Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort.

Estimation of liver function is important to monitor progression of chronic liver disease (CLD). A promising method is magnetic resonance imaging (MRI) combined with gadoxetate, a liver-specific contrast agent. For this method, we have previously developed a model for an average healthy human. Herein, we extended this model, by combining it with a patient-specific non-linear mixed-effects modeling framework. We validated the model by recruiting 100 patients with CLD of varying severity and etiologies. The model explained all MRI data and adequately predicted both timepoints saved for validation and gadoxetate concentrations in both plasma and biopsies. The validated model provides a new and deeper look into how the mechanisms of liver function vary across a wide variety of liver diseases. The basic mechanisms remain the same, but increasing fibrosis reduces uptake and increases excretion of gadoxetate. These mechanisms are shared across many liver functions and can now be estimated from standard clinical images.

Biomarkers of liver fibrosis: prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.

BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available. METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score). RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively. CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.

Liver R2* is affected by both iron and fat: A dual biopsy-validated study of chronic liver disease.

BACKGROUND: Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement. PURPOSE: To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD. STUDY TYPE: Prospective. POPULATION: Eighty-one patients with suspected CLD. FIELD STRENGTH/SEQUENCE: 1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF. ASSESSMENT: Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated. STATISTICAL TESTS: Pearson correlation, linear regression, and area under the receiver operating curve. RESULTS: There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively. DATA CONCLUSION: PDFF increases R2*. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.

Using a 3% Proton Density Fat Fraction as a Cut-Off Value Increases Sensitivity of Detection of Hepatic Steatosis, Based on Results From Histopathology Analysis.

It is possible to estimate hepatic triglyceride content by calculating the proton density fat fraction (PDFF), using proton magnetic resonance spectroscopy (1H-MRS), instead of collecting and analyzing liver biopsy specimens to detect steatosis. However, the current PDFF cut-off value (5%) used to define steatosis by magnetic resonance was derived from studies that did not use histopathology as the reference standard. We performed a prospective study to determine the accuracy of 1H-MRS PDFF in the measurement of steatosis using histopathology analysis as the standard. We collected clinical, serologic, 1H-MRS PDFF, and liver biopsy data from 94 adult patients with increased levels of liver enzymes (≥6 mo) referred to the Department of Gastroenterology and Hepatology at Linköping University Hospital in Sweden from 2007 through 2014. Steatosis was graded using the conventional histopathology method and fat content was quantified in biopsy samples using stereologic point counts (SPCs). We correlated the 1H-MRS PDFF findings with SPCs (r = 0.92; P < .001). 1H-MRS PDFF results correlated with histopathology results (ρ = 0.87; P < .001), and SPCs correlated with histopathology results (ρ = 0.88; P < .001). All 25 subjects with PDFF values of 5.0% or more had steatosis based on histopathology findings (100% specificity for PDFF). However, of 69 subjects with PDFF values less than 5.0% (negative result), 22 were determined to have steatosis based on histopathology findings (53% sensitivity for PDFF). Reducing the PDFF cut-off value to 3.0% identified patients with steatosis with 100% specificity and 79% sensitivity; a PDFF cut-off value of 2.0% identified patients with steatosis with 94% specificity and 87% sensitivity. These findings might be used to improve noninvasive detection of steatosis.

Treatment-Refractory Eosinophilic Esophagitis Successfully Managed with benralizumab: A Case Presentation and literature review.

Eosinophilic Esophagitis is a widely-recognized immune-mediated esophagus disease with distinct clinical and histopathological features, exhibiting an increased global incidence. Therapeutic options encompass either dietary measures or pharmacological approaches, including proton pump inhibitors and topical corticosteroids. The use of monoclonal antibodies is currently under comprehensive evaluation, with a plethora of ongoing clinical trials designed to determine their clinical efficacy. The present case report demonstrates an exceptional case of refractory Eosinophilic Esophagitis, unresponsive to conventional treatment, achieving both clinical and histopathological remission subsequent to initiation of benralizumab treatment. Concurrently, our case underscores the necessity for continued research in the field of monoclonal antibodies for their use as a future treatment approach against Eosinophilic Esophagitis.

