Henrik Gjertsen

Liver Transplantation for Familial Amyloidotic Polyneuropathy (FAP): A Single‐Center Experience Over 16 Years

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1‐, 3‐ and 5‐year patient survival rates in patients transplanted during 1996–2005 were 94.6%, 92.3% and 92.3%, respectively, a significant difference from the rates of 76.7%, 66.7% and 66.7%, respectively, during 1990–1995 (p = 0.0003). Multivariate analysis revealed that the age at the time of LTx (≥40 years), duration of the disease (≥7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post‐LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.

The Stockholm experience with ABO-incompatible kidney transplantations without splenectomy

Abstract: Background: ABO‐incompatible kidney transplantations have previously only been performed after several pre‐operative sessions of plasmapheresis followed by splenectomy, and with the conventional triple‐drug immunosuppressive protocol being reinforced with anti‐lymphocyte globulin and B‐cell‐specific drugs. We have designed a protocol without splenectomy, based on antigen‐specific immunoadsorption, rituximab and a conventional triple‐drug immunosuppressive protocol.

Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982–2013

Abstract Aim and background. The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. Materials and methods. The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. Results. Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004–2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. Conclusion. The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts

Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long‐term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2–5 years after the DLT, but with no clinical symptoms. The 1‐, 3‐ and 5‐year actuarial patient survival in hepatocellular carcinoma (HCC) patients (n = 12) and non‐HCC patients (n = 15) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (P = 0.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.

Evolution of fibrosis during HCV recurrence after liver transplantation--influence of IL-28B SNP and response to peg-IFN and ribavirin treatment.

The IL‐28 gene is associated with sustained viral response (SVR) after treatment with peg‐IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL‐28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F ≤ 2 and severe when F ≥ 3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL‐28B SNP CC in the recipients (22%) than in the donors (67%), P < 0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P = 0.01. Recipients with IL‐28 CC and non‐CC had mild fibrosis in 64% and 38% prior to treatment, P = 0.13. At follow‐up, after treatment, significantly more recipients with CC had mild fibrosis than non‐CC recipients (75% versus 32%, P = 0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non‐1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P = 0.0022. In summary, we found that liver transplant recipients with IL‐28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL‐28B CC who achieved SVR had mild fibrosis at follow‐up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non‐1 than 1 infection. Our findings indicate that treatment for post‐transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient.

Concentration‐guided ribavirin dosing with darbepoetin support and peg‐IFN alfa‐2a for treatment of hepatitis C recurrence after liver transplantation

Summary.  Relapse of hepatitis C virus infection after liver transplantation is universal. Standard‐of‐care (SOC) treatment for relapse offers less satisfactory treatment response than in nontransplanted patients. Tolerance for treatment is suboptimal and withdrawals owing to adverse events induced by treatment frequent. To improve tolerance for SOC, and ribavirin (RBV) in particular, concentration‐guided RBV dosing calculated by a formula taking renal function and weight into consideration was utilized. A serum RBV concentration of 10 μm was set as the goal. All patients were given maintenance darbepoetin therapy from 2 weeks prior to initiation of treatment. In total, 21 patients with a mean age of 52 (range 25–64) years were included. The mean RBV concentration at week 4 was 10.2 and 7.36 μm in genotype 1/4 and non‐1/4 patients, respectively, and 11.7 and 9.42 at week 12. The mean haemoglobin drop was 25 g/L vs 21 g/L in the genotype 1/4 and non‐1/4 group, respectively, a nonsignificant difference. With this treatment approach, 80–90% of patients could be kept adherent to treatment. Sustained viral response was achieved 8/16 (50%) with low‐grade fibrosis (fibrosis stage ≤ 2) vs in none of five patients with advanced fibrosis (Fibrosis stage 3 and 4), P < 0.05. We conclude that a treatment algorithm utilizing concentration‐guided RBV dosing during darbepoetin maintenance therapy substantially improves tolerance and allows high adherence to a SOC treatment schedule, and that therapy needs to be initiated before advanced fibrosis is developed.

High adherence with a low initial ribavirin dose in combination with pegylated-IFN alpha-2a for treatment of recurrent hepatitis C after liver transplantation

Patients with recurrent hepatitis C after liver transplantation often cannot tolerate full dose of pegylated interferon (peg-IFN) and ribavirin (RBV) and are often withdrawn prematurely from treatment. We chose a low initial RBV dose, later increased due to tolerance to a mean dose of 600 mg daily (range 200–1000 mg daily) in combination with a peg-IFN alpha-2a 180 mcg weekly in an effort to improve tolerance and minimize withdrawals. 16 patients with hepatitis C recurrence and 1 with de novo HCV infection with a mean age of 54 y (range 43–66 y), 71% males, were treated. All patients completed the intended treatment schedule 24 weeks for genotype 2 and 3 and 48 weeks for genotype 1 and 4. Early viral response was achieved in 12 (71%), non-response in 1 patient with genotype 4, and sustained viral response in 4/5 (80%) patients with genotype 2 or 3 and 3/11 (27%) with genotype 1, p<0.05. To conclude, we found that utilizing a low initial daily RBV dose, later increased due to tolerance in combination with peg-IFN alpha-2a 180 µg weekly, was successful. Hence, all patients completed a full treatment course, which also offered a reasonable efficacy.

