Chronic Pancreatitis PDF - 18-27 (2024)

Universidad Peruana de Ciencias Aplicadas Access Provided by: Current Medical Diagnosis & Treatment 2024 18­27: Chronic Pancreatitis Lawrence S. Friedman ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Chronic or intermittent epigastric pain, steatorrhea, weight loss, abnormal pancreatic imagin...

Universidad Peruana de Ciencias Aplicadas Access Provided by: Current Medical Diagnosis & Treatment 2024 18­27: Chronic Pancreatitis Lawrence S. Friedman ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Chronic or intermittent epigastric pain, steatorrhea, weight loss, abnormal pancreatic imaging. A mnemonic for the predisposing factors of chronic pancreatitis is TIGAR­O: toxic­metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive. GENERAL CONSIDERATIONS The incidence and prevalence of chronic pancreatitis in the United States are 5–8 and 42–73 per 100,000 population, respectively, with a peak in persons aged 46–55 years. Chronic pancreatitis occurs most often in patients with alcoholism (45–80% of all cases). The risk of chronic pancreatitis increases with the duration and amount of alcohol consumed, but pancreatitis develops in only 5–10% of heavy drinkers. Tobacco smoking is a risk factor for idiopathic chronic pancreatitis and has been reported to accelerate progression of alcohol­associated chronic pancreatitis. About 2% of patients with hyperparathyroidism develop pancreatitis. In tropical Africa and Asia, tropical pancreatitis, related in part to malnutrition, is the most common cause of chronic pancreatitis. By contrast, in Western societies, obesity can lead to pancreatic steatosis, which may lead ultimately to pancreatic exocrine and endocrine insufficiency and an increased risk of pancreatic cancer. A stricture, stone, or tumor obstructing the pancreas can lead to obstructive chronic pancreatitis. Autoimmune pancreatitis is associated with hypergammaglobulinemia (IgG4 in particular), often with autoantibodies and other autoimmune diseases, and is responsive to corticosteroids. Affected persons are at increased risk for various cancers. Type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis, or simply autoimmune pancreatitis) is a multisystem disease, typically in a patient over age 60, characterized by lymphoplasmacytic infiltration and fibrosis on biopsy, associated bile duct strictures, retroperitoneal fibrosis, renal and salivary gland lesions, and a high rate of relapse after treatment. It is the pancreatic manifestation of IgG4­related disease. Type 2 (“idiopathic duct­centric chronic pancreatitis”) affects the pancreas alone, typically in a patient aged 40–50 years, and is characterized by intense duct­centric lymphoplasmacytic infiltration on biopsy, lack of systemic IgG4 involvement, an association with IBD in 25% of cases, often a tumor­like mass, and a low rate of relapse after treatment. Type 3 autoimmune pancreatitis is a relatively infrequent complication of immune checkpoint inhibitor therapy. Between 10% and 30% of cases of chronic pancreatitis are idiopathic, with either early onset (median age 20) or late onset (median age 58). Genetic factors may predispose to chronic pancreatitis in nearly half of the early­onset cases and a quarter of the late­onset cases and include pathogenic variants of the CFTR gene, the pancreatic secretory trypsin inhibitory gene (PSTI, also known as the serine protease inhibitor, SPINK1), the chymotrypsin­C (CTRC) gene, and the genes for carboxypeptidase A1 (CPA1) and possibly uridine 5′­diphosphate glucuronosyltransferase (UGT1A7). A variant of the cationic trypsinogen gene on chromosome 7 (serine protease 1, PRSS1) is associated with hereditary pancreatitis, transmitted as an autosomal dominant trait with variable penetrance. In addition, a variant in an X­linked gene CLDN2, which encodes claudin­2, has been associated with chronic pancreatitis; its presence on the X chromosome may partly explain the male predominance of chronic pancreatitis. Variants in the gene for transient receptor cation channel subfamily V member 6 (TRPV6) are associated with early­onset chronic pancreatitis. A useful mnemonic for the predisposing factors to chronic pancreatitis