Pathology_Robbins

Pathology_Robbins. Flagella, which allow the bacteria to be motile in viscous mucus Urease, which generates ammonia from endogenous urea, thereby elevating local gastric pH around the organisms and protecting the bacteria from the acidic pH of the stomach Adhesins, which enhance bacterial adherence to surface foveolar cells Toxins, such as that encoded by cytotoxin-associated gene A (CagA), that may be involved in ulcer or cancer development These factors allow H. pylori to create an imbalance forces that overcome those defenses. MORPHOLOGYGastricbiopsyspecimensgenerallydemonstrateH. pylori ininfectedindividuals( Fig.15.14A ).Theorganismisconcentratedwithinmucusoverlyingepithelialcellsinthesurfaceandneckregions.Theinflammatoryreactionincludesavariablenumberofneutrophilswithinthelaminapropria,includingsomethatcrossthebasementmembranetoassumeanintraepitheliallocation(


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. In addition to histologic identification of the organism, several diagnostic tests have been developed including a noninvasive serologic test for anti–H. pylori antibodies, a stool test for the organism, and the urea breath test, based on the generation of ammonia by bacterial urease. Gastric biopsy specimens also can be analyzed by the rapid urease test, bacterial culture, or polymerase chain reaction (PCR) assay for bacterial DNA. Effective treatments include combinations of antibiotics and proton pump inhibitors. Patients with H. pylori gastritis usually improve after treatment, although relapses can follow incomplete eradication or reinfection. Autoimmune gastritis accounts for less than 10% of cases of chronic gastritis. In contrast H. pylori-associated gastritis, autoimmune gastritis typically spares the antrum and induces marked hypergastrinemia ( Table 15.2 ). Autoimmune gastritis is characterized by the following:


Pathology_Robbins

Pathology_Robbins. Table 15.2 ). Autoimmune gastritis is characterized by the following: Antibodies to parietal cells and intrinsic factor that can be detected in serum and gastric secretions http://ebooksmedicine.net Fig. 15.14 Chronicgastritis.(A)Spiral-shapedHelicobacter pylori bacilliarehighlightedinthisWarthin-Starrysilverstain.Organismsareabundantwithinsurfacemucus.(B)Intraepithelialandlaminaproprianeutrophilsareprominent.(C)Lymphoidaggregateswithgerminalcentersandabundantsubepithelialplasmacellswithinthesuperficiallaminapropriaarecharacteristicof H. pylori gastritis.(D)Intestinalmetaplasia,recognizableasthepresenceofgobletcellsadmixedwithgastricfoveolarepithelium,candevelopandisariskfactorfordevelopmentofgastricadenocarcinoma. Vitamin B12 deficiency leading to pernicious anemia and neurologic changes


Pathology_Robbins

Pathology_Robbins. Vitamin B12 deficiency leading to pernicious anemia and neurologic changes Autoimmune gastritis is associated with immune-mediated loss of parietal cells and subsequent reductions in acid and intrinsic factor secretion. Deficient acid secretion stimulates gastrin release, resulting in hypergastrinemia and hyperplasia of antral gastrin-producing G cells. Lack of intrinsic factor disables ileal vitamin B12 absorption, leading to B12 deficiency and a particular form of megaloblastic anemia called pernicious anemia (Chapter 12). Reduced serum concentration of pepsinogen I reflects chief cell loss. Although H. pylori can cause hypochlorhydria, it is not associated with achlorhydria or pernicious anemia, because the parietal and chief cell damage is not as severe as in autoimmune gastritis.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYAutoimmunegastritisischaracterizedbydiffusedamage of the oxyntic (acid-producing)mucosa withinthebodyandfundus.Damagetotheantrumandcardiatypicallyisabsentormild.Withdiffuse atrophy, theoxynticmucosaofthebodyandfundusappearsmarkedlythinned,andrugalfoldsarelost.Neutrophilsmaybepresent,buttheinflammatoryinfiltratemorecommonlyiscomposedoflymphocytes,macrophages,andplasmacells;incontrastwithH. pylori gastritis, theinflammatoryreactionmostoftenisdeepandcenteredonthegastricglands.Parietal and chief cell loss canbeextensive,andintestinal metaplasia maydevelop. Antibodies to parietal cells and intrinsic factor are present early in the disease, but B12 deficiency and pernicious anemia develop in only a minority of patients. The median age at diagnosis is 60 years, and there is a slight female predominance. Autoimmune gastritis often is associated with other autoimmune diseases but is not linked to specific human leukocyte antigen (HLA) alleles.


