Sarcoidosis Masquerading as Long-Standing Cholestasis.

Hepatic sarcoidosis is an exceedingly rare extrapulmonary manifestation of sarcoidosis, with the majority remaining stable for years without clinical clues, only displaying biochemical abnormalities. Amongst the literature, the timeline to cirrhosis has not been parsed out; hepatomegaly develops in 50% and cirrhosis in 33% of all hepatic sarcoidosis patients, making this an essential issue in this patient population. Interestingly, the risk for hepatocellular carcinoma remains high regardless of cirrhosis development. Corticosteroids and biologics remain the mainstay of therapy, although refractory cases may require deeper immunosuppression. Liver transplantation is seen in a handful of cases with promising results. We present an interesting case of cholestatic pattern livery injury in our outpatient setting that was eventually discovered to be hepatic sarcoidosis. Mild biochemical derangements or sole elevations in alkaline phosphatase are under-recognized, and patients often progress to cirrhosis and end-stage liver disease. This diagnostic miss has significant implications and represents an opportunity to treat liver disease with a reversible cause. Consensus guidelines recommend alkaline phosphatase screening in newly diagnosed cases of sarcoidosis.

Coeliac disease screening is suboptimal in a tertiary gastroenterology setting.

BACKGROUND AND AIMS: Coeliac disease (CD) is widely prevalent in North America, but case-finding techniques currently used may not be adequate for patient identification. We aimed to determine the adequacy of CD screening in an academic gastroenterology (GI) practice. METHODS: Consecutive initial visits to a tertiary academic GI practice were surveyed over a 3-month period as a fellow-initiated quality improvement project. All electronic records were reviewed to look for indications for CD screening according to published guidelines. The timing of screening was noted (before or after referral), as well as the screening method (serology or biopsy). Data were analysed to compare CD screening practices across subspecialty clinics. RESULTS: 616 consecutive patients (49±0.6 years, range 16-87 years, 58.5% females, 94% Caucasian) fulfilled inclusion criteria. CD testing was indicated in 336 (54.5%), but performed in only 145 (43.2%). The need for CD screening was highest in luminal GI and inflammatory bowel disease clinics, followed by biliary and hepatology clinics (p<0.0001); CD screening rate was highest in the luminal GI clinic (p=0.002). Of 145 patients screened, 4 patients (2.4%) had serology consistent with CD, of which 2 were proven by duodenal biopsy. Using this proportion, an additional 5 patients might have been diagnosed in 191 untested patients with indications for CD screening. CONCLUSIONS: More than 50% of patients in a tertiary GI clinic have indications for CD screening, but <50% of indicated cases are screened. Case-finding techniques therefore are suboptimal, constituting a gap in patient care and an important target for future quality improvement initiatives.

Durability of antibody response against hepatitis B virus in healthcare workers vaccinated as adults.

BACKGROUND: Follow-up studies of recipients of hepatitis B vaccine from endemic areas have reported loss of antibody to hepatitis B surface antigen (anti-HBs) in a high proportion of persons vaccinated at birth. In contrast, the long-term durability of antibody in persons vaccinated as adults in nonendemic areas is not well defined. We aimed to assess the durability of anti-HBs among healthcare workers (HCWs) vaccinated as adults and response to a booster among those without protective levels of antibody. METHODS: Adult HCWs aged 18-60 at the time of initial vaccination were recruited. All were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and anti-HBs level. HCWs with anti-HBs <12 mIU/mL were offered a booster and levels were measured 1, 7, and 21 days afterward. RESULTS: Anti-HBs levels were <12 mIU/mL in 9 of 50 (18%), 13 of 50 (26%), and 14 of 59 (24%) HCWs 10-15, 16-20, and >20 years postvaccination, respectively, (P = ns). Four HCWs were anti-HBc positive; none had HBsAg. By logistic regression, older age at vaccination was the only predictor of inadequate anti-HBs level (P = .0005). Thirty-four of 36 subjects with inadequate anti-HBs levels received a booster and 32 (94%) developed levels >12 mIU/mL within 3 weeks. CONCLUSIONS: Anti-HBs levels decrease after 10-31 years and fall below a level considered protective in approximately 25% of cases. The rapid and robust response to a booster vaccine suggests a long-lasting amnestic response. Hepatitis B vaccination provides long-term protection against hepatitis B and booster vaccination does not appear to be necessary in HCWs. Clinical Trials Registration. NCT01182311.