Intraepithelial lymphocyte distribution differs between the bulb and the second part of duodenum.

BACKGROUND: Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb.We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects. METHODS: The number of CD3+ IELs was determined in specimens from the second part of the duodenum and from the bulb in 34 non-celiac subjects. The numbers of IELs in the villus tip and sides were counted and the quotient tip/side was calculated. HLA DQ2/DQ8 and serum antibodies against transglutaminase were analysed. RESULTS: The mean number of IELs per 100 enterocytes (95% CI) in specimens was 14.7 (11.8-17.6) in the bulb, and 21.2 (17.0-25.5) in the second part of the duodenum (p<0.01). There was no difference in IEL count or distribution comparing patients carrying or lacking HLA DQ2/DQ8. CONCLUSIONS: IEL count in non-celiac, HLA DQ2/DQ8 positive or negative patients is significantly lower in the bulb than in the second part of the duodenum. These findings implicate that the site of biopsy should be taken into account when considering duodenal lymphocytosis.

Mucosa-Associated Lymphoid Tissue Lymphoma of the Ascending Colon Successfully Removed With Endoscopic Submucosal Dissection.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of non-Hodgkin lymphoma with characteristic histopathological features and can occur in various extranodal sites, including the gastrointestinal tract. While gastric MALT lymphoma has been extensively researched, primary lymphoma presentation in the colorectal mucosa is rare and lacks any association with Helicobacter pylori infection. Furthermore, there are currently no standardized treatment guidelines for this condition. This report presents a rare case of primary MALT lymphoma that manifested as a broad-based polyp. The diagnosis was confirmed through histopathological and immunohistochemical examination, and the polyp was resected endoscopically with the endoscopic submucosal dissection technique.

Adalimumab in budesonide and methotrexate refractory collagenous colitis.

BACKGROUND: We described three patients with collagenous colitis (CC) who developed side effects or were refractory to both budesonide and methotrexate and were given adalimumab (ADA) as a third-line treatment. METHOD/PATIENTS: Three patients (two women, mean age 45 years and one man, 74 years old) were included. Mean bowel movements per day per week were calculated and stool weight/24 h registered prior to and following ADA treatment. ADA was given in doses 160 mg s.c. (baseline), 80 mg (week 2) and 40 mg (week 4). Sigmoidoscopies with biopsies were performed at baseline and after 6 weeks to examine changes in histology. The Psychological General Well-Being Index (PGWBI) and Short Health Scale (SHS) were used at baseline and after 6 weeks. RESULTS: The two female patients tolerated the treatment well. The male patient developed, despite clinical response, side effects (vomiting, abdominal pain) after 80 mg of ADA and the treatment was stopped as side effects reoccurred after rechallenge. The two women were in clinical remission at week 6 and the mean stool frequency per day decreased from mean 11 to 2. Mean stool weight/24 h changed from 600 to 185 g. The quality of life improved drastically in all patients. There were no consistent changes in histology. CONCLUSION: ADA seems effective in budesonide and methotrexate refractory CC and can be administrated to selected patients to achieve clinical remission, improve quality of life and possibly avoid colectomy. Further studies for induction and maintenance treatment should be conducted to confirm efficacy and examine safety issues, even in long term.

Primary malignant melanoma of the esophagus.

We report a case of primary malignant melanoma of the esophagus.

Mucosa associated invariant T and natural killer cells in active and budesonide treated collagenous colitis patients.