Pathology_Robbins

Pathology_Robbins. There are three important complications of chronic gastritis: Peptic ulcer disease, mucosal atrophy and intestinal metaplasia, and dysplasia. Each of these is discussed shortly. Peptic ulcer disease (PUD) most often is associated with H. pylori infection or NSAID use. The imbalances of Table 15.2 Characteristics of Helicobacter pylori–Associated and Autoimmune Gastritis Feature H. pylori–Associated Autoimmune InflammatoryinfiltrateNeutrophils,subepithelialplasmacellsLymphocytes,macrophages SerologyAntibodiestoH. pylori Antibodiestoparietalcells(H+,K+-ATPase,intrinsicfactor) SequelaePepticulcer,adenocarcinoma,lymphomaAtrophy,perniciousanemia,adenocarcinoma,carcinoidtumor AssociationsLowsocioeconomicstatus,poverty,residenceAutoimmunedisease;thyroiditis,diabetesmellitus,Gravesdiseaseinruralareas http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. AssociationsLowsocioeconomicstatus,poverty,residenceAutoimmunedisease;thyroiditis,diabetesmellitus,Gravesdiseaseinruralareas http://ebooksmedicine.net Fig. 15.13 ) are also responsible for PUD. In the United States, NSAID use is becoming the most common cause of gastric ulcers as H. pylori infection rates are falling and low-dose aspirin use in the aging population is increasing. PUD may occur in any portion of the gastrointestinal tract exposed to acidic gastric juices but is most common in the gastric antrum and first portion of the duodenum. Peptic (acid-induced) injury may occur in the esophagus as a result of acid reflux (GERD) or acid secretion by ectopic gastric mucosa. Peptic injury in the small intestine may also be associated with gastric heterotopia, including that within a Meckel diverticulum.


Pathology_Robbins

Pathology_Robbins. PUD is common and is a frequent cause of physician visits worldwide. It leads to treatment of over 3 million individuals, 190,000 hospitalizations, and 5000 deaths in the United States each year. The lifetime risk for developing an ulcer is approximately 10% for males and 4% for females. H. pylori infection and NSAID use are the primary underlying causes of PUD. More than 70% of PUD cases are associated with H. pylori infection and in these individuals PUD generally develops on a background of chronic gastritis. Because only 5% to 10% of H. pylori–infected individuals develop ulcers, it is probable that host factors as well as variation among H. pylori strains also contribute to the pathogenesis.


Pathology_Robbins

Pathology_Robbins. Gastric acid is fundamental to the pathogenesis of PUD. Hyperacidity may be caused by H. pylori infection, parietal cell hyperplasia, and excessive secretory responses. Insufficient inhibition of stimulatory mechanisms such as gastrin release may also contribute. For example, Zollinger-Ellison syndrome, characterized by multiple peptic ulcerations in the stomach, duodenum, and even jejunum, is caused by uncontrolled release of gastrin by a tumor and the resulting massive acid production. Cofactors in peptic ulcerogenesis include chronic NSAID use, as noted; cigarette smoking, which impairs mucosal blood flow and healing; and high-dose corticosteroids, which suppress prostaglandin synthesis and impair healing. Peptic ulcers are more frequent in individuals with alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, and hyperparathyroidism. In the latter two conditions, hypercalcemia stimulates gastrin production and thereby increases acid secretion.


Pathology_Robbins

Pathology_Robbins. Fig.15.15C ).Ongoingbleedingwithintheulcerbasemaycauselife-threateninghemorrhage.Perforation isacomplicationthatdemandsemergentsurgicalintervention. Peptic ulcers are chronic, recurring lesions that occur most often in middle-aged to older adults without obvious precipitating conditions, other than chronic gastritis. A majority of peptic ulcers come to clinical attention after patient complaints of epigastric burning or aching pain, although a significant fraction manifest with complications such as iron deficiency anemia, frank hemorrhage, or perforation. The pain tends to occur 1 to 3 hours after meals during the day, is worse at night, and is relieved by alkali or food. Nausea, vomiting, bloating, and belching may be present. Healing may occur with or without therapy, but the tendency to develop subsequent ulcers remains.


Pathology_Robbins

Pathology_Robbins. Fig. 15.15 Pepticulcerdisease.(A)EndoscopicviewoftypicalantralulcerassociatedwithNSAIDuse.(B)Grossviewofasimilarulcerthatwasresectedduetogastricperforation,presentingasfreeairunderthediaphragm.Notethecleanedges.(C)Thenecroticulcerbaseiscomposedofgranulationtissueoverlaidbydegradedblood.(Endoscopic image courtesy of Dr. Ira Hanan,The University of Chicago, Chicago, Illinois.) http://ebooksmedicine.net PUD causes much more morbidity than mortality. A variety of surgical approaches were formerly used to treat PUD, but current therapies are aimed at H. pylori eradication with antibiotics and neutralization of gastric acid, usually through use of proton pump inhibitors. These efforts have markedly reduced the need for surgical management, which is reserved primarily for treatment of ulcers with uncontrollable bleeding or perforation.


Pathology_Robbins

Pathology_Robbins. Long-standing chronic gastritis may be associated with intestinal metaplasia, recognized by the presence of goblet cells. This is strongly associated with increased risk for development of gastric adenocarcinoma. In addition, the achlorhydria of gastric mucosal atrophy, which is commonly associated with intestinal metaplasia, permits overgrowth of bacteria that produce carcinogenic nitrosamines. Intestinal metaplasia caused by chronic H. pylori gastritis may regress after eradication of the organism.


