Safety, feasibility, and tolerability of ileocolonoscopy in inflammatory bowel disease.

BACKGROUND AND STUDY AIMS: Ileocolonoscopy including biopsies is the first-line investigation in the diagnosis, management, and monitoring of inflammatory bowel disease (IBD). However, data on its safety, feasibility, and tolerability, especially in patients with extensive or severe inflammation, are rare. The aim of this study was to assess prospectively the risks of ileocolonoscopy in relation to various disease patterns and to compare possible burdens of the procedure in the endoscopist's and the patient's perception. PATIENTS AND METHODS: We prospectively analyzed a total of 558 consecutive patients, 482 with a confirmed diagnosis of IBD and 76 with suspected IBD. Data were recorded regarding the indication for ileocolonoscopy, sedation, procedure time, completion rate, feasibility of the procedure, patient tolerance, and procedure-related and postprocedure complications. Endoscopic data included the region involved, the nature of the involvement, activity of the disease, and number of biopsies. RESULTS: In 558 endoscopic procedures performed by 14 gastroenterologists no procedure-related deaths occurred. Major complications, defined as bleeding (n = 1) or perforation (n = 3), occurred in 4/558 patients (0.7 %). Minor complications, which included intense flatulence, tachycardia, allergic reaction to a sedation drug, and autonomic symptoms such as nausea, vomiting, and intense perspiration, occurred in 22/558 patients (3.9 %). There was no relationship between the complication rate and the activity of the disease. Mean procedure time was 21.0 minutes and the completion rate, defined by intubation of the terminal ileum, was 94.6 %. We documented a high tolerability independent of the severity of the disease. CONCLUSIONS: Ileocolonoscopy is a safe and feasible procedure in patients with IBD and is well tolerated by patients when carried out by well-trained endoscopists.

[Bile acid-independent effect of hymecromone on bile secretion and common bile duct motility]. / Gallensäure-unabhängige Wirkung von Hymecromon auf die Gallesekretion und die Motilität der Gallenwege.

BACKGROUND AND OBJECTIVE: Hymecromone (4-methyl-umbiliferone) has been used for more than 20 years for the treatment of functional and obstructive spasms of the biliary tract. Its mode of action however is still largely unknown. We investigated the effect of 4-methyl-umbiliferone p. o. and i. v. on gall bladder and common bile duct motility and studied potentially indirect effects via alterations in bile acid metabolism. PATIENTS AND METHODS: Twenty healthy volunteers, aged 25 - 37, 10 males, 10 females, were included into a Placebo-controlled, randomised, cross-over double-blind study. Subjects were treated with 800 mg hymecromone p. o.; in addition a standardized meal (Biloptin, 40 gs) was given. Gall bladder volume and common bile duct diameter were determined by ultrasound. Conjugated and unconjugated bile acids were analysed by gas chromatography. Additionally, in a third open label phase hymecromone was given i. v. RESULTS: Common bile duct diameter was significantly larger after a standard meal with hymecromone given p. o. or i. v. than with placebo (each p < 0.01). However, alterations in gall bladder volume after a standard meal were not different between placebo and hymecromone (p. o. or i. v.). Unconjugated and conjugated bile acids rose after standard meal in all three groups without significant differences between hymecromone and placebo. CONCLUSIONS: Hymecromone was associated with significant dilation of the common bile duct. In contrast to previous reports an effect of hymecromone on gall bladder motility could not be observed. The unchanged values of bile acids in serum after hymecromone compared to placebo, together with the dilatation of the common bile duct after hymecromone, may indicate a bile acid-independent effect of hymecromone on bile secretion.

[Diverticulosis and diverticulitis]. / Divertikulose und Divertikulitis.

