Registry-derived stage (RD-Stage) for capturing stage at diagnosis for pancreatic carcinoma in Australia.

INTRODUCTION: Stage of pancreatic carcinoma at diagnosis is a strong prognostic indicator of morbidity and mortality, yet is poorly notified to population-based cancer registries ("cancer registries"). Registry-derived stage (RD-Stage) provides a method for cancer registries to use available data sources to compile and record stage in a consistent way. This project describes the development and validation of rules to capture RD-Stage (pancreatic carcinoma) and applies the rules to data currently captured in each Australian cancer registry. MATERIALS AND METHODS: Rules for deriving RD-stage (pancreatic carcinoma) were developed using the American Joint Commission on Cancer (AJCC) Staging Manual 8th edition and endorsed by an Expert Working Group comprising specialists responsible for delivering care to patients diagnosed with pancreatic carcinoma, cancer registry epidemiologists and medical coders. Completeness of data fields required to calculate RD-Stage (pancreatic carcinoma) and an overall proportion of cases for whom RD stage could be assigned was assessed using data collected by each Australian cancer registry, for period 2018-2019. A validation study compared RD-Stage (pancreatic carcinoma) calculated by the Victorian Cancer Registry with clinical stage captured by the Upper Gastro-intestinal Cancer Registry (UGICR). RESULTS: RD-Stage (pancreatic carcinoma) could not be calculated in 4/8 (50%) of cancer registries; one did not collect the required data elements while three used a staging system not compatible with RD-Stage requirements. Of the four cancer registries able to calculate RD-Stage, baseline completeness ranged from 9% to 76%. Validation of RD-Stage (pancreatic carcinoma) with UGICR data indicated that there was insufficient data available in VCR to stage 174/457 (38%) cases and that stage was unknown in 189/457 (41%) cases in the UGICR. Yet, where it could be derived, there was very good concordance at stage level (I, II, III, IV) between the two datasets. (95.2% concordance], Kendall's coefficient = 0.92). CONCLUSION: There is a lack of standardisation of data elements and data sources available to cancer registries at a national level, resulting in poor capacity to currently capture RD-Stage (pancreatic carcinoma). RD-Stage provides an excellent tool to cancer registries to capture stage when data elements required to calculate it are available to cancer registries.

ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.

BACKGROUND & AIMS: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target. METHODS: We used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function. RESULTS: Prophylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG. CONCLUSIONS: As IL-17 and IgG-Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis. LAY SUMMARY: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.

Sampling and Reporting of Inflammatory Bowel Disease.

Pathologists have an important and expanding role in the diagnosis and management of inflammatory bowel disease. This role includes the initial diagnosis of the disease, assessment of the response to treatment and the identification of short-term complications such as cytomegalovirus infection and long-term complications such as dysplasia. Furthermore, the assessment of resection specimens for complication of disease is important to determining the risk of subsequent disease or inflammation within an ileal pouch. Adequate sampling of the disease at endoscopy and from the surgical resection specimen is vital to determining the ultimate information that can be provided by the pathologist. This sampling is determined by the clinical scenario. Similarly, a standardized approach to reporting and synthesizing the histologic findings will improve patient management. This is best exemplified by the increasing interest in histologic activity indices, such as the Nancy index in ulcerative colitis, and in the standardized reporting for inflammatory bowel disease dysplasia recommended by the SCENIC international consensus.

Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non-conventional (or special-type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non-conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.

