Chronic Pancreatitis: Landmark Papers, Management Decisions, and Future.

On May 16, 2015 at the invitation of the American Gastroenterological Association Institute Council E.P.D. presented a state-of-the-art lecture at Digestive Disease Week 2015. The aims were to discuss a selection of landmark papers in chronic pancreatitis (CP) that influence modern management and to conclude by suggesting some future directions. This is based on that presentation. We will specifically review the following: duct anatomy and pancreas divisum, description of chronic relapsing pancreatitis and its differentiation from recurrent acute pancreatitis and established CP (ECP), natural histories and gene discoveries of alcoholic, idiopathic and hereditary pancreatitis, development of pancreatic cancer in CP, exocrine pancreatic insufficiency and calculation of dose and delivery of enzymes, endoscopic ultrasonography, and autoimmune pancreatitis. With some exceptions, we exclude basic science and surgery.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review selected important clinical observations reported in 2012. RECENT FINDINGS: Celiac disease is a risk factor for pancreatitis. Patients with recurrent acute pancreatitis likely have chronic pancreatitis, do not benefit from pancreatic sphincterotomy, and may not benefit from biliary sphincterotomy. Analysis of endoscopic ultrasonography (EUS) images with an artificial neural network (ANN) program may improve chronic pancreatitis diagnosis compared with clinical interpretation of images. In a multicenter, randomized controlled trial of chronic pancreatitis patients, 90 000 USP U of pancreatin with meals decreased fat malabsorption compared with placebo. Detection of visceral pain in chronic pancreatitis predicts pain relief from various treatments, but nonvisceral pain due to altered central pain processing may respond to agents such as pregabalin. Predictors of surgical pain relief include onset of symptoms less than 3 years and preoperatively no opioid use and less than five endoscopic procedures. Total pancreatectomy for presumed painful chronic pancreatitis remains controversial. SUMMARY: Celiacs are at risk for pancreatitis. The diagnosis of chronic pancreatitis may be enhanced by ANN analysis of EUS imaging. Treatment of fat malabsorption requires 90,000 USP U of lipase with meals. Relief of pain from organ directed treatment of chronic pancreatitis may depend upon timing of interventions and whether pain is visceral or nonvisceral.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review important new clinical observations in chronic pancreatitis reported in 2011. RECENT FINDINGS: Smoking increases the risk of nongallstone acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. Binge drinking during Oktoberfest did not associate with increased hospital admissions for acute pancreatitis. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in chronic pancreatitis is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90 000 United States Pharmacopeia units of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared with endoscopic treatment in patients advanced chronic pancreatitis with a dilated main duct ±â€Špancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with chronic pancreatitis but approximately 30% of patients have significant side effects. SUMMARY: Patients with nongallstone-related acute pancreatitis or chronic pancreatitis of any cause should cease smoking. Results of this year's investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in chronic pancreatitis, and the mechanisms and treatment of neuropathic pain in chronic pancreatitis.

Pancreas divisum does not cause pancreatitis, but associates with CFTR mutations.