is TIGAR­O: Toxic­metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis, or Obstructive. Another multi­risk factor classification system that provides criteria for etiology, clinical and diagnostic stage, and severity is M­ ANNHEIM—the pancreatitis with multiple risk factors—alcohol consumption, nicotine consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors, miscellaneous and rare metabolic factors system. The pathogenesis of chronic pancreatitis be explained by the SAPE (Sentinel Acute Pancreatitis Event) hypothesis by which the first (sentinel) Downloaded 2023­11­30 7:44 P Your IPmay is 52.36.32.128 acute pancreatitis event initiates an inflammatory process that results in injury and later fibrosis (“necrosis­fibrosis”). In many cases, chronicPage 1 / 8 18­27: Chronic Pancreatitis, Lawrence S. Friedman ©2023 McGraw Hill. All Rights Reserved. Terms of Use Privacypain Policy • Notice •episodes Accessibility pancreatitis is a self­perpetuating disease characterized by•chronic or recurrent of acute pancreatitis and ultimately by pancreatic exocrine or endocrine insufficiency (sooner in alcohol­associated pancreatitis than in other types). After many years, chronic pain may resolve spontaneously or following surgery tailored to the cause of pain. Over 80% of adults develop diabetes mellitus within 25 years after the clinical onset of predisposing factors to chronic pancreatitis is TIGAR­O: Toxic­metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis, Universidad Peruana de Ciencias Aplicadas or Obstructive. Another multi­risk factor classification system that provides criteria for etiology, clinical and diagnostic stage, and severity is M­ Access Provided by: ANNHEIM—the pancreatitis with multiple risk factors—alcohol consumption, nicotine consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors, miscellaneous and rare metabolic factors system. The pathogenesis of chronic pancreatitis may be explained by the SAPE (Sentinel Acute Pancreatitis Event) hypothesis by which the first (sentinel) acute pancreatitis event initiates an inflammatory process that results in injury and later fibrosis (“necrosis­fibrosis”). In many cases, chronic pancreatitis is a self­perpetuating disease characterized by chronic pain or recurrent episodes of acute pancreatitis and ultimately by pancreatic exocrine or endocrine insufficiency (sooner in alcohol­associated pancreatitis than in other types). After many years, chronic pain may resolve spontaneously or following surgery tailored to the cause of pain. Over 80% of adults develop diabetes mellitus within 25 years after the clinical onset of chronic pancreatitis. CLINICAL FINDINGS A. Symptoms and Signs Persistent or recurrent episodes of epigastric and left upper quadrant pain are typical. The pain results in part from impaired inhibitory pain modulation by the CNS, and the pattern may vary over time, with no correlation with disease duration or imaging findings. Anorexia, nausea, vomiting, constipation, flatulence, and weight loss are common. During attacks, tenderness over the pancreas, mild muscle guarding, and ileus may be noted. Attacks may last for only a few hours or for as long as 2 weeks; pain may eventually be almost continuous. Steatorrhea (as indicated by bulky, foul, fatty stools) may occur late in the course. B. Laboratory Findings Serum amylase and lipase may be elevated during acute attacks; however, normal values do not exclude the diagnosis. Serum alkaline phosphatase and bilirubin may be elevated owing to compression of the bile duct. Glycosuria may be present. Excess fecal fat may be demonstrated on chemical analysis of the stool. Exocrine pancreatic insufficiency generally is confirmed by response to therapy with pancreatic enzyme supplements; the secretin stimulation test can be used if available (and has a high negative predictive value for ruling out early acute chronic pancreatitis), as can detection of decreased fecal chymotrypsin or elastase levels, although the latter tests lack sensitivity and specificity. Vitamin B12 malabsorption is detectable in about 40% of patients, but clinical deficiency of vitamin B12 and fat­soluble vitamins is rare. Accurate diagnostic tests are available