Influence of COVID-19 Pandemic on Colorectal Cancer Presentation, Management and Outcome during the COVID-19 Pandemic.

The aim of the study was to investigate whether the COVID-19 pandemic and related measures had an influence on colorectal cancer (CRC) presentation, management, and outcomes; it was a retrospective monocentric study. CRC patients undergoing surgery during the COVID-19 pandemic (1 March 2020-28 February 2022) (group B) were compared with patients operated on in the previous two years (1 March 2018-29 February 2020) in the same unit (group A). The primary outcome was to investigate whether there were differences in concern regarding the stage at presentation, as a whole and after dividing groups based on cancer location (right colon cancer, left colon cancer, rectal cancer). Secondary outcomes included differences in the number of patients admitted from emergency departments and emergency surgeries between periods, and differences in the postoperative outcomes. A subanalysis within the pandemic group was conducted on the same outcomes, dividing the aforementioned group based on pandemic trends. Two hundred and eighty (280) were operated on during the study period: 147 in group A and 133 in group B. Stage at presentation was similar between groups; however, the subgroups analysis showed that in the pandemic group, the number of early-stage left colon cancer occurrences almost halves, yet not significantly. Emergency department referral was more common in group B (p-value: 0.003); in group B, they also had longer operations and there was a more frequent use of ostomy. No differences in the number of postoperative complications nor in the postoperative outcomes were found. Patients with CRC were more frequently referred through the emergency department during the COVID-19 pandemic and left-sided cancers appear to be generally diagnosed at a more advanced stage. Postoperative outcomes showed that high specialized colorectal units can deliver standard high-level treatment under high-pressure external conditions.

Ambulatory Surgery for Perianal Crohn's Disease: Study of Feasibility.

BACKGROUND: One-third of Crohn's disease (CD) patients present perianal fistula. The gold standard in the diagnosis and treatment of symptomatic perianal disease (PAD) in CD is the exploration of the anal canal and distal rectum under anesthesia (EUA). This procedure is mainly conducted as a day case surgery. Unfortunately, it is not always possible to proceed within the ideal timing and any delay may well represent a relevant clinical issue. The aim of this study was to evaluate the feasibility of outpatient treatment of symptomatic perianal fistulas in CD patients. METHODS: All CD patients under regular follow-up at our inflammatory bowel disease referral center, presenting with symptomatic perianal fistulas, were offered surgical consultation. The data of patients were prospectively collected for three years (February 2014 to February 2017) for the purpose of the study. All clinical information, including previous EUA and/or records from MRI and endoscopic ultrasound, was included. Outpatient anal canal and distal rectum exploration and treatment (OE) were undertaken during the specialist surgical consultation. Fistulas were classified according to Parks's classification; the type of outpatient treatment and compliance of patients were recorded. Pain was assessed by VAS at the time of the procedure and during the first control. Patients were followed up in the surgical clinic in relation to the study. RESULTS: Ninety-two CD patients with symptomatic perianal fistulas had surgical consultation during the study period. OE was offered to all but 18 patients who fulfilled the exclusion criteria or had an extremely severe disease; six patients refused the OE (8.11%). Of the 68 patients undergoing OE, eleven (16.18%) had previous surgery for perianal disease. The OE was accomplished in sixty-one patients (89.71%), while in 7 patients, it was abandoned for scarce compliance. Nine patients (14.75%) underwent drainage of perianal abscess; in 3 of them, it was possible to probe the fistula tract, find the internal orifice, and pass a loose seton. Overall, setonage was performed in 50 patients (81.97%). Rectovaginal setons were placed in 3 patients and more than one seton (up to 3) in 6 cases. Fistulotomy was performed in 4 simple subcutaneous fistulous tracts. Concordance with the preoperative findings was found in 54 out of 61 patients. EUA was scheduled at the time of OE for the 7 patients who did not complete the procedure. All sixty-one patients who had the OE were followed up for a minimum of 12 months. CONCLUSIONS: This preliminary study indicates that OE in CD patients with symptomatic perianal fistulas is safe and feasible in a high-volume referral center. It might provide several benefits, including patients' logistics, reduce or remove patients' symptoms and discomfort, allow for a timely start of medical therapy, and avoid further complications.

