Domino liver transplantation (DLT) has become an accepted procedure designed to address problems with organ limited supply. However, cases of acquired amyloid neuropathy are increasingly being recognized following this procedure. Until now, only one patient had undergone liver retransplantation and follow-up findings were not reported. We describe the case of a 72-year-old patient with partial recovery from acquired amyloid neuropathy following retransplantation with a deceased donor 7 years after DLT performed for end-stage liver disease. His clinical and paraclinical improvement is described, and the impact of this case on the indication for a domino procedure and the challenges linked to retransplantation are discussed.
autonomy dysfunction score
domino liver transplantation
estimated creatinine clearance rate
familial amyloidotic polyneuropathy
hepatitis B virus
labial salivary gland biopsy
neuropathy impairment scale
visual analogue pain scale.
Familial amyloidosis with polyneuropathy (FAP) is an invariably fatal, autosomal dominant systemic disease. It is characterized by progressive sensory motor neuropathy associated with vegetative dysfunction and cardiomyopathy secondary to transthyretin (TTR) gene mutation, and usually occurs in adults during the third decade of life. TTR mutants are responsible for destabilizing the native TTR tetrameric structure, leading to toxic amyloid tissue deposits. It is because the liver produces 90% of TTR that Ericzon performed the first orthotopic liver transplantation (LT) to halt amyloid formation . To date, more than 2000 patients have thus been transplanted, as LT has become the treatment of choice for this disorder  leading to stabilization of the neuropathy in up to 70% of patients .
Domino liver transplantation (DLT) was originally proposed to overcome organ shortages by using FAP recipients as potential organ donors because FAP liver is functionally normal except for the production of mutant TTR . Furthermore, the procedure was considered as being harmless to the donor  and for the recipient, because of the supposed 20-year delay before the declaration of FAP. By December 31, 2010, a total of 977 DLT had been performed worldwide in 958 patients . However, surprisingly, in 2005, Stangou et al.  described the first case of acquired transthyretin amyloidosis secondary to DLT. The neuropathy, confirmed by a nerve biopsy, had developed 8 years after DLT. Since then, several authors have reported other cases occurring at intervals ranging from 3.5 to 9 years after DLT [8-11]. We previously described four cases of de novo amyloid polyneuropathy following DLT ; these included patient no. 2 in whom a reversible course after retransplantation is reported in the present paper.
Patients and Methods
Between 1997 and 2011, 153 consecutive DLT were performed in our center after obtaining signed informed consent from the patients. Our protocols specify that retransplantation with a normal deceased donor will be discussed if the recipient develops symptoms of amyloidosis and has survived for more than 5 years, provided there has been no recurrence of the malignant disease in patients transplanted for cancer. To detect early signs of acquired amyloid polyneuropathy, we closely monitored DLT recipients by means of an annual, comprehensive neurological examination which included a neuropathy impairment score, a modified NORRIS score (normal 75–0), an autonomic dysfunction score (ADS) and the Polyneuropathy Disability Score (PND score: 0: normal; 1: sensory disturbances in the extremities with preserved walking capacity; 2: difficulty with walking but without the need for a stick; 3a: one stick required for walking; 3b: two sticks required for walking, and 4: wheelchair-bound or confined to bed). Nerve conduction studies were performed in all four limbs. A sensory sum score (sum of sensory potential amplitudes of both ulnar and both sural nerves) and a motor sum score (sum of motor response amplitudes of both ulnar and both peroneal nerves), were calculated. Surface electrocardiography was also systematically recorded.
On January 2000, a 60-year-old man of Cambodian origin underwent DLT for end-stage liver disease related to HBV cirrhosis. He had no previous history of diabetes mellitus. His renal function was normal. At the time of LT, the patient displayed no signs of polyneuropathy, and the results of nerve conduction studies were normal except for slightly decreased right peroneal motor and sensory amplitudes.
Posttransplantation, his immunosuppressive therapy comprised tacrolimus and corticosteroids, which were gradually tapered and then withdrawn 14 months after LT. Recurrence of HBV was prevented by prophylaxis with anti-HBs immunoglobulin combined with lamivudine in accordance with the practices of our center . No breakthrough of HBV viral load was observed during follow-up. The patient's short-term post-LT follow-up was characterized by arterial hypertension.
The donor was a 40-year-old Portuguese female with Met-30 TTR-FAP who developed initials symptoms at the age of 38 years.