Hypertonic HBOC-201 decreases neutrophil activation after hemorrhagic shock.

OBJECTIVE: To evaluate neutrophil activation after exposure to standard HBC-201 (suspended in lactate Ringer's solution) versus HBOC-201 suspended in hypertonic 7.5% saline solution. METHODS: We use plasma and tissue obtained from pigs subjected to controlled hemorrhagic shock and an ex vivo model of stimulated human whole blood. The pigs were resuscitated with the following (n = 8 per group) standard HBOC-201, or hypertonic HBOC-201. We used HTS 7.5%, Ringer's lactate as control resuscitation. Human blood was stimulated with same fluids. We measured the following neutrophil markers; IL-8, H2O2 in pig plasma, MPO in pig tissue, and H2O2, IL-8, and CD11b/CD18 in human whole blood. RESULTS: H2O2 and IL-8 as well as tissue MPO were significantly decreased in pigs resuscitated with HT-HBOC-201 and HT 7.5%. Ex vivo experiments blood diluted with HTS and HT-HBOC-201 revealed lower expression of CD11b/CD18, H2O2, and IL-8. Blood diluted with HBOC-201 had a higher CD11b/CD18 expression than blood diluted with LR solution. CONCLUSION: Our in vivo and ex vivo experiments indicate that HBOC-201 suspended in hypertonic 7.5% saline solution is associated with significantly less neutrophil activation when compared to standard HBOC-201 suspended in lactate Ringer's solution.

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C.

OBJECTIVE: Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. DESIGN: 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000-1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. RESULTS: After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. CONCLUSIONS: Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

The hepatitis B vaccine protects re-exposed health care workers, but does not provide sterilizing immunity.

BACKGROUND & AIMS: Infection with hepatitis B virus (HBV) can be prevented by vaccination with HB surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for health care workers who were vaccinated as adults. METHODS: We investigated the immune mechanisms (antibody and T-cell responses) of long-term protection by the HBV vaccine in 90 health care workers with or without occupational exposure to HBV, 10-28 years after vaccination. RESULTS: Fifty-nine of 90 health care workers (65%) had levels of antibodies to HBs antigen above the cut-off (>12 mIU/mL) and 30 of 90 (33%) had HBs-specific T cells that produced interferon-gamma. Titers of antibodies to HBs antigen correlated with numbers of HBs-specific interferon-gamma-producing T cells, but not with time after vaccination. Although occupational exposure to HBV after vaccination did not induce antibodies to the HBV core protein (HBcore), the standard biomarker for HBV infection, CD4(+) and CD8(+) T cells against HBcore and polymerase antigens were detected. Similar numbers of HBcore- and polymerase-specific CD4(+) and CD8(+) T cells were detected in health care workers with occupational exposure to HBV and in patients who acquired immunity via HBV infection. Most of the HBcore- and polymerase-specific T cells were CD45RO(+)CCR7(-)CD127(-) effector memory cells in exposed health care workers and in patients with acquired immunity. In contrast, most of the vaccine-induced HBs-specific T cells were CD45RO(-)CCR7(-)CD127(-) terminally differentiated cells. CONCLUSIONS: HBs antigen vaccine-induced immunity protects against future infection but does not provide sterilizing immunity, as evidenced by HBcore- and polymerase-specific CD8(+) T cells in vaccinated health care workers with occupational exposure to HBV. The presence of HBcore- and HBV polymerase-specific T-cell responses is a more sensitive indicator of HBV exposure than detection of HBcore-specific antibodies.

Outcomes of patients with microscopic colitis treated with corticosteroids: a population-based study.

OBJECTIVES: To evaluate the outcomes of corticosteroid-treated microscopic colitis (MC) in a population-based cohort, and to compare these outcomes in patients treated with prednisone or budesonide. METHODS: A historical cohort study of Olmsted County, Minnesota residents diagnosed with collagenous or lymphocytic colitis (LC) between 1986 and 2010 was performed using the Rochester Epidemiology Project. RESULTS: Of 315 patients with MC, 80 (25.4%) were treated with corticosteroids. The median age at colitis diagnosis was 66.5 years (range: 16-95) and 78.7% were female. Forty patients (50%) had LC and 40 (50%) had collagenous colitis. Prednisone was used in 17 patients (21.2%) and budesonide in 63 (78.8%); 56 (75.6%) had complete response and 15 (20.3%) had partial response. Patients treated with budesonide had a higher rate of complete response than those treated with prednisone (82.5 vs. 52.9%; odds ratio, 4.18; 95% CI, 1.3-13.5). Six patients were lost to follow-up. The remaining 74 had a median follow-up of 4 years (range 0.2-14). Fifty patients out of the 71 who responded (70.4%) had a recurrence after corticosteroid discontinuation. Patients treated with budesonide were less likely to recur than those treated with prednisone (hazard ratio, 0.38; 95% CI, 0.18-0.85; P=0.02). After 397 person years of follow-up in the 73 patients with long-term data, 47 (64.4%) required maintenance with corticosteroids. CONCLUSION: Patients with MC often respond to corticosteroid therapy, but with a high relapse rate. Budesonide had a higher response rate and a lower risk of recurrence than prednisone.