Introduction: Collagenous colitis (CC) is an inflammatory bowel disease, which usually responds to budesonide treatment. Our aim was to study the immunological background of the disease. Methods: Analyses of peripheral and mucosal MAIT (mucosa associated invariant T cells) and NK (natural killer) cells were performed with flow cytometry. Numbers of mucosal cells were calculated using immunohistochemistry. We studied the same patients with active untreated CC (au-CC) and again while in remission on budesonide treatment. Budesonide refractory patients and healthy controls were also included. The memory marker CD45R0 and activation marker CD154 and CD69 were used to further study the cells. Finally B cells, CD4+ and CD8+ T cells were also analysed. Results: The percentages of circulating CD56dimCD16+ NK cells as well as MAIT cells (CD3+TCRVa7.2+CD161+) were decreased in au-CC compared to healthy controls. This difference was not seen in the mucosa; where we instead found increased numbers of mucosal CD4+ T cells and CD8+ T cells in au-CC. Mucosal immune cell numbers were not affected by budesonide treatment. In refractory CC we found increased mucosal numbers of MAIT cells, CD4+ and CD8+ T cells compared to au-CC. Discussion: Patients with active collagenous colitis have lower percentages of circulating MAIT and NK cells. However, there was no change of these cells in the colonic mucosa. Most mucosal cell populations were increased in budesonide refractory as compared to au-CC patients, particularly the number of MAIT cells. This may indicate that T cell targeting therapy could be an alternative in budesonide refractory CC.

Low hepatic manganese concentrations in patients with hepatic steatosis - A cohort study of copper, iron and manganese in liver biopsies.

BACKGROUND AND AIMS: Hepatic steatosis is the most common histopathological finding on liver biopsy, with the most prevalent etiology being NAFLD. The pathogenesis of hepatic steatosis and NAFLD is multifactorial, however, studies on the importance of manganese in NAFLD are limited. We aimed to study hepatic manganese content, and other trace elements, in relation to hepatic steatosis in patients with chronic liver diseases of different etiology, mainly NAFLD. METHODS: Patients with chronically elevated liver function tests underwent a diagnostic work-up, including routine blood tests and two liver biopsies. One of the biopsies was sent for histopathological evaluation, and the other for ultra-trace elemental determinations. Steatosis was graded using conventional histopathological methodology, and fat content was also quantitated in biopsy samples by measuring the steatotic area of the section using stereological point counting (SPC). Ultra-trace elemental analysis was utilized for determining manganese, iron, and copper using inductively coupled plasma sector field mass spectrometry (ICP-SFMS). RESULTS: 76 patients were included in the study. Hepatic manganese concentrations in patients with steatosis were lower than in patients without hepatic steatosis (3.8 ± 1.1 vs. 6.4 ± 1.8, P < 0.001). Similar results were seen for blood manganese levels and hepatic steatosis. We found a strong inverse correlation between steatosis grade and hepatic manganese content (ρ=-0.743, P < 0.001). Also, low levels of manganese independently predicted the presence of steatosis (aOR 0.07 [95%CI: 0.01-0.63]). CONCLUSION: Patients with NAFLD, or other CLD and concomitant hepatic steatosis, showed lower levels of hepatic manganese content with increasing grade of steatosis.

Eosinophilic Esophagitis and Gastroesophageal Reflux Disease: An Overlapping of Clinical, Endoscopic and Manometric Features.

The cause of eosinophilic esophagitis (EoE) is not well understood. Most patients with EoE have allergic disorders. Here, we describe a patient with gastroesophageal reflux and EoE with dysphagia, substernal discomfort and retrosternal pain. Based on symptomatology consistent with gastroesophageal reflux disease (GERD), treatment started with proton pump inhibitors (PPIs) but no effect was observed. Next, the patient underwent esophagogastroduodenoscopy and multiple biopsies were acquired from the lower and upper esophagus. Cortisone treatment was given and high-resolution manometry was performed before and after treatment. The results suggested that esophageal motility improved after cortisone therapy together with improvements in the clinical and histological pictures.

Collagenous Colitis Mucosa Is Characterized by an Expansion of Nonsuppressive FoxP3+ T Helper Cells.

