Maria Cristina Morelli

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

Background: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. Methods: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. Results: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a “probable autoimmune hepatitis” (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). Conclusions: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Predictors of sustained virological response after antiviral treatment for hepatitis C recurrence following liver transplantation

Factors associated with sustained virological response (SVR) in patients treated for hepatitis C virus (HCV) recurrence after liver transplantation (LT) are unclear. Ninety‐nine HCV‐positive/hepatitis B surface antigen–negative patients received antiviral treatment (AVT) with interferon/peginterferon plus ribavirin for HCV recurrence after LT. Cyclosporine (CyA) or tacrolimus (TAC) was used as the main immunosuppressor in 37 (37%) and 62 (63%) patients, respectively. Twenty‐five patients (25%) achieved an SVR. Twenty‐seven donor‐related, recipient‐related, HCV‐related, and immunosuppression‐related variables were investigated for their association with SVR. In logistic regression analysis, donor age < 60 years (odds ratio = 4.45, 95% confidence interval = 1.39‐14.19, P = 0.01), viral genotype other than 1 (odds ratio = 4.97, 95% confidence interval = 1.59‐15.48, P = 0.006), and the use of CyA during treatment (odds ratio = 6.85, 95% confidence interval = 2.15‐21.73, P = 0.001) were predictors of SVR. Patients treated with CyA (SVR rate: 43%) and those treated with TAC (SVR rate: 14%) were comparable for all variables, except for a shorter ischemia time and shorter timing of AVT initiation in the TAC group (P = 0.02 and P = 0.005, respectively) and a greater use of anti‐CD25 antibodies, azathioprine, and mycophenolate mofetil in the CyA group (P = 0.03, P < 0.001, and P = 0.001, respectively). The rate of AVT discontinuation due to side effects was similar between groups (16% versus 8%, P = 0.3). In conclusion, the type of immunosuppression during AVT may predict SVR in patients treated for HCV recurrence after LT. Liver Transpl 15:782–789, 2009.

Harm and Benefits of Primary Liver Resection and Salvage Transplantation for Hepatocellular Carcinoma

Primary transplantation offers longer life‐expectancy in comparison to hepatic resection (HR) for hepatocellular carcinoma (HCC) followed by salvage transplantation; however, livers not used for primary transplantation can be reallocated to the remaining waiting‐list patients, thus, the harm caused to resected patients could be balanced, or outweighed, by the benefit obtained from reallocation of livers originating from HCC patients first being resected. A Markov model was developed to investigate this issue based on literature data or estimated from the United Network for Organ Sharing database. Markov model shows that primary transplantation offers longer life‐expectancy in comparison to HR and salvage transplantation if 5‐year posttransplant survival remains higher than 60%. The balance between the harm for resected patients and the benefit for the remaining waiting list depends on (a) the proportion of HCC candidates, (b) the percentage shifted to HR and (c) the median expected time‐to‐transplant. Faced with a low proportion of HCC candidates, the harm caused to resected patients was higher than the benefit that could be obtained for the waiting‐list population from re‐allocation of extra livers. An increased proportion of HCC candidates and/or an increased median time‐to‐transplant could lead to a benefit for waiting‐list patients that outweighs this harm.

Priority of candidates with hepatocellular carcinoma awaiting liver transplantation can be reduced after successful bridge therapy

The allocation rules for patients with hepatocellular carcinoma (HCC) who are awaiting liver transplantation (LT) are a difficult issue and are continually evolving. To reduce tumor progression or down‐stage advanced disease, most transplant centers have adopted the practice of treating HCC candidates with resection or locoregional therapies. This study was designed to assess the effectiveness of bridge therapy in preventing removal from the waiting list for death/sickness severity or tumor progression beyond the Milan criteria and in determining posttransplant outcomes. The removal rates for 315 adult patients with HCC who were listed for LT were analyzed and were correlated to responses to bridge therapy with a competing risk analysis. The 3‐, 6‐, and 12‐month dropout rates were 3.5%, 6.5%, and 19.9%, respectively, and they were significantly affected by the Model for End‐Stage Liver Disease score (P = 0.032), the tumor stage at diagnosis (P = 0.041), and the response to bridge therapy (P < 0.001). The stratification of candidates by the tumor stage and the response to bridge therapy showed that patients with T2 tumors who achieved only a partial response or no response to bridge therapy had the highest dropout rates, and they were followed by patients with successfully down‐staged T3‐T4a tumors (P = 0.037). Patients with T2 tumors who had a complete response and patients with T1 tumors had similar dropout rates (P = 0.964). The response to bridge therapy significantly affected both the recurrence rate of 176 transplant patients (P = 0.017) and the overall intention‐to‐treat survival rate (P = 0.001). In conclusion, the response to therapy is a potentially effective tool for prioritizing HCC patients for LT as well as select cases with different risks of tumor recurrence after transplantation. Liver Transpl 17:1344–1354, 2011.

The risk of adenomatous polyps in asymptomatic first-degree relatives of persons with colon cancer

BACKGROUND & AIMS Increasing evidence indicates that inherited susceptibility is important in the pathogenesis of colorectal neoplasia. The aim of this study was to clarify whether having only one first-degree relative with colorectal cancer increases the risk of developing adenomatous polyps and whether total colonoscopy is an appropriate screening measure in these patients. METHODS The frequency of such a history was evaluated in 397 asymptomatic patients who underwent total colonoscopy. Of these patients, 155 had colorectal polyps and the remaining 242 did not have polyps. RESULTS Among polyp cases, 27 of 155 (17.4%) had a positive history; among those without polyps, 12 of 242 (5.0%) had a positive history. Alternatively expressed, 27 of 39 patients (69%) with family history and 128 of 358 patients (36%) without family history had adenomas. The estimated risk for polyps associated with family history was 1.9. Among polyp cases, 14 of 27 patients (51.9%) with family history and 32 of 128 patients (25.0%) without family history had only proximal polyps (chi 2 test; P = 0.006; odds ratio, 3.2), In the same groups, frequency of high-grade dysplasia was 8 of 27 patients (29.6%) and 16 of 128 patients (12.5%), respectively (chi 2 test; P = 0.04; odds ratio, 2.9). CONCLUSIONS Relative to subjects with no family history, asymptomatic patients with one first-degree relative with colorectal cancer had nearly double the risk of developing adenomatous polyps, greater frequency of severely dysplastic lesions, and significantly higher frequency of proximal polyp location. This suggests that total colonoscopy screening is indicated in these subjects.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation

Background  Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates.

