Serum Amyloid A as a Potential Biomarker in Inflammatory Bowel Diseases, Especially in Patients with Low C-Reactive Protein.

The acute phase protein Serum Amyloid A (SAA) is synthesised by the liver in response to inflammatory stimuli. Previous studies have revealed that SAA may be a better biomarker of disease activity in inflammatory bowel disease (IBD) compared to C-reactive protein (CRP). This retrospective monocentric study evaluated whether SAA correlates with biomarkers like faecal calprotectin (FC), CRP, the Neutrophil to Lymphocyte ratio (NLR), the platelet count and clinical disease activity of IBD patients. Serum samples from the IBD outpatient clinic of the University Hospital Heidelberg were analysed for SAA concentrations if an FC concentration measurement was available from ±14 days to collection of the serum sample. Three hundred and six serum samples from 265 patients (166 with Crohn's disease, 91 with ulcerative colitis and 8 with IBD unclassified) met the inclusion criteria. There was a significant positive correlation between SAA and FC, CRP, NLR, platelet count and the Simple Clinical Colitis Activity Index (SCCAI). The cut-off for SAA serum concentration at 4.55 mg/L achieved a sensitivity of 57.5% and a specificity of 69.7% for the detection of active inflammation in IBD. SAA may be used as an additional biomarker in the disease monitoring strategy of IBD patients, especially in patients with low CRP concentrations.

Questions to consider when caring for patients with ulcerative colitis.

Although the management of patients with ulcerative colitis (UC) is well defined by national and international guidelines, there are many debates and open questions related to daily care of UC patients. Here, we aimed to review topics with high clinical relevance including therapy algorithms, potential biomarkers for disease prognosis and response to therapy, the role of interventions targeting the gut microbiota, insights from head-to-head trials, novel UC medications, exit strategies, the impact of COVID19 on UC, care of patients with acute severe disease, cancer screening, and the role of surgery.

Pregnancy with inflammatory bowel disease: Outcomes for mothers and their children at a European tertiary care center.

AIM: The study aimed at investigating pregnancy complications, birth outcomes, and postnatal child development in pregnancies of women with inflammatory bowel diseases (IBDs). METHODS: This is an uncontrolled retrospective single-center study between 2014 and 2019. It is a mixed-method cross-sectional study using data from (1) electronic patient records and (2) questionnaires and copies of mothers' and children's health booklets. Disease activity and IBD medications were analyzed and related to pregnancy complications, birth outcomes, and postnatal child development using mixed models for statistical analyses. RESULTS: Fifty live births from 46 patients were included. Disease activity anytime during pregnancy occurred in 56%. Biologics were applied in ca. 25% of pregnancies, mostly only through the second trimester. Pregnancies of mothers with active disease were slightly shorter than those of mothers with inactive disease (37.4 weeks vs. 38.9 weeks). Adverse pregnancy outcomes were reported in 28% of the live births, including small for gestational age in 6%, low birth weight in 18%, and preterm birth in 20%. Postnatal developmental abnormalities and health problems were reported in 26.8% of the children. Mixed model analyses failed to reveal significant associations between IBD activity and IBD medications during pregnancy and pregnancy complications, perinatal birth outcomes, and postnatal child development. CONCLUSION: Despite a tendency of shorter pregnancies in patients with active IBD and lower birth weight and birth size in patients with IBD-related therapy during pregnancy, disease activity and medications did not significantly influence pregnancy, birth, and developmental outcomes.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

The Validity of Somatic Symptom Disorder in Patients With Gastrointestinal Complaints.

BACKGROUND AND GOAL: The current diagnostic concept of somatic symptom disorder (SSD) aims to capture psychological burden due to bodily complaints independent of the medical cause. The aim of this study was to compare patients with chronic gastrointestinal (GI) complaints with SSD (SSD+) and without SSD (SSD-) along sociodemographic, clinical, and psychological characteristics. STUDY: This cross-sectional study included 199 patients (n=92 SSD+ and n=107 SSD-) with distressing and chronic abdominal/lower GI complaints (≥6 mo) recruited from several primary, secondary, and tertiary medical care units. SSD+ patients were separated from SSD- patients by psychobehavioral positive criteria. Psychological distress (somatization, depression, anxiety, and illness anxiety) and risk factors (adverse childhood experiences, insecure attachment, mentalizing capacity, and levels of personality functioning) were measured. Nonparametric group comparisons were performed to analyze the differences of sociodemographic, clinical, and psychological characteristics between SSD+ and SSD- patients. RESULTS: About half of the SSD+ patients had a functional GI disorder and a third had an inflammatory bowel disease. SSD+ patients reported higher GI pain severity, higher health-related and work-related impairment, and higher psychological distress, especially illness anxiety, as well as higher mentalizing and personality functioning deficits. CONCLUSIONS: Overall, psychobehavioral positive criteria of SSD seem to be a valid identifier of patients exhibiting a high psychological burden, independent of the medical explanation of the GI complaints. There is a substantial overlap of SSD and general mental burden, but also evidence for a specific disease entity.

