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PART 10 Disorders of the Gastrointestinal System Section Disorders of the Alimentary Tract 321 Approach to the Patient with Gastrointestinal Disease William L Hasler, Chung Owyang ANATOMIC CONSIDERATIONS The gastrointestinal (GI) tract extends from the mouth to the anus and is composed of organs with distinct functions Sphincters that assist in gut compartmentalization separate the organs The gut wall is organized into distinct layers that contribute to regional activities The mucosa is a barrier to luminal contents or a site for fluid and nutrient transfer Smooth muscle in association with the enteric nervous system mediates propulsion between regions Many GI organs possess a serosal layer that provides a supportive foundation and permits external input Interactions with other systems serve the needs of the gut and the body Pancreaticobiliary conduits deliver bile and enzymes into the duodenum The vascular supply is modulated by GI activity Lymphatic channels assist in gut immune activities Intrinsic nerves provide the controls for propulsion and fluid regulation Extrinsic neural input provides volitional or involuntary control that is specific for each gut region FUNCTIONS OF THE GI TRACT The GI tract serves two main functions—assimilating nutrients and eliminating waste In the mouth, food is processed, mixed with salivary amylase, and delivered to the gut lumen The esophagus propels the bolus into the stomach; the lower esophageal sphincter prevents oral reflux of gastric contents The squamous esophageal mucosa protects against significant diffusion or absorption Aboral esophageal contractions coordinate with relaxation of the upper and lower esophageal sphincters on swallowing The stomach triturates and mixes the food bolus with pepsin and acid Gastric acid also sterilizes the upper gut The proximal stomach serves a storage function by relaxing to accommodate the meal Phasic contractions in the distal stomach propel food residue against the pylorus, where it is ground and thrust proximally for further mixing before it is emptied into the duodenum The stomach secretes intrinsic factor for vitamin B12 absorption Most nutrient absorption occurs in the small intestine The mucosal villus architecture provides maximal surface area for absorption and is endowed with specialized enzymes and transporters Triturated food from the stomach mixes with pancreatic juice and bile in the duodenum Pancreatic juice contains enzymes for nutrient digestion and bicarbonate to optimize the pH for enzyme activation Bile secreted by the liver and stored in the gallbladder is essential for lipid digestion The proximal intestine is optimized for rapid absorption of most nutrients and minerals, whereas the ileum is better suited for absorbing vitamin B12 and bile acids Bile contains by-products of erythrocyte degradation, toxins, medications, and cholesterol for fecal evacuation Intestinal motor function delivers indigestible residue into the colon for processing The ileocecal junction is a sphincter that prevents coloileal reflux, reducing microbial density The colon prepares waste for evacuation The mucosa dehydrates the stool, reducing daily ileal volumes of 1000–1500 mL to 100–200 mL expelled from the rectum The colon possesses a dense bacterial colonization that ferments undigested carbohydrates and short-chain fatty acids The gut microbiome also modulates immune and physiologic activity Esophageal transit takes seconds, and times in the stomach and small intestine range from minutes to a few hours, but colon propagation requires >1 day in most individuals Colon contractions exhibit a to-and-fro character that promotes fecal desiccation The proximal colon mixes and absorbs fluid, while the distal colon exhibits peristaltic contractions and mass movements to expel the stool The colon terminates in the anus, which possesses volitional and involuntary controls to permit fecal retention until it can be released in a convenient setting EXTRINSIC MODULATION OF GUT FUNCTION GI function is modified by influences outside the gut Unlike other organs, the gut is in continuity with the outside environment Protective mechanisms are vigilant against injury from foods, medications, toxins, and microbes Mucosal immune mechanisms include epithelial and lamina propria lymphocytes and plasma cells supported by lymph node chains to prevent noxious agents from entering the circulation Antimicrobial peptides secreted by Paneth cells defend against pathogens Drugs and toxins absorbed into the bloodstream are filtered and detoxified in the liver via the portal venous circulation Although intrinsic nerves control most basic gut activities, extrinsic neural input modulates many functions Many GI reflexes involve extrinsic vagus or splanchnic nerve pathways The brain-gut axis alters function in regions not under volitional regulation Stress can disrupt gut motor, secretory, and sensory function OVERVIEW OF GI DISEASES GI diseases develop as a result of abnormalities within or outside of the gut and range in severity from those that produce mild symptoms and no long-term morbidity to those with intractable symptoms or adverse outcomes Diseases may be localized to one organ or exhibit diffuse involvement at many sites ■ CLASSIFICATION OF GI DISEASES GI diseases are manifestations of alterations in nutrient assimilation or waste evacuation or in the