Spatial analysis of injury-related deaths in Dallas County using a geographic information system.

This study applied a geographic information system (GIS) to identify clusters of injury-related deaths (IRDs) within a large urban county (26 cities; population, 2.4 million). All deaths due to injuries in Dallas County (Texas) in 2005 (N = 670) were studied, including the geographic location of the injury event. Out of 26 cities in Dallas County, IRDs were reported in 19 cities. Geospatial data were obtained from the local governments and entered into the GIS. Standardized mortality ratios (SMR, with 95% CI) were calculated for each city and the county using national age-adjusted rates. Dallas County had significantly more deaths due to homicides (SMR, 1.76; 95% CI, 1.54-1.98) and IRDs as a result of gunshots (SMR, 1.23; 95% CI, 1.09-1.37) than the US national rate. However, this increase was restricted to a single city (the city of Dallas) within the county, while the rest of the 25 cities in the county experienced IRD rates that were either similar to or better than the national rate, or experienced no IRDs. GIS mapping was able to depict high-risk geographic "hot spots" for IRDs. In conclusion, GIS spatial analysis identified geographic clusters of IRDs, which were restricted to only one of 26 cities in the county.

The Mayo Dysphagia Questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease.

The aim of this study was to develop the Mayo Dysphagia Questionnaire-30 Day (MDQ-30), a tool to measure esophageal dysphagia, by adapting items from validated instruments for use in clinical trials, and assess its feasibility, reproducibility, and concurrent validity. Outpatients referred to endoscopy for dysphagia or seen in a specialty clinic were recruited. Feasibility testing was done to identify problematic items. Reproducibility was measured by test-retest format. Concurrent validity reflects agreement between information gathered in a structured interview versus the patients' written responses. The MDQ-30, a 28-item instrument, took 10 min (range = 5-30 min) to complete. Four hundred thirty-one outpatients [210 (49%) men; mean age = 61 years] participated. Overall, most concurrent validity kappa values for dysphagia were very good to excellent with a median of 0.78 (min 0.28, max 0.95). The majority of reproducibility kappa values for dysphagia were moderate to excellent with a median kappa value of 0.66 (min 0.07, max 1.0). Overall, concurrent validity and reproducibility kappa values for gastroesophageal reflux disease (GERD) symptoms were 0.81 (95% CI = 0.72, 0.91) and 0.66 (95% CI = 0.55, 0.77), respectively. Individual item percent agreement was generally very good to excellent. Internal consistency was excellent. We conclude that the MDQ-30 is an easy-to-complete tool to evaluate reliably dysphagia symptoms over the last 30 days.

Impact of feedback and didactic sessions on the reporting behavior of upper endoscopic findings by physicians and nurses.

BACKGROUND & AIMS: Guidelines for reporting Barrett's esophagus and hiatal hernia measurements and reflux esophagitis grades have been developed to improve consistency, communication, and, ultimately, patient care. Our aims were to assess the percentage of cases in which findings were reported in accordance with guidelines and to assess the impact of education and feedback on reporting behavior. METHODS: Prospective cross-sectional study design was used. Chart reviews were performed for all adult patients who underwent esophagogastroduodenoscopy at a tertiary care center during three 2-month time periods during a 12-month interval: Time 1 (March 1, 2004-April 30, 2004), Time 2 (July 1, 2004-August 31, 2004), and Time 3 (March 1, 2005-April 30, 2005). Standardized educational sessions began 2 years before Time 1. No intervention took place between Time 1 and Time 2; data were collected to examine secular change. Between Time 2 and Time 3, individual and group feedback and refresher sessions were given. RESULTS: Five thousand six hundred nine eligible esophagogastroduodenoscopies were performed, of which 2675 demonstrated Barrett's esophagus, hiatal hernia, and/or reflux esophagitis. At baseline, Barrett's esophagus and hiatal hernia measurements were dictated correctly in a median of 67% and 86% of cases, respectively, improving to 100% (P < .05) and 98% (P < .01) of cases, respectively. The Los Angeles Classification system was used in a median of 100% of cases at baseline and at follow-up. CONCLUSIONS: Anonymous individual and group feedback, in combination with brief, structured didactic educational sessions, significantly improves compliance with established guidelines for the reporting of Barrett's esophagus and hiatal hernia. Once successfully incorporated into clinical practice, adherence to the esophagitis Los Angeles Classification System is easy to maintain.

