Andrew Szilagyi

Meta-analysis of Outcome of Cytomegalovirus Colitis in Immunocompetent Hosts

There are only a few anecdotal reports of cytomegalovirus (CMV) colitis in immunocompetent hosts. The impact of the disease in this patient population remains poorly understood. The aim of this study was to perform a meta-analysis using individual patient data to determine outcomes of CMV colitis in immunocompetent patients and identify risk factors that might influence prognosis. A literature search was performed from 1980 to 2003 looking for immunocompetent patients with CMV colitis. Immunocompetence was defined as absence of congenital or acquired immune deficiency, transplant, or immunosuppressive medication. Patients were divided by age (< 55 versus ≥55) and grouped according to coexisting illnesses. Kaplan–Meier curves were plotted to assess survival. Variables included age, sex, site of acquisition of infection, extent of disease, coexisting illnesses, and treatment modality. A total of 44 patients were identified, with an average age of 61.1. Only 10 were free of any comorbidity. The mean follow-up was 13.4 months. Spontaneous remission occurred in 31.8%, mostly individuals < 55 years old. Fourteen deaths occurred, all of which were in patients ≥55. There was a higher mortality rate among male patients ≥55 (56.9%; P = 0.08), patients with immune-modulating diseases (75.2%; P = 0.10), and those having a colectomy (68.9%; P = 0.09). This analysis underlines the rarity of CMV colitis in patients with an intact immune system. Advanced age, male gender, presence of immune-modulating comorbidities, and need for surgical intervention are factors negatively influencing survival. Conversely, young healthy patients have a good prognosis with no intervention.

Use of Interferon for Prevention of Hepatocellular Carcinoma in Cirrhotic Patients with Hepatitis B or Hepatitis C Virus Infection