Nine months before the onset of symptoms, the recipient was asymptomatic and his clinical parameters were normal. Six and a half years after DLT, he started complaining of burning pain in the feet associated with unusual constipation. A visual analogue pain scale (VAS) was scored at 7. He lost 9 kg in three months. Symptomatic Pregabaline® treatment was initiated. Three months after the onset of symptoms, clinical examination revealed a marked deterioration, with reduced sensory reactions to temperature and pinpricks in a stocking distribution but with normal reflexes and strength. Autonomic function was slightly affected, with intermittent nausea, dysuria and constipation but no orthostatic hypotension (OH). His neuropathy impairment scale (NIS) and PND scores were scored as 10 and 1, respectively, and the ADS score was 13. Nerve conduction studies revealed a 48% reduction in sensory nerve action potentials in the feet when compared to the examination performed 9 months earlier (Figure 1). During the following year, the patient's clinical and electrophysiological parameters deteriorated considerably, with an extension of sensory deficits up to the knees and slight weakness in the small hand muscles, associated with OH. Nerve conduction studies showed a further 24% reduction in the amplitude of sural nerve sensory action potentials (Figure 1). A left sural nerve biopsy was performed. Histological examination revealed moderate asymmetrical axonal loss with few fibers undergoing Wallerian degeneration. Congo red-stained endoneurial amorphous deposits were found. Serum immunofixation and TTR gene analysis were normal. The patient was diagnosed as suffering from post-DLT acquired amyloid polyneuropathy. A comprehensive cardiac evaluation did not reveal any intraventricular conduction failure or signs of cardiomyopathy. The estimated creatinine clearance rate (eCCr) calculated using the Cockcroft–Gault formula indicated moderate renal insufficiency (45 mL/min). Renal biopsy revealed interstitial glomerular amyloidosis with endovascular amyloid deposits.
Therefore, at the age of 67 years, he underwent combined liver-kidney transplantation to halt amyloid progression. A clinical examination immediately prior to retransplantation revealed slight motor weakness of the toe extensors, no ankle jerk reflexes and thermal hypoesthesia and pinprick anesthesia up to the ankles.
His immunosuppressive therapy comprised tacrolimus and corticosteroids and he received HBV prophylaxis as described above.
After the second LT, the patient's deterioration of clinical and neurophysiological parameters halted. His autonomic dysfunction improved but asymptomatic OH persisted. The patient recovered his normal weight. Eighteen months after the second LT, his nerve conduction parameters showed a slight increase in both the sensory and motor sum scores when compared to posttransplantation values, but his clinical condition only partially improved after 2.5 years. Four years after the second liver transplant the patient is decreasing painkillers doses (Figure 2). He has no sensory motor deficit and his deep tendon reflexes are normal. His NIS score has fallen to 4. Sub-clinical OH remains. His nerve conduction parameters are stable. A control cardiac evaluation performed 2 years after re-transplantation revealed normal parameters, and the patient's last eCCR determination was still stable (52 mL/min).
We describe here for the first time the reversibility of post-DLT acquired amyloidosis after a second transplant with a non-FAP liver. These findings could have a major impact on the indication for DLT and the information given to patients who are waiting to undergo DLT.
DLT has become an accepted procedure designed to overcome organ shortage problems, and it accounts for more than 16% of liver transplants performed in Portugal . Thus, to date, around 1000 DLT have been performed worldwide, for various indications . As most donors are FAP patients, the recipients are at risk of developing acquired amyloidosis.
In our series of 153 DLT procedures, five patients were diagnosed with acquired amyloid polyneuropathy and the condition is strongly suspected in three others, although not yet confirmed. This represents an incident rate of at least 3.3% (5/153). Two others patients have been re-transplanted in our center but follow up data are not yet available. Retransplantation was not performed in the other two patients because they were older than 70 years when acquired amyloid neuropathy developed. Several factors were suspected as explaining this early onset neuropathy in DLT recipients described in previous reports [7-11, 13] (Table 1), such as advanced recipient age or an inflammatory reaction after the transplantation procedure, the latter being a known risk factor for amyloidosis . The usual causes of peripheral neuropathy were ruled out before amyloidosis was incriminated as being responsible for the emerging neuropathy. Systemic amyloid deposits are likely to be found in various tissues after DLT but do not necessarily imply a causal relationship between amyloidosis and neuropathy, as various neuropathies of nonamyloid origin have previously been reported in DLT patients and amyloid deposits have been found in half of these patients on labial salivary gland biopsy (LSGB) 5 years after DLT. Although much more invasive than LSGB, a nerve biopsy is crucial in this context in order to prevent a misdiagnosis .