activities supporting these main functions Impaired Digestion and Absorption Diseases of the stomach, intestine, biliary tree, and pancreas can disrupt digestion and absorption The most common maldigestion syndrome, lactase deficiency, produces gas and diarrhea after ingesting dairy products and has no adverse outcomes Other intestinal enzyme deficiencies produce similar symptoms after consuming other simple sugars Celiac disease, bacterial overgrowth, infectious enteritis, Crohn’s ileitis, and radiation damage, which affect digestion and/or absorption more diffusely, produce anemia, dehydration, electrolyte disorders, or malnutrition Gastric hypersecretory conditions such as gastrinoma damage the intestinal mucosa, impair pancreatic enzyme activation, and accelerate transit due to excess gastric acid Benign or neoplastic biliary obstruction impairs fat digestion Impaired pancreatic enzyme release in chronic pancreatitis or pancreatic cancer decreases intraluminal digestion and can lead to malnutrition Altered Secretion Some GI diseases result from dysregulation of gut secretion Gastric acid hypersecretion occurs in gastrinoma, Gcell hyperplasia, retained antrum syndrome, and some patients with duodenal ulcers Gastric acid is reduced in atrophic gastritis and pernicious anemia Inflammatory and infectious small-intestinal and colonic diseases produce fluid loss through impaired absorption or enhanced secretion Common hypersecretory conditions that cause diarrhea include acute bacterial or viral infection, chronic Giardia or cryptosporidia infections, small-intestinal bacterial overgrowth, bile salt diarrhea, microscopic colitis, and diabetic diarrhea Less common causes include large colonic villus adenomas and endocrine neoplasias with tumor overproduction of secretagogue transmitters such as vasoactive intestinal polypeptide Altered Gut Transit Impaired gut transit may result from mechanical obstruction Esophageal occlusion most often is due to stricture (due to acid exposure or eosinophilic esophagitis) or neoplasm Gastric obstruction develops from ulcer disease or gastric cancer Smallintestinal obstruction most commonly results from adhesions but also occurs with Crohn’s disease, radiation- or drug-induced strictures, and less likely malignancy The most common cause of colonic obstruction is colon cancer, although inflammatory strictures develop with inflammatory bowel disease (IBD), after certain infections such as diverticulitis, or with some drugs Retardation of propulsion can develop from altered motor function Achalasia is characterized by impaired esophageal body peristalsis and incomplete lower esophageal sphincter relaxation Gastroparesis is the delay in gastric emptying of meals due to hinhanhykhoa.com impaired gastric motility Intestinal pseudoobstruction is the disruption of small-bowel contractility due to enteric nerve or smoothmuscle injury Slow-transit constipation results from diffusely impaired colon propulsion Constipation also is produced by outlet abnormalities such as rectal prolapse, intussusception, or dyssynergia—a failure of anal or puborectalis relaxation upon attempted defecation Disorders of rapid propulsion are less common than those with delayed transit Rapid gastric emptying occurs with postvagotomy dumping syndrome, gastric hypersecretion, and some cases of functional dyspepsia and cyclic vomiting syndrome Exaggerated intestinal or colonic motor patterns may be responsible for diarrhea in irritable bowel syndrome (IBS) Accelerated transit with hyperdefecation is noted in hyperthyroidism Immune Dysregulation Many inflammatory GI conditions are consequences of altered gut immune function Mucosal inflammation in celiac disease results from dietary ingestion of gluten-containing grains Some patients with food allergy also exhibit altered immune populations Eosinophilic esophagitis and eosinophilic gastroenteritis are inflammatory disorders with prominent mucosal eosinophil infiltration Ulcerative colitis and Crohn’s disease are disorders that produce mucosal injury primarily in the lower gut The microscopic colitides, lymphocytic and collagenous colitis, exhibit colonic subepithelial infiltrates without visible mucosal damage Bacterial, viral, and protozoal organisms produce ileitis or colitis in selected patients Alterations in the gut microbiome (termed dysbiosis) are proposed to trigger IBD, celiac disease, and IBS flares and may be factors in oncogenesis in some cases of pancreatic cancer Impaired Gut Blood Flow Different GI regions are at variable risk for ischemic damage from impaired blood flow Rare cases of gastroparesis result from blockage of the celiac and superior mesenteric arteries More commonly encountered are intestinal and colonic ischemia that are consequences of arterial embolus, arterial thrombosis, venous thrombosis, or hypoperfusion from dehydration, sepsis, hemorrhage, or reduced cardiac output These may produce mucosal injury, hemorrhage, or even perforation Chronic ischemia may result in intestinal stricture Some cases of radiation enterocolitis exhibit reduced mucosal blood flow Neoplastic Degeneration All GI regions are susceptible to malignant degeneration In the United States, colorectal cancer is most common and usually presents after age 45 years Worldwide, gastric cancer is prevalent, especially in certain Asian populations Esophageal cancer develops with chronic acid reflux or after extensive