Traditional serrated adenoma-like lesions in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal carcinoma. The significance of serrated lesions resembling traditional serrated adenoma (TSA) in IBD patients is unclear. In this retrospective study, we analyzed 52 TSA-like lesions arising in 30 IBD patients and diagnosed in colectomy or endoscopic specimens. The 27 colectomy lesions presented predominantly as ill-defined areas with granular appearance, with a median size of 15 mm, located throughout the large bowel and associated with synchronous advanced colorectal lesions in 58%. Low-grade serrated dysplasia was present in 56%, high-grade serrated dysplasia in 37%, and TSA-type cytology in 7%. Increased Ki-67 immunostaining and abnormal p53 expression were identified in 96% and 48%, respectively; 74% had a KRAS mutation, and 4% had a BRAF mutation. Endoscopically resectable TSA-like lesions were all discrete polypoid lesions, smaller in size (median 9 mm), predominantly in the distal large bowel, with an adjacent precursor polyp in 24%, and associated with synchronous and metachronous advanced colorectal lesions in 6%. Most (92%) show TSA-type cytology. p53 overexpression was present in 4%, KRAS mutation in 41%, and BRAF mutation in 32%. None of the 52 TSA-like lesions demonstrated loss of MLH1 or SATB2 expression by immunohistochemistry. On follow-up, 4 patients were diagnosed with colorectal carcinoma or high-grade adenomatous IBD-associated dysplasia. None of the patients with lesions showing TSA-type cytology only developed an advanced lesion. Our findings suggest that some TSA-like lesions, essentially from colectomy, may represent a form of IBD-associated dysplasia associated with an increased risk of advanced neoplasia.

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease.

INTRODUCTION: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled. METHODS: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year). RESULTS: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1-9); L3-20, 1 (0-9); and L3-40, 0 (0-3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, -0.6 [-1.3 to 0.2]; L3-20, -0.5 [-0.8 to 0.2]; and L3-40, -1.1 [-1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9-44] vs 45.9 [39.2-52.6]). DISCUSSION: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.

Clinicopathological features of pyloric gland adenomas of the duodenum: a multicentre study of 57 cases.

AIMS: To determine the clinicopathological features of pyloric gland adenomas (PGA) that arise in the duodenum. METHODS AND RESULTS: Fifty-seven cases of duodenal PGA were identified and analysed from 56 patients. Clinicopathological and immunohistochemical analyses were performed. PGA tend to occur in older individuals (median age = 73.5), with a slight female predominance (25 males, 31 females). PGA arise more commonly in the proximal duodenum (68.75% in D1, 25% in D2 and 6.25% in D3) and usually present as mucosal nodules (98.2%) or plaques (1.8%), with a mean size of 14.8 mm. There is associated gastric heterotopia in 22.8% of cases. PGA showing features of high-grade dysplasia were significantly larger in size than PGA, showing only low-grade dysplasia (23.1 versus 8.7 mm; P = 0.0001) and more likely to show a tubulovillous rather than a pure tubular architecture (P = 0.025). In our series, 10 of 56 patients had intramucosal or invasive carcinoma associated with the duodenal PGA (17.9%). Three of these carcinomas showed lymph node metastasis. Following definitive treatment, local recurrence occurred in only three patients. CONCLUSIONS: Duodenal PGA tend to occur in the proximal duodenum of older individuals. Larger size and tubulovillous architecture correlates with high-grade dysplasia and associated adenocarcinoma. The low recurrence rate of these lesions would suggest that endoscopic management is appropriate, provided that the lesion can be completely resected.

Nonconventional dysplasia in patients with inflammatory bowel disease and colorectal carcinoma: a multicenter clinicopathologic study.

Several types of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). However, strict morphologic criteria are lacking, and their clinicopathologic features (including potential association with conventional dysplasia and/or colorectal cancer [CRC]) are poorly understood. A total of 106 dysplastic or serrated lesions in 58 IBD patients with CRC were retrospectively identified from five institutions. Thirty-six cases of nonconventional dysplasia were identified in 26 (45%) of the 58 patients and occurred with similar frequency in men and women (58% and 42%, respectively), with a mean age of 54 years (range: 24-73) and a long history of IBD (mean: 17 years, range: 2-43). Six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a 'pure type' (n = 5; 14%) or a 'mixed type' with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare. Twelve (46%) of the 26 patients had only nonconventional dysplasia, whereas the remaining 14 patients (54%) had both nonconventional and conventional dysplasias. Nonconventional dysplasia was most often graded as low-grade dysplasia (81%), which was less common in conventional dysplasia (37%) (p = 0.003). When present alone, nonconventional dysplasia was predominantly found in the left colon (81%, p = 0.006) as a polypoid or raised lesion (75%, p < 0.001) compared with when it occurred simultaneously with conventional dysplasia (35% and 50%, respectively). When both nonconventional and conventional dysplasias occurred simultaneously, they were found in the same colonic segment in all but 3 patients (79%). Nonconventional dysplasia was also commonly detected in the same colonic segment as CRC or immediately adjacent to the CRC at a rate (85%) similar to conventional dysplasia (96%). CRC occurring in patients with only nonconventional dysplasia was more likely to be high-grade (poorly differentiated; 36%) than CRC that occurred in association with conventional dysplasia (10%) (p = 0.026). In conclusion, nonconventional dysplasia is common in IBD patients with CRC. It appears to develop in the same field of carcinomatous development, and it is not uncommonly associated with conventional dysplasia.

