The pharmacotherapy of cirrhosis: concerns and proposed investigations and solutions.

WHAT IS KNOWN AND OBJECTIVE: The presence of cirrhosis has a multifaceted impact on hepatic drug metabolism. An area of concern and uncertainty in the care of patients with cirrhosis is the safe use of both prescription and over-the-counter medications. COMMENT: Retrospective studies indicate a high incidence of adverse drug reactions (ADRs) among patients with cirrhosis related to use of certain medication classes including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory drugs. Conversely, use of appropriate medications, such as statins, may be decreased in this population due to fear of precipitating hepatotoxicity. WHAT IS NEW AND CONCLUSION: Pharmacotherapy in cirrhosis is an area of uncertainty and heterogeneity in clinical practice. Prescribing and dosing guidelines are needed to decrease the risk of serious ADRs in this high-risk patient population.

Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis.

Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8(+) T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.

An update on primary sclerosing cholangitis:from pathogenesis to treatment.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology despite advances in medical research that have focused on uncovering its pathogenesis. Recent developments in the diagnosis of PSC including technological advances in magnetic resonanace cholangiography and the recognition of distinct clinical subtypes have led to more frequent early detection and appropriate therapy when indicated. Continued work in the areas of identifying genetic predisposing factors and novel molecular therapeutic targets are expected to create new opportunities for treating patients suffering from this chronic illness. In this review we highlight recent advances in PSC pathogenesis, diagnosis and management.

Recurrent primary biliary cirrhosis after liver transplantation.

Recurrent primary biliary cirrhosis (PBC) is an important clinical outcome after liver transplantation (LT) in selected patients. Prevalence rates for recurrent PBC (rPBC) reported by individual LT programs range between 9% and 35%. The diagnostic hallmark of rPBC is histologic identification of granulomatous changes. Clinical and biochemical features are frequently absent with rPBC and cannot be used alone for diagnostic purposes. Some of the risk factors of rPBC may include recipient factors such as age, gender, HLA status and immunosuppression, as well as donor factors such as age, gender and ischemic time, although controversy exists. Most patients have early stage disease at the time of diagnosis, and there may be a role for therapy with ursodeoxycholic acid. While short- and medium-term outcomes remain favorable, especially if compared to patients transplanted for other indications, continued follow-up may identify reduced long-term graft and patient survival.

Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is a highly vascular tumour that expresses vascular endothelial growth factor (VEGF). Various studies have evaluated the prognostic value of VEGF levels in HCC. Its overall test performance remains unclear, however. The aim was to perform a systematic review and meta-analysis of prognostic cohort studies evaluating the use of VEGF as a predictor of survival in patients with treated HCC. Eligible studies were identified through multiple search strategies. Studies were assessed for quality using the Newcastle-Ottawa Tool. Data were collected comparing disease-free and overall survival in patients with high VEGF levels as compared to those with low levels. Studies were pooled and summary hazard ratios were calculated. A total of 16 studies were included for meta-analysis (8 for tissue and 8 for serum). Methodological analysis indicated a trend for higher study quality with serum studies as compared to tissue-based investigations. Four distinct groups were pooled for analysis: tissue overall survival (n=251), tissue disease-free survival (n=413), serum overall survival (n=579), and serum disease-free survival (n=439). High tissue VEGF levels predicted poor overall (HR=2.15, 95% CI: 1.26-3.68) and disease-free (HR=1.69, 95% CI: 1.23-2.33) survival. Similarly, high serum VEGF levels predicted poor overall (HR=2.35, 95% CI: 1.80-3.07) and disease-free (HR=2.36, 95% CI 1.76-3.16) survival. A high degree of inter-study consistency was present in three of four groups analysed. Tissue and serum VEGF levels appear to have significant predictive ability for estimating overall survival in HCC and may be useful for defining prognosis in HCC.

Improving long-term outcomes after liver transplantation in children.

The objective was to review the current state of knowledge and recommend future research directions related to long-term outcomes for pediatric liver transplant recipients. A 1-day Clinical Research Workshop on Improving Long-Term Outcomes for Pediatric Liver Transplant Recipients was held on February 12, 2007, in Washington, DC. The speaker topics were germane to research priorities delineated in the chapters on Pediatric Liver Diseases and on Liver Transplantation in the Trans-NIH Action Plan for Liver Disease Research. Issues that compromise long-term well-being and survival but are amenable to existing and new research efforts were presented and discussed. Areas of research that further enhanced the research priorities in the Action Plan for Liver Disease Research included collection of longitudinal data to define emerging trends of clinical challenges; identification of risk factors associated with long-term immunosuppression complications; development of tolerance-inducing regimens; definition of biomarkers that reflect the level of clinical immunosuppression; development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver transplantation and identification of barriers and facilitators that impact nonadherence and transition of care for adolescents.

Natural history and prognostic models in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. Despite the recognition of immunological and genetic alterations cited as factors in its pathogenesis, the exact cause for PSC remains unknown. Observational cohort studies, however, have demonstrated that PSC is a progressive disease culminating in liver failure or death. Natural history assessment in PSC, however, has been complicated by variable rates of disease progression and the impact of clinical symptoms upon initial presentation. The development of mathematical models by multivariable regression techniques (most notably Cox proportional hazards regression) has allowed for an improved description of overall survival on an individual basis among patients with PSC. Additionally, these models have also been employed for determining the optimal selection and timing for liver transplantation when advanced disease is imminent.

The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) are at an increased risk of colorectal neoplasia, but it is unknown if liver transplantation (LT) alters neoplasia progression. AIM: To examine the natural history of indefinite dysplasia (IND) and low-grade dysplasia (LGD) that develop in patients with PSC-UC with and without LT. METHODS: We performed a retrospective review of patients with PSC and UC evaluated at our institution between 1993 and 2011 who were diagnosed with IND or LGD before or after LT for PSC. The primary end point was neoplasia progression or persistent LGD. RESULTS: Ninety-six patients (non-LT n = 63, LT n = 33) were examined. For the IND group, multifocal lesions were significantly associated with time to neoplasia progression [hazard ratio (HR), 3.5; 95% confidence interval (CI), 1.3-9.7], while 5-aminosalicylate (5-ASA) use was protective (HR, 0.2; 95% CI, 0.1-0.6). For patients with LGD, multifocal lesions were significantly associated with the primary end point (HR, 7.1; 95% CI, 1.7-28.3), while LT was protective (HR, 0.3; 95% CI, 0.1-0.9). CONCLUSIONS: In PSC-UC patients with IND, 5-ASA use was associated with a decreased the risk of neoplasia progression, regardless of transplant status. In contrast, multifocal IND and LGD were associated with neoplasia progression or persistent LGD. Patients who developed LGD following LT for PSC were less likely to have progressive neoplasia or persistent LGD, compared with those who had not been transplanted.

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study.

BACKGROUND: Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited. AIMS: To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC. METHODS: Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis. RESULTS: The primary endpoint was reached in the low-dose (-43% change in ALK, P = 0.03) and high-dose (-40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (-20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (-33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (-0.55, P = 0.02) and low-dose metronidazole group (-0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (-3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole. CONCLUSIONS: Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).

Liver stiffness measurement by magnetic resonance elastography is not associated with developing hepatocellular carcinoma in subjects with compensated cirrhosis.

BACKGROUND: Liver stiffness assessed using transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated. AIM: To determine if liver stiffness of nonmalignant hepatic parenchyma using magnetic resonance elastography (MRE) is higher in patients with HCC compared with controls. METHODS: Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh score <7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched with cases by gender and disease aetiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases. RESULTS: Thirty patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64±10 years (range, 45-85) with 70% being men. Major disease aetiologies were chronic viral hepatitis (57%), non-alcoholic fatty liver disease (33%) and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2-14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions, when compared with controls without HCC (mean, 6.1±2.0 vs. 6.3±2.5 kPa, P=0.7). CONCLUSION: In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed using MRE and the presence of HCC in patients with compensated cirrhosis.

Predicting clinical and economic outcomes after liver transplantation using the Mayo primary sclerosing cholangitis model and Child-Pugh score. National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database Group.

Issues in the selection and timing of liver transplantation for primary sclerosing cholangitis (PSC) remain controversial. Although the Child-Pugh classification (CP) score and Mayo PSC model have similar abilities to estimate pretransplantation survival, a comparison of these 2 scores in predicting survival after liver transplantation has not been conducted. The aim of this study is to compare the Mayo PSC model and CP score in predicting patient survival and related economic outcomes after liver transplantation. Data from 128 patients with PSC, identified from the NIDDK database, were used to calculate patient-specific Mayo PSC and CP scores before transplantation. Levels reflecting a poor outcome were defined a priori. Receiver operating characteristic (ROC) curves and regression methods (Cox proportional hazards and linear regression models) were used to assess the relationship between these 2 scores and 5 post liver transplantation outcome measures. CP score was found to be a significantly (P <.05) better predictor of death 4 months or less after liver transplantation than: (a) length of hospital stay >21 days (or death before discharge) and (b) resource utilization >200,000 units (measured by area under the ROC curve). The Cox model identified statistically significant (P <.05) associations between CP score and each outcome after adjusting for the Mayo PSC risk score. Similar results were not observed for the Mayo PSC model when adjusted for CP score. Among patients with PSC undergoing liver transplantation, CP score was a better overall predictor of both survival and economic resource utilization compared with the Mayo PSC model.

Severe cholestasis related to intraconazole for the treatment of onychomycosis.

We describe a case of prolonged cholestasis temporally associated with the use of itraconazole for onychomycosis. Peak bilirubin level of 32.0 mg/dl was documented approximately 2 months after discontinuation of the patient's itraconazole therapy, with symptoms of cholestasis persisting more than 1 month after the peak in bilirubin. Physicians should be aware of the potential for severe cholestasis associated with itraconazole usage.