Felicity T. Enders

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction: A Community-Based Study

OBJECTIVES This study sought to define the prevalence, severity, and significance of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) in the general community. BACKGROUND Although HFpEF is known to cause PH, its development is highly variable. Community-based data are lacking, and the relative contribution of pulmonary venous versus pulmonary arterial hypertension (HTN) to PH in HFpEF is unknown. We hypothesized that PH would be a marker of symptomatic pulmonary congestion, distinguishing HFpEF from pre-clinical hypertensive heart disease. METHODS This community-based study of 244 HFpEF patients (age 76 +/- 13 years; 45% male) was followed up using Doppler echocardiography over 3 years. Control subjects were 719 adults with HTN without HF (age 66 +/- 10 years; 44% male). Pulmonary artery systolic pressure (PASP) was derived from the tricuspid regurgitation velocity and PH defined as PASP >35 mm Hg. Pulmonary capillary wedge pressure (PCWP) was estimated from the ratio of early transmitral flow velocity to early mitral annular diastolic velocity. RESULTS In HFpEF, PH was present in 83% and the median (25th, 75th percentile) PASP was 48 (37, 56) mm Hg. PASP increased with PCWP (r = 0.21; p < 0.007). Adjusting for PCWP, PASP was higher in HFpEF than HTN (p < 0.001). The PASP distinguished HFpEF from HTN with an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) and strongly predicted mortality in HFpEF (hazard ratio: 1.3 per 10 mm Hg; p < 0.001). CONCLUSIONS PH is highly prevalent and often severe in HFpEF. Although pulmonary venous HTN contributes to PH, it does not fully account for the severity of PH in HFpEF, suggesting that a component of pulmonary arterial HTN also contributes. The potent effect of PASP on mortality lends support for therapies aimed at pulmonary arterial HTN in HFpEF.

Age-Associated Increases in Pulmonary Artery Systolic Pressure in the General Population

Background— In contrast to the wealth of data on isolated systolic hypertension involving the systemic circulation in the elderly, much less is known about age-related change in pulmonary artery systolic pressure (PASP) and its prognostic impact in the general population. We sought to define the relationship between PASP and age, to evaluate which factors influence PASP, and to determine whether PASP is independently predictive of mortality in the community. Methods and Results— A random sample of the Olmsted County, Minn, general population (n=2042) underwent echocardiography and spirometry and was followed up for a median of 9 years. PASP was measured from the tricuspid regurgitation velocity. Left ventricular diastolic pressure was estimated with Doppler echocardiography (E/e′ ratio), and arterial stiffening was assessed from the brachial artery pulse pressure. Among 1413 subjects (69%) with measurable PASP (age, 63±11 years; 43% male), median PASP was 26 mm Hg (25th to 75th percentile, 24 to 30 mm Hg) and increased with age (r=0.31, P<0.001). Independent predictors of PASP were age, pulse pressure, and mitral E/e′ (all P≤0.003). Increasing PASP was associated with higher mortality (hazard ratio, 2.73 per 10 mm Hg; P<0.001). In subjects without cardiopulmonary disease (any heart failure, coronary artery disease, hypertension, diabetes mellitus, or chronic obstructive lung disease), the age-adjusted hazard ratio was 2.74 per 10 mm Hg (P=0.016). Conclusions— We provide the first population-based evidence of age-related increase in pulmonary artery pressure, its association with increasing left heart diastolic pressures and systemic vascular stiffening, and its negative impact on survival. Pulmonary artery pressure may serve as a novel cardiovascular risk factor and potential therapeutic target.

Long‐term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation

The recurrence of primary biliary cirrhosis (PBC) in the hepatic allograft may impact patient and graft survival with long‐term follow‐up. The efficacy of ursodeoxycholic acid (UDCA) for treatment of recurrent PBC after liver transplantation (LT) remains less well known. The aims of this study were as follows: 1) to determine the significance of recurrent PBC on overall survival among PBC patients who underwent LT, and 2) to determine the efficacy of UDCA treatment after LT in patients with recurrent PBC. A retrospective cohort study was conducted of 154 PBC patients who underwent LT with at least 1 yr of follow‐up after transplantation from 1985 through 2005. A total of 52 patients with recurrent PBC were identified. After adjusting for age and gender, recurrent PBC was not associated with death or liver retransplantation (hazard ratio, 0.97, 95% confidence interval, 0.41–2.31; P = 0.9). A total of 38 patients with recurrent PBC received UDCA at an average dose of 12 mg/kg/day for a mean duration of 55 months. Over a 36‐month period, an estimated 52% of UDCA‐treated patients experienced normalization of serum alkaline phosphatase and alanine aminotransferase compared to 22% of untreated patients. There was no significant difference in the rate of histological progression between subgroups. UDCA did not influence patient and graft survival. In conclusion, the development of recurrent PBC has little impact on long‐term survival or need for retransplantation. While UDCA therapy is associated with biochemical improvement, its role in delaying histologic progression remains unknown. In this short period of treatment, UDCA was not associated with improved patient and graft survival compared to untreated patients. Liver Transpl 13:1236–1245, 2007.