Adult onset of genetic disorders in bile acid transport in the liver.

Although severe deficiencies of canalicular transporter enzymes due to biallelic mutations are well known as causes of progressive cholestatic liver disease in children, it is increasingly recognized that milder disease may occur if a single, heterozygous gene mutation is present. This mild disease, generally presenting initially in adulthood, may have a variety of clinical and histological appearances. Bland canalicular cholestasis is the prototypic change, but it is now clear that some gene mutations, particularly in ABCB4 (encoding MDR3), can cause other patterns that include early cholesterol calculus formation, bile duct injury and disappearance, ductular reactions mimicking large duct obstruction, and, in rare cases, progressive fibrosis. Because the features can be subtle and not diagnostic in isolation, it is generally the combination of a biliary pattern of injury with a suggestive clinical and family history that allows the diagnosis to be suspected. Increased awareness and improved access to genetic testing are likely to result in more frequent diagnosis of these disorders.

Actinomyces in Crohn's-like appendicitis.

AIMS: Appendicitis with a Crohn's-like histological appearance generally raises concern for Crohn's disease, Yersinia infection, and interval appendectomy. Actinomyces infection is a recognised cause of chronic appendicitis that can histologically mimic Crohn's disease. METHODS AND RESULTS: We report on 20 cases of appendicitis with Crohn's-like histological features that were due to Actinomyces. Most patients presented with acute or chronic abdominal pain. Imaging studies suggested a mass in five cases. Two patients had interval appendectomy. Histological features showed Crohn's-like appendicitis in 16 cases, with moderate to marked fibrosis and granulomas in seven cases. The other four cases had less consistent histological findings. None of the patients developed Crohn's disease during the follow-up interval (median, 37 months). CONCLUSIONS: Actinomyces can be associated with Crohn's-like appendicitis with marked fibrosis, transmural inflammation, lymphoid hyperplasia, and granulomas.

Subclassification of hepatocellular adenomas: practical considerations in the implementation of the Bordeaux criteria.

Hepatocellular adenomas are benign liver lesions with a risk of rupture and malignant transformation. Various molecular subgroups have been identified which appear to have characteristic morphological and immunohistochemical features. We examined the morphology and immunohistochemical profile of a series of 121 HCA from 97 patients to identify the HCA subtypes present and determine the number at risk for malignant transformation according to the World Health Organization (WHO) criteria for hepatocellular adenomas. There were 34 HNF1α inactivated HCA (28%), 61 inflammatory HCA (50%), 15 ß-catenin activated HCA (12%) and 11 unclassified adenomas (9%). This proportion of cases was similar to that seen in other series utilising molecular classification. The morphological features of the adenomas were suggestive but not definite indicators of the subtypes present. Morphological features that showed overlap between the subtypes included steatosis within the lesion, a ductular reaction and focal atypia, so that immunohistochemical typing was required for accurate classification. In conclusion, immunohistochemistry is a clinically useful surrogate for identifying underlying molecular changes in the HCA subtypes.

Brunner's gland cyst: a clinicopathological study of 25 cases highlighting an underappreciated lesion.