Adenoma, advanced adenoma and colorectal cancer prevalence in asymptomatic 40- to 49-year-old subjects with a first-degree family history of colorectal cancer.

AIM: First-degree relatives (FDRs) of patients with colorectal cancer (CRC) have an increased CRC risk. Few studies have addressed if adenoma and advanced adenoma risk is increased among individuals, 40-49 years of age, with a family history of CRC. Therefore, the aim of the study was to define the prevalence and location of adenoma, advanced adenoma and CRC, according to age, in asymptomatic individuals with a family history of CRC. METHOD: Retrospective study of asymptomatic FDRs, 40 to ≥70 years of age undergoing first screening colonoscopy over a 3-year period, of CRC patients. RESULTS: Among 464 individuals studied, the prevalence of adenoma and advanced adenoma was 18.1% and 6.4%, respectively. According to age intervals, the prevalences of adenoma and advanced adenoma were 14% and 3.5%, respectively, in subjects 40-49 years of age; 14.4% and 6.3%, respectively, in subjects 50-59 years of age; 27% and 8%, respectively, in subjects 60-69 years of age; and 25% and 14%, respectively, in subjects ≥70 years of age; no significant difference was found among the four groups. No difference in lesion location was found, with similar numbers of preneoplastic lesions being present in the right colon and the left colon. CRC was diagnosed in three (0.64%) subjects, one of whom was in the 40-49 years age group. CONCLUSION: In our population of FDRs of CRC patients, 40-49 years of age, the prevalences of adenoma and advanced adenoma were similar to those observed in older subjects with the same CRC risk. Our data support the current indication to perform screening colonoscopy earlier than 45 years of age in subjects at high CRC risk.

IL-15 positively regulates IL-21 production in celiac disease mucosa.

Celiac disease (CD)-associated inflammation is characterized by high interleukin- 21 (IL-21), but the mechanisms that control IL-21 production are not fully understood. Here we analyzed IL-21 cell sources and examined how IL-21 production is regulated in CD. Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs), isolated from CD patients and non-CD controls, were analyzed for cell markers, cytokines, and transcription factors by flow cytometry. IL-21 was highly produced by CD4+ and CD4+/CD8+ IELs and LPLs in active CD. IL-21-producing cells coexpressed interferon-γ (IFN-γ) and to a lesser extent T helper type 17 (Th17) cytokines. Treatment of control LPLs with IL-15, a cytokine overproduced in CD, activated Akt and STAT3 (signal transducer and activator of transcription 3), thus enhancing IL-21 synthesis. Active CD biopsies contained elevated levels of Akt, and blockade of IL-15 in those samples reduced IL-21. Similarly, neutralization of IL-15 in biopsies of inactive CD patients inhibited peptic-tryptic digest of gliadin-induced IL-21 expression. These findings indicate that in CD, IL-15 positively regulates IL-21 production.

Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer.

BACKGROUND: MicroRNAs are tiny non-coding small endogenous RNAs that regulate gene expression by translational repression, mRNA cleavage and mRNA inhibition. The aim of this study was to investigate the hypermethylation of miR-34b/c and miR-148a in colorectal cancer, and correlate this data to clinicopathological features. We also aimed to evaluate the hypermethylation of miR-34b/c in faeces specimens as a novel non-invasive faecal-DNA-based screening marker. METHODS: The 5-aza-2'-deoxycytidine treatment and methylation-specific PCR were carried out to detect the hypermethylation of miR-34b/c and miR-148a. RESULTS: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110. In 75% (21 out of 28) of faecal specimens we found a hypermethylation of miR-34b/c while only in 16% (2 out of 12) of high-grade dysplasia. In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features. However, a trend with female gender and advanced age was found, P=0.083. We also observed a trend to lower survival rate in patients with miR-148a hypermethylation with 10-year survival probability: 48 vs 65%, P=0.561. CONCLUSIONS: These findings show that aberrant hypermethylation of miR-34b/c could be an ideal class of early screening marker, whereas miR-148a could serve as a disease progression follow-up marker.