Pathology_Robbins

Pathology_Robbins. Chronic gastritis exposes the epithelium to inflammation-related free radical damage and proliferative stimuli. Over time, this can lead to the accumulation of genetic alterations that result in carcinoma. Preinvasive in situ lesions can be recognized histologically as dysplasia, which is marked by variations in epithelial size, shape, and orientation along with coarse chromatin texture, hyperchromasia, and nuclear enlargement. These overlap with and are sometimes difficult to distinguish from injury-associated regenerative changes. Gastritisisamucosalinflammatoryprocess.Wheninflammatorycellsareabsentorrare,thetermgastropathy canbeapplied. Thespectrumofacutegastritisrangesfromasymptomaticdiseasetomildepigastricpain,nausea,andvomiting.Causativefactorsincludeanyagentordiseasethatinterfereswithgastricmucosalprotection.Acutegastritiscanprogresstogastriculceration.


Pathology_Robbins

Pathology_Robbins. ThemostcommoncauseofchronicgastritisisH. pylori infection;mostremainingcasesarecausedbyNSAIDs,alcohol,or autoimmune gastritis. H. pylori gastritistypicallyaffectstheantrumandisassociatedwithincreasedgastricacidproduction. H. pylori gastritisinducesmucosa-associatedlymphoidtissue(MALT)thatcangiverisetoB-celllymphomas(MALTomas). Autoimmune gastritis causesatrophyofthegastricbodyoxynticglands,whichresultsindecreasedgastricacidproduction,antralG-cellhyperplasia,achlorhydria,andvitaminB12deficiency.Anti–parietalcellandanti–intrinsicfactorantibodiesaretypicallypresent. Intestinal metaplasia developsinbothformsofchronicgastritisandisariskfactorfordevelopmentofgastricdysplasiaandadenocarcinoma. PepticulcerdiseasecanbecausedbyH. pylori chronicgastritisandtheresultanthyperchlorhydriaorNSAIDuse.Ulcerscandevelopinthestomachorduodenumandusuallyhealaftersuppressionofgastricacidproduction,discontinuationofNSAIDuse,or,ifpresent,H. pylori eradication.


Pathology_Robbins

Pathology_Robbins. Polyps are nodules or masses that project above the level of the surrounding mucosa. They are identified in up to 5% of upper gastrointestinal tract endoscopies. Polyps may develop as a result of epithelial or stromal cell hyperplasia, inflammation, ectopia, or neoplasia. Although many different types of polyps can occur in the stomach, only hyper-plastic and inflammatory polyps, fundic gland polyps, and adenomas are considered here. Up to 75% of all gastric polyps are inflammatory or hyperplastic polyps. In the stomach, inflammatory and hyperplastic polyps represent opposite ends of the morphologic spectrum of a single entity; the distinction is based solely on the degree of inflammation. They most commonly affect individuals between 50 and 60 years of age, usually arising in a background of chronic gastritis that initiates the injury and reactive hyperplasia that cause polyp growth. If associated with H. pylori gastritis, polyps may regress after bacterial eradication.


Pathology_Robbins

Pathology_Robbins. The frequency with which dysplasia, a precancerous in situ lesion, develops in these polyps correlates with size; there is a significant increase in risk with polyps larger than 1.5 cm. Fundic gland polyps occur sporadically and in individuals with familial adenomatous polyposis (FAP) Polyps associated with FAP (but not sporadic) may show dysplasia, but they almost never progress to become malignant. The incidence of sporadic lesions has increased markedly as a result of the widespread use of proton pump inhibitors. This likely results from increased gastrin secretion, in response to reduced acidity, and glandular hyperplasia driven by gastrin. Fundic gland polyps are nearly always asymptomatic, and are usually an incidental finding. These well-circumscribed polyps occur in the gastric body and fundus, often are multiple, and are composed of cystically dilated, irregular glands lined by flattened parietal and chief cells.


Pathology_Robbins

Pathology_Robbins. Gastric adenomas represent up to 10% of all gastric polyps. Their incidence increases with age and varies among different populations in parallel with that of gastric adenocarcinoma. Patients usually are between 50 and 60 years of age, and males are affected three times more often than females. Adenomas almost always occur on a background of chronic gastritis with atrophy and intestinal metaplasia. All gastrointestinal adenomas exhibit epithelial dysplasia, which can be classified as low-or high-grade. The risk for development of adenocarcinoma in gastric adenomas is related to the size of the lesion and is particularly elevated with lesions greater than 2 cm in diameter. Overall, the malignant potential of gastric adenomas is far greater than that of their colonic counterparts. Carcinoma may be present in up to 30% of gastric adenomas. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Adenocarcinoma is the most common malignancy of the stomach, comprising more than 90% of all gastric cancers. Early symptoms resemble those of chronic gastritis, including dyspepsia, dysphagia, and nausea. As a result, the cancer is often diagnosed at advanced stages when clinical manifestations such as weight loss, anorexia, altered bowel habits, anemia, and hemorrhage trigger diagnostic evaluation.


Pathology_Robbins

Pathology_Robbins. Gastric cancer rates vary markedly with geography. The incidence is up to 20 times higher in Japan, Chile, Costa Rica, and Eastern Europe than in North America, northern Europe, Africa, and Southeast Asia. Mass endoscopic screening programs have been successful in regions of high incidence, such as Japan, where 35% of newly detected cases are early gastric cancer (i.e., tumors limited to the mucosa and submucosa). Unfortunately, mass screening programs are not cost-effective in regions in which the incidence is low, and less than 20% of cases are detected at an early stage in North America and northern Europe.


