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Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC-IBD).To investigate whether patients with PSC-IBD benefit from a gluten-free and amylase trypsin inhibitor (ATI)-free diet (GFD).We performed a prospective clinical pilot study administering an eight-week GFD. The primary outcomes were colonic inflammation assessed by proctosigmoidoscopy, and liver stiffness (surrogate for fibrosis, inflammation and cholestasis) measured by transient elastography before and after GFD. Amongst the secondary (exploratory) outcomes were colonic mucosal and serum cytokine/chemokine changes, the intestinal microbiome and transcriptome dynamics, and shifts in serum markers of hepatic fibrogenesis.Fifteen patients with PSC-IBD completed the study. The study did not meet its primary outcome: the endoscopic score and liver stiffness remained unchanged. However, the expression of pro-inflammatory mucosal cytokines and chemokines such as IL6, IL8, CCL2, and TNFα was significantly down-regulated. Two critical markers of liver fibrosis and matrix remodelling, thrombospondin-2 and -4, decreased significantly. The microbiota composition changed slightly, including a decrease in the pathogen Romboutsia ilealis. The intestinal transcriptome indicated a gut barrier improvement. Pruritus, fatigue, overall well-being, faecal calprotectin levels, and serum alkaline phosphatase did not change significantly.This study did not demonstrate a clinical improvement with short-term GFD in patients with PSC-IBD. However, a gluten/ATI-free diet may improve biomarkers of intestinal inflammation and barrier function in these patients with associated with changes in the enteric microbiota. Further investigation of the therapeutic potential of gluten-free diets in PSC-IBD is warranted.

AbstractTimely detection of portal hypertension as a manifestation in a subgroup of patients with common variable immunodeficiency (CVID) represents a challenge since it is usually not associated with liver cirrhosis. To identify relevant markers for portal hypertension, we evaluated clinical history, laboratory parameters, and abdominal ultrasound including liver elastography and biomarkers of extracellular matrix formation. Twenty seven (6%) of 479 CVID patients presented with clinically significant portal hypertension as defined by either the presence of esophageal varices or ascites. This manifestation occurred late during the course of the disease (11.8 years after first diagnosis of CVID) and was typically part of a multiorgan disease and associated with a high mortality (11/27 patients died during follow up). The strongest association with portal hypertension was found for splenomegaly with a longitudinal diameter of > 16 cm. Similarly, most patients presented with a liver stiffness measurement (LSM) of above 6.5 kPa, and a LSM above 20 kPa was always indicative of manifest portal hypertension. Additionally, many laboratory parameters including Pro-C4 were significantly altered in patients with portal hypertension without clearly increasing the discriminatory power to detect non-cirrhotic portal hypertension in CVID. Our data suggest that a spleen size above 16 cm and an elevated liver stiffness above 6.5 kPa should prompt further evaluation of portal hypertension and its sequelae, but earlier and better liquid biomarkers of this serious secondary complication in CVID are needed.

There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.

Context Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease (NAFLD), but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). Objective We studied the association of PRO-C3 and PRO-C6 with liver fibrosis before BS, examined their evolution after BS, and evaluated how much patients’ ATF contribute to their levels. Methods Serum PRO-C3 and PRO-C6 were measured in 158 BS patients and compared with liver, subcutaneous, and omental adipose tissue histology obtained during surgery. PRO-C3 and PRO-C6 levels of 63 patients were determined in follow-up at 3 and 12 months post-BS. Results Patients in the highest quartile of PRO-C3 had a higher risk of advanced liver fibrosis (stage F3-4; odds ratio 5.8; 95% CI [1.5-29.9]; P = 0.017) vs the lowest quartile (adjustment for age, gender, and BMI). PRO-C3 was positively correlated with markers of insulin resistance and liver enzymes. After BS, PRO-C3 levels decreased in patients with high baseline liver fibrosis. This decrease correlated with improvement of metabolic and liver parameters. PRO-C6 was not related to stage of liver fibrosis. ATF did not correlate with PRO-C3 or PRO-C6 levels at baseline or after BS. Conclusion PRO-C3 was associated with advanced liver fibrosis in patients with severe obesity, and decreased after BS, without being affected by ATF. These data suggest that BS prominently eliminates drivers of hepatic fibrogenesis in NAFLD.

