Carine Richou

Should possible recurrence of disease contraindicate liver transplantation in patients with end‐stage alveolar echinococcosis? A 20‐year follow‐up study

Liver transplantation (LT) is currently contraindicated in patients with residual or metastatic alveolar echinococcosis (AE) lesions. We evaluated the long‐term course of such patients who underwent LT and were subsequently treated with benzimidazoles. Clinical, imaging, serological, and therapeutic data were collected from 5 patients with residual/recurrent AE lesions who survived for more than 15 years. Since 2004, [18F]‐2‐fluoro‐2‐deoxyglucose (FDG)–positron emission tomography (PET) images were available, and the levels of serum antibodies (Abs) against Echinococcus multilocularis–recombinant antigens were evaluated. Median survival time after LT was 21 years. These patients were from a prospective cohort of 23 patients with AE who underwent LT: 5 of 8 patients with residual/recurrent AE and 4 of 9 patients without residual/recurrent AE were alive in September 2009. High doses of immunosuppressive drugs, the late introduction of therapy with benzimidazoles, its withdrawal due to side effects, and nonadherence to this therapy adversely affected the prognosis. Anti‐Em2plus and anti‐rEm18 Ab levels and standard FDG‐PET enabled the efficacy of therapy on the growth of EA lesions to be assessed. However, meaningful variations in Ab levels were observed below diagnostic cutoff values; and in monitoring AE lesions, images of FDG uptake taken 3 hours after its injection were more sensitive than images obtained 1 hour after its injection. In conclusion, benzimidazoles can control residual/recurrent AE lesions after LT. Using anti‐rEm18 or anti‐Em2plus Ab levels and the delayed acquisition of FDG‐PET images can improve the functional assessment of disease activity. The potential recurrence of disease, especially in patients with residual or metastatic AE lesions, should not be regarded as a contraindication to LT when AE is considered to be lethal in the short term. Liver Transpl 17:855‐865, 2011.

The Role of Delayed 18F-FDG PET Imaging in the Follow-up of Patients with Alveolar Echinococcosis

18F-FDG PET has already proved its usefulness in the follow-up of patients with alveolar echinococcosis (AE) and has been proposed as a surrogate marker for therapeutic decisions on structured treatment interruption by benzimidazoles. However, standard PET acquisition (1 h after 18F-FDG injection) lacks sensitivity, and the parasite may stay viable even if 18F-FDG perilesional uptake has disappeared. The aim of our study was to evaluate the usefulness of delayed 18F-FDG PET in the management of AE patients. Methods: During a 6-y period, 120 PET scans using 18F-FDG were obtained for 70 AE patients treated by benzimidazoles, without selection. All patients underwent whole-body imaging on a PET/CT device 1 h after 18F-FDG injection (4 MBq/kg), as well as an acquisition focused on the liver 3 h after the injection. We also analyzed the results of serologic tests. Results: Of the 57 scans considered negative at the standard acquisition, 13 (22.8%) became clearly positive at the delayed acquisition, and 6 (10.5%) became indeterminate at the delayed acquisition. Furthermore, 20 of 22 scans interpreted as indeterminate at the standard acquisition were considered positive because of clear perilesional 18F-FDG uptake at the delayed acquisition. Thus, delayed acquisition changed the interpretation in 32.5% of cases. Moreover, of 44 patients treated by benzimidazoles and followed for more than 2 y by regular 18F-FDG PET scans and specific AE serology, 11 (25%) presented pathologic 18F-FDG uptake at the delayed acquisition but not at the standard one. In these patients, the treatment was continued despite negative results on standard 18F-FDG PET and negative serologic findings. On the other hand, in 7 patients with negative delayed 18F-FDG PET and negative serology, the treatment was safely interrupted with no evidence of disease recurrence during 8–37 mo (mean, 23 mo). Conclusion: Our study clearly demonstrated that delayed 18F-FDG PET greatly facilitated the differentiation between active and inactive liver lesions in AE patients. Also, our results strongly suggested that the combination of delayed 18F-FDG PET and specific serology would prevent most of the recurrences observed after premature interruption of the treatment based only on standard 18F-FDG PET.