Hepatocellular carcinoma is a leading cause of death worldwide and is particularly prominent in developing countries. It is usually associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Cirrhosis of the liver is an important preneoplastic condition. In patients with HCV infection, hepatocellular carcinoma occurs almost exclusively in the context of cirrhosis. In contrast, HBV-related liver tumors occur in HBV-infected patients with cirrhosis and those without, although cirrhosis is usually present. Treatment of chronic HBV and HCV infection with interferon- has not achieved sustained virologic benefit in most patients. Clinical trials of interferon therapy in patients with hepatocellular carcinoma have also had varying but usually low rates of success (1-3). However, the immunomodulatory and antitumor effects of interferon may differ from its antiviral effect at any stage of disease development (4). Therefore, an important unanswered question is whether interferon can delay or prevent hepatocellular carcinoma independent of its antiviral effect in patients with cirrhosis. We searched MEDLINE for pertinent English-language literature published from 1985 to March 1999 by using the MeSH terms and textwords cirrhosis, interferon, hepatoma or hepatocellular carcinoma, hepatitis B, and hepatitis C. Accepted studies used prospective or historical cohorts that specifically included treated and untreated patients with cirrhosis and information about type of therapy, dosing schedule, length of follow-up, and outcome of hepatocellular carcinoma. Although many studies discussed a reduction in the incidence of hepatocellular carcinoma in patients with HCV- or HBV-related liver disease, only 10 studies specifically addressed the role of interferon in the treatment of cirrhosis. Of these 10 studies, 2 were randomized, controlled trials (5, 6) and the remainder were observational cohort studies with diverse study variables (7-14). We included 1 additional study on hepatocellular carcinoma because it provided enough information to allow a subgroup analysis of the relative risk for hepatocellular carcinoma in interferon-treated patients with cirrhosis (15). Relative risk and CIs were calculated for each study. We discuss the origin of the debate about interferon therapy to prevent hepatocellular carcinoma in patients with cirrhosis, briefly review the pathogenesis of hepatocellular carcinoma in patients with HCV-related and HBV-related cirrhosis, and summarize the results of clinical studies that examined the effect of interferon on delaying or preventing hepatocellular carcinoma in patients with cirrhosis and HBV or HCV infection. No financial source was involved in the gathering, analysis, or interpretation of our data. The Debate In 1995, Nishiguchi and colleagues (5) published a small randomized, controlled trial of interferon treatment in HCV-infected patients with cirrhosis. After a 12- to 24-week course of interferon-, 6 MU three times per week, only 4% of treated patients developed hepatocellular carcinoma during 2 to 7 years of follow-up. In contrast, hepatocellular carcinoma occurred in 38% of untreated patients. These results were remarkable because only 16% of interferon-treated patients achieved a sustained virologic response compared with 0% of controls, and the observed decrease in the rate of hepatocellular carcinoma was independent of virologic response. Critiques of this trial emphasized the short follow-up and duration of treatment and the relatively high rate of hepatocellular carcinoma in the control group (16-19). Despite these criticisms, the study by Nishiguchi and coworkers (5) triggered the debate about whether interferon treatment is indicated to prevent hepatocellular carcinoma in HCV-infected patients with cirrhosis and whether a measurable virologic response is necessary to achieve this benefit. The effect of interferon therapy on hepatocarcinogenesis in patients with HBV infection is also unclear. Similarities and differences can be seen in the potential mechanism of HBV and HCV hepatocarcinogenesis. Because HBV integrates into the host genome and the mechanism of oncogenesis is different than that in HCV, conclusions drawn from studies of HCV-infected patients may not be directly applicable to HBV-infected patients. Hepatitis B Virus-Associated Hepatocellular Carcinoma In the natural history of chronic HBV infection, a phase of active viral replication of variable duration is followed by a dormant or nonreplicative phase. Ongoing HBV replication is associated with a less favorable clinical outcome independent of cancer. A frequently cited meta-analysis of 15 randomized, controlled trials concluded that approximately one third of HBV-infected patients treated with interferon converted from an active to a dormant phase of infection (20). Hepatitis B surface antigen (HBsAg) was cleared in only 10% of patients, and this usually occurred months or years after completion of