Outcomes of Pregnancy in Recipients of Liver Transplants.

BACKGROUND & AIMS: Despite increasing reports of pregnancy in women who received liver transplants, it is not clear how transplantation and immunosuppression affect pregnancy. We collected data from liver transplant recipients who became pregnant on immunosuppression regimens, pregnancy management, graft morbidity, and outcomes of mothers and neonates. METHODS: We searched the liver transplant database in Birmingham, United Kingdom, for women who reported pregnancy after liver transplantation from August 1986 through May 2016. We collected information on morbidities and outcomes of 139 pregnancies in 83 women (median age at conception, 27 y; range, 15-46 y). Fisher exact tests were used to compare categoric variables and Mann-Whitney U and Kruskal-Wallis tests were used to compare continuous variables. The primary outcome was the live birth rate in the entire cohort. Additional outcomes analyzed included differences in immunotherapy regimens, and outcomes associated with exposure to cyclosporine and tacrolimus, time to transplantation (<12 vs >12 mo), and time period of pregnancy (1986-2000 vs 2001-2016). RESULTS: Of the pregnancies, 69% resulted in live births, 19% resulted in miscarriages or still births, and 9% were terminated. A higher proportion of patients who conceived more than 1 year after liver transplantation had live births than of women who conceived before this time (98% vs 80%; P = .006). Tacrolimus exposure was associated with higher risks of premature delivery (P = .045) and caesarian section (P = .031) than cyclosporine exposure. Compared with the period from 1986 to 2000, women who conceived from 2001 to 2016 had a significantly shorter time between transplantation and conception (median, 3 vs 7 y; P = .027), frequent use of tacrolimus vs cyclosporine (84% vs 26%; P = .001), and a higher incidence of cesarean section (44% vs 32%; P = .025). CONCLUSIONS: Almost 70% of women who conceive after liver transplantation have live births, although this rate is lower than that of women in the overall population. These cases require involvement of hepatologists and obstetricians.

Severe asymptomatic non-alcoholic fatty liver disease in routine diabetes care; a multi-disciplinary team approach to diagnosis and management.

OBJECTIVES: To prospectively use a non-invasive algorithm to identify asymptomatic, advanced non-alcoholic fatty liver disease (NAFLD) in a secondary care diabetes clinic and to determine the short-term effect of a multi-disciplinary team (MDT) approach in a liver clinic. RESEARCH DESIGN AND METHODS: NAFLD Fibrosis Score (NFS) was calculated in 64 asymptomatic patients with type 2 diabetes. Advanced fibrosis was identified using transient elastography and confirmed with liver biopsy. In a subsequent retrospective study, 95 patients newly referred to the NAFLD MDT clinic were investigated and the impact of the MDT approach assessed. RESULTS: 25/64 (39.0%) of patients with diabetes had a low NFS (<-1.455). 39/64 (61.0%) patients had a high or indeterminate NFS and were referred for review in the NAFLD MDT clinic, of which 23/39 attended for assessment. 19/23 (82.6%) were diagnosed with NAFLD, of which 6/19 (31.6%) patients had a positive transient elastography (≥8 kPa). Liver biopsy confirmed advanced fibrosis in 5/6 cases, with moderate fibrosis in 1 case. In the retrospective study, 65/95 (68.4%) new referrals to the NAFLD MDT clinic had a diagnosis of NAFLD. Over a median 98 days (IQR 70-182) follow-up, there was a significant improvement in weight (-0.8 kg; P = 0.024), total cholesterol (-0.2 mmol/L; P = 0.044), ALT (alanine transmaminase, -12.5 IU/L; P < 0.001) and GGT (gammu-glutamyl transferase, -13.0 IU/L; P < 0.0001). 7/28 (25%) of patients with diabetes achieved >5% weight loss. CONCLUSIONS: A significant proportion of asymptomatic patients attending type 2 diabetes clinics have undiagnosed advanced NAFLD fibrosis. An MDT approach to NAFLD results in short-term improvements in metabolic and liver parameters.

Symptomatic portal biliopathy: a single centre experience from the UK.

