Global liver disease burdens and research trends: Analysis from a Chinese perspective.

Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.

Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies.

The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, identifying public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the World Health Organization European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse, with variations in the exact composition of diseases and the trends in risk factors which drive them. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across most European countries. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity, and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease.

[Allocation problems in organ transplantation: practical medical experience]. / Allokationsprobleme in der Transplantationsmedizin--Arztliche Erfahrungen.

Solid organ transplantation is one the most successful medical innovations of the 20th century. Due to an increasing number of patients on the waiting lists for transplantation in the context of persisting organ shortage the aim of optimal allocation policy is the best possible balance between medical urgency and postoperative outcome. Because of scientific evolution and increasing waiting list mortality the allocation system for liver transplantation was altered in December 2006. As intended, the preferential treatment of sicker patients resulted in a reduced waiting list mortality. On the other hand, an unintentional decrease in postoperative survival was observed. This obvious imbalance between medical urgency and postoperative outcome has led to the current allocation problem. Several scientific approaches for optimising allocation policy will be presented and discussed in this paper. Finally, continuous review and adaptation will be a persisting challenge for people working in the field of solid organ transplantation.

RIFLE criteria and hepatic function in the assessment of acute renal failure in liver transplantation.

Renal dysfunction in cirrhotic patients is primary related to disturbances of circulatory function, triggered by portal hypertension with chronic intrarenal vasoconstriction and hypoperfusion. Pretransplant renal function is an important factor implicated in the development of acute renal failure (ARF) after liver transplantation (OLT), but other factors mostly related to liver function seem to influence the development of ARF. The Acute Dialysis Quality Initiative workgroup developed the RIFLE classification to define ARF. We sought to evaluate the incidence of ARF among patients undergoing OLT, to evaluate the association of ARF with pre-OLT renal and hepatic functions, and to evaluate the influence of ARF on chronic kidney disease (CKD) at 1 month post-OLT. Clinical, renal, hepatic function, and donor risk index data of 24 patients who underwent deceased donor OLT were collected before transplantation, in the perioperative period and in the first month post-OLT. ARF occurred in 37.5% of patients with 56% developing the R grade and 44% the I grade; no patient showed the F grade. An association was observed between ARF and a higher Model for End-Stage Liver Disease (MELD) score and between ARF and a reduced pre-OLT serum albumin. No association was noted between ARF and other pre-OLT parameters. In cirrhotic patients serum creatinine is a bias for renal function assessment and the Modification of Diet in Renal Disease formula overestimates GFR. Post-OLT CKD was present in 6.7% of patients without ARF and in 44.4% of patients with ARF. The R grade developed more frequently among patients with viral cirrhosis. The association of ARF with MELD and hypoalbuminemia may be the result of a close relationship between renal and hepatic functions among cirrhotic patients. Post-OLT CKD may be the result of unrecognized, preexisting CKD and/or the effects of not fully resolved acute damage to an injured kidney.

[Preoperative management of patients with liver disease]. / Lebereingriffe--präoperatives Management.

Patients undergoing liver surgery due to benign or malignant liver tumors are evaluated in a multidisciplinary way: surgeons, gastroenterologists, anesthesiologists, intensive care physicians, radiologists, oncologists and pathologists are involved in the perioperative evaluation. Surgical know-how, combined with a broad spectrum of diagnostic and therapeutic options stand for a high degree of safety and effectiveness of perioperative treatment. The general physical status of the patient, the type and extend of liver disease, as well as the complexity of liver resection have significant impact on perioperative morbidity and mortality. Appropriate preoperative evaluation and preparation of the patient is therefore of utmost importance. This allows for adequate risk assessment and further helps to define risk management strategies.

Survival benefit-based deceased-donor liver allocation.

Currently, patients awaiting deceased-donor liver transplantation are prioritized by medical urgency. Specifically, wait-listed chronic liver failure patients are sequenced in decreasing order of Model for End-stage Liver Disease (MELD) score. To maximize lifetime gained through liver transplantation, posttransplant survival should be considered in prioritizing liver waiting list candidates. We evaluate a survival benefit based system for allocating deceased-donor livers to chronic liver failure patients. Under the proposed system, at the time of offer, the transplant survival benefit score would be computed for each patient active on the waiting list. The proposed score is based on the difference in 5-year mean lifetime (with vs. without a liver transplant) and accounts for patient and donor characteristics. The rank correlation between benefit score and MELD score is 0.67. There is great overlap in the distribution of benefit scores across MELD categories, since waiting list mortality is significantly affected by several factors. Simulation results indicate that over 2000 life-years would be saved per year if benefit-based allocation was implemented. The shortage of donor livers increases the need to maximize the life-saving capacity of procured livers. Allocation of deceased-donor livers to chronic liver failure patients would be improved by prioritizing patients by transplant survival benefit.