Thumb sucking or nail biting in childhood and adolescence is associated with an increased risk of Crohn's disease: results from a large case-control study.

BACKGROUND: The hygiene hypothesis suggests that a reduction in microbial exposure contributes to an impaired immune response later in life and increases the incidence of immune-mediated diseases such as inflammatory bowel diseases (IBD). Thumb sucking and nail biting are two early habits that modulate the oral microbiota composition and antigen load. OBJECTIVE: We hypothesized a lower risk of Crohn's disease (CD) and ulcerative colitis (UC) in adults with prior thumb sucking and nail biting. METHODS: 918 IBD cases and their 918 siblings without IBD were asked to fill out a survey containing 32 questions on environmental factors in childhood and early adulthood. Prevalence of thumb sucking and/or nail biting at the usually well-remembered time of (1) school enrollment and (2) coming-of-age ceremonies was the predefined combined risk factor of this study. RESULTS: 65% of the patients were female and 57% suffered from CD. About 49% of IBD patients but only 44% of their siblings reported thumb sucking/nail biting at the time of school enrollment or coming-of-age (p = .007). Sensitivity analysis revealed that this difference was observed in patients with CD (50% versus 41%; RR= 1.22; 95% CI 1.09-1.37, p = .001) but not in patients with UC (49% versus 48%; RR= 1.02; 95% CI 0.90-1.17; p = .83). CONCLUSION: Contrary to our expectation and challenging the hygiene hypothesis, we found that common oral habits are not protective against IBD. Instead, nail biting at the time of school enrollment and coming-of-age was a statistically significant risk factor for CD in our cohort. Key summary Evidence available before this study: The hygiene hypothesis suggests that a reduction in microbial exposure due to improved health activities has contributed to an immunological imbalance in the intestine and an increased incidence of allergic and autoimmune diseases. A population-based birth cohort study has demonstrated that thumb-sucking and nail biting in children lead to a reduction of the risk of atopic sensitization, asthma, and hay fever. Added value of this study: Contrary to the hypothesis, thumb sucking and nail biting were not associated with a reduced risk of IBD. Instead, thumb sucking and/or nail biting at the usually well-remembered points in time of school enrollment and of religious or secular coming-of-age ceremonies was associated with a higher risk of Crohn's disease but not of ulcerative colitis. Our data did not support the hygiene hypothesis, one pathogenic concept in the context of IBD.

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn's disease - a regional multi-center pilot study.

BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.

Pregnancy in Wilson's disease: Management and outcome.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births. CONCLUSION: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269).

Long-term evaluation of urinary copper excretion and non-caeruloplasmin associated copper in Wilson disease patients under medical treatment.

OBJECTIVE: Urinary copper excretion rates and non-caeruloplasmin associated copper concentrations are increased in patients with Wilson disease. However, there is little literature describing the monitoring of these parameters over the long term. METHODS: This is a monocentric retrospective study including data collected between 2003 and 2015 from 321 patients with Wilson disease by chart review. The patients were under therapy with D-penicillamine, trientine, or zinc. 24-h urinary copper excretion rates, non-caeruloplasmin associated copper, and total serum copper concentrations were determined at the start of therapy, as well as 6, 12, 18, 24, 36, and ≥ 60 months after the start of therapy. For patients taking chelating agents, all parameters were measured while under continued therapy, as well as after a 48-h dose interruption. A mathematical formula to predict 24-h urinary copper excretion rates under different therapies was established. RESULTS: In all treatment groups, urinary copper excretion rates decreased over time, but the inter-individual variation of the results was high. Non-caeruloplasmin associated copper concentrations tended to decline over time, but with a higher variation of results than that observed for urinary copper excretion rates. CONCLUSION: Due to their variability, urinary copper excretion rates and serum copper concentrations are less than ideal parameters by which to monitor the benefit of a copper-reducing therapy. Urinary copper excretion rates seem to be more suitable than non-caeruloplasmin associated copper concentrations for this purpose.

Real-World Outcomes of Vedolizumab Therapy in Ulcerative Colitis and Crohn's Disease at a Tertiary Referral Center.