Role of CA19.9 in predicting bevacizumab efficacy for metastatic colorectal cancer patients.

CEA and CA19.9 are biomarkers routinely measured for monitoring treatment response in metastatic colorectal cancer (MCRC) patients, yet their predictive value during therapies containing new antineoplastic drugs (i.e. FOLFIRI/OLFOX/Bevacizumab) has not yet been investigated. Consecutive chemotherapy-naive MCRC patients treated with either standard chemotherapy-alone (FOLFIRI/FOLFOX) or chemotherapy+bevacizumab (FOLFIRI+bevacizumab) were included in the analysis. Patients had to have serial biweekly measurement of CEA and CA19.9 available for at least three months of treatment. Primary study endpoint was Progression Free Survival (PFS). Biomarker levels and type of treatment as well as major demographic and clinical factors were analyzed for their impact on PFS. Out of 243 evaluated MCRC patients, 87 had biomarkers available as per inclusion criteria. Among all evaluated factors only type of treatment (chemotherapy-alone vs chemotherapy+bevacizumab) and baseline CA19.9 (> vs < normal) were independently associated with PFS, whilst neither baseline CEA nor biomarker reduction during therapy reached statistical significance. When patients with different baseline CA19.9 levels were analysed separately, only patients with abnormal CA19.9 benefited significantly from the administration of bevacizumab.The current study demonstrated a significant predictive value of CA19.9, but not of CEA and biomarker reduction, for MCRC patients treated with new antineoplastic drugs. Moreover, only patients with abnormal baseline CA19.9 levels benefited significantly from bevacizumab.

Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease.

BACKGROUND: In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon gamma (IFNgamma) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown. OBJECTIVE: To examine whether interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD. METHODS: Duodenal mucosal samples were taken from CD patients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNgamma was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CD patients. Finally, the role of IL21 in controlling T-bet and IFNgamma was also evaluated in cultures of biopsies taken from treated CD patients and cultured with a peptic-tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody. RESULTS: Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CD patients. Blockade of IL21 activity in biopsies of untreated CD patients reduced T-bet and IFNgamma secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNgamma induction. CONCLUSIONS: IL21 is overproduced in the mucosa of CD patients, where it helps sustain T-bet expression and IFNgamma production.

Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa.

BACKGROUND: In coeliac disease (CD) mucosa, the histological lesion is associated with marked infiltration of T helper cell type 1 (Th1) cells. However, the molecular mechanisms which regulate Th1 cell differentiation in CD mucosa are unknown. AIMS: To analyse expression of transcription factors which control the Th1 cell commitment in CD. PATIENTS: Duodenal mucosal samples were taken from untreated CD patients and normal controls. METHODS: Interferon gamma (IFN-gamma) and interleukin (IL)-4 RNA expression was examined in T lamina propria lymphocytes by quantitative reverse transcription-polymerase chain reaction. T-bet and STAT-4, two Th1 promoting transcription factors, and STAT-6 and GATA-3, transcription factors which govern T helper cell type 2 (Th2) cell polarisation, were examined in duodenal biopsies by western blotting. The effect of gliadin and IFN-gamma on expression of T-bet was examined in an ex vivo culture of biopsies taken from normal and treated CD patients. RESULTS: As expected, IFN-gamma but not IL-4 RNA transcripts were increased in the mucosa of CD patients in comparison with controls. CD mucosal samples consistently exhibited higher levels of T-bet than controls. However, no difference in active STAT-4 expression was seen between CD patients and controls, suggesting that Th1 polarisation was not induced by local IL-12. GATA-3 and STAT-6 were also low in both CD and control mucosa. In normal duodenal biopsies, IFN-gamma stimulated T-bet through a STAT-1 dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced T-bet and this effect was also inhibited by STAT-1 inhibition. CONCLUSIONS: This study shows that activation of STAT-1 by IFN-gamma promotes T-bet in CD mucosa.

