Marco Giunta

Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach

BACKGROUND/AIMS To evaluate by meta-analysis of available literature whether interferon (IFN) reduces the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV)-related Child A cirrhosis. METHODS Three randomized controlled trials and 15 nonrandomized controlled trials, including 4614 patients and comparing IFN to no treatment, were selected. Data on the incidence of HCC in IFN treated and untreated patients were extracted from each study. Meta-analysis by the DerSimonian and Laird risk difference (RD) method was used to pool observations. RESULTS A different incidence of HCC between treated and untreated cirrhotic patients was observed for HCV (overall RD -12.8%; 95% CI -8.3 to -17.2%, P < 0.0001) and HBV (overall RD -6.4%; 95% CI -2.8 to -10%, P < 0.001). In HCV-related cirrhosis, the rate of HCC development was lower in sustained responders to IFN than in untreated patients (overall RD -19.1%; 95% CI -13.1 to -25.2%, P < 0.00001), with low heterogeneity among trials (P=0.053), and also in nonresponders vs. untreated patients (overall RD -11.8%; 95% CI -6.4 to -19.1%, P < 0.0001), although with significant heterogeneity. Inconsistency among the studies was a major problem, both for HCV (chi2 = 58.16 with 13 DF; P < 0.0001) and HBV (chi2 = 26.4 with 6 DF; P = 0.0001) related cirrhosis, and also when follow-up was shorter than 60 months. Consistent results were only observed when assessing data from European reports: in this subgroup no preventive effect of HCC was shown for HBV (overall RD -4.8%; 95% CI -11.1-1.5%, P, not significant), and only a weak effect for HCV (overall RD -10%; 95% CI -5.9 to -14.2%; P < 0.0001). CONCLUSIONS Literature data pooling suggests a slight preventive effect of IFN on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit might be due to spurious associations. The preventive effect is more evident among sustained responders to IFN. IFN does not seem to affect the rate of HCC in HBV-related cirrhosis.

Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis

BACKGROUND The role of interferon treatment on the natural history of hepatitis C virus related cirrhosis is under debate. AIM To evaluate the effect of interferon on the clinical course of compensated hepatitis C virus related cirrhosis. PATIENTS AND METHODS Seventy two cirrhotic patients treated with interferon and 72 untreated controls matched treated patients with for quinquennia of age, sex, and Child-Pughs score were enrolled in a prospective non-randomised controlled trial. Treated patients received leucocytic interferon alfa, with an escalating schedule for 12 months. The incidence and risk (Cox regression analysis) of clinical complications (hepatocellular carcinoma, ascites, jaundice, variceal bleeding, and encephalopathy) and death were calculated. RESULTS Over median follow up periods of 55 months for treated and 58 for untreated subjects, seven and nine patients, respectively, died, and 20 and 32, respectively, developed at least one clinical complication (ns). Hepatocellular carcinoma developed in six treated and 19 untreated patients (p=0.018). Seven treated patients showed sustained aminotranferase normalisation and none died or developed complications. Clinical complications were significantly associated with low albumin, bilirubin, and prothrombin activity while hepatocellular carcinoma was significantly related to no treatment with interferon, oesophageal varices, and high α fetoprotein levels. By stratified analysis, the beneficial effect of interferon was statistically evident only in patients with baseline α fetoprotein levels ⩾20 ng/ml. CONCLUSIONS Interferon does not seem to affect overall or event free survival of patients with hepatitis C virus related cirrhosis while it seems to prevent the development of hepatocellular carcinoma. Patients who achieved sustained aminotransferase normalisation survived and did not develop any complications during follow up.

The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis

BACKGROUND/AIMS Several randomized clinical trials of interferon in chronic hepatitis C have examined the histological changes in paired biopsy specimens. We have attempted a quantitative evaluation by meta-analysis. METHODS Randomized Clinical Trials found by MEDLINE search were included if: a) they compared different IFN regimens with non-active treatment or with each other, b) they obtained biopsies before starting and at the time of stopping IFN in a sizable proportion of the treated and control patients, and c) they assessed the biopsy-specimens semi-quantitatively according to Scheuers numerical scoring system or Knodells Histological Activity Index, with quantitation of fibrosis and of lobular, portal and periportal necroinflammation. RESULTS Seventeen trials were identified, in which 1223 adult patients had been studied. All trials homogeneously pointed towards a favorable interferon effect. The pooled data show a statistically significant histological improvement in treated patients as compared with controls for each of the four Histological Activity Index components and for the total Histological Activity Index score (overall improvement was -0.82 in favor of interferon, p<0.0001, 95% Confidence Interval -1.25 to -0.40). In the ten trials reporting histological changes separately in biochemical responders (primary and sustained responders) and non-responders, histological improvement was confined to the subset of biochemical responders. No change or very little change occurred in non-responders. CONCLUSIONS Interferon treatment in chronic hepatitis C significantly improves liver histology. The effect of interferon is closely related to biochemical response. Studies assessing histological outcome 1 year or more after interferon treatment in long-term responders and comparatively in non-responders or relapsers would be important to confirm the regression of the necroinflammatory process in the former, as suggested by the normal serum alanine aminotransferase levels.

