Groove pancreatitis has a spectrum of severity and can be managed conservatively.

BACKGROUND & AIMS: The natural history of groove pancreatitis is incompletely characterized. Published literature suggests a high rate of surgery. We describe the short- and long-term outcomes in a cohort of patients with groove pancreatitis treated at our institution. METHODS: Medical records of patients hospitalized in the University of Pittsburgh Medical Center system from 2000 to 2014 and diagnosed with groove pancreatitis based on imaging were retrospectively reviewed. Clinical presentation and outcomes during index admission and follow-up were recorded. RESULTS: Forty-eight patients with groove pancreatitis were identified (mean age 53.2 years, 79% male). Seventy-one percent were alcohol abusers and an equal number were cigarette smokers. Prior histories of acute and chronic pancreatitis were noted in 30 (62.5%) and 21 (43.8%), respectively. Forty-four (91.7%) met criteria for acute pancreatitis during their index admission. Alcohol was the most common etiology (68.8%). No patient experienced organ failure. The most frequent imaging findings were fat stranding in the groove (83.3%), duodenal wall thickening (52.1%), and soft tissue mass/thickening in the groove (50%). Over a mean follow-up of 5.0 years, seven (14.6%) required a pancreas-related surgery. Patients had a high burden of pancreatitis-related readmissions (68.8%, 69.4/100 patient-years). Incident diabetes and chronic pancreatitis were diagnosed in 5 (13.9% of patients at risk) and 8 (29.6% of patients at risk) respectively. CONCLUSIONS: Groove pancreatitis has a wide spectrum of severity; most patients have mild disease. These patients have a high burden of readmissions and progression to chronic pancreatitis. A small minority requires surgical intervention.

Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.

Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice.

BACKGROUND & AIMS: Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8(+) T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. METHODS: Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8(+) T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. RESULTS: IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8(+) T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-ß) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. CONCLUSIONS: IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. LAY SUMMARY: We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. TRANSCRIPT PROFILING ACCESSION NUMBER: GSE45612, GSE 68001 and GSE 25097.

Porokeratotic Adnexal Ostial Nevus-Report of a Case With Unusual Clinical and Histologic Features.

An 11-year-old Tanzanian girl presented with diffuse verrucous lesions of varying morphology, scarring alopecia, and keloid scars over the face with a predilection for the ears. Physical examination revealed dark keratoderma and patches of hypopigmentation near the midline of the dorsal trunk (Figure 1a). Her forearms were densely covered by verrucous lesions with the exception of a clear linear patch on the dorsal aspect of the left forearm (Figure 1b). The perioral area was notable for white spires projecting from verrucous papules (Figure 1c) while the oral mucosa and teeth appeared normal on visual examination. The rest of her body, including the palms and soles, was covered by patchy, scaly lesions of varying severity.

A synthetic TLR3 ligand mitigates profibrotic fibroblast responses by inducing autocrine IFN signaling.

Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN. Scleroderma patients with progressive skin fibrosis display an IFN-regulated gene signature, implicating TLR3 signaling in the disease. In this study, we show that TLR3 expression was detected on foreskin, adult skin, and lung fibroblasts, and TLR3 levels were significantly elevated in a subset of scleroderma skin biopsies. In explanted skin and lung fibroblasts, the synthetic TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)), a dsRNA analog, caused dose- and time-dependent stimulation of IFN-ß production and generation of an IFN-response gene signature that was accompanied by substantial downregulation of collagen and α-smooth muscle actin gene expression. Furthermore, poly(I:C) abrogated TGF-ß-induced fibrotic responses and blocked canonical Smad signaling via upregulation of inhibitory Smad7. Surprisingly, the inhibitory effects of poly(I:C) in fibroblasts were independent of TLR3 and were mediated by the cytosolic receptors retinoic acid-inducible gene 1 and melanoma differentiation-associated gene 5, and involved signaling via the IFN receptor. Taken together, these results demonstrate that induction of a fibroblast IFN response gene signature triggered by dsRNA is associated with potent TLR3-independent anti-fibrotic effects. The characteristic IFN response gene signature seen in scleroderma lesions might therefore signify a tissue-autonomous protective attempt to restrict fibroblast activation during injury.

The early growth response gene Egr2 (Alias Krox20) is a novel transcriptional target of transforming growth factor-ß that is up-regulated in systemic sclerosis and mediates profibrotic responses.

