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ACG Clinical Guideline: Chronic Pancreatitis
Chronic pancreatitis (CP) is historically defined as an irreversible inflammatory condition of the pancreas leading to varying degrees of exocrine and endocrine dysfunction. Recently however, the paradigm for the diagnosis has changed in that it breaks with the traditional clinicopathologic-based definition of disease, focusing instead on diagnosing the underlying pathologic process early in the disease course and managing the syndrome more holistically to change the natural course of disease and minimize adverse disease effects. Currently, the most accepted mechanistically derived definition of CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress. The most common symptom of CP is abdominal pain, with other symptoms such as exocrine pancreatic insufficiency and diabetes developing at highly variable rates. CP is most commonly caused by toxins such as alcohol or tobacco use, genetic polymorphisms, and recurrent attacks of acute pancreatitis, although no history of acute pancreatitis is seen in many patients. Diagnosis is made usually on cross-sectional imaging, with modalities such as endoscopic ultrasonography and pancreatic function tests playing a secondary role. Total pancreatectomy represents the only known cure for CP, although difficulty in patient selection and the complications inherent to this intervention make it usually an unattractive option. This guideline will provide an evidence-based practical approach to the diagnosis and management of CP for the general gastroenterologist.
Journal Article
The role of alcohol and smoking in pancreatitis
Chronic alcohol use has been linked to pancreatitis for over a century, but its role in the disease has only been recently elucidated. This Review focuses on what is known from animal models and association studies conducted in humans about the relationship between alcohol consumption, smoking, and chronic pancreatitis. The authors discuss the incidence, pathogenesis and etiology of pancreatitis as well as mechanisms of disease.
Chronic alcohol use has been linked to chronic pancreatitis for over a century, but it has not been until the last decade that the role of alcohol in chronic pancreatitis has been elucidated in animals and, only in recent years, in human populations. Although a dose-dependent association between alcohol consumption and chronic pancreatitis may exist, a staistical association has been shown only with the consumption of ≥5 alcoholic drinks per day. Smoking also confers a strong, independent and dose-dependent risk of pancreatitis that may be additive or multiplicative when combined with alcohol. Alcohol increases the risk of acute pancreatitis in several ways and, most importantly, changes the immune response to injury. Genetic factors are also important and further studies are needed to clarify the role of gene–environment interactions in pancreatitis. In humans, aggressive interventional counseling against alcohol use may reduce the frequency of recurrent attacks of disease and smoking cessation may help to slow the progression of acute to chronic pancreatitis.
Key Points
Studies suggest that a threshold of approximately 5 alcoholic drinks per day must be exceeded before the risk of chronic pancreatitis in individuals who drink alcohol exceeds that of the nondrinking population
Only a minority of patients with pancreatitis have a significant history of alcohol consumption, suggesting that most patients have a complex genetic disorder that is similar to other chronic inflammatory diseases
Smoking is a dose-dependent risk factor for pancreatitis, and its effects are additive or multiplicative when combined with alcohol
Chronic alcohol use at high daily doses (that is, ≥5 drinks daily) increases susceptibility to, and severity of, acute pancreatitis and accelerates the progression of chronic pancreatitis
Aggressive counseling leading to reduced alcohol consumption may reduce the likelihood of recurrent acute pancreatitis
Smoking cessation may slow the progression of chronic pancreatitis
Journal Article
Hereditary Pancreatitis in the United States: Survival and Rates of Pancreatic Cancer
OBJECTIVESHereditary pancreatitis (HP), an autosomal dominant disease typically caused by mutations in PRSS1, has a broad range of clinical characteristics and high cumulative risk of pancreatic cancer. We describe survival and pancreatic cancer risk in the largest HP cohort in the US.MethodsHP probands and family members prospectively recruited from 1995 to 2013 completed medical and family history questionnaires, and provided blood for DNA testing. Overall survival (until 12/31/2015) was determined from the Social Security Death Index (SSDI), National Death Index (NDI), and family members. Cause of death was obtained from the NDI.Results217 PRSS1 carriers (181 symptomatic) formed the study cohort. The most frequently detected mutations were p.R122H (83.9%) and p.N29I (11.5%). Thirty-seven PRSS1 carriers (30 symptomatic, 7 asymptomatic) were deceased at conclusion of the study (5 from pancreatic cancer). Median overall survival was 79.3 years (IQR 72.2–85.2). Risk of pancreatic cancer was significantly greater than age- and sex- matched SEER data (SIR 59, 95% CI 19-138), and cumulative risk was 7.2% (95% CI 0–15.4) at 70 years.DiscussionWe confirm prior observations on survival and pancreatic cancer SIR in PRSS1 subjects. Although risk of pancreatic cancer was significantly high in these patients, its cumulative risk was much lower than previous reports.
Journal Article
Elevated Serum Triglycerides are Independently Associated With Persistent Organ Failure in Acute Pancreatitis
Hypertriglyceridemia (HTG) represents a major health problem with prevalence exceeding 30% in the U.S. The present study aims to assess the effect of elevated serum triglyceride (TG) levels on the severity of acute pancreatitis (AP).
