Didier Samuel

Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?

Background Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. Methods Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. Results From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease. Conclusions Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence

Wilsons disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper‐transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X‐ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High‐resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X‐ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin‐fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilsons disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting.

Que faire chez les patients atteints de cirrhose virale C et les patients transplantés

Liver disease caused by the hepatitis C virus is the main indication for liver transplantation. However, HCV re-infection after transplantation is constant and it significantly impairs patient and graft survival. Pretransplant antiviral therapy may reduce or eliminate the risk of recurrent infection. However, this approach is limited because of side effects and a risk of complications in decompensated patients. The best candidates for therapy are Child-Pugh class A patients and patients with good predictive factors of response (non-1 genotype and low viral load). Multiple host, donor and viral factors are associated with fibrosis progression after transplantation. Treatment of established graft lesions with pegylated interferon and ribavirin combination therapy gave promising results, with sustained virological response in around 30% of patients. Sustained virologic responders had a long-term benefic effect on fibrosis progression and graft and patient survival. Variables associated with SVR are non-1 genotype, absence of prior antiviral therapy, early virologic response, adherence to therapy and low pre-treatment viral load. HCV-infected pre-and post-transplant patients are the population which will benefit the most of new classes of direct antiviral agents.

Stratégies thérapeutiques chez les patients atteints de cirrhose décompensée et chez les patients transplantés

En Europe, 5 a 10 % des transplantations hepatiques sont effectuees pour hepatopathie B. L’utilisation d’antiviraux comme la lamivudine, l’adefovir, l’entecavir, le tenofovir, permet le controle de la replication virale B des patients avec cirrhose B decompensee en attente de greffe. Cependant, l’emploi de ces antiviraux est limite par le risque d’emergence de mutants resistants. Le pronostic est lie a la prevention de la recidive virale B sur le greffon. En l’absence de prophylaxie, il existe un risque eleve de recidive virale. Quelle que soit la prophylaxie, ce risque est lie a la charge virale B avant la greffe. La prophylaxie par Ig anti-HBs (HBIG) au long cours ou antiviraux en monotherapie (lamivudine) permet de reduire de maniere significative le risque de recidive surtout en l’absence de replication virale B avant la greffe. L’association d’antiviraux et d’HBIG apres la greffe permet d’obtenir un taux de recidive B inferieur a 10 % meme en cas de replication virale B en pregreffe. En l’absence de replication virale avant la greffe, l’arret des HBIG sous couvert d’antiviraux ou d’une vaccination antivirale B peut etre discute a distance de la greffe. L’utilisation des nouveaux antiviraux a egalement totalement modifie le pronostic des recidives virales B sur le greffon en permettant un controle efficace de la replication virale.