Teru Kumagi

Baseline Ductopenia and Treatment Response Predict Long-Term Histological Progression in Primary Biliary Cirrhosis

OBJECTIVES:Laboratory and pathological predictors of future histological progression in primary biliary cirrhosis (PBC) are needed for routine practice and clinical trials. We sought to develop clinically meaningful markers for those with predominantly early disease at risk of progressive liver damage.METHODS:Patients with PBC (n=69) with a follow-up liver biopsy performed approximately 10 years after initial histological diagnosis were identified and reviewed.RESULTS:Histological progression in the stage of fibrosis observed in paired liver biopsies from the same patient was associated with the absence of biochemical response to ursodeoxycholic acid (UDCA) at 2 years: alkaline phosphatase (ALP) >1.67 × ULN (upper limit of normal) (P=0.001, odds ratio (OR) 12.14, 95% confidence interval (CI) 2.69–54.74) when defined as an increase in one stage and ALP > 1.76 × ULN (P=0.03, OR 5.07, 95% CI 1.17–21.95) when defined as an increase in two stages. Ductopenia (>50% loss), as formally evaluated through blinded biopsy review of liver tissue obtained at initial diagnosis in a subset of 34 patients, predicted histological progression (P=0.012), along with biochemical response to UDCA (P=0.002). The presence of interface hepatitis in the same biopsies did not.CONCLUSIONS:Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogrens syndrome, scleroderma, Raynauds phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciation for novel treatment in PBC.

Percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinoma with artificially induced pleural effusion and ascites.

BackgroundUltrasound-guided procedures are sometimes of limited use because the tumor is located under the diaphragm or near the surface of the liver. We investigated the safety and efficacy of radiofrequency ablation (RFA) with artificial pleural effusion and/or artificial ascites.MethodsBetween January 2002 and May 2006, 43 lesions in 36 patients with hepatocellular carcinoma (HCC) were treated by RFA with artificial pleural effusion and/or artificial ascites.ResultsArtificial pleural effusion allowed visualization of the whole tumor for 36 (83.7%) of the 43 lesions that were otherwise not detectable or poorly visible. Artificial ascites was also helpful in visualizing whole tumors that could not be visualized with only artificial pleural effusion. In all lesions, artificial pleural effusion and/or artificial ascites were helpful in performing percutaneous RFA. Artificial ascites was useful for creating a space between the livers surface and the skin or diaphragm to avoid burns. Adverse effects after the induction of artificial pleural effusion included pneumonia in one patient and temporary atelectasis in another patient. Severe side effects were not observed. Complete necrosis after RFA was obtained in 43 (100%) of the 43 lesions. During a mean follow-up period of 31.8 ± 5.8 months, local recurrence at the ablation site was found in none of the 43 lesions.ConclusionsPercutaneous RFA with artificial pleural effusion and/or artificial ascites was a safe and useful treatment that resulted in good local control of HCC.

Virtual Sonographic Radiofrequency Ablation of Hepatocellular Carcinoma Visualized on CT but Not on Conventional Sonography

OBJECTIVE Some nodules cannot be visualized clearly on conventional sonography but can be visualized on CT. In the present study, we evaluated the usefulness of real-time percutaneous ablation therapy under virtual sonographic guidance for these nodules. SUBJECTS AND METHODS In vitro experiments were performed with gelatin gel to evaluate the accuracy of virtual sonography. We also studied 50 patients with 58 hepatocellular carcinoma nodules, of whom 18 patients (21 nodules) underwent radiofrequency ablation by virtual sonography. This was the initial treatment for seven of these patients and an additional treatment for 11 patients. Thirty-two patients (37 nodules) received radiofrequency ablation without virtual imaging. The patients receiving standard radiofrequency ablation were retrospectively selected as the historical control group under the same conditions as the study group. RESULTS The in vitro gelatin gel study revealed that all punctures had been performed accurately. In both the initial-treatment group and the additional-treatment group, the mean number of treatments with virtual sonography was significantly lower than that without virtual sonography (p = 0.003 for both groups). The rates of local recurrence and complications did not differ significantly between the two groups. CONCLUSION In the treatment of nodules not depicted on sonography, radiofrequency ablation assisted by virtual sonography is an efficacious alternative.

Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis

The number of patients with autoimmune hepatitis with histological features of acute hepatitis (AIH-AH) has been increasing recently. Here, the clinical features of patients with AIH-AH have been compared with those of patients with AIH with histological findings of chronic hepatitis (AIH-CH) and liver cirrhosis (AIH-LC). The levels of total serum bilirubin (P<0.05) and serum transaminases (P<0.05) were significantly higher in patients with AIH-AH than in patients with AIH-CH and AIH-LC. However, the serum levels of gamma-globulin (P<0.05) and immunoglobulin G (P<0.05) were significantly lower in AIH-AH than in patients with AIH-CH and AIH-LC. The aggregate score according to the criteria of the International Autoimmune Hepatitis Group in 1999 was also significantly lower in AIH-AH patients than in patients with AIH-CH and AIH-LC (P<0.05). Eleven patients with AIH-AH were treated with corticosteroids, however, the clinical response was insignificant in three patients. In summary, it is difficult to diagnose of patients with AIH-AH using the criteria of the International AIH scoring system. We wish that this scoring system would be modified in the near future.

Macrophage migration inhibitory factor in hepatocellular carcinoma and liver cirrhosis; relevance to pathogenesis ☆

The levels of macrophage migration inhibitory factor (MIF), a proinflammatory and carcinogenic cytokine, were significantly higher in the sera from patients with hepatocellular carcinoma (HCC; 25.6+/-15.3 ng/ml, n=55) and liver cirrhosis (LC; 18.9+/-10.7 ng/ml, n=26) compared with sera from patients with gastrointestinal cancer (6.8+/-7.5 ng/ml, n=29) and normal controls (5.6+/-1.2 ng/ml, n=45; P<0.01). Hepatocytes from patients with LC and HCC, but not from chronic hepatitis, expressed very high levels of MIF. A possible association between overexpression of MIF and hepatocarcinogenesis is suggested.

Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response

BACKGROUND & AIMS Outcomes in primary biliary cirrhosis (PBC) can be predicted by biochemical response to ursodeoxycholic acid (UDCA). Such stratification inadequately captures cirrhosis/portal hypertension, recognised factors associated with adverse events. METHODS We evaluated a cohort of PBC patients (n=386) attending the Liver Unit in Birmingham (derivation cohort), seeking to identify risk-variables associated with transplant-free survival independent of UDCA-response. A validation cohort was provided through well-characterised patients attending the Toronto Center for Liver Diseases (n=479) and Jena University Hospital (n=150). RESULTS On multivariate analysis, factors at diagnosis associated with liver transplant (LT)/death were patient age (HR:1.06; p<0.001), elevated bilirubin (HR:1.27; p<0.001), early-onset cirrhosis (HR:2.40; p<0.001) and baseline AST/platelet ratio index (APRI) (HR:1.95; p<0.001). At 1-year, UDCA biochemical non-response predicted poorer transplant-free survival, and additional factors (multivariate) associated with adverse outcome were age (HR:1.02; p<0.05) and 1-year APRI (HR:1.15; p<0.001). Obtaining a cut-point from our derivation cohort, APRI >0.54 at baseline was predictive of LT/death (adjusted HR: 2.40; p<0.001), and retained statistical significance when applied at 1-year (APRI-r1, adjusted HR:2.75; p<0.001) despite controlling for UDCA-response. Across both cohorts, transplant-free survival was poorer for biochemical-responders with an APRI-r1 >0.54 vs. biochemical-responders with a lower APRI-r1 (p<0.01 and p<0.001, respectively); non-responders with high APRI-r1 had the poorest outcomes (p<0.001 and p<0.001). CONCLUSION In PBC, elevated APRI is associated with future risk of adverse events, independently and additively of UDCA-response. This cross-centre, robustly validated observation will contribute to ongoing efforts to refine existing risk-stratification tools, as well as direct focus for new therapies in patients with PBC.

Recent clinical features of Wilson’s disease with hepatic presentation

BackgroundWe carried out this study to evaluate recent clinical features of Wilson’s disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC).MethodsSixteen patients with hepatic manifestations were diagnosed with WD in the period 1976–2003. We divided this period into two periods, “past” and “recent”. The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital.ResultsFour patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects.ConclusionsRecently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Usefulness of contrast‐enhanced ultrasonography with abdominal virtual ultrasonography in assessing therapeutic response in hepatocellular carcinoma treated with radiofrequency ablation

Abstract: Objective: Contrast‐enhanced computed tomography (CECT) is regarded as the gold standard for assessing the efficacy of radiofrequency ablation (RFA) against hepatocellular carcinoma (HCC). We evaluated the efficacy of virtual ultrasonography (VUS) with contrast‐enhanced ultrasonography (CEUS) vs. CECT for assessing the response to RFA.

The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice.

Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC‐40 multidomain disease‐specific quality of life responses and clinical findings. Three hundred twenty‐seven patients from a single clinic with PBC (94% female, 92% AMA‐positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC‐40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta‐blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. Conclusion: Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes. (HEPATOLOGY 2010)