|Stangou et al. ||Goto et al. ||Barreiros et al. ||Conceição et al. ||Adams et al. ||Pradotto et al. ||Present case|
|Age at DLT||47||50||65||5||45–72||59||60|
|Neuropathy's onset (age)||55||57||75||63||53–75.5||71||67|
|Cause of DLT||HCV cirrhosis||PBC||HCC||Hemangio endothelioma||2 HCC 2 Cirrhosis||HBV-HCV cirrhosis||HBV cirrhosis|
|Symptoms||Dys LL||None||Dys LL||Par LL||Par + pain LL||Par LL||Pain LL + GI|
|Examination sensory loss||NR||SF LL + UL||LL||LL||SF LL||LL + UL||LL + UL|
|Other||NR||Reduced strength LL||WL (2/4)||Motor weakness LL + UL gait disturbance, AD||AD, Reduced strength LL, RI, WL 9 kg|
|Follow-up||1 year||2 years||NR||1 year||NR||2 years||1.5 + 4 years|
|Evolution||“Overt progression”||NR||NR||“Stable”||Progressive||“Rapidly progressive”||Progressive|
|Histology||Nerve + GI wall||GI wall||GI wall||Nerve||Nerve + LSGB||Periumbilical FT||Nerve|
|Outcome||LT||NR||NR||NR||NR||NR||LT + RT 4 years FU|
The clinical presentation of acquired amyloid polyneuropathy mimics that of FAP. Our case was striking for its rapid and severe course, affecting both sensory and autonomic nerve fibers and causing OH and also renal impairment.
To date, the only therapeutic option in such cases is re-transplantation. By removing the site of mutant TTR production [1, 3], LT is intended to halt disease progression in FAP patients and improve survival . Up to 70% of transplanted FAP patients have displayed a degree of stabilization; the others have continued to deteriorate although following a less acute course . By contrast, an improvement has been described in some FAP patients after LT if treated at an early stage of the disease . Until now, only one case of liver retransplantation has been reported in the context of acquired amyloid polyneuropathy following DLT but without follow-up data . Because of progressively debilitating effects of systemic amyloidosis in the nerves and kidneys we decided on performing combined liver and kidney transplantation in our patient.
When considering retransplantation, the patient's clinical condition must be thoroughly evaluated because the survival rate for patients following a retransplantation is about 84% at 1 year . Patient consent, an age below 70 years and a rapid clinical deterioration are major parameters leading to re-transplantation. Furthermore, until now, the neurological and cardiologic success of retransplantation was unclear. Even removal of the only site of mutant TTR in DLT recipients can be considered as providing a good chance of stabilization, deposits of mutant and nonmutant amyloid substance have been demonstrated in FAP patients after LT . For the first time, based on clinical and paraclinical data (NCS, ECG and echocardiography), after four years of follow-up, we were able to demonstrate the arrest and later partial recover of nerve dysfunction, associated with acquired amyloid neuropathy following liver retransplantation. Because of ethical considerations, a nerve biopsy following retransplantation was not performed, thus precluding any further hypotheses.
Neurological, renal and cardiologic monitoring is of paramount importance to the follow-up of DLT patients since for the first time we were able to demonstrate the possibility of reversing acquired amyloid polyneuropathy. The role of new treatment options in amyloidosis, such as Vyndaqel which has a Marketing Authorization in FAP , or combination therapy with doxycyclin-TUDCA needs to be determined in the future, particularly if retransplantation is contraindicated . The possible reversibility of acquired amyloidosis after retransplantation is of prime importance when discussing the indications for DLT but may not hold for non Met-30 variants. These findings need to be confirmed by further studies.
All authors certify that they substantially contributed to this manuscript:
- T.M. Antonini, P. Lozeron: analysis and interpretation of the data, drafting, correction and editing of the manuscript
- C. Lacroix, Z. Mincheva: analysis and interpretation of the data, critical revision and final approval of the manuscript
- E. Vibert, D. Samuel, D. Adams, M. Slama: critical revision and final approval of the manuscript.
This study received no external funding.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.