal failure, arterial hypertension, and diabetes is 30%, 40% and 10-20% of cases, respectively. In addition, there is an overall increase of cardiovascular complications and of de novo tumors. Frequently, mycophenolate mofetil, a non-nephrotoxic immunosuppressor, is added to CNI to avoid overdose of CNI and to preserve post-transplant renal function.
Timing of surgery
We must take into account the waiting list which varies between 6 and 18 months; during this time the disease may worsen (). As LT is able to stop progress of the disease, LT should be performed as soon as possible, early in the course of the disease [Yamashita et al. 2012
Figure 2. Therapeutic strategy in patients with familial amyloid polyneuropathy (FAP) according to the stage of the disease [Coutinho et al. 1980]. Stage III (wheelchair bound or bedridden) is a contraindication for any transplantation, liver alone or combined (more ...)