Alterations in the colon wall, motility disorders, and certain nutritional habits are the essential factors in the development of colon diverticula. Thus, with advancing age this results in a high incidence in Western industrialized countries. The clinical picture is usually one of symptom-free diverticulosis. Diverticular disease can be associated with minor symptoms, but in complicated cases with diverticulitis and diverticular hemorrhage, it is potentially fatal. Further complications include abscess formation, fistula development, and obstruction. Barium double-contrast imaging exhibits the highest diagnostic sensitivity in diverticulosis but is contraindicated in cases of suspected complicated diverticular disease due to the danger of perforation. In these instances, sonography, computed tomography, or magnetic resonance imaging are performed. For diverticular hemorrhage, coloscopy not only represents a possible diagnostic tool but also a therapeutic option for various techniques of hemostasis. Treatment of diverticulitis and its complications requires careful consideration of conservative and surgical approaches and close interdisciplinary cooperation.

Chronic diarrhea as a result of intestinal microsposidiosis in a liver transplant recipient.

BACKGROUND: Microsporidia are common pathogens among patients infected with human immunodeficiency virus. They account for a substantial proportion of chronic diarrhea and malabsorption in acquired immune deficiency syndrome, but their appearance after solid organ transplantation has only rarely been reported. Methods. We report what we believe is the first case of documented Enterocytozoon bieneusi infection in a liver transplant recipient. Results. Our patient presented with chronic diarrhea and colicky abdominal pain. Although symptoms were severe, only mild microscopical mucosal changes were found in the intestinal tract. A modified trichrome stain of stool specimens revealed microsporidial spores, and species differentiation by restriction fragment length polymorphism polymerase chain reaction identified Enterocytozoon bieneusi. Albendazole therapy brought symptomatic relief but no microbiological clearance. CONCLUSIONS: Enterocytozoon bieneusi may cause chronic diarrhea not only in immunosuppression as a result of human immunodeficiency virus infection but also among patients with therapeutic immunosuppression after organ transplantation. Therefore, microsporidial infection should be considered in immunosuppressed patients with otherwise unexplained diarrhea.

Liver transplantation from controlled non-heart-beating donors.

BACKGROUND: The use of organs from non-heart-beating donors (NHBDs) has been proposed as one way to increase the donor pool. However, few centers have transplanted livers from NHBDs. We report here the results of 19 liver transplants from controlled NHBDs. METHODS: From January 1993 through August 1999, 364 liver transplantations were performed from heart-beating donors (HBDs) and 19 liver transplantations were performed from NHBDs. Donor and recipient characteristics, posttransplant complications, and patient and allograft survival were compared. RESULTS: No differences in hepatic artery, portal vein, or biliary complications were noted between the groups. However, the rate of primary nonfunction was higher in recipients of livers from NHBDs (10.5% vs. 1.3%; P = .04). No difference in patient survival was seen between recipients of NHBDs or HBDs (72.6% vs. 84.8%; P =.36); however, allograft survival was lower in recipients who received livers from NHBDs (53.8% vs. 80.9%; P =.007). CONCLUSIONS: Liver transplantation from controlled NHBDs results in similar patient survival and post-transplant complications. However, primary nonfunction was higher and allograft survival was less in recipients of livers from NHBDs. The results of liver transplantation from controlled NHBDs are encouraging and should continue to be cautiously pursued as one way to help alleviate the current shortage of donor livers.

[Patient suffers from insomnia. Proscribing bed rest]. / Patient leidet unter Schlaflosigkeit. Erteilen Sie ihm Bettverbot!

Roughly every fifth patient attending the doctor's office complains of insomnia. The first thing that needs to be done is to determine whether a particular patient has primary insomnia of pathological significance, or a temporary disturbance of his/her sense of well-being, or whether the sleep disorder is a secondary consequence of some other somatic or psychiatric condition. For the treatment of insomnia in the doctor's office, a number of basic rules derived from behavioral medicine can be recommended, for example systematic self-observation and record-keeping in a sleep diary, reassurance as to the harmlessness of a temporary sleep problem, practicing relaxation to reduce the general level of activity, reduction of the time spent in bed, and sleep-deprivation treatment. For all of these forms of treatment, a good doctor-patient relationship is mandatory, in particular when--as is to be expected--setbacks occur, which should not be dramatized. A diagnosis-treatment diagram is presented, in which proposals for medication should also be integrated.