Access to liver transplantation in the MELD era: role of ethnicity and insurance.

Factors contributing to inequitable access to liver transplantation include socioeconomic status, geographic location, and delayed referral. The aim of this study is to identify the factors associated with a high MELD at the time of listing. Using the UNOS database, we identified all adults listed from 2002 to 2006. Data collected included demographics, insurance payor (private and government, i.e., Medicaid and non-Medicaid), diagnosis, and MELD score categorized as low (<20) and high (>or=20). The results obtained show that a high MELD was associated with age, ethnicity, and insurance (P < 0.001). By multivariate analysis, insurance (OR = 1.21, 95% CI = 1.13-1.30, P < 0.001) and ethnicity (OR = 1.55, 95% CI = 1.28-1.88, P < 0.001) were independently associated with high MELD. In conclusion, ethnic minorities and liver transplant candidates with Medicaid are more likely to have a high MELD score at initial listing. The above results suggest that the type of insurance and ethnicity are independently associated with a high MELD (i.e., sicker patients).

[Liver transplantation: new organ allocation system in Switzerland]. / Transplantation hépatique: introduction en Suisse d'un nouveau système d'allocation des organes.

This article describes the new organ allocation system for liver transplantation introduced in Switzerland on July 1, 2007. In its newly adopted transplantation law, Switzerland chose the MELD score (Model for end-stage liver disease), based on three laboratory values: total bilirubin, serum creatinine and INR. Advantages and limitations of the MELD score are discussed. Finally the West Switzerland joint liver transplantation program is briefly introduced.

Hepatic dysfunction in sickle cell disease: a new system of classification based on global assessment.

BACKGROUND & AIMS: Hepatic dysfunction in adults with sickle cell disease varies in character and severity from self-limited cholestasis to life-threatening acute liver failure and cirrhosis. Because previous attempts to describe patterns of liver disease have not reflected clinical experience, we aimed to characterize the presentation, clinicopathologic findings, and natural history of such patients. METHODS: We reviewed the clinical, laboratory, radiographic, and histologic features with the natural history of 38 patients (mean age, 33 years) with Hb SS, SC, or S-beta thalassemia referred to a tertiary liver center for assessment. RESULTS: Distinct disease patterns were identified that comprised massive hepatocellular necrosis (5%), acute severe sequestration and cholestasis in the context of sepsis (18%), cirrhosis (18%), chronic, fluctuating sequestration without cholestasis (21%), mechanical biliary obstruction (8%), siderosis without cirrhosis (8%), generalized cholangiopathy (8%), venous outflow obstruction (3%), and miscellaneous (11%). Of the 20 who required emergency admission, 8 did not survive their index admission, and 3 patients died during follow-up admissions (4 months-4 years later). There were 3 instances of hemorrhage related to liver biopsy. One patient underwent transplantation but died. Hematologic and biochemical markers did not discriminate well between survivors and nonsurvivors. The incidence of a second hepatic pathology (ie, viral hepatitis, autoimmune disease, transfusional siderosis) was 37% and was associated with the finding of more advanced histologic fibrosis. CONCLUSIONS: Patterns of hepatic dysfunction in sickle cell disease are diverse and demand clear characterization for each individual; however, groups with a poor prognosis can be identified after collation of clinical, laboratory, and radiologic data. Findings at biopsy (which is associated with higher risk of bleeding in this group) might be anticipated by noninvasive test results.

Laboratory test variability and model for end-stage liver disease score calculation: effect on liver allocation and proposal for adjustment.

BACKGROUND: The use of the Model for End-Stage Liver Disease (MELD) score to prioritize patients on liver waiting lists must take the bias of different laboratories into account. METHODS: We evaluated the outcome of 418 patients listed during 1 year whose MELD score was computed by two laboratories (lab 1 and lab 2). The two labs had different normality ranges for bilirubin (maximal normal value [Vmax]: 1.1 for lab 1 and 1.2 for lab 2) and creatinine (Vmax: 1.2 for lab 1 and 1.4 for lab 2). The outcome during the waiting time was evaluated by considering the liver transplantations and the dropouts, which included deaths on the list, tumor progression, and patients who were too sick. RESULTS: Although the clinical features of patients were similar between the two laboratories, 36 (13.1%) out of 275 were dropped from the list in lab 1, compared to 5 (3.5%) out of 143 in lab 2 (P<0.01). The differences were mainly due to the deaths on the list (8% lab 1 vs. 2.1% lab 2, P<0.05). The competing risk analysis confirmed the different risk of dropout between the two labs independently of the MELD score, blood group, and preoperative diagnosis. The bias on MELD calculation was considered and bilirubin and creatinine values were "normalized" to Vmax of lab 1 (corrected value=measured value x Vmax lab 1/Vmax lab 2). By comparing receiver operating characteristic curves, the ability of MELD to predict the 6-month dropouts significantly increased from an area under the curve of 0.703 to 0.716 after "normalization" (P<0.05). CONCLUSIONS: Normalization of MELD is a correct and good compromise to avoid systematic bias due to different laboratory methods.