Cytoskeletal proteins and resident flora.

Recent observations demonstrate that enteropathogenetic and enterohaemorrhagic bacteria, as well as other non enteropathogenetic bacteria (Listeria, Coxiella Burnetii), may subvert the host cell cytoskeleton. Models from enteropathogenic bacteria demonstrate that cytoskeletal proteins are required for bacteria binding to the enterocytes and that they play a role in the immune response of the host to intestinal bacteria. The cytoskeletal protein family Tropomyosins is present in all eukaryotic cells, with multiple isoforms regulated by multiple genes. Of the different Tropomyosin isoforms, TM5 has been shown to be expressed in colonic and jejunal epithelial cells, while TM1 in colonic and jejunal smooth muscle. In vitro studies have shown the presence of serum and mucosal IgG against TM5 in almost two thirds of patients with ulcerative colitis, suggesting: a. a possible autoimmune response to Tropomyosin in these patients; b. the hypothesis that the development of pouchitis may be related to the expression of TM5 in the ileal pouch; c. the use of probiotics in the treatment of pouchitis. Overall, the new expression of cytoskeletal proteins on the cell surface appears to be possibly induced by several mechanisms, including intestinal bacteria and apoptosis. The expression of cytoskeletal proteins on the cell surface may induce tolerance or autoimmune response on target cells. Further investigations are, however needed on the possible role of cytoskeletal proteins in human diseases.

Resident bacterial flora and immune system.

The "controlled inflammation" of the normal human gut is a closely controlled phenomenon and any change in the cell type number and/or functions, including the release of soluble mediators can lead to an "uncontrolled" inflammation. The physiological inflammation in the human gut plays a crucial role in maintaining a local immune response that is appropriate, efficiently protective and which respects the gut structure and function. The intestinal mucosa represents a considerable proportion of the human immune system. Disregulation of the mucosal immune response can switch a "controlled" toward an "uncontrolled" intestinal inflammation. A key role in the maintenance of an adequate balance between antigenic stimulation and host immune response is played by the immunoregulatory molecules released by activated immunocytes in the human gut. The role of the host immune system in the maintenance of an adequate balance between luminal antigens, including the resident bacterial flora and host immune response, is strongly supported by animal models of uncontrolled intestinal inflammation. Besides the aetiology of inflammatory bowel disease, luminal antigens (including food, viral and bacterial antigens) contribute to the maintenance of the inflammatory process in inflammatory bowel disease, by stimulating the immunocompetent cells in the intestinal mucosa. Of the luminal antigens, the resident bacterial flora seems to play a major role in the development of animal models of "uncontrolled" intestinal inflammation. Recent evidence also suggest that bacterial flora can modulate the function of the intestinal mucosal cells. These observations support the role of the intestinal bacterial flora in the induction of an uncontrolled inflammation in the human gut, leading to tissue damage. Probiotics, defined as living micro-organisms which, when taken in appropriate amounts, improve the health status, have been proposed in the treatment of inflammatory bowel disease, but their mechanisms of action still remain to be fully elucidated.

Review article: monitoring the activity of Crohn's disease.

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Hepatitis B and C virus infection in Crohn's disease.

