Fredrik Åberg

Risk of Malignant Neoplasms After Liver Transplantation: A Population-Based Study

Posttransplant malignancies have become a serious long‐term complication after liver transplantation. Our aim was to compare the incidence of posttransplant cancers with national cancer incidence rates. The study included all Finnish liver transplant patients transplanted at the Helsinki University Central Hospital between 1982 and 2005. The cohort was linked with the nationwide Finnish Cancer Registry. Observed numbers of cancers were compared to site‐specific expected numbers based on national cancer incidence rates stratified by age, sex, and calendar time. The standardized incidence ratios (SIRs) were calculated as observed‐to‐expected ratios. Thirty‐nine posttransplant de novo cancers and 11 basal cell carcinomas were found in the cohort of 540 patients during 3222 person years of follow‐up. The overall SIR was 2.59 (95% confidence interval 1.84‐3.53). SIR was higher for males (SIR 4.16) than for females (SIR 1.74), higher among children (SIR 18.1) than among adults (SIR 5.77 for ages of 17‐39 years and 2.27 for ages ≥ 40 years), and more elevated in the immediate posttransplant period (SIR 3.71 at < 2 years) compared to later periods (SIR 2.46 at 2‐10 years and 1.53 at >10 years). The most common cancer types were nonmelanoma skin cancer (SIR 38.5) and non‐Hodgkin lymphoma (SIR 13.9). Non‐Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy increased skin cancer risk. In conclusion, cancer incidence is increased among liver transplant patients compared to the general population. This study points out the importance of cancer surveillance after liver transplantation. Liver Transpl 14:1428–1436, 2008.

Health-Related Quality of Life and Employment Status of Liver Transplant Patients

Health‐related quality of life (HRQoL) is one preferable outcome measure of medical interventions such as liver transplantation (LT). The aim of this study was to compare HRQoL of LT patients with that of the general population and to assess the employment status of LT patients. HRQoL was measured with the 15D instrument, a validated, non–disease‐specific, 15‐dimensional, self‐administered HRQoL instrument. The questionnaire was sent to all adult LT patients in Finland (401 patients) alive in June 2007. The response rate was 89% (353 patients). The results were compared to those of 6050 age‐standardized and gender‐standardized controls from the general population. LT patients (mean age, 55 years; range, 20‐82) had slightly worse HRQoL scores than the general population (mean 15D score, 0.889 versus 0.907; P < 0.002). Survival time and retransplantation did not affect HRQoL significantly in age‐adjusted and gender‐adjusted analyses. HRQoL decreased with increasing age (P < 0.0001). Patients transplanted for acute liver failure (ALF) or chronic liver disease (CLD) had significantly worse HRQoL than the general population (P = 0.014 and P = 0.040). Forty‐four percent of working‐age patients were employed at the time of the study. Persons that were employed had significantly better HRQoL than those unemployed (15D scores, 0.934 versus 0.859; P < 0.0001). Eighty‐seven percent of patients experienced improved working capacity after LT. Early retirement was the most common cause of unemployment (56% of unemployed patients), and those patients presented with worse HRQoL than patients unemployed for other reasons. In conclusion, HRQoL of LT patients is very close to that of the general population. Older age, CLD, and ALF impair HRQoL. Employment is an indicator of HRQoL. Liver Transpl 15:64–72, 2009.

Cost of a quality-adjusted life year in liver transplantation: the influence of the indication and the model for end-stage liver disease score.

Cost issues in liver transplantation (LT) have received increasing attention, but the cost‐utility is rarely calculated. We compared costs per quality‐adjusted life year (QALY) from the time of placement on the LT waiting list to 1 year after transplantation for 252 LT patients and to 5 years after transplantation for 81 patients. We performed separate calculations for chronic liver disease (CLD), acute liver failure (ALF), and different Model for End‐Stage Liver Disease (MELD) scores. For the estimation of QALYs, the health‐related quality of life was measured with the 15D instrument. The median costs and QALYs after LT were €141,768 and 0.895 for 1 year and €177,618 and 3.960 for 5 years, respectively. The costs of the first year were 80% of the 5‐year costs. The main cost during years 2 to 5 was immunosuppression drugs (59% of the annual costs). The cost/QALY ratio improved from €158,400/QALY at 1 year to €44,854/QALY at 5 years, and the ratio was more beneficial for CLD patients (€42,500/QALY) versus ALF patients (€63,957/QALY) and for patients with low MELD scores versus patients with high MELD scores. Although patients with CLD and MELD scores > 25 demonstrated markedly higher 5‐year costs (€228,434) than patients with MELD scores < 15 (€169,541), the cost/QALY difference was less pronounced (€59,894/QALY and €41,769/QALY, respectively). The cost/QALY ratio for LT appears favorable, but it is dependent on the assessed time period and the severity of the liver disease. Liver Transpl 17:1333–1343, 2011.

