Bo Göran Ericzon

Guideline of transthyretin-related hereditary amyloidosis for clinicians

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.

Improving the techniques for human hepatocyte transplantation: Report from a consensus meeting in London

On September 6 and 7, 2009 a meeting was held in London to identify and discuss what are perceived to be current roadblocks to effective hepatocyte transplantation as it is currently practiced in the clinics and, where possible, to offer suggestions to overcome the blocks and improve the outcomes for this cellular therapy. Present were representatives of most of the active clinical hepatocyte transplant programs along with other scientists who have contributed substantial basic research to this field. Over the 2-day sessions based on the experience of the participants, numerous roadblocks or challenges were identified, including the source of cells for the transplants and problems with tracking cells following transplantation. Much of the discussion was focused on methods to improve engraftment and proliferation of donor cells posttransplantation. The group concluded that, for now, parenchymal hepatocytes isolated from donor livers remain the best cell source for transplantation. It was reported that investigations with other cell sources, including stem cells, were at the preclinical and early clinical stages. Numerous methods to modulate the immune reaction and vascular changes that accompany hepatocyte transplantation were proposed. It was agreed that, to obtain sufficient levels of repopulation of liver with donor cells in patients with metabolic liver disease, some form of liver preconditioning would likely be required to enhance the engraftment and/or proliferation of donor cells. It was reported that clinical protocols for preconditioning by hepatic irradiation, portal vein embolization, and surgical resection had been developed and that clinical studies using these protocols would be initiated in the near future. Participants concluded that sharing information between the groups, including standard information concerning the quality and function of the transplanted cells prior to transplantation, clinical information on outcomes, and standard preconditioning protocols, would help move the field forward and was encouraged.

Liver transplantation for familial amyloidotic polyneuropathy: Impact on Swedish patients' survival

Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long‐term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long‐term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty‐one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early‐onset controls (P < 0.001). In contrast, no significant difference for late‐onset cases (≥50 years) was found. Transplanted late‐onset females had significantly improved survival in comparison with transplanted late‐onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (≥7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late‐onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early‐onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late‐onset male patients. Liver Transpl 15:1229–1235, 2009.

Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?

Background Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. Methods Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. Results From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease. Conclusions Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

Impact of autonomic neuropathy on circulatory instability during liver transplantation for familial amyloidotic polyneuropathy

BACKGROUND Circulatory instability with severe hypotension frequently complicates liver transplantation in patients with familial amyloidotic polyneuropathy. Autonomic dysfunction is found early in the course of the disease by analysis of beat-to-beat heart rate variability (HRV). The aim of the present study was to investigate the impact of autonomic neuropathy on intraoperative circulatory instability during liver transplantation for familial amyloidotic polyneuropathy. METHODS Twenty-two patients were evaluated at the Department of Medicine, Umea University Hospital, by spectral analysis of HRV and later received liver transplants at Huddinge University Hospital. The low-and high-frequency bands obtained by spectral analysis of HRV in the supine and upright positions, respectively, were used as representative of sympathetic and parasympathetic activity. Circulatory instability during transplantation was defined as a fall in systolic arterial blood pressure below 70 mmHg for more than 5 min during the preanhepatic phase. RESULTS Both arrhythmia preventing spectral analysis of HRV and a sympathetic variability peak below 2.5 mHz2 were significantly more common among patients with intraoperative circulatory instability (P=0.03 and 0. 004, respectively). A diminished increase in pulse rate when tilting the patients from the supine to the upright position was also more pronounced among patients with circulatory instability (P<0.05). CONCLUSIONS The majority of patients who will develop circulatory instability with a pronounced fall in arterial blood pressure can be identified by Poincare plots of R-R intervals and spectral analysis of HRV. A low sympathetic peak or arrhythmia precluding spectral analysis of HRV is significantly related to operative circulatory instability.

Liver transplantation for unresectable hepatocellular carcinoma in normal livers

BACKGROUND & AIMS The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Mice with chimeric livers are an improved model for human lipoprotein metabolism.

Objective Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. Design FRG [ F ah(−/−) R ag2(−/−)Il2r g (−/−)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. Results Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. Conclusion Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

Renal function in renal or liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus

Abstract:  Two Six‐month pilot studies were conducted in renal (n=17) or liver (n=15) transplant recipients to evaluate renal function after conversion from calcineurin inhibitor (CI)‐ to sirolimus (SRL)‐based immunosuppression. After an SRL loading dose, doses were individualized to achieve whole blood trough levels of 10–22 ng/mL. Overall, serum creatinine did not change from baseline to six months post‐conversion but an improvement from 219.9 to 201.4 μmol/L at three months was noted in renal transplant recipients (p<0.05). Another finding was a numerical increase in the mean glomerular filtration rate (GFR) from 26.8 to 33.2 mL/min/1.73 m2 at six months among liver transplant recipients (NS). All patients survived and all grafts were functioning at the end of the study. In conclusion, renal function remained stable, with a tendency towards improvement, after abrupt conversion from CI‐ to SRL‐based therapy in renal or liver transplant recipients with moderate renal insufficiency.

Allele specific expression of the transthyretin gene in Swedish patients with hereditary transthyretin amyloidosis (ATTR V30M) is similar between the two alleles

Background Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3′ UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3′ UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR’s mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression. Methodology/Principal Findings Allele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3′ UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3′ UTR SNP regardless of added miRNA. Conclusions/Significance The SNP found in the 3′ UTR of the TTR gene has no effect on degrading the variant allele’s expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3′ UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.

Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results.

&NA; This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 “low risk” cases, and may serve as reference to assess outcome of single or any groups of patients. Objective: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. Background: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. Methods: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ⩽20 points, a balance of risk score ⩽9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI®). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. Results: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ⩽4 days for ICU stay, ⩽18 days for hospital stay, ⩽59% for patients with severe complications (≥ Grade III) and ⩽42.1 for 1-year CCI®. Comparisons with the next higher risk group (model for end stage liver disease 21–30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. Conclusions: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.