Patients with Crohn's disease (CD) are at higher risk of hepatitis C (HCV) and B virus (HBV) infection, because of surgical and/or endoscopic procedures. However, the prevalence of HCV and HBV infection in CD is unknown. This issue may be relevant because of the growing use of immunomodulatory drugs in CD. The purpose of this study was to assess, in a multicenter study, the prevalence and risk factors of HCV and HBV infection in CD. The effect of immunomodulatory drugs for CD on the clinical course of hepatitis virus infections and of interferon-alpha (IFN-alpha) on the course of CD was examined in a small number of patients. Sera from 332 patients with CD and 374 control subjects (C) were tested for the following: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), HBcAb, HBeAg, HBeAb, anti-HCV, and HCV-RNA. An additional 162 patients with ulcerative colitis (UC) were tested as a disease control group. Risk factors were assessed by multivariate statistical analysis. Infection by either HCV or HBV was detected in 24.7% of patients with CD. In the age groups younger than 50 years, HCV prevalence was higher in CD than in C (p = 0.01). HCV infection in CD was associated with surgery (OR 1.71; 95% CI 1.00-2.93; p = 0.04), blood transfusions (OR 3.39; 95% CI 1.04-11.04; p = 0.04), and age (OR 2.3; 95% CI 1.61-3.56; p < 0.001). The event CD-related surgery appeared to be the main risk factor for HCV infection in CD. HCV prevalence was higher in CD (7.4%) than in UC (0.6%) (p = 0.001). HBcAb positivity was higher in CD (10.9%) and UC (11.5%) than in C (5.1%) (CD vs. C: p = 0.016; UC vs. C: p = 0.02), associated with age (OR 2.08; 95% CI 1.37-3.17; p = 0.001) and female gender (OR 2.68; 95% CI 1.37-3.17; p = 0.001) in CD and to UC duration (OR 1.20; 95% CI 1.06-1.36; p = 0.002). Immunomodulatory drugs did not influence the course of HBV or HCV infection in seven patients with CD, and IFN-alpha for chronic hepatitis C did not affect CD activity in six patients with CD. It is concluded that HBV prevalence is higher in CD than in C at all ages, whereas HCV prevalence is increased in young patients with CD, because of a greater need for surgery. The higher HCV (but not HBV) prevalence in CD than in UC suggests that the host immune response may influence the risk of HCV infection. Although a relatively high proportion of patients with CD showed HBV and/or HCV infections, this should not influence treatment strategies for CD.

Development of ductopaenic liver allograft rejection includes a "hepatitic" phase prior to duct loss.

BACKGROUND/AIM: Recent reports suggest the possible role of a parenchymal inflammatory reaction in the developing phase of chronic rejection. The aim of this study was to identify both clinical and histological abnormalities related to the development of chronic rejection, especially the topography of the inflammatory reaction occurring in the post-transplant period. METHODS: We studied retrospectively, 103 liver allograft biopsies from 10 patients. These 10 patients represented all the patients who developed chronic rejection (confirmed by duct loss and foamy arteriopathy in these grafts removed at retransplantation) and who had non-viral-related disease originally; in the study period 1990-1998 at the Royal Free Hospital (during which 451 liver transplants were performed). As a control population, we reviewed 28 patients who had been transplanted for non-viral end-stage liver disease at our institution in the same study period and who were retransplanted for complications other than chronic rejection. RESULTS: In nine patients documented histologically lobular hepatitis preceded chronic rejection. In one patient, although non-specific lobular changes were present in the early post-transplant period, lobular hepatitis was identified repeatedly after chronic rejection had been diagnosed. Cytomegalovirus was identified immunohistochemically in one patient. In the remaining nine patients extensive clinical and histological investigations failed to demonstrate the presence of any known viral agent. Features of hepatitis were found in only 3 of the 28 patients of the control group. CONCLUSIONS: A "hepatitic" phase anticipates chronic ductopaenic rejection. Further studies are necessary in order to clarify the pathogenesis of this reaction.

Orocecal transit time and bacterial overgrowth in patients with Crohn's disease.