Pathology_Robbins

Pathology_Robbins. Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia. PUD does not impart an increased risk for development of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk for developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis. In the United States, gastric cancer rates have dropped by more than 85% during the 20th century. Similar declines have been reported in many other Western countries, reflecting the importance of environmental and dietary factors. Despite this decrease in overall gastric adenocarcinoma incidence, cancer of the gastric cardia is on the rise. This trend probably is related to increased rates of Barrett esophagus and may reflect the growing prevalence of obesity and chronic GERD.


Pathology_Robbins

Pathology_Robbins. Gastric cancers are genetically heterogeneous, but certain molecular alterations are common. We will consider these first to be followed by the role of H. pylori–induced chronic inflammation and the association of a subset of gastric cancers with EBV infection. • Mutations. While the majority of gastric cancers are not hereditary, mutations identified in familial gastric cancer have provided important insights into the mechanisms of carcinogenesis in sporadic cases. Germ line mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, usually of the diffuse type. By comparison, mutations in CDH1 are present in about 50% of sporadic diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer.


Pathology_Robbins

Pathology_Robbins. In contrast to CDH1, patients with FAP who have germ line mutations in adenomatous polyposis coli (APC) genes have an increased risk for development of intestinal-type gastric cancer. Sporadic intestinal-type gastric cancer is associated with several genetic abnormalities including acquired mutations of β-catenin, a protein that binds to both E-cadherin and APC protein; microsatellite instability; and hypermethylation of genes including TGFβRII, BAX, IGFRII, and p16/INK4a. TP53 mutations are present in a majority of sporadic gastric cancers of both histologic types.


Pathology_Robbins

Pathology_Robbins. H. pylori. Chronic gastritis, most commonly due to H. pylori infection, promotes the development and progression of cancers that may be induced by diverse genetic alterations (Chapter 6). As is the case with many forms of chronic inflammation, H. pylori–induced chronic gastritis is associated with increased production of proinflammatory proteins, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF). It is therefore not surprising that polymorphisms of genes that encode such factors and enhance production of these cytokines confer increased risk for development of chronic gastritis-associated gastric cancer in those with coexisting H. pylori infection.


Pathology_Robbins

Pathology_Robbins. Epstein-Barr virus (EBV). While H. pylori is most commonly associated with gastric cancer, approximately 10% of gastric adenocarcinomas are associated with Epstein-Barr virus (EBV) infection. Although the precise role of EBV in the development of gastric adenocarcinomas remains to be defined, it is notable that EBV episomes in these tumors frequently are clonal, suggesting that infection preceded neoplastic transformation. Further, TP53 mutations are uncommon in EBV-positive gastric tumors, suggesting that the molecular pathogenesis of these cancers is distinct from that of other gastric adenocarcinomas. Morphologically, EBV-positive tumors tend to occur in the proximal stomach and most commonly have a diffuse morphology with a marked lymphocytic infiltrate.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig.15.16B )andarecomposedofdiscohesivecellswithlargemucinvacuolesthatexpandthecytoplasmandpushthenucleustotheperiphery,creatingasignet ring cell morphology( Fig.15.16C ).Thesecellspermeatethemucosaandstomachwallindividuallyorinsmallclusters.Amassmaybedifficulttoappreciateindiffusegastriccancer,buttheseinfiltrativetumorsoftenevokeadesmoplastic reactionthatstiffensthegastricwallandmaycausediffuserugalflatteningandarigid,thickenedwallthatimpartsa“leatherbottle”appearancetermedlinitis plastica. Intestinal-type gastric cancer predominates in high-risk areas and develops from precursor lesions such as dysplasia and adenomas. The mean age at presentation is 55 years, and the male-to-female ratio is 2:1. By contrast, the Fig. 15.16 Gastricadenocarcinoma.(A)Intestinal-typeadenocarcinomaconsistingofanelevatedmasswithheaped-upbordersandcentralulceration.Comparewiththepepticulcerin


Pathology_Robbins

Pathology_Robbins. Fig. 15.16 Gastricadenocarcinoma.(A)Intestinal-typeadenocarcinomaconsistingofanelevatedmasswithheaped-upbordersandcentralulceration.Comparewiththepepticulcerin Fig.15.15A . (B)Linitisplastica.Thegastricwallismarkedlythickened,andrugalfoldsarepartiallylost.(C)Signetringcellswithlargecytoplasmicmucinvacuolesandperipherallydisplaced,crescent-shapednuclei. incidence of diffuse gastric cancer is relatively uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females. Of note, the decrease in gastric cancer incidence applies only to the intestinal type, which is most closely associated with atrophic gastritis and intestinal metaplasia. As a result, the incidences of intestinal and diffuse types of gastric cancers are now similar in some regions.