for the major trypsinogen gene pathogenic variants, but because of uncertainty about the mechanisms linking heterozygous CFTR and PSTI variants with pancreatitis, genetic testing for mutations in these two genes is recommended primarily in younger patients in whom the etiology of chronic pancreatitis is unclear. Elevated IgG4 levels, ANA, antibodies to lactoferrin and carbonic anhydrase II, and other autoantibodies are often found in patients with autoimmune pancreatitis (especially type 1); antibodies to peptide A1P1­7 and to ubiquitin­protein ligase E3 component n­recognin 2 have been reported in a high percentage of patients with autoimmune pancreatitis but also in some patients with pancreatic cancer. Pancreatic biopsy, if necessary, shows a lymphoplasmacytic inflammatory infiltrate with characteristic IgG4 immunostaining, which is also found in biopsy specimens of the major papilla, bile duct, and salivary glands, in type 1 autoimmune pancreatitis. C. Imaging CT or MRI is recommended as initial testing for diagnosis of chronic pancreatitis, although plain films show calcifications due to pancreatolithiasis in 30% of affected patients (eFigure 18–62). CT may show calcifications not seen on plain films as well as ductal dilatation and heterogeneity or atrophy of the gland. Occasionally, the findings raise suspicion of pancreatic cancer (“tumefactive chronic pancreatitis”). Secretin­enhanced MRCP may be considered in selected cases. When CT or MRI is inconclusive, EUS (with pancreatic tissue sampling) may be needed. Endoscopic ultrasonographic (“Rosemont”) criteria for the diagnosis of chronic pancreatitis include hyperechoic foci with shadowing indicative of calculi in the main pancreatic duct and lobularity with honeycombing of the pancreatic parenchyma. ERCP is the most sensitive imaging study for chronic pancreatitis and may show dilated ducts, intraductal stones, strictures, or pseudocysts but is infrequently used for diagnosis alone; moreover, the results may be normal in patients with so­called minimal change pancreatitis (eFigure 18–63). Histology is the gold standard for diagnosis when clinical suspicion is strong, but imaging studies are inconclusive. eFigure 18–62. Pancreatic calcifications. A plain film of the abdomen shows calcifications in the region of the pancreas (arrows). (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw­Hill Companies, Inc.) Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 8 eFigure 18–62. Universidad Peruana de Ciencias Aplicadas Access Provided by: Pancreatic calcifications. A plain film of the abdomen shows calcifications in the region of the pancreas (arrows). (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw­Hill Companies, Inc.) eFigure 18–63. Dilated pancreatic duct. A : Endoscopic retrograde cholangiopancreatography shows a normal bile duct and biliary tract with a dilated duct (arrowhead). B : Enlarged view of the dilated pancreatic duct. (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw­Hill Companies, Inc.) Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 3 / 8 eFigure 18–63. Universidad Peruana de Ciencias Aplicadas Dilated pancreatic duct. A : Endoscopic retrograde cholangiopancreatography shows a normal bile duct and biliary tract with a dilated duct Access Provided by: (arrowhead). B : Enlarged view of the dilated pancreatic duct. (Reproduced, with permission, from Krebs CA, Giyanani VL, Eisenberg RL. Ultrasound Atlas of Disease Processes. Originally published by Appleton & Lange. Copyright © 1993 by The McGraw­Hill Companies, Inc.) Characteristic imaging features of autoimmune pancreatitis include diffuse enlargement of the pancreas, a peripheral rim of hypoattenuation, and irregular narrowing of the main pancreatic duct. In the United States, the diagnosis of autoimmune pancreatitis is based on the HISORt criteria: Histology, Imaging, Serology, other Organ involvement, and Response to corticosteroid Therapy. COMPLICATIONS Opioid addiction is common. Other frequent complications include often brittle diabetes mellitus, pancreatic pseudocyst or abscess, cholestatic liver enzymes with or without jaundice, bile duct stricture, exocrine pancreatic insufficiency, malnutrition, osteoporosis, and peptic ulcer. Pancreatic cancer develops in 5% of patients after 20 years although surveillance for pancreatic cancer is not recommended in asymptomatic patients; the risk may relate to tobacco and alcohol use. In patients with hereditary pancreatitis, the risk of pancreatic cancer rises after 50 years of age and reaches 19% by age 70 (see Chapter 41). Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman TREATMENT ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility A. Medical Measures Page 4 / 8 Universidad Peruana de Ciencias Aplicadas Opioid addiction is common. Other frequent complications include often brittle diabetes mellitus, pancreatic pseudocyst or abscess, cholestatic liver Access Provided by: peptic ulcer. Pancreatic cancer enzymes with or without jaundice, bile duct stricture, exocrine pancreatic insufficiency, malnutrition, osteoporosis, and develops in 5% of patients after 20 years although surveillance for pancreatic cancer is not recommended in asymptomatic patients; the risk may relate to tobacco and alcohol use. In patients with hereditary pancreatitis, the risk of pancreatic cancer rises after 50 years of age and reaches 19% by age 70 (see Chapter 41). TREATMENT A. Medical Measures A low­fat diet should be prescribed. Alcohol is forbidden because it frequently precipitates attacks. Opioids should be avoided if possible. Preferred agents for pain are acetaminophen, NSAIDs, and, if an opioid is necessary, tramadol, along with pain­modifying agents such as tricyclic antidepressants, SSRIs, and gabapentin or pregabalin. Exocrine pancreatic insufficiency is treated with pancreatic enzyme replacement therapy selected based on high lipase activity (Table 18–12). A total dose of at least 40,000 units of lipase in capsules is given with each meal. Doses of 90,000 units or more of lipase per meal may be required in some cases. The tablets should be taken at the start of, during, and at the end of a meal. Concurrent administration of an H2­receptor antagonist (eg, famotidine, 20 mg orally twice daily), a PPI (eg, omeprazole, 20–60 mg orally daily), or sodium bicarbonate (650 mg orally before and after meals) decreases the inactivation of lipase by acid and may thereby further decrease steatorrhea. In selected cases of alcohol­associated pancreatitis and in cystic fibrosis, enteric­coated microencapsulated preparations may offer an advantage; however, in patients with cystic fibrosis, high­dose pancreatic enzyme replacement therapy has been associated with strictures of the ascending colon. Pain secondary to idiopathic chronic pancreatitis may be alleviated in some cases by pancreatic enzyme replacement therapy (not enteric­coated preparations) or by octreotide, 200 mcg subcutaneously three times daily, although some guidelines recommend against such therapy. Antioxidant therapy to inhibit electrophilic stress on key macromolecules in the pancreas by toxic metabolites has shown promise in some, but not all, studies. Associated diabetes mellitus should be treated (see Chapter 29). Autoimmune pancreatitis is treated with prednisone 40 mg/day orally for 1–2 months, followed by a taper of 5 mg every 2–4 weeks. Nonresponse or relapse occurs in 45% of type 1 cases (particularly in those with concomitant IgG4­ associated cholangitis); rituximab is an effective induction and maintenance agent, and azathioprine or long­term low­dose corticosteroid use appears to reduce the risk of relapse. Colchicine has been reported to be effective. Table 18–12. FDA­approved pancreatic enzyme (pancrelipase) preparations. Enzyme Content/Unit Dose, USP Units Product Protease Lipase Amylase Viokace 10,440 10,440 39,150 39,150 Viokace 20,880 20,880 78,300 78,300 Creon 3000 3000 15,000 9500 Creon 6000 6000 30,000 19,000 Creon 12,000 12,000 60,000 38,000 Creon 24,000 24,000 120,000 76,000 Creon 36,000 36,000 180,000 114,000 Immediate­Release Capsules Nonenteric­coated Delayed­Release Capsules Enteric­coated minimicrospheres Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman Enteric­coated minitablets ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Ultresa 13,800 13,800 27,600 Page 5 / 8 27,600 Creon 12,000 12,000 60,000 Universidad Peruana de Ciencias