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Long-Term Clinical and Neurophysiological Follow-Up of

Familial Amyloid Polyneuropathy Patients after Liver

Transplantation: Comparison between Two HistoricalDifferent Groups of Patients

Isabel M Conceicao, Jose F Castro and Mamede de Carvalho

Affiliation: Department of Neurosciences, Hospital de Santa Maria, Neuromuscular Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of

Lisbon, Portugal

A B S T R A C T

We tested if patients with familial amyloid polyneuropathy (FAP) type I have had a better outcome after liver transplantation (LT) in recentyears. We compared two identical groups of patients: group I, 14 patients who underwent LT between 1993 and 2002; group II, 19 patients

submitted to LT between 2003 and 2007. We found no statistically significant difference in clinical and neurophysiological progressionbetween the two groups after LT; nerve function did not improve. Novel treatments are necessary.

Keywords: electromyography, familial amyloid polyneuropathy, liver transplantation, nerve conduction studies

Correspondence: Isabel Conceicao, Department of Neurology, Hospital de Santa Maria, Av Prof Egas Moniz, 1649-028 Lisbon, Portugal.

Tel/Fax: (35)-1-21-7805219; e-mail: imsconceicao@gmail.com

INTRODUCTION

The main feature of familial amyloid polyneuropathy (FAP)is a length-dependent sensory motor and autonomic neuro-pathy resulting from predominant involvement of unmyeli-nated and small myelinated fibers [1]. Clinical expression ofautonomic dysfunction includes gastrointestinal, cardiac, andgenitourinary dysfunction. In addition, renal and ocularcomplications are common in FAP as well.

The largest focus of the disease is in Portugal (500 kindreds),where the mutation observed is Val30Met. Because transthyr-etin (TTR) is produced mainly by the liver, liver transplantation(LT) has been proposed as a potentially effective treatment [2];indeed, many reports have followed documenting the efficacy

of LT for FAP, halting disease progression [3] with animprovement in general well-being, a gain in weight, and asubjective improvement in the gastrointestinal symptoms [4].

Long-term evaluation of FAP polyneuropathy after LT hasbeen described [5].

In this study, we analyze long-term progression ofpolyneuropathy in two historical different groups of patients,one submitted to LT in the first years of the LT program(19932002) and the other in the last 5 years (20032007).

PATIENTS AND METHODS

PatientsThirty-three transplanted FAP patients followed at our

department were included in this study. The patients were

divided into two groups: group I (GI), 14 FAP patientssubmitted to liver transplantation in the period 19932002,and evaluated for 510 years; group II (GII), 19 FAP patientstransplanted in 20032007 and evaluated for 15 years.

The diagnosis of FAP-I was established in the presence ofsymptoms and electromyographic findings of peripheralaxonal polyneuropathy. In all patients, Val30Met TTRmutation was confirmed by genetic analysis.

Patients details are listed in Table 1.

Methods

All patients were evaluated less than 6 months before LT(time 0).

In GI, all 14 patients were evaluated at 25 years (time 1) and57 years (time 2). Only seven patients were evaluated 710 years after LT (time 3).

In GII, all patients were evaluated at 12 years (time 1), 10patients at 24 years (time 2), and four patients at 45 yearsafter LT (time 3).

A validated clinical scale [6] was applied, which includedmotor and sensory function, as well as autonomic symptomsand weight. This scale is quantified from 0 to 50 (partial score);the final score is calculated by multiplying the partial score by 2(maximal abnormality 100). Autonomic function is quantified

from 0 to 20, with the maximal abnormality being scored forweight loss .15 kg, regular diarrhea, and permanent sphincterincontinence/catheterization. Sensory function was scored from

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0 to 15, with the maximal abnormality being scored for thermaland pain anesthesia at half superior arm, clavicular line, andsuperior tight; motor function was scored from 0 to 10 with themaximal abnormality corresponding to being bedridden; andreflexes were scored from 0 to 5, with the maximal abnormalitybeing their total absence.

A neurophysiological score (NSc) was also estimated at thesame sessions [6, 7].

Neurophysiological score

Electromyographic studies were performed using a KeypointEMG machine (Dantec-Allpine). Neurophysiological score iscalculated according to nerve conduction studies and needleelectromyography (EMG). Motor conduction studies of themedian or ulnar and peroneal, and sensory conductionstudies of the median or ulnar, peroneal and suralis weredone using standard methods [8]. Needle EMG wasperformed of extensor digitorum brevis, tibialis anterior,

vastus medialis, abductor pollicis brevis, or abductor digitiminimi. This score is quantified from 0 to 100 (maximalabnormality) [6, 7].