Parameters Obtained by Hepatobiliary Scintigraphy Have Significant Correlation with Biochemical Factors Early After Liver Transplantation

Background: Early postoperative hepatobiliary scintigraphy after liver transplantation is performed worldwide, but data on its significance for graft function are currently limited. Purpose: To examine the correlation between the result of early postoperative hepatobiliary scintigraphy and pre- and postoperative biochemical parameters in liver transplantation (LTx) patients. Material and Methods: Six parameters of hepatobiliary scintigraphy using 99mTc mebrofenin were statistically analyzed in 108 LTx patients: 1) half-life of the activity of elimination of mebrofenin from the blood; 2) total clearance of mebrofenin from the blood due to all possible routes; 3) half-life of the activity due to liver uptake; 4) clearance of mebrofenin from the blood due to liver uptake; 5) time to maximal uptake in the liver; and 6) the hepatic extraction fraction (HEF) and biochemical data. Analysis between patients with preoperative normal liver function, familial amyloid polyneuropathy (FAP), and end-stage liver disease (non-FAP) was also performed. Results: Univariate and multivariate analysis revealed that total bilirubin postoperative day 3 correlated with all three scintigraphic parameters, and peak aspartate aminotransferase and alanine aminotransferase correlated with HEF. The analysis between patients with FAP and non-FAP revealed no significant difference of scintigraphic data between the two groups. Conclusion: A significant correlation between early postoperative scintigraphic results and biochemical parameters was demonstrated.

Peg-IFN and ribavirin treatment for recurrence of genotype 2 and 3 hepatitis C after liver transplantation

Abstract Background: Relapse of hepatitis C virus (HCV) infection after liver transplantation (LT) is universal. Tolerance for treatment with pegylated-interferon (peg-IFN) and ribavirin (RBV) is suboptimal and withdrawals due to adverse events frequent. We sought to improve tolerance for treatment to improve outcome. Methods: We used concentration-guided RBV dosing to achieve an intended 10 μmol/L concentration with darbepoetin support in combination with peg-IFN alfa-2a, 180 μg for genotype 1 and 135 μg for genotype 2/3 to improve tolerance. Results: A total of 51/54 patients (94%) completed a full treatment course. In the per-protocol analysis 43% of patients (22/51) achieved sustained virological response (SVR), 82% with HCV genotype 2/3 and 22% with genotype 1, p = 0.0001. Patients with IL28B CC achieved SVR in 73% (8/11) and patients with non-CC in 33% (14/43), p = 0.016. Patients with mild fibrosis (fibrosis stage 1–2) achieved SVR in 56% (15/27), and patients with advanced fibrosis (fibrosis stage 3–4) in only 26% (7/27), p = 0.0267. Conclusions: Concentration-guided RBV dosing with darbepoetin support substantially improves tolerance and offers high adherence to a full peg-IFN and RBV treatment course in patients with post-transplant HCV relapse. With this approach genotype 2 and 3 infections can be treated cost-effectively post-transplant. Genotype 1, IL28B non-CC genotype, and advanced fibrosis predicted a low SVR rate.

Living-related liver transplantation in children--a single center evaluation of the outcome of donor candidates and recipients.

Abstract:  The aim was to study the outcome of donor candidate investigations for living‐related donor liver transplantation from adult to child. The charts of 25 donor candidates were reviewed. All 22 recipients, of whom 18 had BA, were already listed for DD organ transplantation. Eleven donor candidates were accepted. Seven of them successfully donated the left lateral liver segment. At follow‐up, all donors and recipients were well from the surgery. However, one donor developed Crohn’s disease. In the four remaining cases the recipient deteriorated before transplantation was possible or other surgical approaches were utilized. For three candidates the investigations were never finalized, due to either clinical deterioration of the recipient or the availability of a DD organ. Eleven donor candidates were rejected. Four of them (three being parents of BA patients) had liver abnormalities. Another three were rejected for cardiopulmonary disorders and the remaining four for other reasons. We conclude that only seven out of 25 (28%) candidates donated a liver segment. The fact that parents of BA patients have potential liver pathology may be of importance for the understanding of the etiology of the disease and have possible implications for the choice of donors.