[Risk factors for orthotopic liver transplantation failure in Rio Grande do Sul, Brazil]. / Fatores de risco para a falência do transplante ortotópico de fígado no Rio Grande do Sul, Brasil.

Risk factors for failure of liver transplantation from cadaveric donors were investigated in this retrospective study using data from medical records of patients in Rio Grande do Sul, Brazil, who were submitted to liver transplantation for the first time from January 1999 to July 2003 and were over 15 years of age at the time of surgery. Some 13% of failures occurred in the first month, 11% from 2 to 12 months, and 5% after 12 months; 88% of failures resulted in death and 12% in retransplantation. In the multivariate models, rate ratios for failure were higher for total family income less than 10 times the minimum wage, recipient's age > 45 years, non-whites, high clinical risk, and donor's age > or = 56 years. Female gender showed an effect in the unadjusted model only. Special attention to patients at increased risk, with income support for those with low family income, and early diagnosis of the need for transplantation may improve the success of liver transplantation.

Liver transplantation in the MELD era: a single-center experience.

Model for Endstage Liver Disease (MELD) score has been used to allocate organs since February 2002. This policy allocates organs to candidates with regard to severity of their underlying liver disease except in the case of hepatocellular carcinoma (HCC) patients. The purpose of this study was to determine the impact of MELD on waiting times, dropout rates, and transplantation rates in all patients awaiting liver transplantation at our center. The records of all patients listed for liver transplantation between May 28, 1999, and February 27, 2004, at the Mayo Clinic, Scottsdale, Arizona, were reviewed. Candidates were grouped by two time periods as pre-MELD or post-MELD based on date of MELD implementation (February 27, 2002). The incidence of deceased donor liver transplantation (DDLT), waiting time to DDLT, dropout rate from the waiting list because of clinical deterioration or death, and survival while waiting for or after DDLT were determined for each group. Three hundred fifty-one patients were listed for liver transplantation (195 pre-MELD, 156 post-MELD) during the study period. HCC patients had an improved rate of transplantation after MELD (pre-MELD, 1.39 persons per year; post-MELD, 3.48 persons per year). In all groups, with the exception of hepatitis C virus, the transplantation rates were the same for both categories. The hepatitis C virus group also had improved transplantation rates in the post-MELD period. HCC candidates under the new allocation policy have an increased incidence of DDLT in our institution. However, this has not disadvantaged patients with non-HCC diagnoses. Thus, the new MELD-based allocation policy has benefited all candidates by allowing more timely transplants.

The incidence and management of acute and chronic rejection after living donor liver transplantation.

Living donor liver transplantation (LDLT) is a good alternative to cadaveric liver transplantation for end-stage liver disease. Herein we report the outcome of 132 LDLTs performed between 1999 and 2005, with special emphasis on the incidence and management of acute and chronic rejection. Among the LDLT population a first acute rejection episode (ARE) was clinically suspected in 24% and proven by liver biopsy in 11%. According to the Banff classification, 50% of AREs were grade 1, and 50%, grade 2. There was no grade 3 AREs. The first ARE occurred between 7 days and 23 months posttransplantation (mean 97 days, median 70 days). Ninety-seven percent (31/32) of the AREs occurred within the first year after transplantation and 3% (1/32) in the second year. Among the patients with ARE, 23% developed a second ARE between 4 and 11 months. A third ARE was detected in 8% of patients after month 18. All AREs responded to adjustment of immunosuppressive doses or steroid boluses. Chronic rejection (CR) was detected in 2%. In conclusion, the incidences of ARE and CR are consistent with the previously reported data. Acute and chronic rejections seem to be mild and easily manageable clinical conditions. Our results also showed a significant difference between clinically suspected and biopsy-proven ARE emphasizing the importance of indicated liver biopsies in the management of the LDLT population.

Cost/efficacy clinical trial about the use of T-tube in cadaveric donor liver transplant: preliminary results.