Statistical analysisA non-parametric test (Friedman test) was applied to

compare measurements at different times; whenever a

significant difference was found, a post hoc analysis wasperformed (Sign test). A P value ,0.05 was considered assignificant.

RESULTS

Two of the 33 transplanted patients died on follow-up, onein GI 8 years after LT and one in GII 5 years after LT. Bothpatients died from chronic liver rejection.

In GI, four patients had renal failure, they started dialysis1 year, 10 years (two patients), and 12 years after LT. Sixpatients required a pacemaker, four before LT, and two 5 and10 years after LT respectively.

In GII, three patients had markedly impaired renal function,not requiring dialysis to date. In all patients, a prophylacticpacemaker was applied before LT, but two patients hadcardiac arrhythmia before LT.

In GI, the clinical score (CS) worsened in seven patients(50%), improved in two (14.3%), and stabilized in five (35.6%).In the same group, NSc worsened in eight patients (57.1%),improved in one (7.1%), and stabilized in five (35.7%). Patients

who showed NSc worsening tended to have a longer diseaseduration (4.21.9 years) than patients in whom NSc stabilizedor improved (3.62.9 years; P50.65). Statistical analysiscomparing T0 with T1, T2, and T3 did not find significantdifferences (CS P50.55; NSc P50.27) (Table 1).

In GII, clinical score worsened in four patients (21%),improved in two (10.5%), and stabilized in 13 (68.4%). In thesame group, NSc worsened in nine patients (47.4%), improved

in one (5.2%), and stabilized in nine (47.4%). Patients withNSc decline had longer disease duration (3.81.5 years) thanthose in whom NSc had stabilized or improved (2.11.1 years;P50.01). Statistical analysis did not find differences at differenttimes (CS P50.38; NSc P50.16) (Table 1).

DISCUSSION

Liver transplantation, which suppresses the main source ofthe amyloidogenic mutated TTR, is an accepted treatment forFAP TTR Met30. When performed at an early phase of FAPtype I, LT sustains disease progression for a long period oftime. An increased survival for FAP patients who underwent

transplantation at an early stage of their disease and had goodnutritional status as been described [9, 10].

In particular, peripheral nerve function is considered toshow no improvement after LT in FAP. We aimed to test

whether patients transplanted at more recent times had abetter outcome compared with earlier cases, some of whom

were accepted for liver transplant with a long disease durationand poor nutritional status.

We observed a trend for earlier procedure over the course ofthe disease progression in recent years, as mean diseaseduration before LT decreased from 4.0 years (range 18 years)to 2.8 years (range 16 years), according to a selection of

patients in the early stages of disease in the recent years.However, clinical outcome after LT did not changed accord-ingly. In particular, renal insufficiency remains a critical

Table 1. Patient Clinical Data

Patient clinical data GI GII P value

No. of patients 14 19

Gender (men/women) 6/8 10/9 0.74

Age at onset (years) 33.76.3 38.414.6 0.27

Age at liver transplantation (LT) (years) 38.56.5 42.411.5 0.26

Duration of disease at LT (years) 4.0 2.15 2.81.5 0.07a

Follow-up of transplant recipients (years) 510 15

Deceased 2 1

Clinical score

Time 0 28.418.7 25.218.5

Time 1 (25 years) 3118.2 27.719.6

Time 2 (57 years) 33.921 35.320.1

Time 3 (710 years) 38.319.7 2619.3

P value 0.55 0.38

Neurophysiological score

Time 0 29.426.9 30.523.3

Time 1 (25 years) 39.730.0 34.629.1

Time 2 (57 years) 44.126.3 44.730.2

Time 3 (710 years) 35.020.4 26.730.6

P value 0.27 0.16

aThere is a trend for decreased disease duration before LT in recent years.

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problem, in spite of a tendency to use less toxic drugs, such asmycophenolate mofetyl and tacrolimus. Clinical deteriorationseemed commoner in GI, but no difference was found betweenclinical GI and GII for clinical outcome. Nonetheless, ourresults suggest that disease duration at the time of LT seems tobe a critical issue as in other studies [9, 10].

The comparison between groups showed no differenceregarding the outcome of peripheral nerve function, assustained by the statistical analysis. It seems that peripheraldysfunction is irreversible. But, as observed for clinical score,shorter disease duration before LT indicates better results [11].

Our investigation suggests that the results obtained from LTin FAP patients are no better now than when observed at thestart of this therapeutic procedure, as shown by other authors[9]. Although shorter disease duration before LT is probably apositive predictor for better outcome, in general the resultsare negative regarding improvement. This reinforces the need

to seek new treatments and that preservation of renal functionshould be strongly considered.

Disclosure: The authors declare no conflict of interest.

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FAP long-term follow-up after LT

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