Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis B in the UK: systematic review and economic evaluation.

We compared the cost-effectiveness of various noninvasive tests (NITs) in patients with chronic hepatitis B and elevated transaminases and/or viral load who would normally undergo liver biopsy to inform treatment decisions. We searched various databases until April 2012. We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes quality-adjusted-life-years (QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four decision-making strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none (watchful waiting) and treat all irrespective of fibrosis. Treating all patients without prior fibrosis assessment had an incremental cost-effectiveness ratio (ICER) of £28,137 per additional QALY gained for HBeAg-negative patients. For HBeAg-positive patients, using Fibroscan was the most cost-effective option with an ICER of £23,345. The base case results remained robust in the majority of sensitivity analyses, but were sensitive to changes in the ≥ F2 prevalence and the benefit of treatment in patients with F0-F1. For HBeAg-negative patients, strategies excluding NITs were the most cost-effective: treating all patients regardless of fibrosis level if the high cost-effectiveness threshold of £30,000 is accepted; watchful waiting if not. For HBeAg-positive patients, using Fibroscan to identify and treat those with ≥F2 was the most cost-effective option.

Systematic review and meta-analysis of intraoperative versus preoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones.

BACKGROUND: Most patients with gallbladder and common bile duct stones are treated by preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy. Recently, intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment. METHODS: Data from randomized clinical trials related to safety and effectiveness of IOES versus POES were extracted by two independent reviewers. Risk ratios (RRs) or mean differences were calculated with 95 per cent confidence intervals based on intention-to-treat analysis whenever possible. RESULTS: Four trials with 532 patients comparing IOES with POES were included. There were no deaths. There was no significant difference in rates of ampullary cannulation (RR 1·01, 0·97 to 1·04; P = 0·70) or stone clearance by ES (RR 0·99, 0·96 to 1·02; P = 0·58) between the groups. The proportion of patients with at least one post-ES complication, including pancreatitis, bleeding, perforation, cholangitis, cholecystitis or gastric ulcer, was significantly lower in the IOES group (RR 0·37, 0·18 to 0·78; P = 0·009). There was no significant difference in morbidity after laparoscopic cholecystectomy or requirement for open operation between the groups. Mean hospital stay was 3 days shorter in the IOES group: mean difference - 2·83 (-3·66 to - 2·00) days (P < 0·001). CONCLUSION: In patients with gallbladder and common bile duct stones, IOES is as effective and safe as POES and results in a significantly shorter hospital stay.

Prospective comparison of Fibroscan, King's score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection.

Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King's score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty-seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono-infection (HCV RNA-positive by RT-PCR), attending King's College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3-F6, and cirrhosis defined as Ishak fibrosis F5-F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43-54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3-F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (>or=F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut-off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3-F6.

Selection of patients for liver transplantation and allocation of donated livers in the UK.

BACKGROUND: The increasing shortfall between the number of patients who would benefit from liver transplantation and the availability of donor livers means that rationing has to occur. The processes of selection of patients for transplantation and for allocation of donor livers should be done according to ethical and, where possible, evidence-based criteria so that there is clarity and that the competing requirements of equity, justice, utility and benefit can be balanced. METHODS: To achieve these goals for patients in the United Kingdom in need of transplantation, we have developed guidelines for the selection of patients to the national waiting list based on the risk of death without a transplant and the ability of the procedure to improve the recipient's quality of life. Guidelines have been developed for both those with acute liver failure and chronic liver disease. Allocation will depend on matching of the donor liver to the recipient. RESULTS: The proposed system, to be introduced into the UK compares with some other systems, where different models for selection and allocation have been introduced.

Review article: renal function assessment in cirrhosis - difficulties and alternative measurements.

BACKGROUND: Renal function in patients with cirrhosis is important prognostically, both before and following liver transplantation. Its prognostic impact is reflected by the inclusion of serum creatinine in the model for end-stage liver disease score, which is now used for recipient prioritization on liver transplantation waiting lists in the USA. AIM: To review the accuracy of the surrogate markers for the assessment of renal function, i.e. glomerular filtration rate, particularly in patients with cirrhosis. METHOD: We reviewed the available literature in PubMed regarding the markers for GFR evaluation and the factors which affect their accuracy in cirrhosis. RESULTS: Although creatinine is widely available, it is an unreliable marker of glomerular filtration rate, particularly in patients with cirrhosis. Clearance of exogenous markers is considered the 'gold standard', but this methodology has many drawbacks, particularly poor applicability. Several mathematical formulae for estimated glomerular filtration rate are used to overcome some of these limitations: Cockcroft-Gault and Modification of Diet in Renal Disease formulae are the most frequently applied, but they are based on serum creatinine. CONCLUSIONS: Due to the inaccuracy of serum creatinine and its derived formulae in estimating glomerular filtration rate, alternative serum markers, such as cystatin C, and new formulae are desirable. These need formal evaluation in patients with cirrhosis so as to have a reliable surrogate of glomerular filtration rate, and to obviate many problems that are associated with using creatinine and estimated glomerular filtration rate.