Retreatment with interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C.

BACKGROUND/AIMS: Combination therapy with interferon-alpha (IFN-alpha) plus ribavirin is more efficacious than IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C and patients with IFN-alpha relapse. Only limited data are available in IFN-alpha non-responders. In a multicenter trial we therefore evaluated the efficacy of combination therapy in IFN-alpha-resistant chronic hepatitis C. METHODS: Eighty-two patients (mean age 46.8 years, 54 males, 28 females) with chronic hepatitis C were treated with IFN-alpha-2a (3 x 6 MIU/week) and ribavirin (14 mg/kg daily) for 12 weeks. Thereafter, treatment was continued only in virological responders (undetectable serum HCV RNA at week 12) with an IFN-alpha dose of 3 x 3 MIU/week and without ribavirin for a further 9 months. The primary study endpoint was an undetectable HCV RNA by RT-PCR at the end of the 24-week follow-up period. RESULTS: After 12 weeks of combination therapy, an initial virological response was observed in 29 of 82 (35.4%) patients. Due to a high breakthrough rate after IFN-alpha dose reduction and ribavirin discontinuation, an end-of-treatment response was only achieved in 12 of 82 (14.6%) patients. After the follow-up period, a sustained virological response was observed in 8 of 82 (9.8%) patients. Infection with HCV genotype 3 was the only pretreatment parameter, which could predict a sustained response (HCV-1, 5%; HCV-3, 57.1%; p < 0.001). CONCLUSIONS: Despite a high initial response rate of 35.4%, sustained viral clearance was achieved only in 9.8% of the retreated primary IFN-alpha non-responders. Higher IFN-alpha induction and maintenance dose, as well as prolonged ribavirin treatment may possibly increase the virological response rates in non-responders, particularly in those infected by HCV-1.

Efficacy of a short-term ribavirin plus interferon alpha combination therapy followed by interferon alpha alone in previously untreated patients with chronic hepatitis C: a randomized multicenter trial.

BACKGROUND: Combination therapy with interferon alpha (IFNalpha) plus ribavirin has been shown to improve the sustained response rate in patients with chronic hepatitis C but there is little information regarding the lengths of time for this therapeutic regimen. In this study we therefore tried to evaluate whether the analysis of different virological parameters could provide new clues with respect to the early determination of the efficacy of this form of combination therapy. Furthermore, we also examined whether short-term induction combination therapy followed by IFNalpha alone is more effective than monotherapy in mounting an initial as well as a sustained virological response. METHODS: 185 patients with histologically proven chronic hepatitis C (mean age 42 years (range 19-65 years); 110 males, 75 females) were enrolled in the study. The patients were randomly assigned to receive, over the first 12 weeks, either interferon alpha 2a 6 million units (MU) three times weekly plus ribavirin 14 mg/kg per day (n=93) or the same dose of IFNalpha alone (n=92). Patients with a virological response (serum HCV RNA undetectable) after 12 weeks were subsequently treated with 3 MU IFNalpha alone thrice weekly for a further 40 weeks. Otherwise, treatment was discontinued. After the end of treatment, patients were followed up for 24 weeks. RESULTS: Patient characteristics at baseline were not significantly different in the two treatment groups. An initial virological response at week 12 was seen in 61 (66%) patients receiving IFNalpha plus ribavirin and in 44 (48%) being treated with IFNalpha alone (p=0.015) and this improvement in the response rate was mainly restricted to HCV genotype 1-infected patients (58% vs. 38%). In contrast, end-of-treatment (week 52) and sustained virological response rates were similar in both groups (37% vs. 29% and 26% vs. 17% [p=0.1], respectively). Interestingly, patients with HCV genotype 3, however, clearly benefited from short-term combination therapy. Thus, sustained virological response rates in these patients significantly increased from 25% (IFNalpha monotherapy) to 59% (combination therapy) (p=0.05). CONCLUSIONS: Short-term combined therapy for 12 weeks is more effective than the monotherapy with respect to the induction of an initial virological response but this effect applies only to genotype 1-infected patients. However, there is no significant difference between both therapeutic schedules with regard to the induction of sustained response. Although HCV genotype 3-infected patients seem to benefit from this short-term combined therapy, prolonged combined therapy may be necessary in HCV genotype 1-infected patients.