Bertin et al. partially dispel arguments that pancreas divisum (PD) causes pancreatitis, but fascinatingly indicate that PD associates with CFTR gene mutations predisposing to pancreatitis. This association, however, does not definitely confer a pathophysiological role for PD in pancreatitis but may denote that PD co-mingles with CFTR mutations without influencing pancreatitis or CFTR mutations influence pancreatic duct embryogenesis. We advise "idiopathic pancreatitis" patients with PD to undergo genetic testing. In lieu of CFTR mutations undertake no endoscopic/surgical procedure; if CFTR mutations are found, then refer patients for genetic counseling and withhold endoscopic/surgical therapy unless randomized studies show benefit.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review important new clinical observations in chronic pancreatitis made in the past year. RECENT FINDINGS: Tropical pancreatitis associates with SPINK1 and/or CFTR gene mutations in approximately 50% of patients, similar to the frequency in idiopathic chronic pancreatitis. Corticosteroids increase secretin-stimulated pancreatic bicarbonate concentrations in autoimmune pancreatitis (AIP) by restoring mislocalized CFTR protein to the apical ductal membrane. Most patients with asymptomatic hyperenzymemia have pancreatic lesions of unclear significance or no pancreatic lesions. Common pitfalls in the use of diagnostic tests for exocrine pancreatic insufficiency (EPI) confound interpretation of findings in irritable bowel syndrome and severe renal insufficiency. Further study is needed to improve the accuracy of endoscopic ultrasonography (EUS) to diagnose chronic pancreatitis. Celiac plexus block provides short-term pain relief in a subset of patients. SUMMARY: Results of this year's investigations further elucidated the genetic associations of tropical pancreatitis, a reversible mislocalization of ductal CFTR in AIP, the association of asymptomatic pancreatic hyperenzymemia with pancreatic disorders, limitations of diagnostic tests for EPI, diagnosis of chronic pancreatitis by EUS and endoscopic pancreatic function testing and treatment of pain.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review important new clinical observations in chronic pancreatitis made in the past year. RECENT FINDINGS: Cigarette smoking is a dose-dependent risk factor for acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. A minority of chronic alcohol consumers develop recurrent acute pancreatitis but very heavy drinking associates with chronic pancreatitis. More patients with alcohol-induced chronic pancreatitis have cirrhosis than patients with cirrhosis have chronic pancreatitis (39 vs. 18%). Most patients with asymptomatic hyperenzymemia have no pancreatic lesions. Pancreatic calcifications are most frequently due to chronic pancreatitis, followed by cystic neoplasms and other disorders. The new Rosemont consensus classification of endoscopic ultrasonography criteria for chronic pancreatitis is unvalidated. Zinc deficiency correlates only with severe chronic pancreatitis and the fecal elastase test is an inaccurate marker of pancreatic steatorrhea. Patients commonly receive insufficient lipase to abolish pancreatic steatorrhea. Ultrastructural neuropathies are common to chronic pancreatitis and pancreatic cancer and correlate with pain severity. SUMMARY: Results of this year's investigations further elucidated risk factors for pancreatic disease, the natural history of alcoholic pancreatitis, the differential diagnosis of pancreatic calcifications, the diagnosis of chronic pancreatitis with the Rosemont criteria, the limited diagnostic utility of fecal elastate test and zinc measurements, the proper dosing of pancreatic enzyme supplements, and treatment of pancreatic pain.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review important new clinical observations in chronic pancreatitis made in the last year. RECENT FINDINGS: Cholecystokinin-stimulated endoscopic pancreatic function testing has low specificity for diagnosis of early chronic pancreatitis, likely because of correctable technical limitations or failure to exclude confounding diseases. Fecal elastase 1 is a poor test for diagnosing pancreatic malabsorption. A 2-week trial of corticosteroids may differentiate autoimmune pancreatitis (AIP) from pancreatic cancer in select patients. A genetic screen may help to predict relapse of AIP. Repeated, 6-month visits to counsel against alcohol use may reduce recurrent attacks of alcoholic pancreatitis. A five-component antioxidant cocktail may reduce the frequency of pain in chronic pancreatitis by 1.5 days per month. SUMMARY: Researchers this last year have further characterized clinical aspects of chronic pancreatitis that may lead to improved detection of early chronic pancreatitis and AIP, risk stratification and application of risk-lowering strategies to prevent relapses in AIP or the development of recurrent (and possibly chronic) alcoholic pancreatitis and new evidence that antioxidants may have a modest effect on reducing the dominant symptom in chronic pancreatitis, abdominal pain.

New advances in acute pancreatitis.