BACKGROUND AND METHODS: Biliary obstruction as a consequence of portal biliopathy, because of extrahepatic portal vein occlusion is an uncommon cause of biliary disease in the western world. We reviewed all patients presenting to the Regional Liver Transplant Unit in Birmingham, UK with symptomatic portal biliopathy between 1992 and 2005 and report the presentation, investigation, management and outcome of these complex patients. RESULTS: Thirteen patients with symptomatic portal biliopathy were followed up for a median of 2 years (range 1-18 years). Jaundice was the presenting feature in all cases and was associated with bile duct stones or debris in 77% (10 of 13) of cases. Successful treatment of biliary problems was achieved by biliary decompression in six cases (metallic stent=three, plastic stent=one, combined procedure=one and sphincterectomy=one) and portal decompression in three cases (transjugular intrahepatic portosystemic shunt=two, meso-caval shunt=one). Successful biliary drainage could not be achieved endoscopically or by portal decompression in one case that was accepted for combined liver and small bowel transplantation. Three patients had spontaneous resolution without recurrence over the follow-up period. Ten patients (77%) experienced gastrointestinal bleeding. Two deaths over the follow-up period occurred; both were associated with portal hypertensive bleeding. CONCLUSION: Endoscopic management (sphincterectomy and stone extraction or stent insertion) is effective initial therapy for patients with symptomatic portal biliopathy. In the case of persistent biliary obstruction porto-systemic shunting (transjugular intrahepatic portosystemic shunt or surgical) should be considered, however, the extent of vascular thrombosis precludes this in most cases.

Tacrolimus and cyclosporin doses and blood levels in hepatitis C and alcoholic liver disease patients after liver transplantation.

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.

A prospective study of standardized nonsurgical therapy in the management of biliary anastomotic strictures complicating liver transplantation.

BACKGROUND: Biliary anastomotic strictures are a common complication of liver transplantation, occurring in up to 7% of patients at our center. Endoscopic therapy has started to replace surgical biliary reconstruction as the favored means of managing these patients in some centers, although the utility of this approach has never been tested in the setting of a standardized prospective study. METHODS: This was a standardized, prospective observational study in the liver transplantation unit, Queen Elizabeth Hospital, Birmingham, United Kingdom. Between June 2000 and August 2006, a total of 791 adults underwent liver transplantation at the Birmingham liver unit and 53 patients were diagnosed with biliary anastomotic strictures. All 53 patients chose to undergo endoscopic therapy and were managed according to the unit's standardized treatment protocol. Data and information from the patient records was collated prospectively, stored in a specific database, and analyzed by intention-to-treat. RESULTS: Endoscopic therapy was successful in 69% of patients referred with anastomotic strictures with a median stent free follow up of 18 months. Most patients required a median of 3 endoscopic procedures and two 24F balloon dilatations to adequately treat the stricture. The median continuous indwelling stent period was 11 months. Two patients were re-stented because of jaundice although only one patient had recurrence of the anastomotic stricture (3%). CONCLUSIONS: Endoscopic balloon dilatation and stenting is a safe and effective means of treating biliary anastomotic strictures complicating liver transplantation.

Thrombocytosis in liver transplant recipients: prevalence, natural history, and impact.

The prevalence, natural history, and implications of reactive thrombocytosis after liver transplantation (LT) are unknown. Prospectively collected data from July 2000 to February 2006 were analyzed. Post-LT thrombocytosis was defined as a platelet count of > 450 x 10(3)/microL lasting for >7 days and starting within 8 weeks of transplantation. In patients who survived >8 weeks, graft and patient outcomes were compared with liver transplant recipients who survived >8 weeks and did not develop any thrombocytosis. Post-LT thrombocytosis was seen in 92 (14.7%) of 627 patients. The median onset was on day 13 (range, days 1-44) and the peak platelet count was seen on day 17 (range, days 3-110). The median duration of thrombocytosis was 25 days (range, 7-1,253 days), with a median peak platelet count of 625 x 10/microL (range, 472-1,381 x 10/microL). Seronegative fulminant hepatic failure was the indication for transplantation in 18% of patients with post-LT thrombocytosis compared with 3% of controls (P < 0.001). There was a lower proportion of patients transplanted for hepatitis C-related cirrhosis in the thrombocytosis group (10% vs. 18%, P = 0.04). The occurrence of hepatic arterial thrombosis was similar in the 2 groups (5% vs. 4%, P = NS). None of the 4 patients with platelet count higher than 1,000 x 10/microL developed thrombotic complications. Post-LT thrombocytosis is more often associated with seronegative fulminant hepatic failure, and there is a negative association with hepatitis C-related cirrhosis. Post-LT thrombocytosis does not increase the risk of hepatic artery thrombosis, and patients without thrombotic complications should not be treated.