therapy. Similarly, overall and complication-free survival of patients chronically infected with HBV was substantially improved by successful interferon treatment, and cirrhosis did not preclude a beneficial response (21). These findings were confirmed by a more recent long-term randomized, controlled trial with 1.1 to 11.5 years of follow-up (22). Patients with chronic liver disease, especially cirrhosis, are at an increased risk for hepatocellular carcinoma. This may be related to an ongoing, compensatory, proliferative response of remaining hepatocytes and to regenerative nodule formation. Hepatic regenerative activity may induce several acquired DNA anomalies, which may inhibit apoptosis and promote malignant transformation (23). In some cases of HBV-associated hepatocellular carcinoma, integration of viral sequences has been shown to alter expression of important cellular regulatory genes, including dominant and recessive oncogenes. In addition, the viral X gene encodes a transactivating protein that may alter the expression of host regulatory proteins. These phenomena may contribute to the frequent observation of HBV-related hepatocellular carcinoma in the absence of cirrhosis (24, 25). In HBV, both the early cellular genetic alterations and the later development of cirrhosis have been implicated in the formation of hepatocellular carcinoma. Hepatitis C Virus-Associated Hepatocellular Carcinoma Chronic HCV infection may develop over the course of years or decades. When it is progressive, it follows an orderly sequence from chronic hepatitis to cirrhosis. In contrast to its incidence in HBV-infected patients, hepatocellular carcinoma occurs almost exclusively among HCV-infected patients with cirrhosis (26). Some researchers have suggested that HCV itself may be carcinogenic. Recent studies have indicated that the core protein of HCV may modulate gene transcription, proliferation, and apoptosis of host cells. In the transgenic mouse model, HCV core protein has been shown to induce hepatic adenomas that progress morphologically and biochemically to hepatocellular carcinoma (27). Additional factors, such as alcohol consumption, diet, medications, genetic predisposition of the host, and concomitant viral infections, may contribute to hepatocarcinogenesis. Large individual studies and meta-analyses have examined interferon treatment in patients with chronic HCV infection (28-31). Successful treatment is currently defined as a sustained loss of serum HCV RNA 6 months after completion of therapy. A recent controlled trial comparing interferon monotherapy with combination therapy (interferon and ribavirin) showed that only 6% of patients treated with interferon alone for 24 weeks and 13% of those treated with interferon alone for 48 weeks achieved a sustained response (32). Studies have also suggested that sustained virologic response is associated with histologic and biochemical improvement (28-31). The Role of Interferon Therapy in Preventing Hepatocellular Carcinoma in Hepatitis B Virus- and Hepatitis C Virus-Infected Patients with Cirrhosis The literature suggests that interferon therapy may prevent hepatocellular carcinoma in cirrhotic patients infected with HBV or HCV. The mechanism of this benefit seems to differ for the two viruses, however. Among patients with HBV-related cirrhosis, the greatest reduction in risk for hepatocellular carcinoma was seen in those who had a virologic response to treatment. In contrast, the risk reduction among patients with HCV-related cirrhosis was largely independent of the virologic response; this suggests a different or additional mechanism of effect. Studies of Interferon Therapy in Patients with Hepatitis B Virus-Related Cirrhosis Incidence of hepatocellular carcinoma seems to decrease slightly among patients with HBV-related cirrhosis who are treated with interferon. The Table summarizes five studies that examined the risk for hepatocellular carcinoma in patients with HBV-related cirrhosis (7, 8, 11-13). A total of 817 treated patients and 574 untreated patients were studied. We did not combine data from these heterogeneous studies because doing so would have been statistically unsound. Interferon treatment reduced the risk for hepatocellular carcinoma in each study, but only the studies by Oon (12) and Ikeda and associates (13) achieved statistical significance. Table. Details of Studies of Treatment with Interferon- for Prevention of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Related Cirrhosis and Hepatitis C Virus-Related Cirrhosis Virologic response (defined as seroconversion from hepatitis e antigen [HBeAg] to antibodies to HBeAg) was strongly associated with reduced risk for hepatocellular carcinoma in at least two studies (7, 12). This suggests that the arrest of viral replication is a critical factor. It is important to note that none of these studies were randomized, controlled trials. Therefore, substantial bias may have occurred, and the