Differences in long‐term survival among liver transplant recipients and the general population: A population‐based nordic study

Dramatic improvement in first‐year outcomes post‐liver transplantation (LT) has shifted attention to long‐term survival, where efforts are now needed to achieve improvement. Understanding the causes of premature death is a prerequisite for improving long‐term outcome. Overall and cause‐specific mortality of 3,299 Nordic LT patients (1985‐2009) having survived 1 year post‐LT were divided by expected rates in the general population, adjusted for age, sex, calendar date, and country to yield standardized mortality ratios (SMRs). Data came from the Nordic Liver‐Transplant Registry and WHO mortality‐indicator database. Stagnant patient survival rates >1 year post‐LT were 21% lower at 10 years than expected survival for the general population. Overall SMR for death before age 75 (premature mortality) was 5.8 (95% confidence interval [CI] 5.4‐6.3), with improvement from 1985‐1999 to 2000‐2010 in hepatitis C (HCV) (SMR change 23.1‐9.2), hepatocellular carcinoma (HCC) (SMR 38.4‐18.8), and primary sclerosing cholangitis (SMR 11.0‐4.2), and deterioration in alcoholic liver disease (8.3‐24.0) and acute liver failure (ALF) (5.9‐7.6). SMRs for cancer and liver disease (recurrent or transplant‐unrelated disease) were elevated in all indications except primary biliary cirrhosis (PBC). Absolute mortality rates underestimated the elevated premature mortality from infections (SMR 22‐693) and kidney disease (SMR 13‐45) across all indications, and from suicide in HCV and ALF. SMR for cardiovascular disease was significant only in PBC and alcoholic liver disease, owing to high mortality in the general population. Transplant‐specific events caused 16% of deaths. Conclusion: standardized premature mortality provided an improved picture of long‐term post‐LT outcome, showing improvement over time in some indications, not revealed by overall absolute mortality rates. Causes with high premature mortality (infections, cancer, kidney and liver disease, and suicide) merit increased attention in clinical patient follow‐up and future research. (Hepatology 2015;61:668‐677)

Infectious complications more than 1 year after liver transplantation: a 3-decade nationwide experience.

Because few reports have addressed infections late (≥1 year) after liver transplantation (LT), we evaluated the incidence, risk factors and pathogens involved. Infection data were from the Finnish LT registry, with starting date, type and relevant pathogens for 501 Finnish adult LT patients surviving ≥1 year post‐transplant. Follow‐up end points were end of study, death or retransplantation. Logistic regression to assess risk factors was adjusted for age, gender and follow‐up time. With 3923 person‐years of follow‐up, overall infection incidence was 66/1000 person‐years; 155 (31%) suffered 259 infections, and two‐thirds experienced only one infection. Cholangitis (20%), pneumonia (19%) and sepsis (14%) were most common. The most frequent bacteria were Enterococcus spp. and Escherichia coli, and the most frequent viruses cytomegalovirus and varicella zoster virus. Fungal infections were rare (n = 7). With 13 fatal infections, 17% of all late deaths involved infection. Primary sclerosing cholangitis (PSC) and Roux‐en‐Y‐type biliary anastomosis were associated with cholangitis; 18% of PSC patients suffered late cholangitis. Late acute rejection was associated with sepsis. Age, gender or cytomegalovirus did not significantly influence late infections. In conclusion, although infection risk under maintenance immunosuppression therapy is relatively low, particular vigilance regarding cholangitis, pneumonia and sepsis seems appropriate.

Influence of liver-disease etiology on long-term quality of life and employment after liver transplantation.

The etiology of liver disease would expectedly affect health‐related quality of life (HRQoL) and employment after liver transplantation (LT), but studies are scarce. We sent the 15D HRQoL instrument and an employment questionnaire to all 401 adult LT patients alive in Finland in 2007. The response rate was 89% (n = 353; mean of eight yr since LT). In age‐adjusted analysis, patients transplanted for primary sclerosing cholangitis (PSC; n = 56), primary biliary cirrhosis (PBC; n = 72), acute liver failure (ALF; n = 76), alcoholic cirrhosis (n = 38), or liver tumor (n = 22) exhibited comparable HRQoL, whereas the combined group of miscellaneous chronic liver diseases (n = 89) exhibited significantly higher HRQoL scores (p = 0.003). Among working‐aged patients (20–65 yr at LT), employment rates were highest in the PSC (56%) group and lowest in the ALF (39%) and PBC (29%) groups. In age‐adjusted logistic regression, patients with PSC or alcoholic cirrhotics were 2.4‐ and 2.5‐fold more likely to resume work after LT than patients with PBC. In conclusion, HRQoL scores late after LT were in general relatively high and comparable among disease groups. Patients with PSC or alcoholic cirrhosis were most likely to resume work after LT. The relatively low employment among patients with ALF may merit enhanced rehabilitation efforts.