Liver transplantation for hepatic epithelioid hemangioendothelioma: a case series.

Epithelioid hemangioendothelioma is a rare soft-tissue tumor with unpredictable malignant potential. This type of tumor can occur in the liver but is very rare. Signs and symptoms are often nonspecific, and even if the problem is not misdiagnosed, arriving at a clear diagnosis can take some time. This article describes 3 patients who had very different signs and symptoms, all of whom were referred to a specialist center for liver transplantation in 1 year. All 3 patients proceeded to transplantation and made a good recovery. They have regular follow-up at the transplant center, and to date, no recurrence of hepatic epithelioid hemangioendothelioma has been seen in these 3 patients.

Results of combination treatment with pegylated interferon and ribavirin in cirrhotic patients with hepatitis C infection.

BACKGROUND: The treatment of hepatitis C patients with advanced cirrhotic liver disease remains challenging and data on the outcome of treatment for this patient group is limited. RESULTS: Between September 2000 and August 2004, 61 cirrhotic patients started treatment with pegylated interferon and ribavirin (42 male, age range 29-69 years, 26 Asian). Forty-three (70%) patients were serum hepatitis C virus (HCV) RNA negative at the end of treatment and 24 (39%) achieved a sustained virological response (SVR). SVR was achieved for 35% (6/17) of patients with genotype 1, and for 39% (16/41) with genotype 3. Caucasians with genotype 3 demonstrated a higher cure rate (SVR 10/18 = 56%) than Asians (SVR 6/24 = 25%). Failure to achieve SVR was associated with lower platelet count, neutrophil count and albumin at baseline. Twenty patients suffered clinical or laboratory decompensation, five patients required hospitalization, and two patients died. Patients who experienced hepatic decompensation were older and had baseline characteristics associated with more advanced liver disease. CONCLUSION: The treatment of patients with advanced HCV is challenging, although many treated patients achieve SVR. Significant toxicity is experienced and there is treatment-related mortality. This balance of efficacy and toxicity needs to be considered before commencing treatment.

Self-organizing maps can determine outcome and match recipients and donors at orthotopic liver transplantation.

BACKGROUND: There is a relative lack of donor organs for liver transplantation. Ideally, to maximize the utility of those livers that are offered, donor and recipient characteristics should be matched to ensure the best possible posttransplant survival of the recipient. METHODS: With prospectively collected data on 827 patients receiving a primary liver graft for chronic liver disease, we used a self-organizing map (SOM) (one form of a neural network) to predict outcome after transplantation using both donor and recipient factors. The SOM was then validated using a data set of 2622 patients undergoing transplantation in the United Kingdom at other centers. RESULTS: SOM analysis using 72 inputs and two survival intervals (3 and 12 months) yielded three neurons with either higher or lower probabilities of survival. The model was validated using the independent data set. With 20 patients on the waiting list and 10 sequential donor livers, it was possible to demonstrate that the model could be used to identify which potential recipients were likely to benefit most from each liver offered. CONCLUSIONS: With this approach to matching donor livers and recipients, it is possible to inform transplant clinicians about the optimum use of donor livers and thereby effectively make the best use of a scarce resource.

Hepatitis B and C virus infections in the immune compromised.