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease—The McGill experience

BACKGROUND Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohns disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS A retrospective observational open-label study. Clinical response was defined by physicians global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Pharmacological Therapy of Vascular Malformations of the Gastrointestinal Tract

Vascular malformation (AVM) in the gastrointestinal tract is an uncommon, but not rare, cause of bleeding and iron deficiency anemia, especially in an aging population. While endoscopic coagulative therapy is the method of choice for controlling bleeding, a substantial number of cases require additional therapy. Adjunctive or even primary phamacotherapy may be indicated in recurrent bleeding. However, there is little evidence-based proof of efficacy for any agent. The bulk of support is derived from anecdotal reports or case series. The present review compares the outcome of AVM after no intervention, coagulative therapy or focus on pharmacological agents. Most of the literature encompasses two common AVMs, angiodysplasia and hereditary hemorrhagic telangiectasia. Similarly, the bulk of information evaluates two therapies, hormones (estrogen and progesterone) and the somatostatin analogue octreotide. Of these, the former is the only therapy evaluated in randomized trials, and the results are conflicting without clear guidelines. The latter therapy has been reported only as case reports and case series without prospective trials. In addition, other anecdotally used medications are discussed.

Vitamin B12 Deficiency in Inflammatory Bowel Disease: Prevalence, Risk Factors, Evaluation, and Management

Background:Management of vitamin B12 (cobalamin, Cbl) deficiency in inflammatory bowel disease (IBD) is often not evidenced-based because of uncertainty on whether it causes enough malabsorption to result in clinical disease. This systematic review examines whether IBD predisposes to Cbl deficiency. We provide an approach to the management of abnormal Cbl values in IBD based on current literature and consensus-based guidelines. Methods:An extensive search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 42 articles with a total of 3732 patients evaluating Cbl deficiency in IBD. Results:Crohns disease without ileal resection, regardless of disease location in the ileum, did not increase the risk for Cbl deficiency. Ileal resections greater than 30 cm were associated with Cbl deficiency in Crohns disease, whereas those less than 20 cm were not. The effects of 20 to 30 cm resections were inconsistent. Ulcerative colitis did not predispose to deficiency. All studies failed to use confirmatory biomarker testing as stipulated by diagnostic guidelines for Cbl deficiency. Conclusions:This literature does not support an association of Crohns disease in general, regardless of ileal involvement, with Cbl deficiency. Only ileal resections greater than 20 cm in Crohns disease predispose to deficiency and warrant treatment. Based on these findings, we suggest a diagnostic and therapeutic algorithm. All findings and recommendations require verification in further studies using confirmatory biomarkers as per diagnostic guidelines for Cbl deficiency. Serum Cbl levels alone are likely insufficient to diagnose deficiency in asymptomatic patients.

Redefining Lactose as a Conditional Prebiotic

Lactose in dairy products is maldigested by up to 70% to 75% of the worlds population and many people may therefore suffer symptoms reminiscent of irritable bowel syndrome. As a result, most research to date has concentrated on ways of improving lactose tolerance to enhance dairy as a source of nutrition. However, research on other possible benefits of lactose and its maldigestion has lagged. In view of an exponential growth in the understanding of intestinal microfloral host interactions and the expanding therapeutical potential of probiotics, a reassessment of the role of lactose as a potential prebiotic in lactase nonpersistent subjects is required. Gibson and Roberfroid introduced the concept of prebiotics and outlined definitive requirements for such a compound. The present article examines scientific and clinical knowledge about the properties of lactose and argues that in lactase nonpersistent subjects, lactose qualifies as a prebiotic.

Manipulation of Intestinal Microbial Flora for Therapeutic Benefit in Inflammatory Bowel Diseases: Review of Clinical Trials of Probiotics, Prebiotics and Synbiotics

Pathogenesis of Inflammatory Bowel Diseases(Ulcerative Colitis, Crohns disease and Pouchitis) includes an abnormal immunological response to disturbed intestinal microflora. Therapeutic strategies are designed to intervene in these abnormal host microbial communications. A novel approach in the last decade has been to use other bacteria or selective foods to induce beneficial bacteria to normalize inflammation. In this review we discuss rationale for such use and describe 46 clinical trials gleaned from the literature. Reports are divided into type, indications, and agents used. The search revealed 15 nonrandomized and 31 randomized trials. Of the latter 23 were double-blind and 8 were open-label randomized controlled. In 32 of the total, different probiotics were used, while 10 and 4 used different prebiotics or synbiotics respectively. In 14 nonrandomized trials, outcome was successful. In the randomized controlled trials 12 of 16 ulcerative colitis but only 2 of Crohns disease trials of biotic therapy were successful. No superiority of any probiotic was clearly evident, but a multi-agent mixture, VSL3# may be better suited in ulcerative colitis and pouchitis while the probiotic Lactobacillus rhamnosus GG appears less useful in inflammatory bowel disease, especially Crohns disease. Further studies with uniform stringent criteria are needed to provide proof of this therapy in inflammatory bowel disease.