Assessment of adrenal function in cirrhotic patients using concentration of serum-free and salivary cortisol

Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid‐binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum‐free and salivary cortisol concentrations.

Increased Incidence and Characteristics of Alveolar Echinococcosis in Patients With Immunosuppression-Associated Conditions

BACKGROUND An increased incidence of alveolar echinococcosis (AE) in patients with immunosuppression (IS) has been observed; our aim was to study this association and its characteristics. METHODS Fifty AE cases with IS-associated conditions (ISCs) before or at AE diagnosis were collected from the French AE registry (1982-2012, 509 cases). There were 30 cancers, 9 malignant hematological disorders, 14 chronic inflammatory diseases, 5 transplants, and 1 case of AIDS; 9 patients had ≥2 ISCs. Characteristics of the 42 IS/AE cases and the 187 non-IS/AE cases diagnosed during the period 2002-2012 were statistically compared. RESULTS There was a significant increase in IS/AE cases over time. Risk factors did not differ between IS/AE and non-IS/AE patients. However, AE was more frequently an incidental finding (78% vs 42%) and was diagnosed at earlier stages (41% vs 23%) in IS/AE than in non-IS/AE patients. Serology was more often negative (14% vs 1%) and treatment efficacy was better (51% regression after 1-year treatment vs 27%) in IS/AE patients. All IS/AE patients but 7 took IS drugs; 7 received biotherapeutic agents. When not concomitant, AE occurred in IS patients within a 48-month median time period. Atypical presentation and abscess-, hemangioma-, and metastasis-like images delayed AE diagnosis in 50% of IS/AE patients, resulting in inappropriate treatment. Liver images obtained for 15 patients 1-5 years before diagnosis showed no AE lesions. Albendazole efficacy was good, but 19 of 48 treated patients experienced side effects. CONCLUSIONS Patients with immunosuppression are at increased risk for occurrence, delayed diagnosis, and progression of AE.

Prognostic value of C-reactive protein levels in patients with cirrhosis

Identifying cirrhosis with a poor short‐term prognosis remains crucial for improving the allocation of liver grafts. The purpose of this study was to assess the prognostic value of a model combining the variation of C‐reactive protein (CRP) levels within 15 days, the Model for End‐Stage Liver Disease (MELD) score, and the presence of comorbidities in patients with decompensated cirrhosis with a Child‐Pugh score > B7 and to test the relevance of this model in patients with compensated cirrhosis. We collected data for cirrhotic patients without hepatocellular carcinoma, extrahepatic malignancy, human immunodeficiency virus infection, organ transplantation, seen between January 2010 and December 2011. Multivariate analyses of predictors of 3‐month mortality used Cox models adjusted with the age‐adjusted Charlson comorbidity index. The prognostic performance [area under receiver operating characteristic curves (AUROCs)] of the 3‐variable model was compared to that of the MELD score. The 241 patients who met the inclusion criteria included 109 patients with a Child‐Pugh score > B7 who were hospitalized for decompensation. In these patients with severe cases, the 3‐month mortality was independently predicted by the MELD score [hazard ratio (HR), 1.10; 95% confidence interval (CI), 1.05‐1.14; P < 0.001] and a CRP level > 32 mg/L at the baseline and on day 15 (HR, 2.21; 95% CI, 1.03‐4.76; P = 0.042). This model was better than MELD alone (AUROC, 0.789 versus 0.734; P = 0.043). In the whole population with cirrhosis, the 3‐month mortality was also predicted by high MELD scores (HR, 1.11; 95% CI, 1.07‐1.16; P < 0.001) and a CRP level > 10 mg/L at the baseline and on day 15 (HR, 2.89; 95% CI, 1.29‐6.48; P < 0.001), but the AUROCs of the 3‐variable model and the MELD score alone were no longer significantly different (0.89 versus 0.88, not significant). In conclusion, prognostic models incorporating variations in CRP predict 3‐month mortality in patients with cirrhosis. Such models are particularly relevant for patients with decompensated cirrhosis but provide a limited increase in prediction in comparison with the MELD score in the whole population with cirrhosis. Liver Transpl 21:753–760, 2015.