Risk factors, sequential organ failure assessment and model for end-stage liver disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit.

BACKGROUND: Prognostic scores in an intensive care unit (ICU) evaluate outcomes, but derive from cohorts containing few cirrhotic patients. AIMS: To evaluate 6-week mortality in cirrhotic patients admitted to an ICU, and to compare general and liver-specific prognostic scores. METHODS: A total of 312 consecutive cirrhotic patients (65% alcoholic; mean age 49.6 years). Multivariable logistic regression to evaluate admission factors associated with survival. Child-Pugh, Model for End-stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were compared by receiver operating characteristic curves. RESULTS: Major indication for admission was respiratory failure (35.6%). Median (range) Child-Pugh, APACHE II, MELD and SOFA scores were 11 (5-15), 18 (0-44), 24 (6-40) and 11 (0-21), respectively; 65% (n = 203) died. Survival improved over time (P = 0.005). Multivariate model factors: more organs failing (FOS) (<3 = 49.5%, > or =3 = 90%), higher FiO(2), lactate, urea and bilirubin; resulting in good discrimination [area under receiver operating characteristic curve (AUC) = 0.83], similar to SOFA and MELD (AUC = 0.83 and 0.81, respectively) and superior to APACHE II and Child-Pugh (AUC = 0.78 and 0.72, respectively). CONCLUSIONS: Cirrhotics admitted to ICU with > or =3 failing organ systems have 90% mortality. The Royal Free model discriminated well and contained key variables of organ function. SOFA and MELD were better predictors than APACHE II or Child-Pugh scores.

Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients.

BACKGROUND: Measuring wedged hepatic venous pressure and hepatic venous pressure gradient as indices of portal pressure is being increasingly used in assessing the prognosis and response to pharmacological treatment for portal hypertension in cirrhotic patients. AIM: To re-evaluate the agreement and correlation between wedged hepatic pressures and directly measured portal pressures. METHODS: Medline search for studies comparing direct portal with wedged hepatic pressure measurement and assessment of correlation and agreement of the pooled data. RESULTS: Eleven suitable studies included 320 patients. Coefficient of determination (r2) was 0.87 in all patients, 0.87 in 102 patients with alcoholic liver disease, 0.83 in 88 patients with non-alcoholic liver disease and 0.75 in 53 patients with hepatitis C-related liver disease. Coefficient of determination was 0.85 in the 194 patients in whom a wedge catheter and 0.90 in the 113 patients in whom a balloon catheter was used. Agreement according to the method of Bland and Altman was also found to be good, with only 4-8% of the measurements outside 2 standard deviations. CONCLUSIONS: Wedged hepatic pressure measurement correlates well with direct portal pressure measurement and the agreement is sufficiently good to use this as a surrogate measurement.

Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point?

Chronic hepatitis C is a major healthcare problem. The response to antiviral therapy for patients with chronic hepatitis C has previously been defined biochemically and by PCR. However, changes in the hepatic venous pressure gradient (HVPG) may be considered as an adjunctive end point for the therapeutic evaluation of antiviral therapy in chronic hepatitis C. It is a validated technique which is safe, well tolerated, well established, and reproducible. Serial HVPG measurements may be the best way to evaluate response to therapy in chronic hepatitis C.

A simulation modelling approach to evaluating alternative policies for the management of the waiting list for liver transplantation.

A shortage of donor liver grafts unfortunately results in approximately 10% of patients dying whilst listed for a liver transplant in Europe and the United States. Thus it is imperative that all available organs are used as efficiently as possible. This paper reports upon the application of a simulation modelling approach to assess the impact of several alternative allocation policies upon the cost effectiveness of this technology at one liver transplant centre in the UK. The impact of changes in allocation criteria on the estimated net life expectancy, average net costs and overall cost effectiveness of the transplantation programme were evaluated. The incremental cost effectiveness ratio (ICER) for the base case allocation policy, based upon the time spent on the waiting list (i.e., longest wait first) was 11,557 pounds sterling at 1999 prices. The ICERs associated with an allocation policy based upon age (lowest age first), and an allocation policy based upon the severity of the pre-transplant condition of the patient (with most severely ill patients given a lower priority) were lower than the base case at 10,424 pounds sterling and 9,077 pounds sterling, respectively. The results of this modelling study suggest that the overall cost effectiveness of the liver transplantation programme could be improved if the current allocation policy were modified to give more weight to the age of the patient and the reduced chances of success of the most severely ill patients.

Psychiatric and social outcome following liver transplantation for alcoholic liver disease: a controlled study.

Psychiatric outcome, quality of life, and alcohol consumption were compared between patients transplanted for alcoholic liver disease and those transplanted for other chronic liver diseases. Instruments used included the Clinical Interview Schedule, the 28-item General Health Questionnaire, the Hospital Anxiety and Depression Scale, and the Nottingham Health Profile. There was no difference between the two groups with regard to median scores or "caseness" on these instruments, except for physical mobility on the Nottingham Health Profile, where the alcoholic group was more likely to experience difficulties (p = 0.03). The majority of those transplanted for alcoholic liver disease remained abstinent, although 7 of the 31 in the alcoholic group (23%) were drinking above recommended safe limits. Psychosocial outcome is similar for individuals transplanted for alcoholic liver disease and those transplanted for other chronic liver diseases. Patients should not be excluded from transplantation on grounds of their drinking history.