Brunner's gland cysts are rare, benign lesions of the duodenum usually seen as incidental, polypoid or cystic lesions of the duodenum. We present a series of 25 cases of Brunner's gland cyst, the largest case series to date. All the cases were identified during endoscopic assessment for unrelated causes. The mean age of the patients was 66.2 years and the sex ratio was approximately equal. Most were detected as a small (3-10 mm) polypoid lesion in the second part of the duodenum, away from the ampulla. Most of the cysts were unilocular and all were lined by undulating, cytologically bland cuboidal to columnar cells with clear cytoplasm and small, basal nuclei. No mitotic activity or proliferative activity was seen. No recurrence was noted, despite incomplete removal in many cases. We agree with the hypothesis that Brunner's gland cysts are likely to be caused by local obstruction to the draining duct of Brunner's glands.

Synthesis and Membrane Properties of Sulfonated Poly(arylene ether sulfone) Statistical Copolymers for Electrolysis of Water: Influence of Meta- and Para-Substituted Comonomers.

Two series of high molecular weight disulfonated poly(arylene ether sulfone) random copolymers were synthesized as proton exchange membranes for high-temperature water electrolyzers. These copolymers differ based on the position of the ether bonds on the aromatic rings. One series is comprised of fully para-substituted hydroquinone comonomer, and the other series incorporated 25 mol % of a meta-substituted comonomer resorcinol and 75 mol % hydroquinone. The influence of the substitution position on water uptake and electrochemical properties of the membranes were investigated and compared to that of the state-of-the-art membrane Nafion. The mechanical properties of the membranes were measured for the first time in fully hydrated conditions at ambient and elevated temperatures. Submerged in water, these hydrocarbon-based copolymers had moduli an order of magnitude higher than Nafion. Selected copolymers of each series showed dramatically increased proton conductivities at elevated temperature in fully hydrated conditions, while their H2 gas permeabilities were well controlled over a wide range of temperatures. These improved properties were attributed to the high glass transition temperatures of the disulfonated poly(arylene ether sulfone)s.

Histopathological findings of extra-ileal manifestations at initial diagnosis of Crohn's disease-related ileitis.

Crohn's disease is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract. Our objective was to review the histological findings in index biopsies from the terminal ileum and other gastro-intestinal tract sites of Crohn's disease patients prior any treatment and to compare them with the findings from patients with non-specific ileitis. A total of 111 consecutive Crohn's disease cases (55 females, median age 27 years) with extra-ileal biopsies were retrospectively selected. Upper gastrointestinal inflammatory changes were found in 68 % of gastric biopsies, 60 % of oesophageal biopsies and 43 % of duodenal biopsies with no significant difference in frequency between paediatric and adult cases. Crohn's colitis was more common in paediatric cases than adult cases (85 % versus 57 %). Granuloma in at least one extra-ileal site was observed in 40 %, more frequently in paediatric cases than in adults (78 vs 27 %). Compared with Crohn's disease cases, the group of 151 non-specific ileitis cases (75 females, median age 52 years) were more likely to have normal upper and lower gastrointestinal biopsies and to show less frequent crypt architectural changes in the terminal ileum. In summary, Crohn's disease ileitis is often associated with inflammation elsewhere in the gastrointestinal tract while non-specific ileitis was infrequently associated with inflammation elsewhere for both paediatric and adult patients. These findings support the role of systematic biopsies in multiple gastrointestinal sites to help distinguishing Crohn's ileitis from non-specific ileitis in paediatric and adult population.

The pathological findings seen in laparoscopic sleeve gastrectomies for weight loss.

Sleeve gastrectomy specimens are increasingly common surgical specimens received for examination following bariatric surgery for weight loss. The spectrum of pathological changes seen in these cases is not well documented. Retrospective examination was undertaken of 1463 consecutive sleeve gastrectomy specimens received at Envoi Specialist Pathologists. Most cases showed no pathological changes (80.2%). The most common changes seen were non-specific, non-Helicobacter associated chronic gastritis (7.2%), Helicobacter associated gastritis (6.8%) and benign fundic gland polyps (4.0%). Other, rarer changes were lymphocytic gastritis, autoimmune atrophic gastritis, chronic gastritis with intestinal metaplasia, hyperplastic polyps, pancreatic heterotopia, gastrointestinal stromal tumours (GISTs) and a leiomyoma. A wide range of pathological changes are seen in resection specimens following sleeve gastrectomies for weight loss. Many cases will require further treatment or ongoing investigation and surveillance.

