Giuseppe Malizia

Growth factor and procollagen type I gene expression in human liver disease

BACKGROUND/AIMS Growth factors have been implicated in the pathogenesis of liver fibrosis, a major determinant of the clinical course of chronic liver disease. The aim of this study was to study the relationship of growth factor expression to inflammation and fibrosis in a variety of human liver diseases. METHODS We studied by in situ hybridization the expression of transforming growth factor (TGF) beta 1, platelet-derived growth factor (PDGF) A and PDGF-B, and procollagen type I (pro-I) messenger RNAs (mRNAs) in liver diseases of various etiologies. RESULTS Pro-I mRNA was expressed by mesenchymal cells at sites of inflammation and scarring, where TGF-beta 1 immunoreactivity was often found, and by perisinusoidal cells. TGF-beta 1 and PDGF-A mRNAs were expressed mainly by mononuclear cells and proliferating ductular cells. TGF-beta 1 mRNA was also expressed by perisinusoidal cells. PDGF-A gene expression was more common than that of PDGF-B. Pro-I and TGF-beta 1 expression correlated with both ductular proliferation and tissue inflammation, whereas PDGF-A and PDGF-B only correlated with ductular proliferation. CONCLUSIONS Our data suggest that TGF-beta 1 and PDGF are involved in human liver inflammation and fibrosis. The expression of growth factor mRNAs in proliferating ductular cells may indicate a role for these cells in liver fibrogenesis and may help explain the pathophysiology of conditions such as biliary atresia progressing to fibrosis despite the absence of marked inflammation.

PROCOLLAGEN TYPE I PRODUCTION BY HEPATOCYTES: A MARKER OF PROGRESSIVE LIVER DISEASE?

The presence of collagen-producing cells and its relation to disease activity were determined in cryostat liver tissue sections from subjects with active cirrhosis (n = 15), inactive cirrhosis (n = 5), chronic persistent hepatitis (n = 8), or normal histology (n = 3) by means of an immunofluorescence technique using a monoclonal antibody to the carboxy-terminal domain of procollagen type I (anti-Pc). In all patients with active cirrhosis hepatocytes showed a strong intracellular staining with anti-Pc; in 4 of them bileducts also showed a membrane-like reaction. By contrast, tissue sections from chronic inactive liver disease and normal liver were essentially negative. These findings suggest that in chronic liver disease hepatocytes and sometimes biliary epithelium produce collagen and that production is related to disease activity. The detection of active production of procollagen type I by hepatocytes could become a useful marker of progressive liver disease.

Prognosis research and risk of bias

The interest in prognosis research has been steadily growing during the past few decades because of its impact on clinical decision making. However, since the methodology of prognosis research is still incompletely defined, the quality of published prognosis studies is largely unsatisfactory. Seven major domain for risk of bias in prognosis research have been identified, including study participation, attrition, selection of candidate predictors, outcome definition, confounding factors, analysis, and interpretation of results. The methodology for performing prognostic studies is currently aimed at avoiding such potential biases. Amongst methodologic requirements in prognosis research, the following should be considered most relevant: beforehand publication of the study protocol including the full statistical plan; inclusion of patients at a similar point along the course of the disease; rationale and biological plausibility of candidate predictors; complete information; control of overfitting and underfitting; adequate data handling and analysis; publication of the original data. Validation and analysis of the impact that prediction models have on patient management, are key steps for translation of prognosis research into clinical practice. Finally, transparent reporting of prognostic studies is essential for assessing reliability, applicability and generalizability of study results, and recommendations are now available for this aim.

Clinical states of cirrhosis and competing risks

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

Delayed-Onset Superior Mesenteric Artery Syndrome Presenting as Oesophageal Peptic Stricture

Superior mesenteric artery (SMA) syndrome is an infrequent cause of vomiting and weight loss due to compression of the third part of the duodenum by the SMA. We describe the case of a 17-year-old woman, admitted to our department for progressive dysphagia and severe weight loss due to an oesophageal peptic stricture, caused by chronic acid reflux secondary to duodenal compression by the SMA. Symptoms improved after (par)enteral nutrition and repeated oesophageal dilatation, thus supporting the role of intensive medical and endoscopic intervention as an alternative to surgery, at least in some cases.

Beta-blockers in 2016: Still the safest and most useful drugs for portal hypertension?