Simultaneous pancreas-kidney (SPK) transplantation from controlled non-heart-beating donors (NHBDs).

From January 1993 through June 1999, 18 simultaneous pancreas-kidney transplants (SPKs) were performed from controlled non-heart-beating donors (NHBDs) and 339 SPKs were performed from heart-beating donors (HBDs). No difference in donor characteristics was noted except for warm ischemic time, which was 14.8 min (range 4-46 min) for NHBDs. Following transplantation, no difference in pancreatic function was noted; however, a higher rate of enteric conversions was seen in pancreas transplants from NHBDs (32% vs. 13%; p < 0.01). Hemodialysis for acute tubular necrosis (ATN) was higher in kidney transplants from NHBDs (22.2% vs. 4.1%; p = 0.009) as was discharge serum creatinine (1.7 mg/dl vs. 1.5 mg/dl; p < 0.05). Also, the number of patients remaining rejection free was lower for NHBDs and approached significance (33.3% vs. 50.1%; p = 0.07). However, no difference in patient survival (100% vs. 95.4%) or pancreatic (87.4% vs. 86.5%) and renal (86.3% vs. 86.3%) allograft survival was noted during the study period. Our results indicate that SPK transplantation from controlled NHBDs is a viable method for increasing the number of pancreas and kidney transplants available for transplantation.

Interferon-antibodies and the breakthrough phenomenon during ribavirin/interferon-alpha combination therapy and interferon-alpha monotherapy of patients with chronic hepatitis C.

BACKGROUND/AIMS: The significance of interferon antibodies with respect to response to treatment in patients with chronic hepatitis C treated with interferon-alpha (INF-alpha) remains a matter of debate. The influence of ribavirin on IFN-antibody formation in combination therapy with IFN-alpha has not yet been studied. Therefore we evaluated the relationship between IFN-antibodies and response to ribavirin/IFN-alpha combination therapy and IFN-alpha monotherapy. METHODS: We studied 169 patients with chronic hepatitis C who were treated either with IFN alpha 2a (6 MU, thrice weekly) alone or in combination with ribavirin (14 mg/kg per day) for twelve weeks. Thereafter, patients who achieved a virological response (HCV-RNA-negative) were treated with 3 MU IFN-alpha thrice weekly for another 40 weeks. IFN antibodies were analyzed and quantified by a double-antigen sandwich enzyme immunoassay (EIA). In 86 patients two neutralization assays--an antiviral neutralization assay as well as an antiproliferative neutralization assay--were performed in addition. The relationship of the development of IFN-antibodies with the virologically defined response to treatment was analyzed. RESULTS: Ribavirin did neither influence the prevalence nor the level of IFN-antibodies. The frequencies of IFN-antibody formation did not differ in the response groups. However, patients with breakthrough showed significantly higher IFN-antibody titers as compared to responder at end of treatment (median 1,336 BU/ml vs. 148 BU/ml; p = 0.018). Among the breakthrough patients those with IFN-antibodies showed the reappearance of HCV-RNA during therapy significantly earlier (median week 24) than those without IFN-antibodies (median week 32; p = 0.03). CONCLUSION: The addition of ribavirin to IFN-alpha does not influence the formation of IFN-antibodies. The development of high-titer IFN-antibodies during IFN-alpha or ribavirin/IFN-alpha therapy of patients with chronic hepatitis C may account for the early occurrence of breakthrough in some patients, while other mechanisms seem to be responsible for this phenomenon in the majority of the afflicted patients.