Although the early growth response-2 (Egr-2, alias Krox20) protein shows structural and functional similarities to Egr-1, these two related early-immediate transcription factors are nonredundant. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, and immune tolerance; however, its regulation and role in tissue repair and fibrosis remain poorly understood. We show herein that transforming growth factor (TGF)-ß induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts. Overexpression of Egr-2 was sufficient to stimulate collagen gene expression and myofibroblast differentiation, whereas these profibrotic TGF-ß responses were attenuated in Egr-2-depleted fibroblasts. Genomewide transcriptional profiling revealed that multiple genes associated with tissue remodeling and wound healing were up-regulated by Egr-2, but the Egr-2-regulated gene expression profile overlapped only partially with the Egr-1-regulated gene profile. Levels of Egr-2 were elevated in lesional tissue from mice with bleomycin-induced scleroderma. Moreover, elevated Egr-2 was noted in biopsy specimens of skin and lung from patients with systemic sclerosis. These results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-ß-induced profibrotic responses and is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma. Together, these findings suggest that Egr-2 plays an important nonredundant role in the pathogenesis of fibrosis. Targeting Egr-2 might represent a novel therapeutic strategy to control fibrosis.

Assessment of Weight Loss and Gastrointestinal Symptoms Suggestive of Exocrine Pancreatic Dysfunction After Acute Pancreatitis.

INTRODUCTION: Studies evaluating the natural history of exocrine pancreatic dysfunction (EPD) after acute pancreatitis (AP) are sparse. This study aims to assess incidence and predictors of weight loss and gastrointestinal (GI) symptoms suggestive of EPD 12 months after an AP episode. METHODS: Patients enrolled in the Pancreatitis-associated Risk of Organ Failure Study at the time of an AP episode were included. Weight and GI symptom data were prospectively collected by self-report at enrollment and at 3- and 12-month (windows 2-7 and 8-20) telephone follow-ups. Multivariable logistic regression was used to assess factors associated with ≥10% total body weight loss (EPD surrogate) at 12 months. A generalized estimating equation was used to measure each factor's population effect (in pounds) over 12 months after AP. RESULTS: Follow-up at 12 months in 186 patients (median age = 54 years, 46% men, 45% biliary, 65% first AP attack) revealed weight loss ≥10% from baseline, occurring in 44 patients (24%). Risk of weight loss increased with higher baseline body mass index, previous diagnosis of diabetes mellitus, and worsening AP severity (all P < 0.010). GI symptoms were reported in 13/31 (42%) patients at 12 months. AP severity was independently associated with ≥10% weight loss at 12 months. Over 12 months, men lost more weight than women (average 9.5 lbs); patients with severe AP lost, on average, 14 lbs. DISCUSSION: Weight loss after AP occurs in one-quarter of patients and is associated with AP severity. EPD incidence after AP is likely underappreciated. Further work is needed to assess EPD and potential for pancreatic enzyme supplementation.

Impact of endoscopic ultrasound on diagnosis and management of presumed mucinous neoplasms when done for pancreatic cyst morphology change on non-invasive surveillance imaging.

Background and study aims Guidelines for management of presumed neoplastic pancreatic cysts have encouraged noninvasive imaging for low-risk surveillance, while reserving endoscopic ultrasound for worrisome features including morphologic change. We aim to study the impact of endoscopic ultrasound on diagnosis and management compared with non-invasive imaging. Patients and methods A single-institution pancreatic cyst database was retrospectively queried for patients who underwent endoscopic ultrasound for the indication of change in cyst morphology. Diagnoses were classified as presumed mucinous neoplasm with or without worrisome features or high-risk stigmata and non-mucinous lesions. Management decisions were defined a priori as surgical evaluation for patients with high-risk stigmata, positive cytology or mural nodule, or continued surveillance for all others. Results Between January 2013 and October 2016, 709 pancreas cyst endoscopic ultrasounds were performed of which 89 were for cyst morphology change seen on noninvasive imaging including 10 presumed pseudocysts, nine presumed serous cystadenomas, and 70 presumed mucinous cystic neoplasms. Cyst morphologic changes included increase in caliber of the main pancreatic duct (7 cases), increase in cyst size (68 cases), cyst ≥ 30 mm (10 cases), and presence of a solid nodule (1 case). Median cyst size increase was 5 mm with interquartile range of 4 mm over 2.1 ±â€Š1.9 years. Endoscopic ultrasound done for morphologic change resulted in a change in diagnosis and management in 16 % and 13 % of cases, respectively. Conclusion Endoscopic ultrasound has a modest but clinically significant role in impacting diagnosis and management for presumed mucinous cystic neoplasms when performed for the indication of cyst morphology change.

Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials.

Non-alcoholic steatohepatitis (NASH) results from inflammation and hepatocyte injury in the setting of hepatic steatosis. Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis, and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA. Weight loss and lifestyle modification remain the standard first-line treatment, as no USA Food and Drug Administration-approved pharmacotherapy currently exists. The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis, with numerous phase 2 and 3 trials currently in progress. Here, we concisely review the major targets and mechanisms of action by class, summarize results from completed pivotal phase 2 studies, and provide a detailed outline of key active studies with trial data for drugs in development, including obeticholic acid, elafibranor, cenicriviroc and selonsertib.

Surveillance and Outcomes of Nonresected Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms: A Meta-analysis.

OBJECTIVES: Guidelines regarding the surveillance of intraductal papillary mucinous neoplasms (IPMNs) are controversial because of uncertain risk of malignancy, agnosticism regarding the use of endoscopic ultrasound, and their recommendation to stop surveillance after 5 years. We present a systematic review and meta-analysis of the risk of malignancy and other end points and estimate the value of endoscopic ultrasound for surveillance. METHODS: We systematically searched MEDLINE for studies with a cohort of patients with presumed branch-duct IPMN who initially were managed nonsurgically. Data regarding study characteristics, surveillance, and outcomes were extracted. Incidence rates of morphologic progression, malignancy, surgery, and death were calculated with a random effects model. RESULTS: Twenty-four studies with 3440 patients and 13,097 patient-years of follow-up were included. Rates of morphologic progression, surgery, malignancy, and death were 0.0379, 0.0250, 0.0098, and 0.0043 per patient-year, respectively. Endoscopic ultrasound was not associated with significantly different rates of these outcomes. CONCLUSIONS: The risk of malignancy calculated in this study was low and in line with recent systematic reviews. Endoscopic ultrasound does not have marginal use in surveillance. Given the limitations of a systematic review of nonrandomized studies, further studies are needed to determine the optimal surveillance of branch-duct IPMNs.

Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy.

With 185 million people chronically infected globally, hepatitis C is a leading bloodborne infection. All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable. However, trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation. Yet, these patients-most often suffering from malignancy or autoimmune diseases-could stand to benefit from these treatments. In this study, we systematically review the literature on the treatment of hepatitis C in these neglected populations. Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically. Our systematic review produced 2273 unique works, of which 56 met our inclusion criteria and were used in our review. The quality of data was low; only 3 of the 56 studies were randomized controlled trials. Sustained virologic response was reported sporadically. Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals. Severe adverse effects and death were rare. Data on all-oral regimens were sparse, but in the most robust study, rates of sustained virologic response were again comparable to immunocompetent individuals (40/41). Efficacy and safety of interferon-containing regimens and all-oral regimens were similar to rates in immunocompetent individuals; however, there were few interventional trials. The large number of case reports and case series makes conclusions vulnerable to publication bias. While firm conclusions are challenging, given the dearth of high-quality studies, our results demonstrate that antiviral therapy can be safe and effective. The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects. Preliminary data reveal that these regimens may confer such benefits in immunosuppressed individuals as well. More prospective interventional trials would greatly benefit the many patients with chronic hepatitis C on immunosuppressive therapies.

Protective altruistic phlebotomy: hereditary haemochromatosis presenting as hepatocellular carcinoma in a non-cirrhotic 83-year-old man.

Hereditary haemochromatosis is a multisystem disorder of iron metabolism. Hepatic manifestations include hepatomegaly, cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma is almost always preceded by cirrhosis. We present a case of an 83-year-old man without history of liver disease or iron overload who presented with abdominal pain. Workup revealed mildly elevated transaminases, ferritin of 3996 and a solitary liver tumour. Biopsy was consistent with hepatocellular carcinoma in a background of haemosiderosis without cirrhosis. He was diagnosed with hereditary haemochromatosis and hepatocellular carcinoma. He underwent a partial hepatectomy and was started on routine phlebotomy and surveillance imaging. He has improved and has not had signs of recurrence or new complications of haemochromatosis. We suggest a possible reason for his unique and late presentation.