Development and Validation of a Symptom-Based Activity Index for Adults With Eosinophilic Esophagitis

BACKGROUND & AIMS Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Factors That Affect Risk for Hepatocellular Carcinoma and Effects of Surveillance

BACKGROUND & AIMS The incidence of hepatocellular carcinoma (HCC) in the United States is increasing. Surveillance may affect the stage at diagnosis and consequently the treatment options available for HCC. We evaluated risk factors for HCC, the proportion of cases detected via surveillance, tumor characteristics, treatment approaches, and overall patient survival in a referral center cohort. METHODS The study included all patients diagnosed with HCC at the Mayo Clinic, Rochester, Minnesota, from 2007 to 2009 (n = 460). Clinical information was retrospectively abstracted from the medical record. RESULTS Hepatitis C virus (HCV, 36%), alcohol use (29%), and nonalcoholic fatty liver disease (NAFLD, 13%) were the most common risk factors for HCC. HCV was present in 56% of patients younger than 60. NAFLD was present in 19% of patients older than 60. HCC was detected during surveillance in 31% of patients. Patients with worse liver function were more likely to be on surveillance. Transarterial chemoembolization, surgical resection, and liver transplantation were the most common treatment approaches for HCC. Patients diagnosed with HCC during surveillance had less advanced disease, were more likely to be eligible for potentially curative treatments, and had increased survival times (P < .001). CONCLUSIONS At a major US referral center, the predominant HCC etiologies were HCV, alcohol use, and NAFLD. HCCs were detected during surveillance in the minority of patients. HCCs detected during surveillance were of less advanced stage, and patients were more likely to receive treatment that prolonged their survival.

Simulation-Based Objective Assessment Discerns Clinical Proficiency in Central Line Placement : A Construct Validation

BACKGROUND Central venous catheterization (CVC) is associated with patient risks known to be inversely related to clinician experience. We developed and evaluated a performance assessment tool for use in a simulation-based central line workshop. We hypothesized that instrument scores would discriminate between less experienced and more experienced clinicians. METHODS Participants included trainees enrolled in an institutionally mandated CVC workshop and a convenience sample of faculty attending physicians. The workshop integrated several experiential learning techniques, including practice on cadavers and part-task trainers. A group of clinical and education experts developed a 15-point CVC Proficiency Scale using national and institutional guidelines. After the workshop, participants completed a certification exercise in which they independently performed a CVC in a part-task trainer. Two authors reviewed videotapes of the certification exercise to rate performance using the CVC Proficiency Scale. Participants were grouped by self-reported CVC experience. RESULTS One hundred and five participants (92 trainees and 13 attending physicians) participated. Interrater reliability on a subset of 40 videos was 0.71, and Cronbach a was 0.81. The CVC Proficiency Scale Composite score varied significantly by experience: mean of 85%, median of 87% (range 47%-100%) for low experience (0-1 CVCs in the last 2 years, n = 27); mean of 88%, median of 87% (range 60%-100%) for moderate experience (2-49 CVCs, n = 62); and mean of 94%, median of 93% (range 73%-100%) for high experience (> 49 CVCs, n = 16) (P = .02, comparing low and high experience). CONCLUSIONS Evidence from multiple sources, including appropriate content, high interrater and internal consistency reliability, and confirmation of hypothesized relations to other variables, supports the validity of using scores from this 15-item scale for assessing trainee proficiency following a central line workshop.

Autoimmune Hepatitis–PBC Overlap Syndrome: A Simplified Scoring System May Assist in the Diagnosis

OBJECTIVES:Primary biliary cirrhosis (PBC) with features consistent with autoimmune hepatitis (AIH) has been described as an overlap syndrome. Recently, a simplified AIH scoring system has been proposed by the International Autoimmune Hepatitis Group (IAIHG), which is based on only four clinical components. We aimed to evaluate the performance of the new simplified AIH scoring system as a diagnostic instrument for PBC–AIH overlap syndrome compared with the revised 1999 IAIHG criteria. Furthermore, we sought to compare the outcome in PBC patients with and without the features of AIH overlap.METHODS:Retrospective analysis of PBC patients was carried out. Parameters relevant to the revised criteria were recorded, and outcomes were compared between those with and without features of overlap.RESULTS:Of 368 patients (318 females) with a definite diagnosis of PBC, 43 (12%) were diagnosed as probable PBC–AIH overlap with the revised criteria and 23 (6%) with the simplified criteria. In both scoring systems the frequency of cirrhosis, portal hypertension, gastrointestinal (GI) bleeding, ascites, and esophageal varices was significantly higher in the overlap group at the time of follow-up. Patients with features of overlap according to the new criteria had more frequent liver-related death and liver transplantation (P=0.0025, log rank test).CONCLUSIONS:The simplified AIH scoring system appears to be more specific in patients with PBC and could assist in clinical assessment. Worse outcome was observed in patients with overlap features, demonstrated as increased liver-related mortality with the new criteria. The new criteria should be able to replace the revised criteria for the diagnosis of PBC–AIH overlap syndrome.

Symptoms Have Modest Accuracy in Detecting Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis

BACKGROUND & AIMS It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission. METHODS Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. RESULTS Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. CONCLUSIONS In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

Thyroid dysfunction in primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease

Background/Aims: Primary biliary cirrhosis (PBC) is frequently associated with autoimmune diseases, including thyroid disease, although it is uncertain that this association is higher than in other liver diseases.

Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia.

Estimation of the prevalence of oesophageal narrowing and its clinical relevance in patients with oesophageal eosinophilia is probably underestimated by endoscopy.