Background & Aims Wheat has become the world's major staple and its consumption correlates with prevalence of noncommunicable disorders such as inflammatory bowel diseases. Amylase trypsin inhibitors (ATIs), a component of wheat, activate the intestine's innate immune response via toll-like receptor 4 (TLR4). We investigated the effects of wheat and ATIs on severity of colitis and fecal microbiota in mice. Methods C57BL/6 wild-type and Tlr4–/– mice were fed wheat- or ATI-containing diets or a wheat-free (control) diet and then given dextran sodium sulfate to induce colitis; we also studied Il10–/– mice, which develop spontaneous colitis. Changes in fecal bacteria were assessed by taxa-specific quantitative polymerase chain reaction and 16S ribosomal RNA metagenomic sequencing. Feces were collected from mice on wheat-containing, ATI-containing, control diets and transplanted to intestines of mice with and without colitis on control or on ATI-containing diets. Intestinal tissues were collected and analyzed by histology, immunohistochemistry, and flow cytometry. Bacteria with reported immunomodulatory effects were incubated with ATIs and analyzed in radial diffusion assays. Results The wheat- or ATI-containing diets equally increased inflammation in intestinal tissues of C57BL/6 mice with colitis, compared with mice on control diets. The ATI-containing diet promoted expansion of taxa associated with development of colitis comparable to the wheat-containing diet. ATIs inhibited proliferation of specific human commensal bacteria in radial diffusion assays. Transplantation of microbiota from feces of mice fed the wheat- or ATI-containing diets to intestines of mice on control diets increased the severity of colitis in these mice. The ATI-containing diet did not increase the severity of colitis in Tlr4–/– mice. Conclusions Consumption of wheat or wheat ATIs increases intestinal inflammation in mice with colitis, via TLR4, and alters their fecal microbiota. Wheat-based, ATI-containing diets therefore activate TLR4 signaling and promote intestinal dysbiosis.

Graphical abstract ., Highlights • Improved LAMP assay for the diagnosis of Malaria in a resource limited settings. • We developed a simple platform for the diagnosis of malaria by genus- and species-specific LAMP and successfully used a simple DNA extraction method. • LAMP-Tube scanner method is capable of detecting the two most common species of malaria parasites within 30 min and it’s proved to be sensitive, reliable and feasible. • Analogous results were obtained for LAMP-Tube scanner versus traditional microscopic method and LAMP-Thermocycler., We attempted to improve the loop-mediated isothermal amplification (LAMP) method for malaria diagnosis by using a simple DNA extraction procedure, and a portable device performing both the amplification and detection of LAMP in one platform. Additionally, the device served as a heating block for the DNA preparation. We refer this method as LAMP-Tube scanner, and evaluated using 209 microscopically positive malaria samples and compared them to RDTs and LAMP-Thermocycler. Two most common human infecting Plasmodium species were detected. The LAMP-Tube scanner method is found to be simple and allowed real-time detection of DNA amplification. The time to amplification varied but was closely less than 60 min. Sensitivity and specificity of LAMP-Tube scanner in detecting Plasmodium falciparum were 95% and 93.3%, compared to microscopy and 98.3% and 100% respectively, compared to standard LAMP-Thermocycler. In addition, it showed a detection limit of 10 and 40 copies of the parasitemia for Plasmodium vivax and P. falciparum. Accordingly, in comparison to the results obtained by microscopy, the LAMP-Tube scanner had a less divergence in sensitivity and specificity, and yielded results similar to those of LAMP-Thermocycler. This method has the great potential as a field usable molecular tool for the diagnosis of malaria and is an alternative to conventional PCR-based diagnostic methods for field use.

Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of-concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.