BACKGROUND: Vedolizumab was approved for the therapy of ulcerative colitis and Crohn's disease in mid-2014. Real-world treatment data are necessary for a balanced assessment of its position among other therapeutic options. SUMMARY: Patients with ulcerative colitis or Crohn's disease, initiating vedolizumab therapy at the outpatient clinic for inflammatory bowel diseases at the University Hospital -Heidelberg between June 1, 2014 and August 31, 2016, were recruited based on electronic medical records. The primary study endpoint was response at week 30, while the secondary endpoints were the need for surgery and discontinuation of therapy due to inadequate response, or adverse events. Twenty-five patients with ulcerative colitis (40% anti-tumor necrosis factor α [TNFα] naive) and 28 patients with Crohn's disease (10.7% anti-TNFα naive, 53.6% having undergone at least one intestinal surgery) were enrolled. Among the ulcerative colitis patients, 20% achieved remission, 32% partial response, and 48% were non-responders to vedolizumab. In Crohn's disease, 14.3% of the patients achieved remission, 46.4% partial response, and 39.4% were non-responders. Two patients discontinued vedolizumab therapy due to suspected side effects. Key Message: In a relatively treatment-refractory cohort of inflammatory bowel disease patients, vedolizumab was efficacious in achieving response. However, the majority of the patients were not satisfactorily treated, as they did not reach remission.

Phosphatidylcholine passes through lateral tight junctions for paracellular transport to the apical side of the polarized intestinal tumor cell-line CaCo2.

Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1±6.3nmolh(-1)mMPC(-1) was observed. Equilibrium distribution studies with PC applied in equal concentrations to the basal and apical compartments showed a 1.5-fold accumulation on the expense of basal PC. Disruption of tight junctions (TJ) by acetaldehyde or PPARγ inhibitors or by treatment with siRNA to TJ proteins suppressed paracellular transport by at least 50%. Transport was specific for the choline containing the phospholipids PC, lysoPC and sphingomyelin. We showed that translocation is driven by an electrochemical gradient generated by apical accumulation of Cl(-) and HCO3(-) through CFTR. Pretreatment with siRNA to mucin 3 which anchors in the apical plasma membrane of mucosal cells inhibited the final step of luminal PC secretion. PC accumulates in intestinal mucus using a paracellular, apically directed transport route across TJs.

Accumulation of phosphatidylcholine on gut mucosal surface is not dominated by electrostatic interactions.

The accumulation of phosphatidylcholine (PC) in the intestinal mucus layer is crucial for the protection of colon epithelia from the bacterial attack. It has been reported that the depletion of PC is a distinct feature of ulcerative colitis. Here we addressed the question how PC interacts with its binding proteins, the mucins, which may establish the hydrophobic barrier against colonic microbiota. In the first step, the interactions of dioleoylphosphatidylcholine (DOPC) with two mucin preparations from porcine stomach, have been studied using dynamic light scattering, zeta potential measurement, and Langmuir isotherms, suggesting that mucin binds to the surface of DOPC vesicles. The enthalpy of mucin-PC interaction could be determined by isothermal titration calorimetry. The high affinity to PC found for both mucin types seems reasonable, as they mainly consist of mucin 2, a major constituent of the flowing mucus. Moreover, by the systematic variation of net charges, we concluded that the zwitterionic DOPC has the strongest binding affinity that cannot be explained within the electrostatic interactions between charged molecules.

Linear IgA Bullous Dermatosis Secondary to Infliximab Therapy in a Patient with Ulcerative Colitis.

Linear IgA bullous disease (LABD) is a rare vesiculobullous autoimmune skin disorder whose etiology and pathogenesis are not completely understood. Its occurrence has been related to malignancies, inflammatory diseases and several drugs. This report describes a 49-year-old Caucasian male with a 14-year history of ulcerative colitis who received infliximab to treat the refractory course of his bowel disease. During induction therapy with infliximab, he developed LABD. Treatment with infliximab was discontinued, and the skin lesions were successfully treated with oral steroids and dapsone. Considering the close chronological relation between administration of the tumor necrosis factor-α inhibitor and onset of the skin disease, we hypothesize that this is the first reported case of infliximab-induced LABD. Similar to psoriasis, it may represent a 'paradoxical' autoimmune reaction triggered by anti-tumor necrosis factor-α therapy.

CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores.

AIMS: Impaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether Child-Pugh (CP) and model for end-stage liver disease (MELD) scores correlate with drug clearance. METHODS: Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis (n = 4, 10 and 10 with CP class A, B and C, respectively) and six patients without liver disease. RESULTS: Both scores correlated well with unbound midazolam clearance (CLu ), unbound midazolam fraction and half-life (all P < 0.01), whereas the unbound steady-state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls (CP C: CLu = 843 ± 346 l h(-1), MELD ≥ 15: CLu = 805 ± 474 l h(-1), controls: CLu = 5815 ± 2649 l h(-1), P < 0.01). CONCLUSION: The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolizing enzyme subfamily in humans.

Pilot study to assess the influence of an enhanced medication plan on patient knowledge at hospital discharge.