Prospectively enrolled AP patients were categorized into normal, mild, moderate, and severe/very severe categories based on their TG levels and compared in respect to demographics, comorbidities, and clinical outcomes. Multivariate analysis determined whether elevated TG levels were independently associated with persistent organ failure.
Two hundred and one out of 400 AP patients had serum TGs measured within 72 h of presentation, of which 115 had normal TG levels and 86 HTG (20 mild, 41 moderate, and 25 severe/very severe). Patients with HTG were of younger age (44 vs. 52 years), predominantly male (65% vs. 45%), obese (57% vs. 34%), diabetic (38% vs. 17%), and developed more frequently persistent organ failure (40% vs. 17%) compared with those with normal TGs (P<0.02). The rate of persistent organ failure increased proportionally with HTG severity grades (17% when normal TGs, 30% in mild, 39% in moderate, and 48% in severe/very severe HTG, Ptrend<0.001). On multivariate analysis controlling for age, gender, body mass index, diabetes, and alcohol etiology, moderate HTG (odds ratio (OR), 2.6; P=0.04) and severe/very severe HTG (OR, 4.9; P=0.009) were independently associated with persistent organ failure.
Elevated serum TGs in AP patients are independently and proportionally correlated with persistent organ failure regardless of etiology. TG-mediated lipotoxicity may be an attractive target to design novel interventions for severe AP.
Journal Article
Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial
Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial (
NCT03452228
) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (
n
= 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (
n
= 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (
n
= 19). Fifty-one patients (males,
n
= 27; females,
n
= 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg
−1
or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov
NCT03452228
.
The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.
Journal Article
What is personalized medicine and what should it replace?
Personalized medicine is a new framework for medical care that involves modelling and simulation of a disease on the basis of underlying mechanisms. In this article, David Whitcomb uses chronic pancreatitis and an example to outline the limitations of the 20
th
century framework for medical care and examines the advantages of personalized medicine.
Personalized medicine is a new framework for medical care that involves modelling and simulation of a disease on the basis of its underlying mechanisms. This strategy must replace the 20
th
century paradigm of defining disease by pathology or associated signs and symptoms and conducting outcomes research that is based on the presence or absence of the disease syndrome. New technologies, including next-generation sequencing, the 'omics' and powerful computers provide massive amounts of accurate data. However, attempts to understand complex disorders by applying these new technologies within the 20
th
century framework have failed to produce the expected medical advances. To help physicians embrace a paradigm shift, the limitations of the old framework and major advantages of the new framework must be demonstrated. Chronic pancreatitis is an ideal complex disorder to study to consider the pros and cons of the two frameworks, because the pancreas is such a simple organ for disease modelling, and the advantages of personalized medicine are so profound.
Journal Article
Comparison of BISAP, Ranson's, APACHE-II, and CTSI Scores in Predicting Organ Failure, Complications, and Mortality in Acute Pancreatitis
Identification of patients at risk for severe disease early in the course of acute pancreatitis (AP) is an important step to guiding management and improving outcomes. A new prognostic scoring system, the bedside index for severity in AP (BISAP), has been proposed as an accurate method for early identification of patients at risk for in-hospital mortality. The aim of this study was to compare BISAP (blood urea nitrogen >25 mg/dl, impaired mental status, systemic inflammatory response syndrome (SIRS), age>60 years, and pleural effusions) with the \"traditional\" multifactorial scoring systems: Ranson's, Acute Physiology and Chronic Health Examination (APACHE)-II, and computed tomography severity index (CTSI) in predicting severity, pancreatic necrosis (PNec), and mortality in a prospective cohort of patients with AP.
Extensive demographic, radiographic, and laboratory data from consecutive patients with AP admitted or transferred to our institution was collected between June 2003 and September 2007. The BISAP and APACHE-II scores were calculated using data from the first 24 h from admission. Predictive accuracy of the scoring systems was measured by the area under the receiver-operating curve (AUC).
There were 185 patients with AP (mean age 51.7, 51% males), of which 73% underwent contrast-enhanced CT scan. Forty patients developed organ failure and were classified as severe AP (SAP; 22%). Thirty-six developed PNec (19%), and 7 died (mortality 3.8%). The number of patients with a BISAP score of > or =3 was 26; Ranson's > or =3 was 47, APACHE-II > or =8 was 66, and CTSI > or =3 was 59. Of the seven patients that died, one had a BISAP score of 1, two had a score of 2, and four had a score of 3. AUCs for BISAP, Ranson's, APACHE-II, and CTSI in predicting SAP are 0.81 (confidence interval (CI) 0.74-0.87), 0.94 (CI 0.89-0.97), 0.78 (CI 0.71-0.84), and 0.84 (CI 0.76-0.89), respectively.
We confirmed that the BISAP score is an accurate means for risk stratification in patients with AP. Its components are clinically relevant and easy to obtain. The prognostic accuracy of BISAP is similar to those of the other scoring systems. We conclude that simple scoring systems may have reached their maximal utility and novel models are needed to further improve predictive accuracy.
Journal Article
Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities
Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients.
We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL.
Mean PCS and MCS scores were 36.7±11.7 and 42.4±12.2, respectively. Significant (P<0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P<0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL.
Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses.
Journal Article