Because of their beneficial effect on the prevention of variceal bleeding, nonselective betablockers (NSBBs) have become a cornerstone of the treatment of portal hypertension for the last three decades. In addition to prevention of variceal bleeding, they also reduce bacterial translocation and the risk of spontaneous bacterial peritonitis (SBP), refractory ascites, hepatorenal syndrome (HRS), and death. However, a few years ago Serst e et al. reported an increased risk of death from NSBBs in patients with refractory ascites in an observational retrospective study. This study bore some risk of bias, however, because the patients who received NSBBs had more advanced liver disease with more severe portal hypertension, and the multivariable adjustment of the reported hazard ratio was insufficient. In addition, almost one half of the patients who were using NSBBs received a standard dosage of 160 mg long-acting propranolol per day, which is unusual in clinical practice. In a small crossover study, the same investigators reported an increased risk of a post-paracentesis surge in plasma renin activity under NSBB treatment, but not after NSBB withdrawal. Although this increase had no deleterious effects on renal function, and despite the major drawbacks of this study (i.e., only 10 patients were included, and diuretic therapy was not considered), a debate ensued about whether and when NSBB treatment should be discontinued in cases of advanced cirrhosis. A window for NSBB treatment has been hypothesized: no benefit in the early disease stage when there are no esophageal varices and the effect of NSBB on portal pressure is very small; benefit in patients with medium-large varices or who have bled; possible harm in patients with more advanced disease, typically characterized by resistant or refractory ascites, when the cardiac compensatory reserve might be impaired and may be further reduced by NSBB, especially at high doses. More recently, Mandorfer et al. investigated the interaction between NSBBs and SBP in a retrospective study that included 607 patients at their first paracentesis. NSBB treatment improved transplant-free survival significantly in patients who did not experience SBP, but reduced significantly survival after SBP. The uncertainty raised by the aforementioned studies has been mitigated recently by a single-center retrospective study including 322 patients with ascites listed for liver transplantation, 159 of whom were receiving treatment with NSBBs. Competing-risks multivariable regression analysis (for transplant competing) showed that NSBBs were associated with a nonsignificant survival benefit that was however significant in 208 patients (104 NSBB, 104 nonNSBB) matched by propensity score. In the subgroup of 117 patients with refractory ascites, treatment with NSBBs was associated with significant improvement of survival, both in the whole group and in the propensity score2matched patients, suggesting that the results reported by Serst e and colleagues are at least not generalizable. The Abbreviations: HRS, hepatorenal syndrome; NSBB, nonselective beta-blocker; RCT, randomized clinical trial; SBP, spontaneous bacterial peritonitis.

JC Virus, Helicobacter pylori, and oesophageal achalasia: preliminary results from a retrospective case-control study.

To the Editor: JC virus (JCV) is a member of the polyomavirus family. It infects humans worldwide, and 90 % of the population carry antibodies to the virus by adult life [1]. The initial infection is asymptomatic, but it may become persistent. JCV DNA is frequently present in the upper and lower gastrointestinal tract of healthy adults [2, 3]. Several studies have suggested the involvement of certain DNA viruses in chronic gastrointestinal motility disorders such as chronic intestinal pseudo-obstruction [4–7]. Although a close causal relationship between neurotropic viruses and enteric neuromuscular lesion is not easily demonstrated, the identification of neurotropic viruses and/ or molecular components associated with them may help to clarify their role in the highly severe gastrointestinal disease. The aim of our study was to assess the prevalence of JC virus in a cohort of patients with oesophageal achalasia, comparing it with a cohort of healthy subjects, in order to evaluate whether JC virus could be play a role in this disease; we evaluated also the relationship between JC virus and Helicobacter pylori (HP). In the cohort of patients with achalasia, 12 out of 15 (80 %) had a positive JC-PCR, while in the cohort of healthy controls, ten out of 15 (66.7 %) had a positive JC-PCR (chi-square 0.68, odds ratio 2, p = 0.409). In the cohort of patients with achalasia, 13 out of 15 (86.7 %) had a positive hystologic HP test, while in the cohort of healthy controls, eight out of 15 (53.3 %) had a positive hystologic HP test. Curiously, in the entire cohort of patients, JC virus infection proved to be protective against HP infection (chisquare 11.35, odds ratio 0.09, p = 0.0008). The prevalence of HP and JC virus infection in the entire cohort is shown in Table 1. Because of the known neuropathic capability of JC virus, and its frequent presence in the upper gastrointestinal tract, as well as in the gut, we proposed that JCV might be detectable in tissues of patients with oesophageal achalasia, and possibly be involved in the pathogenesis of this disease. However, in this study the difference between the prevalence of JC virus in achalasia patients and in healthy controls was not statistically significant, probably due to the small number of cases and control subjects. Few data are available about the relationship between JC virus and HP. Selgrad and coworkers, in their case–control study, showed that JC virus is present in HP induced gastritis and gastric cancer [9]. By contrast, the findings of our case–control study show that JC virus could be a protective factor against HP infection, though the biological and pathophysiological reasons for this microbiological interference are not yet known. Electronic supplementary material The online version of this article (doi:10.1007/s10620-012-2485-9) contains supplementary material, which is available to authorized users.

Screening and surveillance for hepatocellular carcinoma: perspective of a new era?

ABSTRACT Introduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death with an increasing prevalence worldwide. Early diagnosis of HCC is important since observational studies have reported that, in patients undergoing surveillance, cancer is diagnosed at an earlier stage with increased chances of curative therapies. Anyway, despite the extensive use of screening for HCC, its effectiveness is still a controversial topic since supporting evidence is not unequivocal and some issues need to be explored. Areas covered: The aim of this paper is to review main literature data supporting performance and effectiveness of screening for early detection of hepatocellular carcinoma. Expert commentary: Clinical benefit of screening for HCC is controversial and there are no sufficient data supporting its effectiveness in reducing cancer specific mortality. Since it is unlikely that RCTs will be performed in the future, surveillance should be still reasonably recommended in all at-risk population, until potential data against its effectiveness will be provided. In the future additional and more effective non-invasive tests will be needed, as well as proper surveillance intervals and risk threshold for surveillance enrollment must be assessed and refined by prospective studies.

An open-safety study of dual antiviral therapy in real-world patients with chronic hepatitis C

Treatment of patients with chronic hepatitis C with alpha‐interferon and ribavirin usually produces adverse events within the first 3 months. We aimed to assess safety and predictors of discontinuation or dose modification of these drugs.