BACKGROUND AND AIM: Increased frequencies of T regulatory (Treg) cells, key players in immune regulation, have been reported in inflammatory bowel diseases, including collagenous colitis (CC). However, traditional Treg identification techniques might have misinterpreted the frequencies of Treg cells in CC. Thus, we investigated the presence of genuine Treg cells in CC. METHODS: Treg cells were analyzed in mucosal and peripheral blood samples of CC patients before and during treatment with the corticosteroid drug budesonide and in healthy controls. Samples were analyzed by flow cytometry by classifying CD3+CD4+ cells as activated FoxP3highCD45RA- Treg cells, resting FoxP3dimCD45RA+ Treg cells, and nonsuppressive FoxP3dimCD45RA- T helper cells. Traditional gating strategies that classified Treg cells as CD25highCD127low, FoxP3+CD127low, and CD4+CD25+FoxP3+ were also used to facilitate comparison with previous studies. RESULTS: Activated and resting Treg cell frequencies did not change in active CC mucosa or peripheral blood and were not affected by budesonide treatment. Instead, nonsuppressive FoxP3dimCD45RA- T helper cells were increased in active CC mucosa, and budesonide helped restore them to normal levels. In contrast, traditional Treg cell gating strategies resulted in increased Treg cell frequencies in active CC mucosa. No alterations were found in peripheral blood samples, independently of patient treatment or gating techniques. CONCLUSION: Previously reported increase of Treg cells is a result of incomplete Treg phenotyping, which included nonsuppressive FoxP3dimCD45RA- T helper cells. Because budesonide did not affect Treg percentage, its therapeutic effect in CC might involve alternative mechanisms.

A Well-Defined Endobronchial Tumor in a 26-Year-Old Man.

CASE PRESENTATION: A 26-year-old man presented with a 2-week history of productive cough and a 1-year history of effort-related dyspnea. His medical history was significant for hay fever and exertion-triggered asthma. He was not taking medicines regularly but was using inhaled salbutamol as needed. He was an ex-smoker, with a previous history of 2-pack years.

Single-centre experience with anti-tumour necrosis factor treatment in budesonide-refractory microscopic colitis patients.

Background: Microscopic colitis is an inflammatory bowel disease that causes chronic, watery diarrhoea. Microscopic colitis is usually effectively treated with budesonide, but some patients are refractory. Data on alternative treatments are sparse. Aims: The purpose of this study was to retrospectively evaluate outcome of microscopic colitis patients receiving anti-tumour necrosis factor therapy at our centre. Methods: Treatment results, including side effects, for all microscopic colitis patients receiving anti-tumour necrosis factor therapy were registered at week 12 and at end of follow-up. Clinical remission was defined as a mean of <3 stools and <1 watery stools/day/week and clinical response as a 50% reduction of mean stool frequency/day/week. Induction and maintenance treatment was either adalimumab or infliximab. Results: The study cohort comprised 18 patients; mean age at diagnosis was 47 years (range 19-77). Ten and eight patients, respectively, received adalimumab and infliximab as first-line anti-tumour necrosis factor; seven patients received second-line anti-tumour necrosis factor due to non-response, loss of response or side effects. At week 12, 9/18 patients had achieved remission, 6/18 were responders and 3/18 were non-responders. Of the nine remission patients, 3/18 (16%) had long-lasting clinical remission post-induction therapy alone. Five patients (28%) (one first-line, four second-line anti-tumour necrosis factor) were in remission and one patient (6%) responded to maintenance treatment; follow-up was mean 22 (range 4-60) months. Six patients (33%) had minor, reversible side effects. Conclusions: Over half of budesonide-refractory microscopic colitis patients can achieve clinical remission or response on anti-tumour necrosis factor agents. Prospective studies are mandatory to evaluate the efficacy and safety of anti-tumour necrosis factor treatments in budesonide-refractory microscopic colitis.

Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The complete natural history of NAFLD is unknown because few high-quality follow-up studies have been conducted. Our aim was to find variables predicting disease severity through an extended follow-up with serial biopsies. In a prospective cohort study, 129 patients who enrolled between 1988 and 1993 were asked to participate in a follow-up study on two occasions; biochemical, clinical, and histologic data were documented. The mean time between biopsies was 13.7 (±1.7) and 9.3 (±1.0) years, respectively. At the end of the study period, 12 patients (9.3%) had developed end-stage liver disease and 34% had advanced fibrosis. Out of the 113 patients with baseline low fibrosis (<3), 16% developed advanced fibrosis. Fibrosis progression did not differ among the different stages of baseline fibrosis (P = 0.374). Fifty-six patients (43%) had isolated steatosis, of whom 9% developed advanced fibrosis (3 patients with biopsy-proven fibrosis stage F3-F4 and 2 patients with end-stage liver disease). Fibrosis stage, ballooning, and diabetes were more common in patients who developed end-stage liver disease; however, there were no baseline clinical, histologic, or biochemical variables that predicted clinical significant disease progression. Conclusion: NAFLD is a highly heterogeneous disease, and it is surprisingly hard to predict fibrosis progression. Given enough time, NAFLD seems to have a more dismal prognosis then previously reported, with 16% of patients with fibrosis stage <3 developing advanced fibrosis and 9.3% showing signs of end-stage liver disease. (Hepatology Communications 2018;2:199-210).

How familiar are we with decision-making concerning the treatment of perforation after endoscopic mucosal resection (EMR) in the colon? A case report.

Background and study aims We describe a case of perforation after colonic endoscopic mucosal resection (EMR) that was treated conservatively. We would like to highlight the importance of decision-making mainly based on the endoscopist's point of view in combination with the surgical consultation. Although the radiological imaging is always needed, it cannot solely lead to a decision for operation. Intraperitoneal gas in computed tomography is not always associated with a hole in the endoscopic field and could be possibly explained from a "balloon" phenomenon. The amount of extraluminal air after an EMR does not correlate reciprocally with patient's pain after the procedure. Even though perforation is a radiological diagnosis and endoscopists should be aware of the common post-EMR radiological findings, the surgical examination is mandatory and should be coupled with the endoscopic opinion in order to guide appropriately the treatment in patients with acute pain.

Development of Serum Marker Models to Increase Diagnostic Accuracy of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: The New LINKI Algorithm Compared with Established Algorithms.

BACKGROUND AND AIM: Detection of advanced fibrosis (F3-F4) in nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis. Serum markers have been proposed as alternatives to biopsy. We attempted to develop a novel algorithm for detection of advanced fibrosis based on a more efficient combination of serological markers and to compare this with established algorithms. METHODS: We included 158 patients with biopsy-proven NAFLD. Of these, 38 had advanced fibrosis. The following fibrosis algorithms were calculated: NAFLD fibrosis score, BARD, NIKEI, NASH-CRN regression score, APRI, FIB-4, King´s score, GUCI, Lok index, Forns score, and ELF. Study population was randomly divided in a training and a validation group. A multiple logistic regression analysis using bootstrapping methods was applied to the training group. Among many variables analyzed age, fasting glucose, hyaluronic acid and AST were included, and a model (LINKI-1) for predicting advanced fibrosis was created. Moreover, these variables were combined with platelet count in a mathematical way exaggerating the opposing effects, and alternative models (LINKI-2) were also created. Models were compared using area under the receiver operator characteristic curves (AUROC). RESULTS: Of established algorithms FIB-4 and King´s score had the best diagnostic accuracy with AUROCs 0.84 and 0.83, respectively. Higher accuracy was achieved with the novel LINKI algorithms. AUROCs in the total cohort for LINKI-1 was 0.91 and for LINKI-2 models 0.89. CONCLUSION: The LINKI algorithms for detection of advanced fibrosis in NAFLD showed better accuracy than established algorithms and should be validated in further studies including larger cohorts.