Pathology_Robbins

Pathology_Robbins. The depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis remain the most powerful prognostic indicators for gastric cancer. Local invasion into the duodenum, pancreas, and retroperitoneum is also characteristic. When possible, surgical resection remains the preferred treatment for gastric adenocarcinoma. After surgical resection, the 5-year survival rate for early gastric cancer can exceed 90%, even if lymph node metastases are present. By contrast, the 5-year survival rate for advanced gastric cancer remains below 20%, in large part because current chemotherapy regimens are have limited impact. This is changing slowly with individualized therapies. For example, patients whose tumors over-express the epidermal growth factor receptor HER2 benefit from agents that inhibit HER2 signaling. Nevertheless, most gastric cancers are discovered at advanced stage in the United States, and the overall 5-year survival rate is less than 30%.


Pathology_Robbins

Pathology_Robbins. Although extranodal lymphomas can arise in virtually any tissue, they do so most commonly in the gastrointestinal tract, particularly the stomach. In allogeneic hematopoietic stem cell and organ transplant recipients, the bowel also is the most frequent site for Epstein-Barr virus–positive B cell lymphoproliferations. Nearly 5% of all gastric malignancies are primary lymphomas, the most common of which are indolent extranodal marginal zone B-cell lymphomas. In the gut, these tumors often are referred to as lymphomas of MALT, or MALTomas. This entity and the second most common primary lymphoma of the gut, diffuse large B cell lymphoma, are discussed in Chapter 12.


Pathology_Robbins

Pathology_Robbins. Neuroendocrine tumors, also referred to as carcinoid tumors, arise from neuroendocrine organs (e.g., the endocrine pancreas) and neuroendocrine-differentiated gastrointestinal epithelia (e.g., G cells). A majority of these tumors are found in the gastrointestinal tract, and more than 40% occur in the small intestine. The tracheobronchial tree and lungs are the next most commonly involved sites. Gastric neuroendocrine tumors may be associated with endocrine cell hyperplasia, chronic atrophic gastritis, and Zollinger-Ellison syndrome. These tumors were called “carcinoid” because they are slower growing than carcinomas. The most current WHO classification describes these as low-or intermediate-grade neuroendocrine tumors. High-grade neuroendocrine tumors, termed neuroendocrine carcinoma, resemble small cell carcinoma of the lung (Chapter 13) and, in the gastrointestinal tract, are most common in the jejunum. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.15.17B The peak incidence of neuroendocrine tumors is in the sixth decade, but they may appear at any age. Symptoms are determined by the hormones produced. For example, the carcinoid syndrome is caused by vasoactive substances secreted by the tumor that cause cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea, and right-sided cardiac valvular fibrosis. When tumors are confined to the intestine, the vasoactive substances released are metabolized to inactive forms by the liver—a “firstpass” effect similar to that seen with oral drugs. Thus, carcinoid syndrome occurs in less than 10% of patients and is strongly associated with metastatic disease.


Pathology_Robbins

Pathology_Robbins. The most important prognostic factor for gastrointestinal neuroendocrine tumors is location: • Foregut neuroendocrine (carcinoid) tumors found within the stomach, duodenum proximal to the ligament of Treitz, and esophagus, rarely metastasize and are generally cured by resection. Rare duodenal gastrin-producing neuroendocrine tumors, also termed gastrinomas, may present with symptoms related to increased acid production, including pain and/or bleeding from gastroduodenal ulcers, refractory gastroesophageal reflux, and diarrhea due to inactivation of pancreatic enzymes by excessive gastric acid. Midgut neuroendocrine (carcinoid) tumors arise in the jejunum and ileum, are often multiple and tend to be aggressive. In these tumors, depth of local invasion, size, and the presence of necrosis and mitoses are associated with poor outcome.


Pathology_Robbins

Pathology_Robbins. Hindgut neuroendocrine (carcinoid) tumors arising in the appendix and colorectum are typically discovered incidentally. Those in the appendix occur at any age and are almost uniformly pursue a benign course. Rectal tumors tend to produce polypeptide hormones and may manifest with abdominal pain and weight loss. Because they are usually discovered when small, metastasis of rectal neuroendocrine tumors is uncommon. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach. A wide variety of other mesenchymal neoplasms may arise in the stomach. Many are named according to the cell type they most resemble; for example, smooth muscle tumors are called leiomyomas or leiomyosarcomas, nerve sheath tumors are termed schwannomas, and those resembling glomus bodies in the nail beds and at other sites are termed glomus tumors. These tumors are all rare and are not discussed here.


Pathology_Robbins

Pathology_Robbins. The most common genetic change underlying the pathogenesis of GISTs is gain-of-function mutations of the gene encoding the tyrosine kinase KIT, the receptor for stem cell factor. These are present in 75% to 85% of all GISTs. An additional 8% of GISTs have mutations that activate a related tyrosine kinase, platelet-derived growth factor receptor A (PDGFRA). The term stromal reflects historical confusion about the origin of this tumor, which is now recognized to arise from the interstitial cells of Cajal, or pacemaker cells, of the gastrointestinal muscularis propria. For unknown reasons, GISTs bearing PDGFRA mutations are overrepresented in the stomach. KIT and PDGFRA gene mutations are mutually exclusive, reflecting their activities within the same signal transduction pathway. Germ line mutations in these same genes are present in rare familial GISTs, in which patients develop multiple GISTs and may also have diffuse hyperplasia of Cajal cells.