alcohol or tobacco use Small-intestinal neoplasms are rare but occur with underlying inflammatory diseases Anal cancers arise after prior anal infection or inflammation Pancreatic and biliary cancers elicit severe pain, weight loss, and jaundice and have poor prognoses Hepatocellular carcinoma usually arises in the setting of chronic viral hepatitis or cirrhosis secondary to other causes Most GI cancers exhibit carcinomatous histology; however, lymphomas and other cell types also are observed Disorders without Obvious Organic Abnormalities The most prevalent GI disorders show no abnormalities on biochemical or structural testing and include IBS, functional dyspepsia, and functional heartburn These disorders exhibit altered gut motor function, but the pathogenic relevance of these abnormalities is uncertain Exaggerated visceral sensory responses to noxious stimulation may cause discomfort in these disorders Symptoms in other patients result from altered processing of visceral pain sensations in the central nervous system Functional bowel patients with severe symptoms may exhibit significant emotional disturbances on psychometric testing Subtle immunologic defects may contribute to functional symptoms as well Genetic Influences Although many GI diseases result from environmental factors, others exhibit hereditary components Family members of IBD patients show a genetic predisposition to disease development themselves Colonic, esophageal, and pancreatic malignancies arise in certain inherited disorders Rare genetic dysmotility syndromes are described Familial clustering is observed in the functional bowel disorders, although this may be secondary learned familial illness behavior rather than a true hereditary factor ■ SYMPTOMS OF GI DISEASE Symptoms of GI disease include abdominal pain, heartburn, nausea and vomiting, altered bowel habits, GI bleeding, jaundice, and other manifestations (Table 321-1) TABLE 321-1 Common Causes of Common Gastrointestinal (GI) Symptoms Abdominal Pain Abdominal pain results from GI disease and extraintestinal conditions involving the genitourinary tract, abdominal wall, thorax, or spine Visceral pain generally is midline in location and vague in character, whereas parietal pain is localized and precisely described Painful inflammatory diseases include peptic ulcer, appendicitis, diverticulitis, IBD, pancreatitis, cholecystitis, and infectious enterocolitis Noninflammatory visceral sources include biliary colic, mesenteric ischemia, and neoplasia The most common causes of abdominal pain are IBS and functional dyspepsia Heartburn Heartburn, a burning substernal sensation, is reported intermittently by 40% of the population Classically, heartburn results from excess gastroesophageal acid reflux, but some cases exhibit normal esophageal acid exposure and are caused by reflux of nonacidic material or heightened sensitivity of esophageal nerves Nausea and Vomiting Nausea and vomiting are caused by GI diseases, medications, toxins, infection, endocrine disorders, labyrinthine conditions, and central nervous system disease Mechanical obstructions of the upper gut are commonly excluded as causes of chronic nausea and vomiting, but disorders of propulsion including gastroparesis and intestinal pseudoobstruction elicit similar symptoms Nausea and vomiting also are commonly reported by patients with IBS and functional disorders of the upper gut (including chronic nausea vomiting syndrome, cyclic vomiting syndrome, and cannabinoid hyperemesis syndrome) Altered Bowel Habits Altered bowel habits are common complaints in GI disease Constipation may be reported as infrequent defecation, straining with defecation, passage of hard stools, or a sense of incomplete fecal evacuation and is caused by obstruction, motor disorders, medications, and endocrine diseases such as hypothyroidism and hyperparathyroidism Diarrhea may be reported as frequent defecation, passage of loose or watery stools, fecal urgency, or a similar sense of incomplete evacuation The differential diagnosis of diarrhea includes infections, inflammatory causes, malabsorption, and medications IBS produces constipation, diarrhea, or an alternating bowel pattern Fecal mucus is common in IBS, whereas pus and blood characterize IBD Steatorrhea develops with malabsorption GI Bleeding Hemorrhage may develop from any gut organ Upper GI bleeding presents with melena or hematemesis, whereas lower GI bleeding produces passage of bright red or maroon stools However, briskly bleeding upper sites can elicit voluminous red rectal bleeding, whereas slowly bleeding ascending colon sites may produce melena Chronic occult GI bleeding may present with iron deficiency anemia Causes of upper GI bleeding include ulcer disease, gastroduodenitis, esophagitis, portal hypertensive etiologies, malignancy, tears across the gastroesophageal junction, and vascular lesions Lower GI sources of hemorrhage include hemorrhoids, anal fissures, diverticula, ischemic colitis, neoplasm, IBD, infectious colitis, drug-induced colitis, arteriovenous malformations, and other vascular lesions Jaundice Jaundice results from prehepatic, intrahepatic, or posthepatic disease Posthepatic causes of jaundice include biliary diseases, such as choledocholithiasis, acute cholangitis, primary sclerosing cholangitis, other strictures, and neoplasm, and pancreatic disorders, such as acute and chronic pancreatitis, stricture, and malignancy