Detecting nested clusters of human alveolar echinococcosis.

Recent changes in the epidemiology of alveolar echinococcosis (AE) in Eurasia have led to increasing concerns about the risk of human AE and the need for a thorough evaluation of the epidemiological situation. The aim of this study was to explore the use of a National Register to detect complex distribution patterns on several scales. The data were human AE cases from the FrancEchino register, diagnosed in France from 1982 to 2011. We used the Kulldorff spatial scan analysis to detect non-random locations of cases. We proposed an exploratory method that was based on the successive detection of nested clusters inside each of the statistically significant larger clusters. This method revealed at least 4 levels of disease clusters during the study period. The spatial variations of cluster location over time were also shown. We conclude that National Human AE registers, although not exempted from epidemiological biases, are currently the best way to achieve an accurate representation of human AE distribution on various scales. Finally, we confirm the multi-scale clustered distribution of human AE, and we hypothesize that our study may be a reasonable starting point from which to conduct additional research and explore the processes that underlie such distributions.

Plasma copeptin, a possible prognostic marker in cirrhosis

Copeptin, secreted stoichiometrically with vasopressin, demonstrated its prognostic role in various diseases other than cirrhosis.

Comparison of the serological tests ICT and ELISA for the diagnosis of alveolar echinococcosis in France.

Serological diagnosis of alveolar echinococcosis (AE) is a key element for efficient patient treatment management. A rapid immunochromatography test kit (ICT) using the recombinant Em18 antigen (rEm18) was recently developed. The aim of our study was to assess this test on a panel of sera from French patients with alveolar echinococcosis and control patients. In a blind test, a total of 112 serum samples were tested including samples of AE (n = 30), cystic echinococcosis [CE] (n = 15), and polycystic echinococcosis [PE] (n = 1). For the comparison, 66 sera from patients with hepatocarcinoma, fascioliasis, toxocariasis, Caroli’s disease, or autoimmune chronic active hepatitis were used. The diagnostic test sets we used were the rEm18-ICT and two validated ELISAs with rEm18 and Em2-Em18 antigens, respectively. For the ICT, 27/30 sera from AE patients, 4/15 sera from CE patients and the PE patient serum were positive. One serum from the control panel (toxocariasis) was positive for the ICT. The rEm18-ICT sensitivity (90.0%) and specificity (92.7%) for detection of Em18-specific antibodies confirmed it as a relevant tool for AE diagnosis. The rEm18-ELISA had a sensitivity of 86.7% and specificity of 91.5%, and the Em2-Em18-ELISA had a sensitivity of 96.7% and specificity of 87.8%. However, when AE patient sera are recorded as weak in intensity with the ICT, we recommend a double reading and use of a reference sample if the ICT is used for patient follow-up.

Current interventional strategy for the treatment of hepatic alveolar echinococcosis

ABSTRACT Introduction: The use of various types of invasive interventions combined with anti-infective drugs in the therapeutic strategy of alveolar echinococcosis (AE) has changed during the last 30 years. Areas covered: This article reviews the current respective indications of surgical, percutaneous and perendoscopic interventions in AE and proposes an integrative therapeutic strategy. Expert commentary: Hepatic resection is indicated whenever it is feasible and curative; palliative surgery should be avoided; percutaneous procedures are best adapted to the drainage of the necrotic cavity present in advanced cases; perendoscopic procedures with stenting are best adapted to alleviating the biliary complications that are common and life-threatening in AE patients. Continuous administration of albendazole or mebendazole, without interruption is mandatory in all cases, temporarily (recommended duration: 2 years) after radical lesion resection in patients without immune suppression; for life in all other cases. Long-term follow-up is essential.

BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10−4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 ‘AAA’ haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19–3.39); false discovery rate (FDR)-P=1.31×10−2]. In the Derivation#2 study, results were confirmed for the BRIP1 ‘GGG’ haplotype [OR, 0.53 (0.36–0.79); FDR-P=3.90×10−3]. In both Validation#1 and #2 studies, BRIP1 ‘AAA’ haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09–2.68); FDR-P=7.30×10−2; and OR, 6.45 (4.17–9.99); FDR-P=2.33×10−19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.