Bacterial overgrowth is frequent in patients with Crohn's disease (CD) and can contribute to symptoms. Motility abnormalities can predispose to bacterial overgrowth. The hydrogen (H2) and methane (CH4) breath test is a sensitive and simple tool for the diagnosis of bacterial overgrowth and for the evaluation of orocecal transit time (OCTT). In this study, we investigated the prevalence of OCTT modifications and bacterial overgrowth in a series of consecutive adult patients with CD. In 43 healthy subjects and 67 patients with CD. we performed the lactulose breath test using a gas analyzer that offers the opportunity of measuring both H2 and CH4. Of the patients, 24 had undergone an ileocolic resection before the test with ablation of the ileocecal valve. At the time of the test 15 patients had active disease, whereas in 52 subjects the disease was quiescent. Fifty-seven patients and forty controls were evaluable for OCTT and bacterial overgrowth. In 10 patients and in 3 controls, no H2 or CH4 peak was recorded during the 8-hour test. Out of 57 patients, 13 (23%) were affected by bacterial overgrowth. The prevalence of bacterial overgrowth was higher in patients with previous surgery (30%) than in nonoperated patients (18%). In all patients with bacterial overgrowth, an antibiotic treatment induced a normalization of the test and an improvement of the symptoms. We observed a longer OCTT in the patients compared to controls, although this difference was not statistically significant (154 +/- 45 vs. 136 +/- 45 minutes). OCTT was significantly longer compared to controls in the 14 CD patients with previous ileocolic resection ( 180 +/- 53 vs. 136 + 45 minutes; p < 0.004). In conclusion, we found that a significant proportion of unselected patients with CD has bacterial overgrowth and prolongation of OCTT. We suggest that the modifications in OCTT in patients with CD can predispose to bacterial overgrowth. The lactulose breath test is a simple method that can be more widely used in patients with CD.

Can dietary intake influence plasma levels of amino acids in liver cirrhosis?

BACKGROUND: Modifications in plasma amino acid patterns in cirrhotics are attributed to impaired liver function, being more evident in alcoholic than in viral cirrhosis. AIM: To evaluate whether diet influences plasma amino acid concentrations in different aetiological groups of cirrhotics. PATIENTS: Study population comprised 40 patients with cirrhosis (25 virus- and 15 alcohol-related], all Child A, and 30 healthy subjects (controls). METHOD: A food frequency and quality questionnaire was utilized to determine dietary history and alcohol intake. Nutritional status was evaluated by anthropometric method. Amino acids were determined, on venous blood samples, using a specific analyzer while cysteine was evaluated by fluorescent high power liquid chromatography RESULTS: The total daily intake of calories, proteins, lipids, and carbohydrates was similar in all individuals. Food quality distinguished the cirrhotics from the controls, but not the different aetiological groups of cirrhotics. Plasma cysteine levels were significantly lower, while aromatic amino acids and methionine were significantly higher, in all cirrhotics (p<0.001 and p<0.01, respectively, versus controls). The decrease in cysteine and the increase in other amino acids were more marked in alcoholics (p<0.01). CONCLUSIONS: Ethanol intake, but not diet, further enhances the changes in plasma aromatic amino acids, methionine and cysteine induced by impaired liver function in patients with cirrhosis, suggesting a direct interference of alcohol in their metabolism.

Hepatitis related to cytomegalovirus infection in two patients with Crohn's disease treated with azathioprine.