Other Symptoms Other symptoms are manifestations of GI disease Dysphagia, odynophagia, and unexplained chest pain suggest esophageal disease A globus sensation is reported with esophagopharyngeal conditions, but also occurs with functional GI disorders Weight loss, anorexia, and fatigue present with neoplastic, inflammatory, motility, pancreatic, and psychiatric conditions IBD is associated with hepatobiliary dysfunction, skin and eye lesions, and arthritis Celiac disease may present with dermatitis herpetiformis Jaundice can produce pruritus Conversely, systemic diseases have GI consequences Systemic lupus may cause gut ischemia, presenting with pain or bleeding Severe burns may lead to gastric ulcer formation EVALUATION OF THE PATIENT WITH GI DISEASE Evaluation of the patient with suspected GI disease begins with a careful history and examination Subsequent investigation with tools to test gut structure or function and luminal constituents is indicated in selected cases In patients with normal findings on diagnostic testing, validated symptom profiles are used to confidently diagnose a functional bowel disorder ■ HISTORY The history in suspected GI disease has several components Symptom timing, patterns, and duration suggest specific etiologies Short-duration symptoms commonly result from acute infection or inflammation, toxin exposure, or ischemia Long-standing symptoms hinhanhykhoa.com Even in individuals in whom alcohol is believed to be the primary cause of chronic pancreatitis, other factors are likely required for the development and progression of disease, which explains why not all heavy consumers of alcohol develop pancreatic disease There is also a strong association between smoking and chronic pancreatitis Cigarette smoke leads to an increased susceptibility to pancreatic autodigestion and predisposes to dysregulation of duct cell CFTR function Smoking is an independent, dose-dependent risk factor for chronic pancreatitis and recurrent acute pancreatitis Both continued alcohol and smoking exposure are associated with disease progression, including pancreatic fibrosis and calcifications Characterization of pancreatic stellate cells (PSCs) has added insight into the underlying cellular responses behind development of chronic pancreatitis Specifically, PSCs are believed to play a role in maintaining normal pancreatic architecture that shifts toward fibrogenesis in those who develop chronic pancreatitis It is believed that alcohol or additional stimuli lead to matrix metalloproteinase– mediated destruction of normal collagen in pancreatic parenchyma, which later allows for pancreatic remodeling Proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin (IL-1), and interleukin (IL-6), as well as oxidant complexes, can induce PSC activity with subsequent new collagen synthesis In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor β (TGF-β)–mediated selfactivating autocrine pathways that may explain disease progression in chronic pancreatitis even after removal of noxious stimuli ■ ETIOLOGIC CONSIDERATIONS Among adults in the United States, alcoholism is the most common cause of clinically apparent chronic pancreatitis, whereas cystic fibrosis is the most frequent cause in children As many as 25% of adults in the United States with chronic pancreatitis have the idiopathic form, including a subset of patients who not develop clinical manifestations until later in life (idiopathic late-onset chronic pancreatitis) Recent investigations have indicated that up to 15% of patients with chronic pancreatitis previously classified as having idiopathic pancreatitis may have an underlying genetic predisposition (Table 348-5) The prototypical genetic defect was identified in the cationic trypsinogen gene (PRSS1) by studying several large families with chronic pancreatitis Additional pathogenic and nonpathogenic mutations have been identified in this gene The defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the intracellular protective effect of trypsin inhibitor It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis Since the initial discovery of the PRSS1 mutation defect, other genetic disease modifiers have been identified (Table 348-5) The CFTR gene functions as a cyclic AMP–regulated chloride channel In patients with cystic fibrosis, the high concentration of macromolecules can block the pancreatic ducts It must be appreciated, however, that there is a great deal of heterogeneity in relationship to the CFTR gene defect More than 1700 putative mutations of the CFTR gene have been identified Attempts to elucidate the relationship between the genotype and pancreatic manifestations have been hampered by the large number and different classes of CFTR mutations The ability to detect CFTR mutations has led to the recognition that the clinical spectrum of the disease is broader than previously thought Two studies have clarified the association between mutations of the CFTR gene and another monosymptomatic form of cystic fibrosis (i.e., chronic pancreatitis) It is estimated that in patients with idiopathic pancreatitis, the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency In these studies, patients were adults when the diagnosis of pancreatitis was made; none had any clinical evidence of pulmonary disease, and sweat test results were not diagnostic of cystic fibrosis The prevalence of such mutations is unclear, and further studies are needed In