A vigorous virus-specific CD4+ T cell response may contribute to the association of HLA-DR13 with viral clearance in hepatitis B.

A strong virus-specific CD4+ and CD8+ T lymphocyte response to hepatitis B virus (HBV) has been associated with viral clearance, but little is known about factors determining the individual's ability to mount such a T cell response. Recently a strong association between the HLA class II allele DR13 and a self-limited course of HBV infection has been described. In the present study of 33 patients with acute hepatitis B we show that individuals carrying HLA-DR13 mount a more vigorous CD4+ T cell response to HBV core (5706 ct/min (25th/75th percentile 3239 ct/min; 10,552 ct/min)) than patients without HLA-DR 13 (1365 ct/min (490 ct/min; 5334 ct/min); P = 0.006). However, peptide epitopes aa 50-69, aa 61-85, and aa 81-105 were recognized most frequently by both patient groups. Moreover, among 14 HBV core-specific CD4+ T cell clones from two patients with HLA-DR13, only one T cell clone was HLA-DR13-restricted. Our data suggest that the beneficial effect of the HLA-DR13 alleles on the outcome of HBV infection could be explained by a more vigorous HBV core-specific CD4+ T cell response, which may either be due to more proficient antigen presentation by the HLA-DR13 molecules themselves or a linked polymorphism in a neighbouring immunoregulatory gene.

Sarcoidosis associated with interferon-alpha therapy for chronic hepatitis C.

BACKGROUND/AIMS: Pulmonary side effects of interferon-alpha therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-alpha treatment of chronic hepatitis C have been described. METHODS/CASES: We report on three patients who were treated with recombinant interferon-alpha2a for chronic hepatitis C, two of them in combination with ribavirin. These patients developed pulmonary sarcoidosis 12, 20 and 21 weeks, respectively, after beginning interferon therapy, one patient with Löfgren's syndrome. In one patient sarcoidosis emerged only after discontinuation of interferon therapy because of treatment failure. Clinical symptoms of sarcoidosis in the three patients were suggestive of side effects of interferon-alpha. Interferon therapy was discontinued and spontaneous remission was observed in all three cases 5, 6, and 8 months, respectively, after the onset of symptoms. CONCLUSION: The occurrence of sarcoidosis in association with interferon-alpha therapy for chronic hepatitis C may have been underestimated so far. This could be due to the fact that symptoms of sarcoidosis and common side effects of interferon are similar, and sarcoidosis may occur after the end of interferon therapy. We hypothesize that interferon-alpha as a potent stimulator for T-helper 1 (Th1) immune responses may trigger the compartmentalized Th1 reaction that has been shown to take place in sarcoidosis.

Procurement, preservation, and transport of cadaver kidneys.

This article discusses the guidelines for brain death determination, the criteria for donor selection, the management of the cadaveric donor, the surgical techniques of isolated renal and multiorgan retrieval, methods of organ preservation, and proper transport of organs to the recipient.

Donor factors affecting outcome after pancreas transplantation.

In this study, we demonstrated that Px grafts from donors older than 45 years are associated with an increased risk of developing poor glycemic control and premature loss of Px function. Previous studies corroborate our finding that age of the donor is the principal donor characteristic impacting postoperative Px survival. Whereas prior studies also implicated hyperamylasemia as a factor which contributes adversely to outcome, we were unable to demonstrate a significant influence of donor hyperamylasemia on long-term graft survival, although it did correlate with the degree of immediate postoperative pancreatitis and with the need for oral hypoglycemic agents. Similarly, elevated blood glucoses in the donor, which can be a result of many other factors unrelated to the quality of the graft, did not predict a poor outcome in the recipient. NHB donor pancreata did as well as HB pancreata with regards to all postoperative functional parameters. A marginally increased risk of developing major complications was associated with older donors. Despite the frequent use of non-ideal donors, including older and NHB donors, excellent overall Px graft survival can be achieved. Although the quality of the pancreas graft was not directly addressed in this study, we believe irrespective of hyperglycemia or hyperamylasemia, subjective assessment of organ quality by an experienced transplant surgeon is the most important determinant of suitability.