Azathioprine-related side-effects occur in about 15% of treated patients. Liver toxicity is a rare complication of this drug, but is considered, in most cases, a contraindication to the continuation of treatment. However, abnormal liver tests may occur in patients under azathioprine treatment also due to infections. The distinction between toxic and infective causes of abnormal liver tests is important in order to identify patients that can be rechallenged with the drug. Cytomegalovirus infection is common in immunosuppressed transplant recipients, while the incidence is lower in patients with inflammatory bowel disease treated with immunosuppressive drugs. To our knowledge, only 2 cases of cytomegalovirus hepatitis occurring during azathioprine treatment for Crohn's disease had been reported so far. Here, we describe two patients who experienced mild hepatitis associated with the onset of cytomegalovirus infection during azathioprine treatment. The infection was documented by the appearance of IgM anti cytomegalovirus. Both cases were self-limiting. In one of the 2 patients, azathioprine was given again after resolution of the hepatitis with good control of Crohn's disease and without other complications. We also retrospectively evaluated the incidence of liver abnormalities assessed by blood tests in 58 consecutive patients with Crohn's disease treated with azathioprine at our institution. Abnormal results were obtained in 8 out of these 58 patients, requiring discontinuation of the drug in 3 patients, two of whom were the cytomegalovirus cases described above.

Serological and clinical markers of autoimmune disease in HCV-infected subjects with different disease conditions.

OBJECTIVE: To investigate whether the serological markers of autoimmunity and the clinical features of autoimmune disease which occur in hepatitis C virus (HCV)-infected subjects are correlated to each other and/or to the clinical pattern of the disease. METHODS: Seventeen symptom-free, anti-HCV antibody positive subjects, 17 patients with chronic hepatitis C, 21 patients with mixed cryoglobulinemia (MC), and as controls 17 anti-HCV negative patients with dyspepsia were enrolled in a prospective study. A patient history, clinical examination, self-administered questionnaire and laboratory investigations (hepatic enzyme levels, serum HCV-RNA and anti-HCV antibody testing, and serum autoantibody profile) were performed to detect liver and/or autoimmune disease. RESULTS: Serological markers of autoimmunity and clinical findings of autoimmune disease were found to be more frequent in the HCV-infected patients considered as a whole than in controls. However, rheumatoid factor and clinical findings of autoimmune disease were more frequent in MC patients, while anti-smooth muscle antibodies not linked to symptoms or signs of autoimmune disease were detected in all groups of HCV-infected individuals, including healthy carriers and subjects who had recovered from a previous HCV infection. CONCLUSION: Anti-smooth muscle antibodies, a serological marker of autoimmunity, are detectable in HCV-infected subjects whatever their clinical status. Clinical findings of autoimmune disease prevalently occur in patients with mixed cryoglobulinemia.

Determination of plasma alpha-glutathione S-transferases in patients with HCV-related chronic infection: its significance and possible clinical relevance.

AIMS/BACKGROUND: Alpha-glutathione S-transferases (alpha-GST) are the cytoplasmatic class of enzymes responsible for cellular detoxifying processes. We evaluated the plasma alpha-GST activity in relation to chronic infection caused by hepatitis C virus (HCV). METHODS: Eighteen anti-HCV-negative healthy subjects (controls), 32 anti-HCV-positive subjects with a constant normality of alanine aminotransferases (ALT) and gamma-glutamyl transpeptidase (gamma-GT) levels ("apparently healthy carriers"), and 85 patients with HCV-related chronic liver disease (40 chronic hepatitis, 27 cirrhosis, and 18 with hepatocellular carcinoma) were studied. We assayed plasma alpha-GST in all subjects upon their entry into the study; and every 6 months for 3 years in the control group and in anti-HCV apparently healthy carriers. RESULTS: Alpha-GST values were significantly higher than normal values in 57% of the 21 HCV-RNA-positive apparently healthy carriers and in none of 11 persistently HCV-RNA-negative subjects; the highest increment of alpha-GST was documented in patients with chronic hepatitis. We did not observe correlation among HCV-RNA, histological activity, gamma-GT and ALT or alpha-GST values. CONCLUSIONS: Therefore, the increment of plasma alpha-GST indicates a liver involvement even when ALT levels are normal. This may be clinically relevant to "apparently healthy carriers" whose plasma alpha-GST values, when increased, might need further evaluation.