addition, the therapeutic and prognostic implication of these findings with respect to managing pancreatitis remains to be determined CFTR mutations are common in the general population, so it is unclear whether the CFTR mutation alone can lead to pancreatitis as an autosomal recessive disease A study evaluated 39 patients with idiopathic chronic pancreatitis to assess the risk associated with these mutations Patients with two CFTR mutations (compound heterozygotes) demonstrated CFTR function at a level between that seen in typical cystic fibrosis and cystic fibrosis carriers and had a fortyfold increased risk of pancreatitis The presence of a separate genetic mutation (N34S SPINK1) increased the risk twentyfold A combination of two CFTR mutations and an N34S SPINK1 mutation increased the risk of pancreatitis 900-fold Knowledge of the genetic defects and downstream alterations in protein expression has led to the development of novel therapies in children with cystic fibrosis that potentiate the CFTR channel, resulting in improvement in lung function, quality of life, and weight gain Some studies have shown that use of CFTR modulators may reduce the frequency of acute pancreatitis in heterozygous carriers Table 348-5 lists other recognized causes of chronic pancreatitis ■ AUTOIMMUNE PANCREATITIS (Table 348-6) TABLE 348-6 Comparison of the Autoimmune Pancreatitis (AIP) Subtypes Autoimmune pancreatitis (AIP) refers to a form of chronic pancreatitis with distinct histopathology and several unique differences in the clinical phenotype Currently, two subtypes of AIP are recognized, type AIP and idiopathic duct-centric chronic pancreatitis (IDCP, also referred to as type AIP) Type AIP is identified as the pancreatic manifestation of a multiorgan syndrome currently referred to as IgG4-related disease (Chap 368) The characteristic histopathologic findings of type AIP include lymphoplasmacytic infiltrate, storiform fibrosis, and abundant IgG4 cells IDCP is histologically defined by the presence of granulocytic infiltration of the duct wall (termed a granulocytic epithelial lesion [GEL]) but without IgG4-positive cells Type AIP is often associated with involvement of other organs in the setting of IgG4-related disease, including bilateral submandibular gland enlargement, characteristic renal lesions, retroperitoneal fibrosis, and stricturing of the suprapancreatic biliary tree In contrast, IDCP is a pancreasspecific disorder that is associated with inflammatory bowel disease in ∼10% of patients AIP is not a common cause of idiopathic recurrent acute pancreatitis Jaundice, weight loss, and new-onset diabetes are the most common presenting symptoms Elevated serum IgG4 levels are supportive of the diagnosis (elevated in two-thirds of patients with type AIP) but have a low positive predictive value when used in isolation of other clinical findings CT imaging demonstrates abnormalities in the majority of patients with either diffuse or focal enlargement during active disease, unless the gland is atrophic due to previous disease (Fig 348-3) The presence of an inflammatory rim, termed a capsule sign, is highly specific (but not sensitive) for AIP ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP, including some patients with isolated intrahepatic bile duct strictures (type AIP only), which can mimic primary sclerosing cholangitis, and is referred to as IgG4-related sclerosing cholangitis (previously termed IgG4-associated cholangitis) FIGURE 348-3 Imaging features of the pancreatic parenchyma in a patient with type autoimmune pancreatitis on computed tomography (CT) A Contrast-enhanced CT scan of the abdomen demonstrates diffuse pancreatic enlargement and a hypoechoic rim (capsule sign) in a patient who presented with jaundice The serum IgG4 level was elevated to 942 mg/dL (reference range 4–86 mg/dL), so the patient was diagnosed with definitive type autoimmune pancreatitis B Contrast-enhanced CT scan of the abdomen following a treatment course with high-dose steroids demonstrates return to normal size of the pancreas, reappearance of normal lobulations along the margin, and absence of the hypoechoic rim The Mayo Clinic HISORt criteria provide a helpful mnemonic to remember the key diagnostic features of this disease, including (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels); (4) other organ involvement; and (5) response to glucocorticoid therapy These diagnostic criteria have been harmonized with those from other countries to develop the International Consensus Diagnostic Criteria for AIP, which are the most widely utilized criteria Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP Patients typically respond dramatically to glucocorticoid therapy within a 2- to 4-week period Prednisone is usually administered at an initial dose of 40 mg/d for weeks followed by a taper of the daily dosage by mg per week based on monitoring of clinical parameters Relief of symptoms, liver biochemistries, and abnormal imaging of the pancreas and bile ducts are followed to assess for treatment response A poor response to glucocorticoids should raise suspicion of an alternate diagnosis, such as pancreatic cancer A recent multicenter international study examined >1000 patients with AIP Clinical remission was achieved in 99% of type AIP and 92% of type AIP patients with steroids However, disease relapse occurred in 31 and 9% of patients with type and type AIP, respectively Patients with multiple relapses may be managed with an immunomodulator (e.g., azathioprine, 6mercaptopurine, or mycophenolate mofetil) or B-cell depletion therapy (e.g., rituximab) The appearance of interval cancers following a diagnosis of AIP is uncommon Clinical Features of Chronic Pancreatitis Patients with chronic pancreatitis primarily seek medical attention due to abdominal pain or symptoms of maldigestion The abdominal pain may be quite variable in location, severity, and frequency The pain can be constant or intermittent with pain-free intervals Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss The spectrum of abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence There is often a disparity between the reported severity of abdominal pain and the physical findings, which primarily consist of nonfocal abdominal tenderness Patients with chronic abdominal pain may or may not experience symptoms of maldigestion, such as chronic diarrhea, steatorrhea, and/or weight loss Fat-soluble vitamin deficiencies are increasingly recognized Importantly, there is an exceedingly high prevalence of metabolic bone disease in chronic pancreatitis, with ∼65% of patients having either osteopenia or osteoporosis Patients with chronic pancreatitis have impaired quality of life and develop significant morbidity, requiring frequent use of health care resources The diagnosis of early or mild chronic pancreatitis can be challenging because there is no accurate biomarker for the disease In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis Rather, low serum pancreatic enzyme levels are moderately specific for a diagnosis of chronic pancreatitis but have poor sensitivity Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation or fibrosis The cumulative prevalence of exocrine pancreatic insufficiency is >80% The presence of overt steatorrhea in a patient with chronic pancreatitis is highly suggestive of this complication However, in those with milder symptoms, additional testing, such as a random fecal elastase-1 level (on a formed stool specimen) may be needed to confirm the diagnosis of exocrine pancreatic insufficiency The radiographic evaluation of a patient with suspected chronic pancreatitis usually proceeds from a noninvasive to more invasive approach Abdominal CT imaging (Fig 348-4) is the initial modality of choice, followed by MRI, endoscopic ultrasound, and pancreas function testing In addition to excluding a pseudocyst and pancreatic cancer, CT imaging may show calcifications, dilated pancreatic or biliary ducts, or an atrophic pancreas Although abdominal CT scanning and MRCP greatly aid in the diagnosis of pancreatic disease, the diagnostic test with the best sensitivity is the hormone stimulation test using secretin The secretin test becomes abnormal when ≥60% of the pancreatic exocrine function has been lost This usually correlates well with the onset of chronic abdominal pain The role of endoscopic ultrasonography (EUS) in diagnosing early chronic pancreatitis is still evolving A total of nine endosonographic features have been described in chronic pancreatitis The presence of five or more features is considered diagnostic of chronic pancreatitis EUS is not a specific enough test for detecting early chronic pancreatitis alone (Chap 347) and may show positive features in patients with diabetes, patients with a history of cigarette smoking, or even in normal aging individuals Recent data suggest that EUS can be combined with endoscopic pancreatic function testing (EUS-ePFT) during a single endoscopy to screen for chronic pancreatitis in patients with chronic abdominal pain Diffuse calcifications noted on plain film of the abdomen usually indicate significant damage to the pancreas and are pathognomic for chronic pancreatitis Although alcohol is by far the most common cause of pancreatic calcification, such calcification may also be noted in hereditary pancreatitis, posttraumatic pancreatitis, idiopathic chronic pancreatitis, and tropical pancreatitis FIGURE 348-4 Distribution of imaging features of chronic pancreatitis on computed tomography (CT) Distinct features of chronic pancreatitis are seen on selected images from contrast-enhanced CT scans of the abdomen from four unique patients, including the following A Numerous punctate calcifications involving the pancreatic parenchyma in the head and body B A moderate-sized calculus visualized in the pancreatic duct with associated ductal dilation C Significant pancreatic duct dilation and adjacent parenchymal atrophy secondary to a pancreatic duct stricture (which is not well seen on this scan) D A large unilocular, encapsulated cyst in the tail of the pancreas consistent with a pseudocyst from prior pancreatitis Note adjacent pancreatic parenchymal atrophy Complications of Chronic Pancreatitis There are a number of disease-related complications from chronic pancreatitis in addition to the aforementioned abdominal pain and exocrine pancreatic insufficiency (Table 348-7) The lifetime prevalence of chronic pancreatitis–related diabetes exceeds 80% Although most patients develop hyperglycemia due to insulin deficiency caused by loss of islet cells, diabetic ketoacidosis and diabetic coma are uncommon Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon Nondiabetic retinopathy may be due to vitamin A and/or zinc deficiency Osteoporosis and osteopenia are increasingly recognized in chronic pancreatitis and likely related to a combination of shared risk factors (e.g., alcohol use, cigarette smoking), vitamin D deficiency, and detrimental effects on the bone from chronic inflammation Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, arterial bleeding into the pancreatic duct (hemosuccus pancreaticus), or ruptured varices secondary to splenic vein thrombosis Jaundice, cholestasis, and biliary cirrhosis may occur from the chronic inflammatory reaction around the intrapancreatic portion of the common bile duct Twenty years after the diagnosis of chronic calcific pancreatitis, the cumulative risk of pancreatic cancer is 4% Patients with hereditary PRSS1 or tropical pancreatitis have an increased risk for pancreatic cancer compared to other forms of chronic pancreatitis TABLE 348-7 Complications of Chronic Pancreatitis TREATMENT Chronic Pancreatitis There are currently no therapies to reverse or delay the disease progression of chronic pancreatitis, so management is primarily focused on screening for and management of disease-related complications STEATORRHEA The treatment of steatorrhea with pancreatic enzyme replacement therapy is conceptually straightforward, yet complete correction of steatorrhea is uncommon Enzyme therapy usually brings diarrhea under control and restores absorption of fat to an acceptable level and affects weight gain Thus, pancreatic enzyme replacement is the cornerstone of therapy In treating steatorrhea, it is important to use a potent pancreatic formulation that will deliver sufficient lipase into the duodenum to correct maldigestion and decrease steatorrhea For adult patients with exocrine pancreatic insufficiency, it is generally recommended to start at a dosage of 25,000–50,000 units of lipase taken during each meal; however, the dose may need to be increased up to 100,000 units of lipase depending on the response in symptoms, nutritional parameters, and/or pancreas function test results Additionally, some may require acid suppression with proton pump inhibitors to optimize the response to pancreatic enzymes Monitoring nutritional parameters such as fat-soluble vitamins, zinc levels, body weight, and periodic bone mineral density measurement should be considered ABDOMINAL PAIN The management of pain in patients with chronic pancreatitis is challenging due to the complex mechanisms of pancreatitis-related pain Recent meta-analyses have shown no consistent benefit of enzyme therapy at reducing pain in chronic pancreatitis Pain relief experienced by patients treated with pancreatic enzymes may be due to improvements in the dyspepsia from maldigestion One short-term randomized trial showed that pregabalin could decrease pain in chronic pancreatitis and lower pain medication requirement Other studies using antioxidants have yielded mixed results Endoscopic treatment of chronic pancreatitis pain may involve sphincterotomy, pancreatic duct stenting, stone extraction, and drainage of a pancreatic pseudocyst Therapy directed to the pancreatic duct would seem to be most appropriate in the setting of a dominant stricture, especially if there is an obstructing intraductal stone The use of endoscopic stenting for patients with chronic pain, but without a dominant stricture, has not been subjected to controlled trials It is now appreciated that significant complications can occur from stenting (e.g., stent migration, stent occlusion, and stent-induced pancreatic duct strictures) Recent guidelines recommend considering celiac plexus block for treatment of pain in chronic pancreatitis, but recommendations were conditional with very low quality of evidence Celiac plexus block has not been rigorously studied for chronic pancreatitis and does not provide durable pain relief It can provide relive in some selected patients, but the a priori identification of those who will respond is difficult In patients with pancreatic duct dilation, ductal decompression with surgical therapy has been the therapy of choice Among such patients, 80% seem to obtain immediate relief; however, at the end of years, one-half of the patients have recurrence of pain Two randomized prospective trials comparing endoscopic to surgical therapy for chronic pancreatitis demonstrated that surgical therapy was superior to endoscopy at decreasing pain and improving quality of life in selected patients with dilated ducts and abdominal pain This would suggest that chronic pancreatitis patients with dilated ducts and pain should be considered for surgical intervention The role of preoperative stenting prior to surgery as a predictor of response has yet to be proven Total pancreatectomy with or without autologous islet cell transplantation has been used in highly selected patients with chronic pancreatitis and abdominal pain refractory to conventional therapy However, some patients will continue to have pain postoperatively, illustrating the complex nature of pain in patients with chronic pancreatitis Patients who benefit most from total pancreatectomy have a shorter duration of symptoms and lower pain medication requirements The role of this procedure remains to be fully defined but may be an option in lieu of ductal decompression surgery or partial pancreatic resection in patients with intractable, painful, small-duct disease or hereditary pancreatitis and particularly as the standard surgical procedures tend to decrease islet cell yield ■ HEREDITARY PANCREATITIS Hereditary pancreatitis (PRSS1) is a rare form of pancreatitis with early age of onset that is typically associated with familial aggregation of cases A genome-wide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene (PRSS1) cause an autosomal dominant form of pancreatitis The codon 122 mutations lead to a substitution of the corresponding arginine with another amino acid, usually histidine This substitution, when it occurs, eliminates a fail-safe trypsin self-destruction site necessary to eliminate trypsin that is prematurely activated within the acinar cell These patients have recurring episodes of acute pancreatitis Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea; in addition, they have an increased incidence of pancreatic cancer with a cumulative incidence of ∼10% A previous natural history study of hereditary pancreatitis in >200 patients from France reported that abdominal pain started in childhood at age 10 years, steatorrhea developed at age 29 years, diabetes at age 38 years, and pancreatic cancer at age 55 years Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease ■ PANCREATIC ENDOCRINE TUMORS Pancreatic endocrine tumors are discussed in Chap 84 OTHER CONDITIONS ■ ANNULAR PANCREAS When the ventral pancreatic anlage fails to migrate correctly to make contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum Such an annular pancreas may cause intestinal obstruction in the neonate or the adult Symptoms of postprandial fullness, epigastric pain, nausea, and vomiting may be present for years before the diagnosis is entertained The radiographic findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but not destruction of the duodenal mucosa, accentuation of the findings in the right anterior oblique position, and lack of change on repeated examinations The differential diagnosis should include duodenal webs, tumors of the pancreas or duodenum, duodenal ulcer, regional enteritis, and adhesions Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer Because of these and other potential complications, the treatment is surgical even if the condition has been present for years Retrocolic duodenojejunostomy is the procedure of choice, although some surgeons advocate Billroth II gastrectomy, gastroenterostomy, and vagotomy ■ PANCREAS DIVISUM Pancreas divisum is present in 7–10% of the population and occurs when the embryologic ventral and dorsal pancreatic anlagen fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory minor papilla Pancreas divisum is the most common congenital anatomic variant of the human pancreas Current evidence indicates that this anomaly does not predispose to the development of pancreatitis in the majority of patients who harbor it However, the combination of pancreas divisum and a small accessory orifice could result in dorsal duct obstruction The challenge is to identify this subset of patients with dorsal duct pathology Cannulation of the dorsal duct by ERCP is technically challenging and associated with a very high risk of post-ERCP pancreatitis, so patients with pancreatitis and pancreas divisum should likely be treated with conservative measures In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum Endoscopic or surgical intervention is indicated only if pancreatitis recurs and no other cause can be found It should be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e., a small-caliber ventral duct with an arborizing pattern) may be mistaken as representing an obstructed main pancreatic duct secondary to a mass lesion ■ MACROAMYLASEMIA In macroamylasemia, amylase circulates in the blood in a polymer form too large to be easily excreted by the kidney Patients with this condition demonstrate an elevated serum amylase value and a low urinary amylase value The presence of macroamylase can be documented by chromatography of the serum The prevalence of macroamylasemia is 1.5% of the nonalcoholic general adult hospital population Usually, macroamylasemia is an incidental finding and is not related to disease of the pancreas or other organs Macrolipasemia has now been documented in patients with cirrhosis or non-Hodgkin’s lymphoma In these patients, the pancreas appeared normal on ultrasound and CT examination Lipase was shown to be complexed with immunoglobulin A Thus, the possibility of both macroamylasemia and macrolipasemia should be considered in patients with elevated blood levels of these enzymes ACKNOWLEDGMENT This chapter represents a revised version of chapters by Drs Norton J Greenberger (deceased), Phillip P Toskes (deceased), Peter A Banks, and Bechien Wu that were in previous editions of Harrison’s ■ FURTHER READING CROCKETT SD et al: American Gastroenterological Association Institute guideline on initial management of acute pancreatitis Gastroenterology 154:1096, 2018 FORSMARK CE et al: Acute pancreatitis N Engl J Med 375:1972, 2016 GARDNER TB et al: ACG clinical guideline: Chronic pancreatitis Am J Gastroenterol 115:322, 2020 HART PA, CONWELL DL: Chronic pancreatitis: Managing a difficult disease Am J Gastroenterol 115:49, 2020 HART PA et al: Recent advances in autoimmune pancreatitis Gastroenterology 149:39, 2015 PETROV MS, YADAV D: Global epidemiology and holistic prevention of pancreatitis Nat Rev Gastroenterol Hepatol 16:175, 2019 YADAV D, LOWENFELS AB: The epidemiology of pancreatitis and pancreatic cancer Gastroenterology 144:1252, 2013 hinhanhykhoa.com
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