PURPOSE OF REVIEW: This review compares and contrasts the natural history and treatment of hepatitis B and C virus infections in three principal populations of immune compromised individuals: (1) patients co-infected with HIV; (2) patients with liver failure secondary to hepatitis B or C virus infection who undergo liver transplantation, and (3) patients with hepatitis B or C virus infection who undergo anticancer chemotherapy. RECENT FINDINGS: Chronic liver disease resulting from hepatitis B or C virus infection progresses more rapidly in patients co-infected with HIV than in HIV negative patients. Treatment protocols for antiviral therapy are, however, similar to those used in immunocompetent individuals and although few long-term results are available, the efficacy of interferon and ribavirin therapy in hepatitis C virus/HIV infection and lamivudine in HIV/hepatitis B virus infection has been proven in the short-term. Perhaps the most important consideration is the timing of administering treatments to co-infected patients. For patients with well preserved CD4 counts and hepatitis C virus/HIV co-infection, the hepatitis infection should be treated as early as possible to avoid drug interactions of hepatitis C virus antivirals with antiretroviral therapy. Also, response to hepatitis C virus treatment appears better when treatment is administered in the context of preserved immune function. Conversely, in hepatitis B virus/HIV co-infection, hepatitis B virus antivirals are best administered with anti-retroviral therapy, thus preventing the selection of HIV viral species which may be resistant to the drugs used for hepatitis B virus. Improved graft and patient survival after liver transplant and with anticancer chemotherapy in hepatitis B virus infected patients has been proven using lamivudine prophylaxis. However, although therapy for hepatitis C virus recurrence after liver transplantation would seem rational, limited success with current treatment protocols has been achieved. SUMMARY: Although the prognosis of hepatitis B and C virus infections in the immune compromised may be inferior to that of immunocompetent individuals, such patients should have full evaluation of their viral hepatitis, and antiviral therapy should be considered.

Lymphocyte recruitment to the liver in alcoholic liver disease.

The normal liver contains a large number of lymphocytes, which include not only specialized natural killer (NK) and NKT cells but also CD4 and CD8 T cells. Whereas some of these cells are terminally differentiated effector cells that are destined to die by apoptosis, many of them are not and include immunocompetent cells that traffic through the liver to provide continuing immune surveillance as well as epithelial-associated effector T cells. In alcoholic liver disease the number of lymphocytes in the liver increases and the type and distribution of these infiltrating cells will determine the nature of the inflammation. For instance, a predominance of parenchymal inflammation is a feature of alcoholic hepatitis, whereas a predominantly portal infiltrate is a feature of cirrhosis. In this article we discuss the molecular mechanisms that regulate the entry of lymphocytes to the inflamed liver in alcoholic hepatitis. Lymphocytes play a critical role in regulating the immune/inflammatory response to alcohol, and understanding how these cells are recruited to the liver has important implications for understanding the pathogenesis of alcoholic liver disease in which parenchymal infiltration is a critical determinant of disease progression. Aberrant recruitment and retention of lymphocytes in the liver may explain why some patients with alcoholic liver disease show progressive inflammatory damage whereas in others the disease takes a more indolent course. Similarly, leukocyte recruitment may present new therapeutic targets in which lymphocyte recruitment to the specific liver compartments can be inhibited, thereby minimizing tissue damage whilst leaving generalized lymphocyte recirculation intact. Potentially the most exciting potential is to modulate the nature of the lymphocyte subsets recruited to the liver, so that harmful cells are excluded and beneficial subsets are preferentially recruited.

Genetically modified interferon: is there a consensus yet?

The treatment of patients with chronic hepatitis C virus infection has evolved during the last decade from interferon monotherapy to combination therapy with interferon and ribavirin. National and international guidelines recommend either 6 or 12 months of interferon/ribavirin combination therapy depending on the pre-treatment virological status of the patient. However, the choice for second-line treatment of patients who do not achieve sustained viral clearance with combination therapy has yet to be defined. This commentary examines previously published studies of the use of consensus interferon for hepatitis C virus infected patients. The characteristics of the treated populations and response to treatment are examined. The current and potential roles for this type of interferon in the treatment of hepatitis C virus infection are considered.