Association between dental infections and the clinical course of chronic liver disease

Dental infections are implicated in several systemic diseases due to bacteremia and pro‐inflammatory effects, but their possible role in liver disease is unclear.

Renal dysfunction in liver transplant patients: comparing patients transplanted for liver tumor or acute or chronic disease

Liver transplant patients are susceptible to renal dysfunction through a number of mechanisms. Our aim was to investigate if renal function differs among transplant indication groups. Consecutive liver transplantations (396) were divided in three groups: 277 with chronic liver disease (CLD), 90 with acute liver failure (ALF), and 29 with liver tumor. Data were recorded before and after transplantation. The glomerular filtration rate (GFR) was based on Cockcroft–Gault formula and renal function staged using the National Kidney Foundation guidelines. On the transplantation day, 4%, 15%, and 0% of patients in the CLD, ALF, and tumor groups, respectively, showed severely decreased GFR (≤29 ml/min/1.73 m2). The percentage with moderately or severely decreased GFR (<60 ml/min/1.73 m2) increased steadily in the CLD group (46% at 5 years) but decreased in the ALF group from the transplantation day (26% at 5 years). Of patients with moderately or severely decreased GFR at listing, 73% of the CLD and 35% of ALF patients continued to exhibit it at 1 year. The cumulative incidence of chronic renal failure was 16% at 10 years. MELD scores did not show notable correlation with post‐transplant GFR. Renal dysfunction prior to transplantation often improved post‐transplant in ALF patients, but was often irreversible in CLD patients. In CLD and tumor patients, renal function steadily deteriorated post‐transplant.

Cardiovascular risk profile of patients with acute liver failure after liver transplantation when compared with the general population.

Background. As opposed to most solid-organ transplant recipients, patients with acute liver failure exhibit a pretransplant health status more comparable with the general population, and any posttransplant cardiovascular risk excess should thus be more attributable to transplantation-related factors alone. Methods. This study compared the cardiovascular risk of 77 consecutive patients with acute liver failure at 5 years after liver transplantation with that of the general population using age, sex, and residence area-standardized prevalence ratios (SPR). Results. At least one cardiovascular risk factor developed in 92% of patients. Treated hypertension, observed in 71% of patients at 5 years, was more common among patients than controls (SPR, 2.73; 95% confidence interval [CI], 2.06–3.55), whereas the 61% prevalence of dyslipidemia and 3% prevalence of impaired fasting glucose were significantly less frequent among patients (SPR, 0.69; 95% CI, 0.51–0.92 and SPR, 0.29; 95% CI, 0.04–1.00). The 5-year prevalence of diabetes (10%), overweight (32%), and obesity (13%) deviated nonsignificantly from controls (SPR 1.90, 0.85, and 0.58). Antibody therapy associated with a 1.49-fold increase in the risk of hypertension (95% CI, 1.15–1.94) and a 6.43-fold increase in the risk of diabetes (95% CI, 1.18–34.9). Immunosuppression-type, steroids, acute rejection, retransplantation, or graft steatosis revealed nonsignificant risk alterations. Conclusions. Liver transplantation and associated immunosuppression evidently cause hypertension, and possibly elicit diabetes in susceptible individuals. Conversely, the often reported transplantation-associated increased burden of overweight/obesity and dyslipidemia might relate mostly to other factors.

Transmission of LDLR Mutation From Donor Through Liver Transplantation Resulting in Hypercholesterolemia in the Recipient

Donor‐transmitted disease in organ transplantation is uncommon, but possible. The LDL receptor (LDLR), a key regulator of lipoprotein metabolism, is abundant in the liver. Mutations in the LDLR gene, leading to reduced LDLR activity, are the main cause for familial hypercholesterolemia (FH). The estimated prevalence of FH is 1/200–1/500 in the population indicating that there are 14–34 million individuals with FH worldwide. We describe a patient who developed severe hypercholesterolemia after liver transplantation (LT). The 42‐year‐old female, who was transplanted because of hepatic epithelioid hemangioendothelioma with normal liver function, exhibited an increase in plasma total cholesterol from 5.6 mmol/L (217 mg/dL) pretransplant to 11.7 mmol/L (452 mg/dL) at 6 months posttransplant. The respective increase in LDL cholesterol was from 3.30 (128 mg/dL) to 8.99 mmol/L (348 mg/dL). At 1 year, total and LDL cholesterol levels were 11.0 (425 mg/dL) and 7.81 (302 mg/dL), respectively. Sequencing of the coding region of LDLR from a liver graft biopsy revealed a splicing heterozygous mutation of LDLR, whereas no FH‐related mutation was found in DNA extracted from the patients blood white cells. This confirmed the first reported case of a patient receiving a mutation in LDLR through LT. The case shows that a donor‐transmitted disorder should not be overlooked as a possible cause for severe hypercholesterolemia.