Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment.

OBJECTIVE: In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown. METHODS: The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities. RESULTS: Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31). CONCLUSION: This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.

Cyclophosphamide therapy in Sweet's syndrome complicating refractory Crohn's disease − Efficacy and mechanism of action.

BACKGROUND: Sweet's syndrome is a rare extraintestinal manifestation of Crohn's disease that is usually treated by corticosteroids. Cyclophosphamide therapy has been shown to be effective in steroid-refractory Crohn's disease with extraintestinal manifestations. The mechanism of action remains obscure. Here, we report about a case of steroid-refractory Sweet's syndrome accompanying Crohn's colitis treated by cyclophosphamide. METHODS: At baseline and two weeks after initiating cyclophosphamide pulse therapy, clinical symptoms were evaluated and apoptosis in mononuclear cells of the colon mucosa was quantified via immunofluorescence TUNEL-labeling. Ongoing clinical follow-up lasts for more than three years. RESULTS: Cyclophosphamide pulse therapy resulted in complete resolution of luminal activity and extraintestinal manifestations. TUNEL-marked CD4(+), CD8(+) and CD68(+) cells in intestinal biopsies showed a 338% increase as compared to baseline. CONCLUSIONS: Cyclophosphamide therapy was highly effective in steroid-refractory Crohn's colitis accompanied by Sweet's syndrome for induction of remission. Furthermore, apoptosis of mononuclear cells in the colon mucosa, including CD68(+) macrophages as well as CD4(+) and CD8(+) cells, appears to be a component of the anti-inflammatory effect of cyclophosphamide in Crohn's disease.

Crohn's targeted therapy: myth or real goal?

The broad spectrum of chronic inflammatory bowel diseases encompasses the two main entities Crohn's disease (CD) and ulcerative colitis (UC). Rapid action and long-term duration is the superordinate goal in most therapeutic approaches facing chronic inflammation including inflammatory bowel diseases (IBD) for induction and maintenance of remission. The availability of antibodies targeting TNF-alpha or alpha 4 integrin has recently offered new opportunities apart from classical remedies for the treatment of CD, a major challenge for future therapeutic concepts. Classical way of treating CD is an escalation scheme ("step-up") whereas the novel and still controverse approach ("top-down") favors a biological as initial drug. Today, four biologicals have proven efficacy and safety in CD treatment strategies and have received approval by FDA and, with the exception of natalizumab and certolizumab, by EMEA. Infliximab was the first TNF-alpha blocker and extended the care in CD. Adalimumab and certolizumab pegol followed as humanized second generation TNF-alpha blockers. Another targeted therapy option is natalizumab, an alpha 4 integrin monoclonal antibody, which blocks the migration of leukocytes into inflamed gut tissue. Nevertheless, a considerable number of patients remain refractory, lose response or render intolerant to these biologicals. An overall long lasting remission of less than 30% with scheduled administration of TNF-alpha blockers in patients with steroid dependent or refractory CD seems to be lifelike and alternative therapeutic options are warranted. Broad acting antimetabolites come into focus again and recent data provide substantial evidence for the efficacy and safety of cyclophosphamide pulse therapy in ileocolonic, refractory CD. This therapeutic option should be kept in mind as a reasonable agent to target the inflammatory process in severely disabled patients. Hence, targeted therapy in CD seems to be still a myth at present owing to the complex nature of disease.