Spatiotemporal Characterization of the Cellular and Molecular Contributors to Liver Fibrosis in a Murine Hepatotoxic-Injury Model.

The interplay between the inflammatory infiltrate and tissue resident cell populations invokes fibrogenesis. However, the temporal and mechanistic contributions of these cells to fibrosis are obscure. To address this issue, liver inflammation, ductular reaction (DR), and fibrosis were induced in C57BL/6 mice by thioacetamide administration for up to 12 weeks. Thioacetamide treatment induced two phases of liver fibrosis. A rapid pericentral inflammatory infiltrate enriched in F4/80(+) monocytes co-localized with SMA(+) myofibroblasts resulted in early collagen deposition, marking the start of an initial fibrotic phase (1 to 6 weeks). An expansion of bone marrow-derived macrophages preceded a second phase, characterized by accelerated progression of fibrosis (>6 weeks) after DR migration from the portal tracts to the centrilobular site of injury, in association with an increase in DR/macrophage interactions. Although chemokine (C-C motif) ligand 2 (CCL2) mRNA was induced rapidly in response to thioacetamide, CCL2 deficiency only partially abrogated fibrosis. In contrast, colony-stimulating factor 1 receptor blockade diminished C-C chemokine receptor type 2 [CCR2(neg) (Ly6C(lo))] monocytes, attenuated the DR, and significantly reduced fibrosis, illustrating the critical role of colony-stimulating factor 1-dependent monocyte/macrophage differentiation and linking the two phases of injury. In response to liver injury, colony-stimulating factor 1 drives early monocyte-mediated myofibroblast activation and collagen deposition, subsequent macrophage differentiation, and their association with the advancing DR, the formation of fibrotic septa, and the progression of liver fibrosis to cirrhosis.

The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

BACKGROUND AND AIMS: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. METHODS: Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. RESULTS: Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. CONCLUSIONS: The ELF score is a valuable tool for risk stratification of patients with chronic liver disease.

Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury.

BACKGROUND: Macrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro- and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice). RESULTS: Fibrosis and HPC activation were exacerbated in LysM-Wls mice compared to littermate controls, in the absence of an apparent increase in myofibroblast activation or interstitial collagen mRNA expression, in both the TAA and CDE models of chronic liver disease. Increased Epcam mRNA levels paralleled the increased HPC activation and more mature ductular reactions, in LysM-Wls mice. Increased Epcam expression in LysM-Wls HPC was also observed, consistent with a more cholangiocytic phenotype. No differences in the mRNA expression levels of key pro-inflammatory and pro-fibrotic cytokines or the macrophage-derived HPC mitogen, Tweak, were observed. LysM-Wls mice exhibited increased expression of Timp1, encoding the key Mmp inhibitor Timp1 that blocks interstitial collagen degradation, and, in the TAA model, reduced expression of the anti-fibrotic matrix metalloproteinases, Mmp12 and Mmp13, suggesting a role for macrophage-derived Wnt proteins in restraining fibrogenesis during ongoing liver injury. CONCLUSION: In summary, these data suggest that macrophage-derived Wnt proteins possess anti-fibrogenic potential in chronic liver disease, which may be able to be manipulated for therapeutic benefit.

ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity.

BACKGROUND & AIMS: There is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available enhanced liver fibrosis (ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (≥9.8) in identifying advanced fibrosis. METHODS: The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area (CPA) and subsinusoidal fibrosis (SSF). RESULTS: Enhanced liver fibrosis score ≥9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort (n = 329), ELF score was more likely to incorrectly classify individuals if age was ≥45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR, odds ratio 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis (OR 0.37). Neither SSF nor CPA explained the discordance in ELF score for patients with or without advanced fibrosis. CONCLUSION: Although ELF score ≥9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease.