1. Recognize the roles of genetic factors and environmental triggers in the etiology of pancreatitis.

2. Choose the appropriate imaging or functional testing method to diagnose chronic pancreatitis (CP).

3. Describe the advantages of medical, endoscopic, and surgical therapies to control pain in patients with CP.

4. Detail the strengths and weaknesses of endoscopic ultrasonography (EUS) for the diagnosis of various disorders of the pancreas, gallbladder, and bile ducts.

5. Evaluate various cysts and neoplastic lesions of the pancreas and choose the most appropriate method to distinguish malignant from benign forms.

Controversies in Chronic Pancreatitis
Chris E. Forsmark, MD, Professor of Medicine and Chief, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, Gainesville

Pathophysiology: acute pancreatitis (AP)—episode of disease and subsequent complete recovery; chronic pancreatitis (CP)—chronic inflammation, fibrosis, and permanent damage; process develops gradually; pancreatic cancer—risk factors include CP

Etiologies of CP: alcohol use (no threshold below which pancreatic damage does not occur, eg, social drinking); tobacco important synergistic cofactor; other etiologies include cystic fibrosis (CF), hereditary pancreatitis (rare), hypertriglyceridemia, autoimmune disease, and fibrocalcific or tropical forms; frequency of idiopathic CP 20%

Genetics of CP: cationic trypsinogen gene (PRSS1)—mutations (eg, R122H and N29) cause activation of trypsin in pancreas instead of duodenum, causing inflammation, cell necrosis, and pancreatitis; pancreatic secretory trypsin inhibitor gene (SPINK1)—gene product fits in active site and blocks damage due to activated trypsin; cystic fibrosis transmembrane conductance regulator (CFTR)—most patients with CF develop CP; 50% of patients with idiopathic CP have CFTR mutations

Summary: mutation in PRSS1 sufficient to cause CP; mutations in SPINK1 and CFTR appear to predispose; other genes involved in process (eg, inflammation, fibrosis, metabolism, innate immunity); possibly similar to ulcerative colitis or Crohn’s disease, in which mutations predispose and acute events trigger

Genetic screening: tests available for mutations in trypsinogen gene, SPINK1, and CFTR; testing for PRSS1 appropriate in patients with family history; 1551 mutations identified in CFTR (only 29 cause disease); significance of most CFTR mutations in patients with CP and benefit of genetic counseling unclear

Autoimmune disease: plasma cells bearing IgG4 can produce tumor-like mass or diffusely enlarged pancreas; patients present with AP or CP; measuring serum levels of IgG4 in patients with pancreatitis or pancreatic masses remains controversial

Epidemiology of CP: CP uncommon; more common in certain parts of world, eg, India; in West, CP caused primarily by alcohol; most CP believed to evolve via episodes of AP; difficult to identify patients in process of evolving into CP, so prevalence of early stages of CP possibly underestimated; endoscopic ultrasonography (EUS) may show diagnostic changes in gland; however, similar features also occur in pancreas of elderly individuals, those with diabetes, or social drinkers without CP

Diagnosis: case example—computed tomography (CT) from patient with long-standing symptomatic CP shows lobular, atrophic gland, large pancreatic duct, and diffuse calcification; calcifications may take decades to appear, and may not be evident in patient in early stage of CP; diagnostic tests—no single test; histology best among tests that evaluate abnormalities in structure of gland, but obtaining sample difficult; test for function (stimulated secretory capacity) unavailable at most centers; widely used tests, eg, CT, endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), lack sensitivity and detect only later stages

Secretin-stimulated MRCP: infusion of secretin causes secretion of bicarbonate and fluid from pancreatic ductal epithelium into duodenum; quantitated by MRCP

ERCP: case example showed dilated duct and stone in patient who had disease for 10 to 30 yr; lacks sensitivity in early disease; difficult to diagnose developing CP in patients who may not have signs; subtle changes in side branches may represent only visible abnormality; changes in pancreas resembling CP may cause falsely positive diagnoses in elderly patients and patients with recent AP, pancreatic duct stents, or cancer; subjective interpretation of ERCP (as with EUS) introduces variability

EUS: provides detailed image of pancreas; reveals features of CP including hyperechoic duct wall, strands, or dots; normal EUS result rules out CP; very abnormal result (presence of 5 to 7 of 9 features) suggests CP; intermediate results inconclusive

Treatment of pain

Medical therapies: cessation of drinking and smoking; analgesics; nonenteric-coated pancreatic enzymes effective in some patients; antioxidants modestly effective; little data on efficacy of octreotide; most do not eliminate pain

Endoscopic therapy: based on hypothesis that pancreatic duct obstruction causes pain; goal to improve drainage by removing stricture or stone and relieve hypertension in gland; first randomized controlled trial (RCT)—72 patients randomized to endoscopic (less aggressive) or surgical (more aggressive) therapy; results showed equivalent relief of pain at 1 yr, superior relief in surgical group at 5 yr; second RCT—39 patients randomized to either more aggressive ERCP or less aggressive surgery (standard Puestow procedure); trial stopped early because of large difference between groups; surgery appears more effective and durable; no placebo-controlled data available

Neurolysis: celiac plexus block guided by EUS provides modest relief lasting months to years; thoracoscopic splanchnicectomy (cutting splanchnic nerves unilaterally or bilaterally) not effective

Surgical therapies: Puestow procedure—improves drainage; resective procedures (eg, Frey, Beger, standard Whipple operations)—similar to Puestow but include resection; provide better long-term pain relief than Puestow procedure (success rate 40%-50% over 5-15 yr); morbidity higher; used first-line in Europe, after failed Puestow procedure in United States; total pancreatectomy with autotransplantation of islet cells—rates of development of diabetes possibly underquoted; relief of pain not always satisfactory

Exocrine insufficiency: develops over decades; causes malabsorption of fat and protein; carries significant risk for osteoporosis; patients require supplementation with vitamin D and calcium, and 40% functionally deficient in B12 (apparent when measuring methylmalonic acid or homocysteine, but not serum B12 )

Diagnosis: measurement of fecal elastase

Enzyme treatment: 30,000 IU of lipase per meal needed to correct steatorrhea; United States Pharmacopeia (USP) units 50% smaller than IU (adjust dosage to account for this); must suppress acid if using nonenteric-coated pills

New Diagnostic and Therapeutic Uses of Endosonography for Pancreatico-biliary Disorders
Tamir Ben–Menachem, MD, Associate Professor of Medicine, Director of Gastrointestinal Endoscopy, University of Medicine and Dentistry of New Jersey; Robert Wood Johnson Medical School, New Brunswick

Applications: benign (stones) and malignant biliary disease, eg, diagnosis and staging of cholangiocarcinoma, facilitation of common bile duct (CBD) decompression; pancreatic diseases (eg, diagnosis of CP, access to duct strictures); neoplastic pancreatic disease (cystic neoplasms); has shown microlithiasis or sludge in 50% of the 20% of patients with idiopathic AP

Methods to detect

Gallbladder stones: efficacy of right upper quadrant (RUQ) US (RUQUS) excellent; MRCP good; EUS limited because visibility extends only 5 cm beyond lumen; ERCP has no role; intraductal ultrasonography (IDUS)

Gallbladder sludge: efficacy of EUS excellent; RUQUS misses some; MRCP limited; ERCP not applicable

Bile duct stones: ERCP gold standard (95% sensitive when sphincterotomy performed to help visualize stones); EUS good; IDUS good but seldom used; MRCP good to very good RUQUS good

Bile duct sludge: efficacy of EUS excellent; ERCP good but requires cannulation sphincterotomy, and aspiration for microcrystals; MRCP and RUQUS poor

Diagnosis of choledocholithiasis: use symptoms, laboratory tests, and imaging to determine pretest probability of disease in bile duct; if disease highly probable (eg, high bilirubin, pain, dilated bile duct), ERCP appropriate; if pretest probability low (eg, absence of elevated enzymes, pain, or dilated bile duct), EUS appropriate because specificity high; if probability intermediate, must weigh risk for complications from ERCP and risk for doing poorly from those complications; sphincterotomy probably necessary if ERCP performed in patients with lower risk; for patients with high risk (eg, elderly, bleeding disorder), EUS recommended by American Society for Gastrointestinal Endoscopy (ASGE)

Endoscopic ultrasonography: advantages—accurate, identifies gallbladder sludge, fast (10 min), and low risk; disadvantages—not widely available; dependent on operator; not appropriate for patients with antrectomy, Billroth 1 or 2, or large masses of ampulla; if stone present, patient still needs ERCP; future developments—echoendoscope that allows performance of ERCP, possibly without fluoroscopy

Extrahepatic cholangiocarcinoma (EHCC): more common than intrahepatic; 25% less common than pancreatic cancer (8000 new cases per year in United States); poor 5-yr survival

Diagnosis: ERCP and brushing to determine whether stricture malignant; CT-guided fine needle aspiration (FNA) if mass present; alternatives include EUS-guided FNA, IDUS, and cholangioscopy

Diagnostic accuracy: CT and MRI have poor accuracy; ERCP—sensitivity 76% using images (sensitivity using brushings only 60%-65%); cholangioscopy allows visualization and access to bile duct for direct biopsy; 87% sensitivity using EUS (with FNA); IDUS has high sensitivity but cannot provide tissue specimen

Staging: requires multimodality approach (ie, EUS, IDUS, CT, and possibly positron emission tomography [PET]) to detect distant metastases as well as local T stage; EUS and IDUS preferable for local involvement; CT best for hilar vessels; EUS best to detect ascites or mediastinal lymph nodes (seen in 20% of cholangiocarcinoma) and obtain tissue; possible to detect liver metastases with CT and PET, but look at as much of liver as possible during EUS; study—167 patients underwent EUS-FNA; if visible, liver metastases accurately detected with low rate of bleeding complications

Therapies: difficult to obtain access to bile duct; 37 reports in literature of EUS-guided punctures of liver and duodenum to reach bile duct; success rate good; complication rate high; transhepatic entry—scope positioned in stomach next to left lobe of liver; puncture with needle and advance wire through bile duct into duodenum; transduodenal entry— duodenum punctured and wire passed; stent then placed antegrade (directly through liver or duodenum) or with rendezvous technique using different scope

Diagnosis of CP with EUS: 9 criteria (visible abnormalities); study results—EUS done on 42 patients undergoing surgery for cancer or nonmalignant neoplasms of pancreas; none of patients had calcifications; 50% had pancreatitis determined by histology; strongest diagnostic criteria by EUS included hyperechoic strands, foci, lobularity, and abnormalities of pancreatic duct; best sensitivity and specificity obtained using any 4 criteria

Usefulness of criteria: absence of criteria indicates very low probability of CP; presence of ≤5 criteria inconclusive; >5 criteria indicates high probability of CP; uncertainty in group with 1 to 5 criteria results from confounding factors (eg, age, clinical context [eg, alcoholism], interobserver variability); study of variability—7 expert endosonographers obtained only moderate agreement on criteria

Additional factors: detection of high interleukin (IL)-8 in pancreatic fluid and presence of 3 criteria by EUS gives almost 100% sensitivity and specificity; Tru-Cut biopsies provide core biopsy of pancreas (helpful in some conditions, eg, autoimmune pancreatitis)

Access to pancreatic duct: EUS provides access to strictures; rendezvous technique—pass wire through duct into duodenum, then insert ERCP scope, grasp wire, and use it as rail for stent; 24 cases reported in literature; useful for palliation of pain in patients with pancreatic cancer, post-Whipple anatomy, or CP

Pancreatic cysts: detected more frequently as technologies improve

Etiologies: congenital cysts uncommon; inflammatory cysts (pseudocysts, abscesses, and hydatid cysts); neoplastic cysts—benign forms include serous cystadenomas, lymphoepithelial cysts, and cystic teratomas; malignant and premalignant forms include mucinous cystadenomas, intraductal papillary mucinous neoplasms, pseudopapillary tumors, islet cell tumors, and metastases from ovarian cancer

Evaluation of cysts: determine whether malignant or benign; clues from history and physical examination; imaging, eg, CT helpful; if patient has had pancreatitis in past, cystic neoplasm probable (if <4 cm in size, cyst less likely to be malignant); elevated serum carcinoembryonic antigen (CEA) or carbohydrate antigen (CA)19-9 suggests malignancy, but low levels do not rule out malignancy; if cyst not malignant, does it have malignant potential?

Pseudocysts: fairly regular with capsule; patient usually has history of AP; aspirated fluid shows very high amylase levels, very low levels of CEA; study—among 220 patients with pancreatic cysts, found amylase and CEA best markers to differentiate lesions

Neoplastic lesions

Serous cystadenoma: benign lesion; on EUS, appears as mass with multiple black areas (diffuse honeycombing); ≈70% appear similar to microcystic adenomas, and 20% to 30% have larger, slightly irregular cysts; amylase levels variable but generally low; CEA <5 ng/mL and CA19-9 low (<50,000 U/mL); vascularity of lesions leads to high risk (10%) of bleeding, infection, and pain from needle insertion

Mucinous cystadenomas: malignant potential; features suggesting high risk include septations, mural nodules, and associated mass; amylase levels usually low; CEA >192 ng/mL associated with 80% sensitivity and specificity that lesion mucinous rather than serous cystadenoma; similarly, CA19-9 >50,000 U/mL indicates mucin production; on biopsy of wall, appearance similar to ovarian stroma also diagnostic; cannot determine malignancy based on fluid alone (CEA level not reliable indicator); important to follow patients carefully with repeat EUS or MRI to ensure cyst not growing

Mucinous cystadenocarcinoma: once cyst malignant, solid component appears on EUS; <50% chance of obtaining malignant cells by aspiration of fluid; tissue biopsy highly accurate

Intraductal papillary mucinous neoplasms: 2 types (main branch or side branch with cyst)

Solid and cystic pseudopapillary tumors: rare, occur mostly in younger women; benign lesions with malignant potential; large heterogeneous mass with black (fluid) areas on EUS; tissue diagnosis accurate

Differentiation of cysts from solid neoplasms: efficacy of EUS excellent; CT poor; MRI good; ERCP no longer has role

Future trends: diagnosis—DNA diagnosis and microarray analysis for proteins secreted by mucinous tumors; treatment—60% to 65% of pancreatic cysts ablated by injection of ethanol; no data yet on long-term outcomes; laparoscopic enucleation of smaller cysts under investigation