Aplicadas 38,000 Access Provided by: Creon 24,000 24,000 120,000 76,000 Creon 36,000 36,000 180,000 114,000 Ultresa 13,800 13,800 27,600 27,600 Ultresa 20,700 20,700 46,000 41,400 Ultresa 23,000 23,000 46,000 41,400 Zenpep 3000 3000 16,000 10,000 Zenpep 5000 5000 27,000 17,000 Zenpep 10,000 10,000 55,000 34,000 Zenpep 15,000 15,000 82,000 51,000 Zenpep 20,000 20,000 109,000 68,000 Zenpep 25,000 25,000 136,000 85,000 Pancreaze 4200 4200 17,500 10,000 Pancreaze 10,500 10,500 43,750 25,000 Pancreaze 16,800 16,800 70,000 40,000 Pancreaze 21,000 21,000 61,000 37,000 Enteric­coated minitablets Enteric­coated beads Enteric­coated microtablets Bicarbonate­buffered enteric­coated microspheres Pertzye 8000 8000 30,250 28,750 Pertzye + 16,000 16,000 60,500 57,500 USP, US Pharmacopeia. B. Endoscopic and Surgical Treatment Endoscopic therapy or surgery may be indicated in chronic pancreatitis to treat underlying biliary tract disease, ensure free flow of bile into the duodenum, drain persistent pseudocysts, treat other complications, eliminate obstruction of the pancreatic duct, attempt to relieve pain, or exclude pancreatic cancer. Liver fibrosis may regress after biliary drainage. Distal bile duct obstruction may be relieved by endoscopic placement of multiple plastic stents or a fully covered self­expandable metal stent in the bile duct. When obstruction of the duodenal end of the pancreatic duct can be demonstrated by ERCP, dilation, placement of a stent in the duct, pancreatic duct stone lithotripsy, or surgical resection of the tail of the pancreas with implantation of the distal end of the duct by pancreaticojejunostomy may be performed. Endoscopic therapy is successful in about 50% of cases. In patients who do not respond to endoscopic therapy, surgery is successful in about 50%. When the pancreatic duct is diffusely dilated, anastomosis between the duct after it is7:44 splitPlongitudinally and a defunctionalized limb of jejunum (modified Puestow procedure), in some cases combined with Downloaded 2023­11­30 Your IP is 52.36.32.128 6/8 18­27: Chronic Lawrence S. Friedman resection of the Pancreatitis, head of the pancreas (Beger or Frey procedure), is associated with relief of pain in 80% of cases. In advanced cases, subtotalPage or total ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility pancreatectomy with islet autotransplantation may be considered as a last resort but has variable efficacy and causes pancreatic insufficiency and diabetes mellitus. Perioperative administration of somatostatin or octreotide may reduce the risk of postoperative pancreatic fistulas. Endoscopic or surgical (including laparoscopic) drainage is indicated for symptomatic pseudocysts and, in many cases, those over 6 cm in diameter. EUS may pancreatic cancer. Liver fibrosis may regress after biliary drainage. Distal bile duct obstruction may be relieved by endoscopic placement of multiple Universidad Peruana de Ciencias Aplicadas plastic stents or a fully covered self­expandable metal stent in the bile duct. When obstruction of the duodenal end of the pancreatic duct can be Access Provided by: demonstrated by ERCP, dilation, placement of a stent in the duct, pancreatic duct stone lithotripsy, or surgical resection of the tail of the pancreas with implantation of the distal end of the duct by pancreaticojejunostomy may be performed. Endoscopic therapy is successful in about 50% of cases. In patients who do not respond to endoscopic therapy, surgery is successful in about 50%. When the pancreatic duct is diffusely dilated, anastomosis between the duct after it is split longitudinally and a defunctionalized limb of jejunum (modified Puestow procedure), in some cases combined with resection of the head of the pancreas (Beger or Frey procedure), is associated with relief of pain in 80% of cases. In advanced cases, subtotal or total pancreatectomy with islet autotransplantation may be considered as a last resort but has variable efficacy and causes pancreatic insufficiency and diabetes mellitus. Perioperative administration of somatostatin or octreotide may reduce the risk of postoperative pancreatic fistulas. Endoscopic or surgical (including laparoscopic) drainage is indicated