Ultrasound screening for hepatocellular carcinoma (HCC) in cirrhosis: the evidence for an established clinical practice.

Improvement in our current knowledge of epidemiology, natural history and treatment modalities form the background to generalize the use of ultrasound screening in cirrhosis. The cumulative probability of developing cancer is extremely high in cirrhotics and allows to focus screening programs on a well defined risk group thus maximizing cost-effectiveness. This review article highlights scientific evidences in favour of a generalized practice of US screening.

Vasoconstrictors in the management of bleeding from oesophageal varices. A clinico-economic appraisal in the UK.

BACKGROUND: Bleeding from oesophageal varices is an uncommon but potentially fatal condition that often leads to expensive hospitalizations in intensive care or high-dependency units. METHODS: To assess the clinical and economic impact of this condition, we have devised a management plan illustrating current clinical practice in the UK. RESULTS: Approximately 6.1 million pounds of NHS resources are devoted to the treatment of 3000 acute hospital admissions for variceal bleeding every year. Vasoconstrictors like vasopressin may save approximately 36 lives per annum for an additional 145 thousand pounds. However, current clinical practice requires vasopressin to be concurrently administered with intravenous glyceryl trinitrate, increasing overall costs by 582 thousand pounds to a total of 6.7 million pounds. The additional cost for each extra life saved is estimated at 16,180 pounds. CONCLUSION: The efficacy of current vasoconstrictors requires further confirmation. In particular, new agents like octreotide (Sandostatin) should be carefully assessed to determine their potential clinical and economic benefits.

Incidence, risk factors, management, and outcome of portal vein abnormalities at orthotopic liver transplantation.

Portal vein thrombosis is often considered a contraindication to orthotopic liver transplantation. We have analyzed the incidence, risk factors, management and outcome of patients with portal vein thrombosis undergoing orthotopic liver transplantation. During the period from October 1988 to October 1992 140 grafts were performed on 132 patients. Fourteen had portal vein thrombosis with either partial (n = 7) or complete (n = 7) occlusion of the portal vein at surgery. Portal vein thrombosis was more common in patients with autoimmune chronic active hepatitis (3/5 vs. 11/127, chi 2 = 13.3, P < 0.001), cryptogenic cirrhosis (4/12 vs. 10/120, chi 2 = 7.2, P < 0.01), or those with tumors (6/22 vs. 10/110, chi 2 = 5.7, P < 0.05). In 13 of the 14 portal inflow was reestablished by flushing, balloon thrombectomy, or passage of a graduated dilator. In one patient complete fibrous obliteration necessitated a portal vein to right gastroepiploic vein anastomosis. On follow-up there have been 6 deaths in this group (6/14 = 43%) from recurrent cancer (n = 1), sepsis (n = 4), and cardiac and renal failure (n = 1). Four of these 6 patients had confirmation of PV patency on imaging. The remaining 8 patients are alive and well (median follow-up 37 months, range 6-53 months). Post-transplant portal vein thrombosis occurred in 3 of the 14 patients (21%) with a portal vein abnormality at surgery and in two of the 118 patients with a normal portal vein (3/14 vs. 2/118, chi 2 = 8.5, P < 0.01). Four of the 5 cases were successfully treated by surgical thrombectomy.

Nature and standards of gastrointestinal and liver services in the United Kingdom.

1. Purpose of the working party: 1.1 To describe the scope of major digestive and liver disorders and identify changes in patterns of disease. 1.2 To identify diagnostic and therapeutic services required to manage these disorders in the United Kingdom. 1.3 To describe the facilities and staffing required to provide these services. 1.4 To examine the training requirements for medical, nursing, and other support staff. 1.5 To define the part that audit and research should play in the provision and maintenance of high quality gastrointestinal and liver services.

Qualitative assessment of von Willebrand factor (vWF) in cirrhotics following repeated doses of desmopressin acetate.

Qualitative abnormalities in von Willebrand Factor (vWF) in patients with cirrhosis have been little studied with contrasting results. We used crossed immunoelectrophoresis (2-DIE) and multimeric analysis of vWF in eight patients with stable hepatic cirrhosis to evaluate abnormalities in vWF before and 1 h following intravenous administration of three doses of desmopressin acetate (0.3 micrograms/kg) given at baseline, 4 and 24 h. We thought that qualitative abnormalities might be more easily detected following desmopressin as this is known to release vWF from storage sites. There was an increased electrophoretic mobility on 2-DIE in all patients with no change following desmopressin. The multimeric analysis did not show an increase in lower molecular weight multimers, but showed a statistically significant increase in higher molecular weight multimers following desmopressin (P less than 0.02). These results suggest that the vWF of cirrhotics has an abnormal charge (not altered by release following desmopressin) which would explain the increased electrophoretic mobility on 2-DIE with a normal pattern of lower molecular weight multimers using multimeric analysis.