Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease.

BACKGROUND & AIMS: Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin-encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidin-induced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. METHODS: The ferroportin disease variants R178Q andA77D and the HH4-variant C326Y were overexpressed in HEK-293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin-ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. RESULTS: In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D-variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. CONCLUSIONS: These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin-mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.

Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list.

Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality. Liver transplantation (LT) is a potential therapy for patients who do not improve with supportive measures, but the efficacy of LT has not been shown. The aim of this study was to investigate the feasibility of LT and to determine the postoperative outcomes of patients with ACLF. All patients referred to our liver unit between 2002 and 2010 were registered in a database. The diagnosis of ACLF was made in accordance with the Asian Pacific Association for the Study of the Liver consensus. The post-LT outcomes were compared with the outcomes of a cohort of patients with chronic liver disease who underwent transplantation for other indications during the same period. One hundred forty four of 238 patients fulfilled the ACLF criteria. In an intention-to-treat analysis, the median transplant-free survival time was 48 days. Multiorgan failure was the most common cause of death. Ninety-four patients (65%) were evaluated for LT, 71 patients (49%) were listed, and 33 patients (23%) finally underwent deceased donor LT; this resulted in a wait-list mortality rate of 54%. Patients who developed infectious complications (particularly pneumonia and/or sepsis) and patients who received renal replacement therapy or mechanical ventilation were less likely to undergo LT. The 1- and 5-year survival rates of 87% and 82% were comparable to the rates for non-ACLF patients. In conclusion, this study shows that LT remains the only therapeutic option for the vast majority of patients with ACLF. However, LT was feasible in less than one fourth of the patients with a 5-year survival rate greater than 80%.

Early viral load and recipient interleukin-28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation.

There have been few detailed studies of viral kinetics after liver transplantation (LT), and conflicting data have been reported on viral loads and the severity of recurrent hepatitis C virus (HCV) disease. This long-term study aimed to examine (1) the impact of HCV RNA levels at specific points in time within the first year and (2) the influence of interleukin-28B (IL-28B) genotypes on patient outcomes and the severity of recurrent HCV disease. The viral loads were measured 2, 4, 12, 24, and 48 weeks after LT, and the recipient/donor IL-28B genotypes of 164 patients were determined. A Cox regression analysis showed that the viral load at week 2 was an independent negative predictor of recipient outcomes. A week 2 viral load ≥ 6.0 log(10) IU/mL was significantly associated with reduced patient survival. After a mean follow-up of 6.5 years, 21 of 164 patients (12.8%) developed a cholestatic type of HCV recurrence and/or rapidly progressed to cirrhosis within 1 year. A multivariate binary regression analysis showed that HCV viremia at week 2 and a non-C/C recipient IL-28B genotype were independent risk factors for cholestatic recurrent HCV. No predictive factors could be found for the occurrence of recurrent liver cirrhosis 5 and 10 years after LT. Our study shows that the HCV RNA level at week 2 and the recipient IL-28B genotype are independent, statistically significant risk factors for post-LT cholestatic HCV, and it emphasizes the importance of viral load monitoring and IL-28B genotyping for identifying HCV recipients at risk for severe HCV recurrence.

Extensive surveillance promotes early diagnosis and improved survival of de novo malignancies in liver transplant recipients.

The aim of our study was to examine whether an extensive surveillance protocol will promote early diagnosis and improved survival in patients with de novo cancer following liver transplantation (LT). Of 779 consecutive LT recipients, 96 (12.3%) developed 105 malignancies. The cumulative risk for the development of de novo cancer was 10%, 24%, 32% and 42% at 5, 10, 15 and 20 years after LT, respectively. The most frequent tumor types were skin (17%), lung (16%), oropharyngeal (11%) and prostate cancer (11%). The overall standard incidence ratio as compared to that of the general population was 1.9 (95% CI: 1.5-2.3). The median survival of patients with de novo non-skin cancers was 3.1 years after diagnosis. Only patients with skin cancers and solid tumors, diagnosed at early stages, showed an excellent outcome. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9% to 13% and more de novo malignancies were diagnosed in earlier stages. For non-skin cancers, the median tumor-related survival significantly improved from 1.2 to 3.3 years as well as the median overall survival post-LT. This study indicates that an extensive tumor surveillance program is highly recommendable in LT recipients.

Subfulminant hepatitis B after infliximab in Crohn's disease: need for HBV-screening?