Long-term course of interferon-treated chronic hepatitis C

BACKGROUND/AIMS To evaluate whether sustained response to a-interferon improves clinical outcome in patients with chronic hepatitis C. METHODS A cohort of 410 consecutive patients (65% with chronic hepatitis, 35% with cirrhosis) were treated with a-interferon in two trials (mean follow-up 62.1 months, range 7-109 months). All were serum HCV RNA positive before therapy and received first 10 then 5 million units of a-2b or a-nl interferon three times weekly for 6 to 12 months. Sustained response was defined as normal aminotransferases 12 months after stopping interferon. RESULTS Sixty-two patients (15.1%: 54 with chronic hepatitis, eight with cirrhosis) were sustained responders. At the end of follow-up, 56 out of 62 sustained responders (90.3%) were serum HCV RNA negative. No biochemical relapse after 12 months was seen in sustained responders, regardless of initial histology, HCV genotype or persistence of HCV RNA. Although three died of non-hepatic causes, no liver-related events were observed among sustained responders. Complications of liver disease occurred in 34 relapsers/non-responders: nine hepatocellular carcinomas, 21 ascites and four portal hypertensive bleedings. Eleven relapsers/nonresponders died: eight of hepatic and three of non-hepatic causes. Event-free survival was significantly longer in sustained responders than in all the remaining patients. In a regression analysis, sustained response to interferon, low age and absence of cirrhosis were independent predictors of event-free survival. CONCLUSIONS Hepatitis C virus is probably eradicated and progression of liver disease is prevented in most patients who remain HCV RNA negative with normal transaminases for more than 1 year after stopping treatment.

Chronic hepatitis C and interferon alpha: conventional and cumulative meta-analyses of randomized controlled trials

Chronic hepatitis C and interferon alpha: conventional and cumulative meta-analyses of randomized controlled trials

Music for colonoscopy: A single-blind randomized controlled trial

BACKGROUND Several methods have been reported to minimize patient discomfort during colonoscopy, none are currently recommended by clinical practice guidelines. We performed a single-blind randomized controlled trial to assess the efficacy of music for colonoscopy. METHODS 109 patients were randomized to music-delivering or mute headphones before and during colonoscopy. Physicians were blinded to the trial. Sedation was given on demand. Primary outcome was pain measured on linear analogue scale from 0 to 10. Secondary endpoints were the difficulty of the procedure, need of sedation, overall patient satisfaction and willingness to repeat the procedure. RESULTS Mean pain score was 5.9±2.2 in the control group vs. 3.8±1.9 in the music group (p<0.00001); correspondingly overall satisfaction and willingness to repeat the procedure were significantly improved by music and the difficulty perceived by physicians was significantly reduced. Total administered midazolam was 36mg in the control group vs. 13 in the music group (p<0.007), pethidine was 860mg vs. 465mg (p=0.07) and patients requiring sedation were 22 vs. 9, respectively (p=0.003). A multivariable analysis to adjust treatment effect for potential confounding factors confirmed the significant beneficial effect of music. CONCLUSIONS Music significantly reduces discomfort and should be routinely offered to patients undergoing colonoscopy.

Clinical aspects of bleeding complications in cirrhotic patients.

&NA; Liver disease is a frequent cause of haemostatic abnormalities, which may lead to overt or occult bleeding. Clinical manifestations of hepatic coagulopathy include upper and lower gastrointestinal haemorrhage, easy bruising and bleeding from gums, nose or the female genital tract. The most significant bleeding problem among patients with chronic liver disease is blood loss due to portal hypertension. About 30% of subjects with oesophageal or gastric varices resulting from cirrhosis have an episode of gastrointestinal bleeding in their lifetime. Risk factors for the first episode of variceal bleeding include the severity of liver dysfunction, large varices, and the presence of endoscopic red colour signs. Bacterial infection in patients with variceal haemorrhage may be critical in triggering bleeding. Nongastrointestinal bleeding events, either spontaneous or induced by minor trauma, are also a common complication of advanced cirrhosis. In women, for instance, dysfunctional uterine bleeding may become so severe that hysterectomy is required. In addition, invasive diagnostic tests (mostly solid tissue biopsies) and surgical procedures have a high risk of haemorrhage and are sometimes withheld in cirrhotic patients for fear of complications. In patients with portal hypertension, surgical procedures aggravate the injury of the hepatic parenchyma and may worsen the condition.

A randomized controlled trial of high-dose maintenance interferon therapy in chronic hepatitis C.

In chronic hepatitis C virus (HCV) infection, the rate of sustained response to interferon is low. We evaluated, in patients responding to a 26‐week course of interferon, the effect of high‐dose maintenance therapy in preventing relapse. Three hundred and ten patients with chronic HCV infection (38.3% with cirrhosis, 80.6% with HCV type 1) received interferon alfa‐2b for 26 weeks (10 MU tiw for 8 weeks, then 5 MU tiw for 18 weeks). One hundred and twenty‐four subjects (40%) normalized aminotransferases, and were allocated randomly either to continue on 5 MU tiw for a further 26 weeks (prolonged therapy group: 60 patients) or to stop interferon (brief therapy group: 64 patients).

Advanced endoscopic imaging for surveillance for dysplasia and colorectal cancer in inflammatory bowel disease: could the pathologist be further helped?

Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal cancer. The magnitude of that increased risk as well as how best to mitigate it remain a topic of ongoing investigation in the field. It is important to quantify the risk of colorectal cancer in association with IBD. The reported risk varies widely between studies. This is partly due to the different methodologies used in the studies. Because of the limitations of surveillance strategies based on the detection of dysplasia, advanced endoscopic imaging and techniques involving the detection of alterations in mucosal antigens and genetic abnormalities are being investigated. Development of new biomarkers, predicting future occurrence of colonic neoplasia may lead to more biomarker-based surveillance. There are promising results that may lead to more efficient surveillance in IBD patients and more general acceptance of its use. A multidisciplinary approach, involving in particular endoscopists and pathologists, together with a centralized patient management, could help to optimize treatments and follow-up measures, both of which could help to reduce the IBD-associated cancer risk.

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.