Pathology_Robbins

Pathology_Robbins. Both sporadic and germ line mutations result in constitutively active KIT or PDGFRA receptor tyrosine kinases and produce intracellular signals that promote tumor cell proliferation and survival (Chapter 6). In GISTs without KIT or PDGFRA mutations, genes encoding components of the mitochondrial succinate dehydrogenase (SDH) complex are most commonly affected. These mutations result in loss of SDH function and confer increased risk for both GIST and paraganglioma. One mutant allele is often inherited, with the second copy of the gene being either mutated or otherwise lost in the tumor. The loss of SDH causes a number of metabolic changes, including increased production of reactive oxygen species, activation of hypoxia induced factor (HIF), and increased dependency on glycolysis for ATP production, but how these alterations lead to transformation is uncertain. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The peak incidence of gastric GIST is around 60 years of age, with less than 10% occurring in individuals younger than 40 years of age. Overall, GISTs are slightly more common in males. Small GISTs may come to clinical attention incidentally during work-up of other GI symptoms, which are common. Larger GISTs may present with symptoms related to mass effects or mucosal ulceration, such as intestinal obstruction or gastrointestinal bleeding. Complete surgical resection is the primary treatment for localized gastric GIST. The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs less than 5 cm in diameter but common for mitotically active tumors larger than 10 cm. Tumors that are unresectable or metastatic often respond, sometimes for years, to tyrosine kinase inhibitors that are active against KIT and PDGFRA, such as imatinib.


Pathology_Robbins

Pathology_Robbins. active tumors larger than 10 cm. Tumors that are unresectable or metastatic often respond, sometimes for years, to tyrosine kinase inhibitors that are active against KIT and PDGFRA, such as imatinib. Unfortunately, as in chronic myeloid leukemia (Chapter 12), resistance to imatinib eventually arises due to outgrowth of subclones with additional mutations in KIT or PDGFRA. In some instances, these tumors respond to other tyrosine kinase inhibitors that retain activity against KIT and PDGFRA.


Pathology_Robbins

Pathology_Robbins. Primary gastric lymphomas mostoftenarederivedfromthemucosa-associatedlymphoidtissuewhosedevelopmentisinducedbychronicgastritis. Low-orintermediate-gradeneuroendocrine (carcinoid) tumors arisefromthediffusecomponentsoftheendocrinesystemandaremostcommoninthegastrointestinaltract,particularlythesmallintestine.Tumorsofthesmallintestinetendtobemostaggressive,whilethoseoftheappendixarealmostalwaysbenign. Gastrointestinal stromal tumor (GIST), themostcommonmesenchymaltumoroftheabdomen,occursmostofteninthestomach.GISTsarisefrombenignpacemakercells,alsoknownastheinterstitial cells of Cajal. Amajorityoftumorshaveactivatingmutationsineitherthec-KITorthePDGFRAtyrosinekinasesandrespondtokinaseinhibitors.


Pathology_Robbins

Pathology_Robbins. The small intestine and colon are the sites of a wide variety of diseases, many of which affect nutrient and water transport. Perturbation of these processes may cause malabsorption and diarrhea. The intestines are also the principal site where the immune system interfaces with a diverse array of antigens present in food and gut microbes. Recent advances have defined the composition and diversity of the gut microbiome, which is largely unculturable, using molecular approaches. One common trend is the association of reduced microbial diversity in disease. The gut microbiome is also exquisitely sensitive to diet, which may partly explain the association between food allergy and other diet-induced diseases and altered composition of the microbiome. Thus, it is not surprising that the small intestine and colon frequently are involved by infectious and inflammatory processes. The colon is the most common site of gastrointestinal neoplasia in Western populations.


Pathology_Robbins

Pathology_Robbins. Obstruction of the gastrointestinal tract may occur at any level, but the small intestine is most often involved because of its relatively narrow lumen. Collectively, hernias, intestinal adhesions, intussusception, and volvulus account for 80% of mechanical obstructions ( Fig. 15.18 ), while tumors and infarction account for most of the remainder. The clinical manifestations of intestinal obstruction include abdominal pain and distention, vomiting, and constipation. Surgical intervention is usually required in cases involving http://ebooksmedicine.net Fig. 15.18 Intestinal obstruction. The four major mechanical causes of intestinal obstruction are (1) herniation of a segment in the umbilical or inguinal regions, (2) adhesion between loops of intestine, (3) volvulus, and (4) intussusception. mechanical obstruction or severe infarction. Volvulus and adhesions between bowel loops are well illustrated in Fig.


Pathology_Robbins

Pathology_Robbins. mechanical obstruction or severe infarction. Volvulus and adhesions between bowel loops are well illustrated in Fig. 15.18 . Brief comments are made next about the other causes of obstruction.


Pathology_Robbins

Pathology_Robbins. Intussusception occurs when a segment of the intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment. Once trapped, the invaginated segment is propelled by peristalsis and pulls the mesentery along. Untreated intussusception may progress to intestinal obstruction, compression of mesenteric vessels, and infarction. Intussusception is the most common cause of intestinal obstruction in children younger than 2 years of age. There usually is no underlying anatomic defect and the child is otherwise healthy. Other cases are associated with viral infection and rotavirus vaccines and may be related to reactive hyperplasia of Peyer patches, which can act as the leading edge of the intussusception. Contrast enemas are diagnostically useful and also are effective in correcting idiopathic intussusception in infants and young children. However, surgical intervention is necessary when an intraluminal mass or tumor serves as the initiating point of traction, as


Pathology_Robbins

Pathology_Robbins. in correcting idiopathic intussusception in infants and young children. However, surgical intervention is necessary when an intraluminal mass or tumor serves as the initiating point of traction, as is typical in older children and in adults.