Infant pediatric liver transplantation results equal those for older pediatric patients.

METHODS: From July 1984 to July 1995, 99 pediatric patients underwent 127 orthotopic liver transplants (OLT) at the University of Wisconsin Children's Hospital. The patients were divided into four groups according to age at time of transplant: group I, 0 to 6 months (n = 20); group II, 6 to 12 months (n = 18); group III, 1 to 2 years (n = 10); and group IV, 2 to 18 years (n = 51). A retrospective analysis was performed to compare these four groups with regard to preoperative indications and demographics, intraoperative technique, complications, and survival. All patients were followed up for 2 to 13 years. RESULTS: Biliary atresia was the most common indication for OLT in all four groups. The average waiting period varied from 19+/-18 days for group I to 44+/-64 days for group IV. Reduced-size liver transplant (I, 41%; II, 52%; III, 28%; IV, 21%), split-liver transplant (I, 0%; II, 7.4%; III, 17%; IV, 2.9%), or whole-liver transplant techniques were used. Although postoperative Intensive Care Unit stay was longer for the 0- to 6-month-old patients (I, 20+/-64; II, 7.6+/-9; III, 13+/-17; IV, 6.8+/-14 days), the total hospital stay (I, 43+/-63; II, 33+/-34; III, 32+/-20; IV, 29+/-31 days) was similar for all patients. The incidence of hepatic artery thrombosis (I, 19%; II, 19%; III, 27%; IV, 16%), biliary tract complications (I, 4.8%; II, 15%; III, 20%; IV, 14%), and retransplantation (I, 9.5%; II, 41%; III, 33%; IV, 14%) were not significantly different between the four groups. Portal vein thrombosis (I, 9.5%; II, 11%; III, 6.6; IV, 0%) and primary nonfunction (I, 9.5%; II, 7.4%; III, 0%; IV, 3.1%) occurred more frequently in the 0- to 6-month and 6- to 12-month groups, however, the 1-, 5-, and 10-year survival rate for patients (I, 85%, 79%, 79%; II, 89%, 74%, 74%; III, 80%, 80%, 80%; IV, 84%, 75%, 75%, respectively) and primary liver allografts (I, 69%, 69%, 69%; II, 72%, 72%, 63%; III, 70%, 70%, 70%; IV, 71%, 57%, 57%, respectively) were not significantly different (P = .98 and P = .83). CONCLUSION: These results demonstrate that OLT can be effectively performed on infants of all ages and that OLT should not be delayed because of age.

Immunodominant CD4+ T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection.

In acute hepatitis C virus infection, 50 to 70% of patients develop chronic disease. Considering the low rate of spontaneous viral clearance during chronic hepatitis C infection, the first few months of interaction between the patient's immune system and the viral population seem to be crucial in determining the outcome of infection. We previously reported the association between a strong and sustained CD4+ T-cell response to nonstructural protein 3 (NS3) of the hepatitis C virus and a self-limited course of acute hepatitis C infection. In this study, we identify an immunodominant CD4+ T-cell epitope (amino acids 1248 to 1261) that was recognized by the majority (14 of 23) of NS3-specific CD4+ T-cell clones from four of five patients with acute hepatitis C infection. This epitope can be presented to CD4+ T cells by HLA-DR4, -DR11, -DR12, -DR13, and -DR16. HLA-binding studies revealed a high binding affinity for 10 of 13 common HLA-DR alleles. Two additional CD4+ T-cell epitopes, amino acids 1388 to 1407 and amino acids 1450 to 1469, showed a very narrow pattern of binding to individual HLA-DR alleles. Our data suggest that the NS3-specific CD4+ T-cell response in acute hepatitis C infection is dominated by a single, promiscuous peptide epitope which could become a promising candidate for the development of a CD4+ T-cell vaccine.