PURPOSE OF REVIEW: We endeavor to review important new advances in acute pancreatitis made in the past year. We focused on clinical aspects of acute pancreatitis, which contained new observations or insights into new or old concepts. For experimental acute pancreatitis we refer readers to a recent comprehensive review. RECENT FINDINGS: Recently, case fatality rates of acute pancreatitis have stabilized; carbohydrate-deficient transferrin was shown to predict alcoholic acute pancreatitis; idiopathic chronic pancreatitis or occult cholelithiasis have been associated with 'recurrent acute pancreatitis' in most patients; and cystic fibrosis transmembrane conductance regulator genetic mutations were frequently found (10-50%) in patients with recurrent acute pancreatitis. In addition, alcohol was shown to increase the risk of pancreatic necrosis regardless of the cause of acute pancreatitis. Persistent organ failure and multiple organ dysfunction syndrome but not necessarily extent of necrosis were demonstrated to predict increased mortality in acute pancreatitis. Chemoprevention of post-endoscopic retrograde cholangiopancreatography acute pancreatitis remains unproven. Enteral feeding has been strongly recommended in severe acute pancreatitis. Finally, data are lacking for routine, prophylactic antibiotic administration to all patients with pancreatic necrosis. SUMMARY: We reviewed studies this past year that further characterize the epidemiology, etiology and risk stratification of acute pancreatitis. Evolving areas include chemoprevention of post-endoscopic retrograde cholangiopancreatography acute pancreatitis and enteral feeding and antibiotics in severe acute pancreatitis. We await translation of novel therapies from the bench to bedside.

Chronic pancreatitis.

PURPOSE OF REVIEW: As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. Topics recently reviewed were truncated to accommodate a surge in publications on clinical aspects of chronic pancreatitis, which contained new observations or insights into new or old concepts. RECENT FINDINGS: Cystic fibrosis carriers have been found to be at increased risk of pancreatitis. Autoimmune pancreatitis may belong to a multiorgan immunoglobulin G4-related autoimmune disease, and the natural history of chronic pancreatitis differs among the etiologies. Diffusion-weighted magnetic resonance imaging improves upon previous methodologies for diagnosing reduced pancreatic exocrine secretion, and fecal elastase-1 has been found to be a poor test for diagnosing pancreatic malabsorption. Visceral hyperalgesia or heightened central pain perception may contribute to pain in chronic pancreatitis. Instruments are evolving to assess quality of life in chronic pancreatitis, and fibrolytic agents have been found to have therapeutic promise. SUMMARY: Researchers this past year have further characterized genetic, molecular and clinical aspects of chronic pancreatitis. Advancing the understanding of fibrogenesis, mechanisms of exocrine insufficiency, calcification, and pain and continuing development/modification of diagnostic tests should lead to improved prevention, detection and treatment of the condition. More accurate quantification of outcomes is critical for translating potential therapies from bench to bedside.

A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma.

BACKGROUND: To compare operative morbidity, mortality, quality of life, and survival after pancreatoduodenectomy (PD) versus pancreatoduodenectomy with extended lymphadenectomy (PD/ELND) in patients with resectable pancreatic cancer. METHODS: From May 1997 to July 2003 there were 132 patients with biopsy examination-proven or suspected adenocarcinoma of the pancreatic head who agreed to participate in a single-institution, prospective, randomized trial. If resectable at operation, patients then were randomized to standard PD (40 patients) or PD/ELND (39 patients). Quality of life was assessed by using the Functional Assessment of Response to Cancer Therapy specific to the pancreas. Morbidity, mortality, and survival were analyzed. RESULTS: Demographics and pathologic characteristics for both groups were similar. When comparing PD/ELND with standard PD, the median operating time was greater for the PD/ELND group (7.6 h vs 6.2 h, P < .01), blood transfusion more likely (44% vs 22%, P < .05), and the median number of lymph nodes resected was greater (36 vs 15 nodes, P < .01). Morbidity and mortality rates were comparable. Median durations of stay were 11 and 10.5 days (P = NS), respectively. There were no significant differences in 1-year (71% vs 82%), 3-year (25% vs 41%), 5-year (16.5% vs 16.4%), and median (19 vs 26 mo) survival (P = .32). At 4 months postoperatively, diarrhea, body appearance, and bowel control scored lower on the Functional Assessment of Response to Cancer Therapy specific to the pancreas after PD/ELND (P < .05). CONCLUSIONS: Although a much larger study would have more power to compare statistically the survival between groups, both the decrement in quality of life and similar studies showing no survival difference make PD/ELND unattractive for further prospective investigation.