UNLABELLED: Biliary reconstruction is the most common cause of morbidity associated with orthotopic liver transplantation. Our objective was to assess the complications and hospital resources related to the use of a T-tube. MATERIAL AND METHODS: Among 95 liver transplants performed from October 2002 to November 2003, 84 patients were randomized to receive a T-tube or no T-tube. We analyzed all patients with a follow-up of at least of 3 months. RESULTS: Fifty-five transplants were analyzed with 8 months mean follow-up, including twenty eight with T-tube and twenty seven without a T-tube. No patient died during the follow-up. The overall rate of biliary complications was 45.4% (25/55) including 21/28 (75%) in the T-tube group and 4/27(14.8%) in the non-T-tube group (P < .0001). Complications related to T-tube extraction occurred in 48.2% (13/27), including 3 cholangitis and 10 leaks. The costs of hospital resources due to radiological studies were 5329 capital JE, Ukrainian for the T-tube group vs 5785 capital JE, Ukrainian for the non-T-tube group. The costs of hospital resources due to treatment were 28,280 capital JE, Ukrainian for the T-tube group vs 10,088 capital JE, Ukrainian for the non-T-tube group. CONCLUSIONS: Use of a T-tube during orthotopic liver transplantation does not seem justified. Biliary anastomosis stenting is followed by an increased incidence of complications, most of which are related to its use. Hospital stay, radiological studies, and cost of hospital resources are higher among the T-tube patients. Therefore its systematic use is not advisable.

Use of extended right grafts from in situ split livers in adult liver transplantation: a comparison with whole-liver transplants.

INTRODUCTION: We report our experience of in situ split-liver transplantation (SLT) for adult patients and compare the results with those achieved with whole-liver transplantation (WLT). METHOD: From November 1997 to December 2003, 109 liver transplantation were performed in 104 adult patients including 90 WLT (83%) and 19 SLT (17%) grafts. Fifteen extended right grafts (ERG, segments I + IV to VIII) were obtained with in situ split-liver procedures, generating also left lateral segment grafts, which were transplanted at our institution or elsewhere. Four left lobe (LL, segments I to IV) and right lobe (segments V to VIII) grafts were obtained by a modified in situ procedure for adult recipients. UNOS status, percentage of primary or secondary transplantation, and underlying liver disease were similar among patients receiving whole versus split grafts. Donors were older in whole than ERG cohorts (53 vs 26 years, P < .001). Procurement parameters and intraoperative profiles of transplant procedure were comparable among the groups. RESULTS: Median follow-up was 18 months (range: 1 to 73). Four patients with whole (4%) and no patient with ERG underwent retransplantation (P = NS). One- and 3-year patient survivals were 86% and 79% with WLT versus 93% and 93% with ERG (P = NS). One- and 3-year graft survivals were 84% and 75% with WLT versus 93%, and 93% with ERG (P = NS). Incidence of vascular complications was 8% with WLT, 13% with ERG (P = NS). The incidence of biliary complications was 13% in WLT, 27% in ERG (P = NS). CONCLUSIONS: The use of ERG from in situ split livers for adult transplantation allowed us to obtain results comparable or even better than those obtained with WLT. Split-liver transplantation is an effective, safe mechanism to expand the cadaveric donor pool.

Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver.

AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver. METHODS: Two hundred and twelve hepatocellular nodules (106 HCC; 74 MRN; 32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA). RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale". Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss, capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool classified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepancies were present for DN and MRN between the routine histological assignment and the classification tool. Of 25 HCC assigned by routine assessment in the validation set, 8 were assigned to the DN category by the classification tool. CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.

Predicting survival among patients listed for liver transplantation: an assessment of serial MELD measurements.

We examined whether consideration of repeated model for end-stage liver disease (MELD) measurements for patients listed for liver transplantation improves predictive value beyond current MELD alone. Clinical data were extracted for all adult primary liver transplantation candidates from our institution who were listed with the United Network for Organ Sharing (UNOS) between 1990 and 1999. Serum creatinine, bilirubin, and international normalized ratio (INR) were obtained from an institutional laboratory database. Cox models were constructed using current MELD, change in MELD (Delta), and number of MELD scores to predict survival on the waiting list. Eight hundred and sixty-one patients met inclusion criteria, 639 underwent transplantation, and 80 died while waiting. A one-unit increment in current MELD imparted significant hazard ratios ranging from 1.12 to 1.19 in all models. Delta MELD was predictive of mortality univariately, but less predictive when current MELD was included, and not predictive when considered with both current and number of MELD scores. Overall, current MELD is the single most important determinant of mortality risk on the waiting list. Delta MELD is predictive of death only within 4 d of the event; however, part of this correlates with the dying process itself, thus limiting Delta MELD's utility in survival prediction models.