Infections are a major adverse effect during the treatment with anti-TNF-alpha. While exclusion of any bacterial infection and screening for tuberculosis are mandatory before initiating a therapy with anti-TNF-alpha-antibodies, there are no guidelines whether to screen for or how to deal with chronic viral infections such as hepatitis B. In this case report, we have described a patient with Crohn's disease who developed subfulminant hepatitis B after the fourth infusion of infliximab due to an unrecognized HBs-antigen carrier state. He recovered completely after lamivudine therapy was started, but this severe adverse event could have been prevented if screening for HBV and pre-emptive therapy with lamivudine would have been started prior to infliximab. We therefore strongly argue in favor of extended screening recommendations for infectious diseases including viral infections before considering a therapy with infliximab.

Transjugular intrahepatic portosystemic shunt in liver transplant recipients.

AIM: To evaluate the efficacy of transjugular intrahepatic portosystemic shunts (TIPSs) after liver transplantation (LT). METHODS: Between November 1996 and December 2005, 10 patients with severe recurrent hepatitis C virus infection (n = 4), ductopenic rejection (n = 5) or portal vein thrombosis (n = 1) were included in this analysis. Eleven TIPSs (one patient underwent two TIPS procedures) were placed for management of therapy-refractory ascites (n = 7), hydrothorax (n = 2) or bleeding from colonic varices (n = 1). The median time interval between LT and TIPS placement was 15 (4-158) mo. RESULTS: TIPS placement was successful in all patients. The mean portosystemic pressure gradient was reduced from 12.5 to 8.7 mmHg. Complete and partial remission could be achieved in 43% and 29% of patients with ascites. Both patients with hydrothorax did not respond to TIPS. No recurrent bleeding was seen in the patient with colonic varices. Nine of 10 patients died during the study period. Only one of two patients, who underwent retransplantation after the TIPS procedure, survived. The median survival period after TIPS placement was 3.3 (range 0.4-20) mo. The majority of patients died from sepsis with multiorgan failure. CONCLUSION: Indications for TIPS and technical performance in LT patients correspond to those in non-transplanted patients. At least partial control of therapy-refractory ascites and variceal bleeding could be achieved in most patients. Nevertheless, survival rates were disappointing, most probably because of the advanced stages of liver disease at the time of TIPS placement and the high risk of sepsis as a consequence of immunosuppression.

Long-term outcome of endoscopic treatment of biliary strictures after liver transplantation.

Biliary strictures are one of the most common complications following liver transplantation (LT), with an incidence of 5.8-34%. Endoscopic techniques have been successfully used to treat biliary complications; however, the long-term efficacy and safety of this treatment option has not yet been fully elucidated. This prospective study was performed to determine the efficacy and safety of endoscopic management of biliary complications after LT and its impact on long-term patient and graft survival. Biliary strictures were suspected in the presence of elevated liver parameters and/or abnormal abdominal sonography and subsequently diagnosed by endoscopic retrograde cholangiography (ERC). The mean follow-up was 39.8 (range, 0.3-98.2) months after first ERC. Between October 1992 and December 2003, a total of 515 patients underwent LT. Biliary complications were diagnosed in 84 patients (16.3 %). Anastomotic strictures (AS) alone were found in 65 (12.6%) and nonanastomotic strictures (NAS) in 19 patients (3.7%). Long-term success was observed in 77% of patients with AS. In patients with NAS, partial long-term responses could be achieved in 63% of patients. Five patients (6.2%) required a percutaneous and 6 (7.4%) patients a surgical approach. In conclusion, the long-term outcome for patients with post-liver transplant biliary strictures after endoscopic treatment is excellent, especially for patients with AS. Development of NAS reduces graft but not patient survival after endoscopic therapy.

Fatal course of parvovirus B19-associated myocarditis in a female liver transplant recipient.

Acute myocarditis may result in severe hemodynamic compromise with fatal outcome. Furthermore, recent studies suggest myocarditis as a major cause of sudden unexpected death. A variety of cardiotropic viral, rickettsial, and bacterial infectious agents have been identified to date. Parvovirus B19 (PVB19) is usually benign in childhood, but it may also cause death due to myocarditis. We present here the case of an adult female who presented with fatigue, dyspnea on exertion, and orthostatic dizziness 8 months after successful liver transplantation. Cardiologic work-up, including left ventricular endomyocardial biopsy, revealed acute myocarditis secondary to PVB19. Since no specific therapy for this virus is available, the patient was treated symptomatically with an angiotensin-converting enzyme inhibitor plus beta-blocker and diuretics. After a period of stabilization, new-onset rapid atrial fibrillation caused acute low-output syndrome within 14 days after hospital admission. The patient eventually died because of refractory cardiogenic shock. In conclusion, to our knowledge this is the first report of PVB19-induced myocarditis confirmed by detection of viral genome in myocardium in a liver transplant recipient.

Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome.

Orthotopic liver transplantation (OLT) has been considered the best treatment option for patients with hepatocellular carcinoma (HCC). Because of a steadily increasing waiting time, a noteworthy proportion of patients are excluded from OLT because of tumor progression. A 20% and more dropout rate from the waiting list has recently been reported. In this prospective study, we evaluated the effect of preoperative transarterial chemoembolization (TACE) on preventing tumor progression while on the waiting list in patients meeting current selection criteria (solitary lesion < or = 5 cm, three lesions < or = 3 cm). In addition, we analyzed the outcome of a separate group of patients with advanced-stage HCC outside the selection criteria but with at least 50% tumor reduction after TACE (downstaging) to expand current criteria. Forty-eight patients met the selection criteria and were eligible for this study. Seven patients are still on the waiting list; 41 underwent OLT. None of these patients had to be removed from the list because of tumor progression after a mean waiting time of 178 days (23 patients > or =180 days). The 1-, 2-, and 5-year intention-to-treat survival was 98%, 98%, and 94%. The outcome after OLT was also excellent with 1-, 2-, and 5-year survival rates of 98%, 98%, and 93%. Tumor recurrence occurred only in 1 patient (2.4%). Fifteen patients with advanced-stage HCC were included in this study. Three developed a tumor progression and had to be removed from the list (20% dropout rate). Despite tumor reduction before OLT, these patients had a significantly less favorable outcome in the intention-to-treat analysis as well as in the posttransplantation survival. Tumor recurrence was seen in 30% of patients after OLT. In conclusion, TACE followed by OLT is associated with an excellent outcome in selected patients. Furthermore, TACE is highly efficacious in preventing tumor progression while waiting for OLT. Although TACE reduced tumor preoperatively, it failed to show a beneficial effect on patient survival in advanced-stage HCCs.

Long-term efficacy and safety of mycophenolate mofetil in liver transplant recipients with calcineurin inhibitor-induced renal dysfunction.

Long-term survival after orthotopic liver transplantation (OLT) is mainly influenced by adverse events caused by immunosuppression. Several studies have shown the efficacy of mycophenolate mofetil (MMF) in improving calcineurin inhibitor (CI)-induced nephrotoxicity with concomitant reduction or withdrawal of CI. In this prospective study we assessed the long-term effect and safety of MMF. Thirty-two OLT recipients with significant renal impairment due to either cyclosporine A ( n=25) or tacrolimus ( n=7) were enrolled in this study. CIs were reduced stepwise by at least 70%. Mean serum creatinine had decreased from 2.63+/-0.39 to 1.74+/-0.34 mg/dl after 1 month, and this improvement was maintained within a follow-up period of 4.8+/-0.6 (range 3.1-6.0) years, without major immunological or non-immunological side effects. Of all participants, 88% showed a significant reduction, and 41% even a normalization, in their serum creatinine level. In addition, MMF conversion, within 6 months of OLT, appears to be crucial in order to improve or even normalize renal function. This study demonstrates the long-term efficacy and safety of MMF in OLT recipients with CI-induced nephropathy.

Impact of high-dose interferon induction and ribavirin therapy in patients with chronic hepatitis C relapsing after or not responding to interferon monotherapy.

BACKGROUND/AIMS: Initial high-dose interferon-alpha induction therapy in combination with ribavirin improves sustained response rates in treatment-naïve patients. This prospective, randomized, controlled study tested whether non-responders or relapsers to interferon monotherapy also benefit from induction therapy. METHODS: Patients with chronic hepatitis C who had not responded to (n=75) or relapsed (n=80) after previous interferon therapy were randomized to receive three different interferon doses during the first 14 weeks of therapy (A: 10 MU IntronA/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; B:5 MU/d for 14 weeks; C: 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. All patients received 1-1.2 g ribavirin/day throughout the whole study. RESULTS: The rates of viral clearance at any time on treatment were similar in all groups. Sustained response rates were also not different among the groups in interferon nonresponders (A 32%, B 29%, C 31%) and relapsers (A 64%, B 68%, C 71%), respectively, as well as in patients with different genotypes. As expected, sustained response rates were higher in patients with genotype non-1 than in those with genotype 1. CONCLUSION: High-dose induction therapy does not improve the outcome of interferon/ribavirin therapy in interferon nonresponders or relapsers.