Pathology_Robbins

Pathology_Robbins. Hirschsprung disease occurs in approximately 1 of 5000 live births and stems from a congenital defect in colonic innervation. It may be isolated or occur in combination with other developmental abnormalities. It is more common in males but tends to be more severe in females. Siblings are at increased risk for development of Hirschsprung disease. Patients typically present as neonates with failure to pass meconium in the immediate postnatal period followed by obstructive constipation. The major threats to life are enterocolitis, fluid and electrolyte disturbances, perforation, and peritonitis. Surgical resection of the aganglionic segment with anastomosis of the normal colon to the rectum is effective, although it may take years for patients to attain normal bowel function and continence.


Pathology_Robbins

Pathology_Robbins. The enteric neuronal plexus develops from neural crest cells that migrate into the bowel wall during embryogenesis. Hirschsprung disease, also known as congenital aganglionic megacolon, results when the normal migration of neural crest cells from cecum to rectum is disrupted. This produces a distal intestinal segment that lacks both the Meissner submucosal plexus and the Auerbach myenteric plexus (“aganglionosis”), and thus fails to develop coordinated peristaltic contractions. Mutations in the receptor tyrosine kinase RET account for a majority of familial cases and approximately 15% of sporadic cases. Mutations in other genes, including disease-modifying genes, as well as environmental factors must also be involved.


Pathology_Robbins

Pathology_Robbins. Hirschsprung disease always affects the rectum, but the length of the additional involved segments varies. Most cases are limited to the rectum and sigmoid colon, but severe disease can involve the entire colon. The aganglionic region may have a grossly normal or contracted appearance, while the normally innervated proximal colon may undergo progressive dilation as a result of functional distal obstruction ( Fig. 15.19 ). Diagnosis is made by demonstrating the absence of ganglion cells in the affected segment. Fig. 15.19 Hirschsprung disease. (A) Preoperative barium enema study showing constricted rectum (bottom) and dilated sigmoid colon. Ganglion cells were absent in the rectum, but present in the sigmoid colon. (B) Corresponding intraoperative appearance of the dilated sigmoid colon. (Courtesy of Dr. Aliya Husain, The University of Chicago, Chicago, Illinois.)


Pathology_Robbins

Pathology_Robbins. Any weakness or defect in the wall of the peritoneal cavity may permit protrusion of a serosa-lined pouch of peritoneum called a hernia sac. Acquired hernias most commonly occur anteriorly, through the inguinal and femoral canals or umbilicus, or at sites of surgical scars. These are of concern because of visceral protrusion (external herniation). This is particularly true of inguinal hernias, which tend to have narrow orifices and large sacs. Small bowel loops herniate most often, but portions of omentum or large bowel also protrude, and any of these may become entrapped. Pressure at the neck of the pouch may impair venous drainage, leading to stasis and edema. These changes increase the bulk of the herniated loop, leading to permanent entrapment, or incarceration, and over time, arterial and venous compromise, or strangulation, can result in infarction.


Pathology_Robbins

Pathology_Robbins. Intussusception isthemostcommoncauseofintestinalobstructioninchildrenyoungerthan2yearsofageandcanusuallybetreatedbybariumenemaorairenema. Hirschsprung disease istheresultofdefectiveneuralcrestcellmigrationfromcecumtorectum.Itgivesrisetofunctionalobstruction. Abdominal herniation mayoccurthroughanyweaknessordefectinthewalloftheperitonealcavity,includinginguinalandfemoralcanals,umbilicus,andsitesofsurgicalscarring.


Pathology_Robbins

Pathology_Robbins. Abdominal herniation mayoccurthroughanyweaknessordefectinthewalloftheperitonealcavity,includinginguinalandfemoralcanals,umbilicus,andsitesofsurgicalscarring. The largest portion of the gastrointestinal tract is supplied by the celiac, superior mesenteric, and inferior mesenteric arteries. As they approach the intestinal wall, the superior and inferior mesenteric arteries fan out to form the mesenteric arcades. Interconnections between arcades, as well as collateral supplies from the proximal celiac and distal pudendal and iliac circulations make it possible for the small intestine and colon to tolerate slowly progressive loss of the blood supply from one artery. By contrast, acute compromise of any major vessel can lead to infarction of several meters of intestine.