Impact of Lactose Containing Foods and the Genetics of Lactase on Diseases: An Analytical Review of Population Data

Dairy foods (DFs) contain complex ingredients that could affect different diseases. The control of lactose digestion phenotypically divides populations into those who can [lactase persistent (LP)] and those who cannot [lactase nonpersistent (LNP)] assimilate lactose. LNP subjects, however, can adapt to lactose intolerance through intestinal bacteria. The DF/LNP status interactions may function as disease risk modifiers. We evaluated the relationship between DF and LNP with colorectal, breast, prostate, ovarian, lung, and stomach cancer and inflammatory bowel diseases (IBD; Crohns disease and ulcerative colitis). Yearly per capita DF consumption, LNP national prevalence, cancer mortality, and incidence of IBD were obtained from several sources. A negative binomial regression model was used to derive incremental risks. There were statistically significant (P ≤ 0.05) increases in risk for colorectal and prostate cancer and ulcerative colitis with DFs and a statistically significant decreased risk for stomach cancer. There were trends (P < 0.1) for lung and ovarian cancers and Crohns disease. As LNP prevalence increased, stomach cancer risk increased, whereas risks of all other conditions decreased (P < 0.01). In 3 cancers (prostate, ovarian, and breast), meta-analyses of case-based studies support ecological data. In colorectal cancer, on the contrary, meta-analyses of case-based studies suggest protection. The possible importance of distinguishing LNP/LP status in studies is discussed.

Failure to improve parameters of lactose maldigestion using the multiprobiotic product VSL3 in lactose maldigesters: A pilot study

Lactose maldigestion is a common genetic trait in up to 70% of the worlds population. In these subjects, the ingestion of lactose may lead to prebiotic effects which can be confirmed by measurement of breath hydrogen. After a period of continuous lactose ingestion, colonic bacterial adaptation is measurable as improved parameters of lactose digestion. There may be inherent benefits in this process of adaptation which may protect against some diseases. We attempt to link therapeutically beneficial probiotics (VSL3, Seaford Pharmaceuticals Inc, Ontario) with improvement in parameters of lactose maldigestion. Two groups of five subjects with maldigestion were fed one or four packets of VSL3 (one packet containing 450 x 10(9) live bacteria) before testing and then 17 days later. A 50 g lactose challenge was carried out before and after feeding. While there was a trend toward increasing rather than reducing of summed breath hydrogen, no statistically significant changes were observed between results from before testing and those from testing 17 days later. The authors conclude that direct consumption of the probiotic VSL3 may not improve parameters of lactose maldigestion without metabolic activation. In its present format, therefore, the test for colonic adaptation cannot be used to demonstrate direct bacterial embedding with VSL3.

Differential Impact of Lactose/Lactase Phenotype on Colonic Microflora

BACKGROUND The ability to digest lactose divides the worlds population into two phenotypes that may be risk variability markers for several diseases. Prebiotic effects likely favour lactose maldigesters who experience lactose spilling into their colon. OBJECTIVE To evaluate the effects of fixed-dose lactose solutions on fecal bifidobacteria and lactobacilli in digesters and maldigesters, and to determine whether the concept of a difference in ability to digest lactose is supported. METHODS A four-week study was performed in 23 lactose maldigesters and 18 digesters. Following two weeks of dairy food withdrawal, subjects ingested 25 g of lactose twice a day for two weeks. Stool bifidobacteria and lactobacilli counts pre- and postintervention were measured as the primary outcome. For secondary outcomes, total anaerobes, Enterobacteriaceae, beta-galactosidase and N-acetyl-beta-D-glucosaminidase activity in stool, as well as breath hydrogen and symptoms following lactose challenge tests, were measured. RESULTS Lactose maldigesters had a mean change difference (0.72 log10 colony forming unitsg stool; P=0.04) in bifidobacteria counts compared with lactose digesters. Lactobacilli counts were increased, but not significantly. Nevertheless, reduced breath hydrogen after lactose ingestion correlated with lactobacilli (r=-0.5; P<0.001). Reduced total breath hydrogen and symptom scorestogether, with a rise in fecal enzymes after intervention, were appropriate, but not significant. CONCLUSIONS Despite failure to achieve full colonic adaptation, the present study provided evidence for a differential impact of lactose on microflora depending on genetic lactase status. A prebiotic effect was evident in lactose maldigesters but not in lactose digesters. This may play a role in modifying the mechanisms of certain disease risks related to dairy food consumption between the two phenotypes.