Separable enhancer sequences regulate the expression of the neural bHLH transcription factor neurogenin 1.

Ngn1 is a basic helix-loop-helix (bHLH) transcription factor expressed in specific regions within the developing brain and spinal cord, sensory ganglia, and olfactory epithelium. We have identified sequences both 5' and 3' of the mouse ngn1 gene that function in regulating ngn1 expression, and each of these sequences contains distinct regulatory cassettes for different subregions of the expression domain. Enhancers for expression in ngn1 domains of the midbrain, hindbrain, trigeminal ganglia, and ventral-neural tube appear redundant and are spread both 5' and 3' of the ngn1 coding sequence. In contrast, a single discrete dorsal-neural tube enhancer was located in the 5' sequence that is conserved among mouse, human, chick, and zebrafish ngn1 genes. Functionally, this enhancer is both necessary and sufficient for driving expression of a heterologous reporter in transgenic mice specifically to the dorsal domain of ngn1 expression in the spinal neural tube. Thus, sequences are identified that can be used to direct temporally and spatially restricted expression of heterologous genes to the developing neural tube.

Math1-driven GFP expression in the developing nervous system of transgenic mice.

Math1 is a bHLH transcription factor expressed in neural progenitor cells in multiple regions of the nervous system. Previously we identified a Math1 enhancer that directs expression of reporter genes in a Math1 specific pattern [Development 127 (2000) 1185]. We have used a portion of this enhancer to drive expression of a nuclear GFP reporter in the Math1 lineage in transgenic mice. In this transgenic mouse strain, GFP is expressed in Math1 domains in the (1). developing spinal cord in progenitors to dI1 dorsal interneurons, (2). granule-cell progenitors in the developing cerebellum, (3). Merkel cells in the skin, and (4). hair cells in the developing vestibular and auditory systems. Furthermore, non-Math1 related expression is detected that is likely due to the absence of inhibitory regulatory sequences from the transgene. These expression domains include (1). the apical ectodermal ridge in developing limbs, (2). post-mitotic cells in the developing cortex and spinal cord, (3). the dentate gyrus, (4). retina, and (5). olfactory epithelium. Because GFP marks specific neuronal cell types in living tissue, this transgenic strain is a powerful tool for future studies on the development and electrophysiological properties of distinct cell types in the central nervous system and in sensory systems.

The role of endoscopy in the treatment of esophageal varices, 2002-2003.

Great strides have been made in the endoscopic and radiologic therapy of esophageal varices in the past few years. With the advent of variceal band ligation and transjugular intrahepatic portosystemic shunt, almost every acute variceal bleed can be controlled. In addition, over the past decade great strides have been made in the noninvasive imaging and pressure measurement of esophageal varices. Yet, the mortality rate from variceal bleeding has not changed significantly and the pharmacologic therapy of esophageal varices and the prophylaxis of the initial variceal bleed has lagged behind these other interventional advances. These authors believe that progress in these areas has been slow because the pathophysiology and hemodynamics of esophageal varices are not well understood. It is through progress in the areas of endoluminal ultrasound imaging of esophageal varices and noninvasive pressure measurement that progress has finally been made in the area of the pathophysiology of variceal bleeding. In this update, two novel ideas regarding the pathophysiology of variceal bleeding are described. The first regards increased variceal pressure during peristaltic contraction. The second describes increased variceal pressure with increasing intraabdominal pressure. These new observations suggest a new pathophysiology in the cause of variceal bleeding and imply new methods to prevent and treat variceal bleeding. This update and review of esophageal varices is given in five sections: new developments in the pathophysiology of esophageal variceal bleeding, screening for esophageal varices, prediction of variceal bleeding, treatment of esophageal varices and new modalities to evaluate esophageal varices.