Chronic pancreatitis.

PURPOSE OF REVIEW: As in our previous reviews, we endeavor to review important new observations in chronic pancreatitis made in the past year. We included articles, including review articles, only if they contained new observations or readdressed old questions and provided new insights into old and new concepts. RECENT FINDINGS: Important observations include the following: (1) Strong association between cystic fibrosis transmembrane regulator dysfunction/mutations and 'recurrent acute pancreatitis', particularly in patients with pancreas divisum (2) Pancreas divisum may be incidental finding in recurrent acute pancreatitis (3) Smoking increases risk of chronic pancreatitis (4) Coxsackie B virus may increase severity of alcoholic chronic pancreatitis (5) CD4+ T cells and an immune reaction against amylase may play a role in pathogenesis of autoimmune pancreatitis (6) 2-(18F)-Fluro-2-deoxy-D-glucose positron emission tomography might be useful to detect pancreatic cancer in chronic pancreatitis patients at risk for developing pancreatic cancer, but contrast-enhanced Doppler ultrasound or endosonography may be as sensitive and better than contrast enhanced computed tomography (7) Superiority of surgery vs endotherapy for long term pain relief and weight gain in painful chronic pancreatitis (8) Early treatment of pain and malabsorption may improve life quality (9) Antifibrogenesis and fibrolytic agents as potential therapies. SUMMARY: Ongoing basic and clinical research this past year has further characterized genetic, molecular and clinical aspects of chronic pancreatitis. The advent of predictable and lasting treatments of chronic pancreatitis is most likely to appear on the wings of carefully conducted studies targeting genetic and molecular mechanisms of chronic pancreatitis, particularly pancreatic fibrogenesis.

'Good mentorship is invaluable' - an interview with Dr. Eugene P. DiMagno. Interview by Martin E. Fernandez-Zapico.

Dr. DiMagno is internationally renowned for his contributions to almost all areas of pancreatology. He helped pioneer discoveries about normal pancreatic function, enzyme-based treatment of exocrine pancreatic insufficiency as well as methods of diagnosing pancreatitis and pancreatic cancer, including the development of function tests and endoscopic ultrasound. Answering Martin Fernandez-Zapico's questions, he stresses the importance of good mentorship and gives us a glimpse of his life and work.

Primer on medical genomics. Part XIII: Ethical and regulatory issues.

Ethics in the new genomics era has become an increasingly complex subject that often arouses passion and confusion. Although 50 years have elapsed since the elucidation of the DNA molecule, the recent near-complete sequencing of the human genome has sharply accelerated the incorporation of genetics into the medical mainstream. Along with these scientific advances, however, have surfaced challenges, liabilities, and issues regarding the processing and management of genetic information as they relate to core ethical principles such as respect for autonomy, beneficence, nonmaleficence, and justice. Institutions and state and federal governments have initiated systematic and preemptive measures in education, resource development, and protective legislation to address these cardinal ethical issues. Genetic research is also being scrutinized carefully by institutional review boards, an activity that should not be perceived as being adversarial but rather as a protective shield for investigators and research participants alike. Ultimately, it is hoped that genomics medicine will diminish rather than enhance existing sex-, race-, and socioeconomic class-based inequities in health care access and delivery. This article describes some but not all aspects of the ethical, legal, and social implications of genomics in clinical practice.