Absence of Neuroinvasive Disease in a Liver Transplant Recipient Who Acquired West Nile Virus (WNV) Infection from the Organ Donor and Who Received WNV Antibodies Prophylactically

We describe the first case of West Nile virus (WNV) infection in Europe with transmission from donor to recipient following liver transplantation. The infection was detected in the recipient 3 days after transplantation, during the asymptomatic phase. We also report an innovative prophylactic strategy based on infusion of WNV hyperimmune plasma and gamma globulins that could be effective in preventing the appearance of a neuroinvasive disease.

Risk Factors for Infection With Carbapenem‐Resistant Klebsiella pneumoniae After Liver Transplantation: The Importance of Pre‐ and Posttransplant Colonization

Improved understanding of risk factors associated with carbapenem‐resistant‐Klebsiella pneumoniae (CR‐KP) infection after liver transplantation (LT) can aid development of effective preventive strategies. We performed a prospective cohort study of all adult patients undergoing LT at our hospital during 30‐month period to define risk factors associated with CR‐KP infection. All patients were screened for CR‐KP carriage by rectal swabs before and after LT. No therapy was administered to decolonize or treat asymptomatic CR‐KP carriers. All patients were monitored up to 180 days after LT. Of 237 transplant patients screened, 41 were identified as CR‐KP carriers (11 at LT, 30 after LT), and 20 developed CR‐KP infection (18 bloodstream‐infection, 2 pneumonia) a median of 41.5 days after LT. CR‐KP infection rates among patients non‐colonized, colonized at LT, and colonized after LT were 2%, 18.2% and 46.7% (p < 0.001). Independent risk factors for CR‐KP infection identified by multivariate analysis, included: renal‐replacement‐therapy; mechanical ventilation > 48 h; HCV recurrence, and colonization at any time with CR‐KP. Based on these four variables, we developed a risk score that effectively discriminated patients at low versus higher risk for CR‐KP infection (AUC 0.93, 95% CI 0.86–1.00, p < 0.001). Our results may help to design preventive strategies for LT recipients in CR‐KP endemic areas.

Impact of very advanced donor age on hepatic artery thrombosis after liver transplantation.

Background. The impact of advanced donor age on hepatic artery thrombosis (HAT) after liver transplantation (LT) is controversial. Methods. We analyzed the incidence of and risk factors for HAT in LT with donors aged 70 years or older. Eighty patients were transplanted between 1998 and 2002 (group A) and 132 between 2003 and 2008 (group B). Results. In the more recent approach to hepatic artery (HA) reconstruction, the donor HA was systematically preferred to the Carrel patch/celiac trunk, the reconstruction of donor accessory right HA on the donor gastroduodenal artery significantly increased, and the use of interposition grafts was minimized. Group B showed higher Model for End-stage Liver Disease score, lower ischemia time, and lower use of the folding technique/mesenteric conduits. There were 10 cases of HAT (4.7%): 8 (10%) in group A and 2 (1.5%) in group B (P=0.007). Early HAT occurred in 7 (8.8%) patients in group A and in 2 (1.5%) in group B (P=0.02). Group A (P=0.01), anatomical variations of HA (P=0.005), and the use of interposition grafts (P=0.004) were all factors independently affecting HAT. Conclusions. A low incidence of late HAT was observed in single-center LTs with very old donors. Early HAT decreased over time to largely acceptable rates because of more appropriate technical management.

Immunosuppression Modifications Based on an Immune Response Assay: Results of a Randomized, Controlled Trial

Background An immune function assay shows promise for identifying solid organ recipients at risk for infection or rejection. The following randomized prospective study was designed to assess the clinical benefits of adjusting immunosuppressive therapy in liver recipients based on immune function assay results. Methods Adult liver recipients were randomized to standard practice (control group; n = 102) or serial immune function testing (interventional group; n = 100) performed with a commercially available in vitro diagnostic assay (ImmuKnow; Viracor-IBT Laboratories, Lee’s Summit, MO) before transplantation, immediately after surgery and at day 1, weeks 1 to 4, 6, and 8, and months 3 to 6, 9, and 12. The assay was repeated within 7 days of suspected/confirmed rejection/infection and within 1 week after event resolution. Results Based on immune function values, tacrolimus doses were reduced 25% when values were less than 130 ng/mL adenosine triphosphate (low immune cell response) and increased 25% when values were greater than 450 ng/mL adenosine triphosphate (strong immune cell response). The 1-year patient survival was significantly higher in the interventional arm (95% vs 82%; P < 0.01) and the incidence of infections longer than 14 days after transplantation was significantly lower among patients in the interventional arm (42.0% vs. 54.9%, P < 0.05). The difference in infection rates was because of lower bacterial (32% vs 46%; P < 0.05) and fungal infection (2% vs 11%; P < 0.05). Among recipients without adverse events, the study group had lower tacrolimus dosages and blood levels. Conclusions Immune function testing provided additional data which helped optimize immunosuppression and improve patient outcomes.