PURPOSE: This study assessed the effect of providing an enhanced medication plan (EMP) to patients during patient-physician conversation at hospital discharge and evaluated its immediate impact on patient knowledge on pharmacotherapy. METHODS: We observed patient-physician conversations at hospital discharge in three internal medicine wards of the University Hospital Heidelberg before and after the EMP was integrated into the discharge process, and documented how and to what extent physicians provided the patients with drug information. After the conversation, the patients' knowledge was evaluated by three standardized questions about their pharmacotherapy. RESULTS: We observed 90 conversations (50 before EMP-implementation, 40 after). In both phases, the conversation duration was 5.6-6 min (p = 0.56). However, the time spent on drug information increased significantly by 61.7% after EMP-implementation (+63 s, p = 0.02). Before implementation, physicians gave at least one drug administration recommendation for 75.1% of all drugs, compared to 84.6% after implementation (p = 0.02). The EMP provided information for almost all drugs (98.9%; p < 0.01) after implementation. Three times more patients answered all questions correctly after EMP-implementation (p < 0.01). CONCLUSION: The provision of an EMP improves information transfer and therefore increases the patients' knowledge of their individual drug treatment without prolonging the overall discharge process.

Indications for intestinal transplantation: recognizing the scope and limits of total parenteral nutrition.

Total parenteral nutrition (TPN) is currently the treatment of choice for patients with intestinal failure. Intestinal failure in adults is mostly due to short bowel syndrome, which is most often caused by ischemia and Crohn's disease. However, TPN fails in a substantial number of cases. For patients with TPN failure, intestinal transplantation (ITx) may be offered as a treatment. TPN failure is considered to be present either if nutrition itself is not possible or if complications of TPN occur. These complications can, for example, originate from recurrent line infections or thrombosis. As TPN is usually a lifelong therapy and is associated with substantial impairment of the quality of life, the tolerance of each patient to this procedure is another important consideration in the decision making about whether to perform transplantation. The survival rates of intestinal transplant recipients have now reached the same level as that of recipients of other solid organ transplants. A five-yr survival of up to 80% has been reported in specialized centers, whereas registry data show rates of <80%. Although in about one-third of patients, isolated ITx is sufficient, patients with concurrent liver disease (mostly due to TPN) benefit from combined intestinal and liver transplantation. In some cases, multivisceral transplantation is necessary. Here, we review the current indications for ITx with a special focus on TPN.

Lecithin as a therapeutic agent in ulcerative colitis.

Lecithin [phosphatidylcholine (PC)] was shown to account for more than 70% of total phospholipids within the intestinal mucus layer. It is arranged in lamellar membranes (surfactant-like particles) and establishes a hydrophobic barrier preventing invasion of the colonic commensal microbiota. In ulcerative colitis (UC), the mucus PC content was demonstrated to be reduced by about 70%, irrespective of the presence of inflammation. This may be of primary pathogenetic significance allowing bacteria to enter the mucus and induce mucosal inflammation. Therefore, a new therapeutic strategy is being developed to substitute the missing mucus PC content in UC. Indeed, a delayed-release PC formulation was able to compensate the lack of PC and improve the inflammatory activity. In randomized controlled studies, delayed-release PC was proven to be clinically and endoscopically effective, which now awaits a phase III authority approval trial.

Flotillin-2 expression in the human gut: from a cell model to human tissue in health and inflammatory bowel diseases.

BACKGROUND AND AIMS: The etiopathogenesis of inflammatory bowel diseases (IBD) remains largely unexplained. Flotillins (flotillin-1 and flotillin-2) are ubiquitous proteins which have been linked to inflammation and regeneration. We hypothesized that alterations in the expression of flotillin-2 in enterocytes may be related to the pathogenesis of IBD as a classical example of an inflammatory disorder of mostly unknown origin. METHODS: Cell and tissue localization of flotillin-2 (and -1) were investigated by immunofluorescent staining in 1. polarized and unpolarized CaCo-2w cells as a model of human enterocytes (native and after TNFα stimulation) and 2. intestinal biopsies from controls, patients with ulcerative colitis (UC) and patients with Crohn's disease (CD). For quantification of flotillin-2, we analyzed its expression in ileal and colonic biopsies from controls, UC patients and CD patients using real-time RT-PCR, Western blot and indirect immunofluorescence. RESULTS: In polarized CaCo-2w cells and human enterocytes in biopsies, flotillins were localized at the basolateral membrane and on subapical vesicles, but not in the apical membrane. Flotillin-2 expression did not differ between UC patients, CD patients and controls. However, it was significantly higher in colonic biopsies compared to ileal biopsies in all groups. CONCLUSIONS: By virtue of its abundant expression in enterocytes, flotillin-2 must have an essential function in intestinal physiology, especially in the colon. Yet our data could not link flotillin-2 to the pathogenesis of IBD.