for symptomatic pseudocysts and, in many cases, those over 6 cm in diameter. EUS may facilitate selection of an optimal site for endoscopic drainage. Pancreatic ascites or pancreaticopleural fistulas due to a disrupted pancreatic duct can be managed by endoscopic placement of a stent across the disrupted duct. Pancreatic sphincterotomy or fragmentation of stones in the pancreatic duct by lithotripsy and endoscopic removal of stones from the duct may relieve pain in selected patients. For patients with chronic pain and nondilated ducts, a percutaneous celiac plexus nerve block may be considered under either CT or EUS guidance, with pain relief (albeit often short­lived) in approximately 50% of patients (see Chapter 5). A single session of radiation therapy to the pancreas has been reported to relieve otherwise refractory pain. PROGNOSIS Chronic pancreatitis often leads to disability and reduced life expectancy; pancreatic cancer is the main cause of death. The prognosis is best in patients with recurrent acute pancreatitis caused by a remediable condition, such as cholelithiasis, choledocholithiasis, stenosis of the sphincter of Oddi, or hyperparathyroidism, and in those with autoimmune pancreatitis. Medical management of hyperlipidemia, if present, may also prevent recurrent attacks of pancreatitis. The Chronic Pancreatitis Prognosis Score based on pain, hemoglobin A1c level, CRP level, BMI, and platelet count has been shown to correlate with hospital admissions and number of hospital days. In alcohol­associated pancreatitis, pain relief is most likely when a dilated pancreatic duct can be decompressed. In patients with disease not amenable to decompressive surgery, addiction to opioids is a frequent outcome of treatment. A poorer quality of life is associated with constant rather than intermittent pain, pain­related disability or unemployment, current smoking, and comorbidities. WHEN TO REFER All patients with chronic pancreatitis should be referred for diagnostic and therapeutic procedures. WHEN TO ADMIT Severe pain. New jaundice. New fever. Beyer G et al. Chronic pancreatitis. Lancet. 2020;396:499. [PubMed: 32798493] Dirweesh A et al. Endoscopic management of complications in chronic pancreatitis. Dig Dis Sci. 2022;67:1624. [PubMed: 35226223] Gardner TB et al. ACG Clinical Guideline: chronic pancreatitis. Am J Gastroenterol. 2020;115:322. [PubMed: 32022720] Hart PA et al. High prevalence of osteopathy in chronic pancreatitis: a cross­sectional analysis from the PROCEED study. Clin Gastroenterol Hepatol. 2022;20:2005. [PubMed: 34571258] Issa Y et al. Dutch Pancreatitis Study Group. Effect of early surgery vs endoscopy­first approach on pain in patients with chronic pancreatitis: the ESCAPE randomized clinical trial. JAMA. 2020;323:237. [PubMed: 31961419] Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman Kempeneers MAHill. et al. patterns in chronic pancreatitis: a nationwide cohort study. Gut. 2021;70:1724. ©2023 McGraw AllPain Rights Reserved. Terms of Use • Privacy Policylongitudinal • Notice • Accessibility [PubMed: 33158979] Page 7 / 8 2022;20:2005. [PubMed: 34571258] Universidad Peruana de Ciencias Aplicadas Access Provided by: Issa Y et al. Dutch Pancreatitis Study Group. Effect of early surgery vs endoscopy­first approach on pain in patients with chronic pancreatitis: the ESCAPE randomized clinical trial. JAMA. 2020;323:237. [PubMed: 31961419] Kempeneers MA et al. Pain patterns in chronic pancreatitis: a nationwide longitudinal cohort study. Gut. 2021;70:1724. [PubMed: 33158979] Lewis MD et al. Differences in age at onset of symptoms, and effects of genetic variants, in patients with early vs late­onset idiopathic chronic pancreatitis in a North American cohort. Clin Gastroenterol Hepatol. 2021;19:349. [PubMed: 32240833] Strand DS et al. AGA Clinical Practice Update on the endoscopic approach to recurrent acute and chronic pancreatitis: expert review. Gastroenterology. 2022;163:1107. [PubMed: 36008176] Vege SS et al. Chronic pancreatitis. N Engl J Med. 2022;386:869. [PubMed: 35235728] Downloaded 2023­11­30 7:44 P Your IP is 52.36.32.128 18­27: Chronic Pancreatitis, Lawrence S. Friedman ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 8 / 8