Pathology_Robbins

Pathology_Robbins. Ischemic damage to the bowel can range from mucosal infarction, extending no deeper than the muscularis mucosa; to mural infarction of mucosa and submucosa; to transmural infarction involving all three layers of the wall. While mucosal or mural infarctions often are secondary to acute or chronic hypoperfusion, transmural infarction is generally caused by acute vascular obstruction. Important causes of acute arterial obstruction include severe atherosclerosis (which is often prominent at the origin of mesenteric vessels), aortic aneurysm, hypercoagulable states, oral contraceptive use, and embolization of cardiac vegetations or aortic atheromas. Intestinal hypo-perfusion can also be associated with cardiac failure, shock, dehydration, or vasoconstrictive drugs. Systemic vasculitides also may damage intestinal arteries. While mesenteric venous thrombosis can lead to ischemic disease, it is uncommon. Other causes include invasive neoplasms, cirrhosis, portal hypertension, trauma, or


Pathology_Robbins

Pathology_Robbins. may damage intestinal arteries. While mesenteric venous thrombosis can lead to ischemic disease, it is uncommon. Other causes include invasive neoplasms, cirrhosis, portal hypertension, trauma, or abdominal masses that compress the portal drainage.


Pathology_Robbins

Pathology_Robbins. The severity of vascular compromise, time frame during which it develops, and vessels affected are the major variables that determine severity of ischemic bowel disease. Intestinal responses to ischemia occur in two phases. The initial hypoxic injury occurs at the onset of vascular compromise and, although some damage occurs, intestinal epithelial cells are relatively resistant to transient hypoxia. The second phase, reperfusion injury, is initiated by restoration of the blood supply and associated with the greatest damage. While the underlying mechanisms of reperfusion injury are incompletely understood, they involve free radical production, neutrophil infiltration, and inflammatory mediators such as complement and cytokines. Two aspects of intestinal vascular anatomy also contribute to the distribution of ischemic damage:


Pathology_Robbins

Pathology_Robbins. Watershed zones refers to intestinal segments at the end of their respective arterial supplies that are particularly susceptible to ischemia. These zones include the splenic flexure, where the superior and inferior mesenteric arterial circulations terminate, and, to a lesser extent, the sigmoid colon and rectum where inferior mesenteric, pudendal, and iliac arterial circulations end. Generalized hypotension or hypoxemia can therefore cause localized injury at these sites, and ischemic disease should be considered in the differential diagnosis for focal colitis of the splenic flexure or rectosigmoid colon.


Pathology_Robbins

Pathology_Robbins. Patterns of intestinal microvessls. Intestinal capillaries run alongside the glands, from crypt to surface, before making a hairpin turn at the surface to empty into the postcapillary venules. This configuration leaves the surface epithelium particularly vulnerable to ischemic injury. Thus, surface epithelial atrophy, or even necrosis and epithelial sloughing, with normal or hyperproliferative crypts constitutes a morphologic signature of ischemic intestinal disease.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYDespitetheincreasedsusceptibilityofwatershedzones,mucosal and mural infarction mayinvolveanylevelofthegutfromstomachtoanus.Involvementisfrequentlysegmentalandpatchy,andthemucosaishemorrhagicandoftenulcerated.Thebowelwallisthickenedbyedemathatmayinvolvethemucosaorextendintothesubmucosaandmuscularispropria.Withseveredisease,pathologicchangesincludeextensivemucosalandsubmucosalhemorrhageandnecrosis,butserosalhemorrhageandserositisgenerallyareabsent.Damageismorepronouncedinacutearterialthrombosisandtransmural infarction. Blood-tingedmucusorbloodaccumulateswithinthelumen. http://ebooksmedicine.net Coagulativenecrosisofthemuscularispropriaoccurswithin1to4daysandmaybeassociatedwithpurulentserositisandperforation. Microscopicexaminationofischemicintestinedemonstratesatrophy or sloughing of surface epithelium (


Pathology_Robbins

Pathology_Robbins. Microscopicexaminationofischemicintestinedemonstratesatrophy or sloughing of surface epithelium ( Fig.15.20A ).Bycontrast,cryptsmaybehyperproliferative.Inflammatoryinfiltratesareinitiallyabsentinacuteischemia,butneutrophilsarerecruitedwithinhoursofreperfusion.Chronicischemiaisaccompaniedbyfibrousscarringofthelaminapropria( Fig. 15.20B )and,uncommonly,strictureformation.Inacutephasesofischemicdamage,bacterialsuperinfectionandenterotoxinreleasemayinducepseudomembraneformationthatcanresembleClostridium difficile–associatedpseudomembranouscolitis(discussedlater).


Pathology_Robbins

Pathology_Robbins. Ischemic bowel disease tends to occur in older adults with coexisting cardiac or vascular disease. Acute transmural infarction typically manifests with sudden, severe abdominal pain and tenderness, sometimes accompanied by nausea, vomiting, bloody diarrhea, or grossly melanotic stool. This presentation may progress to shock and vascular collapse within hours as a result of blood loss. Peristaltic sounds diminish or disappear, and muscular spasm creates boardlike rigidity of the abdominal wall. Because these physical signs overlap with those of other abdominal emergencies, including acute appendicitis, perforated ulcer, and acute cholecystitis, the diagnosis of intestinal infarction may be delayed or missed, with disastrous consequences. As the mucosal barrier breaks down, bacteria enter the circulation and sepsis can develop; the mortality rate in these cases may exceed 50%. The overall progression of ischemic enteritis depends on the underlying cause and severity of injury:


Pathology_Robbins

Pathology_Robbins. The overall progression of ischemic enteritis depends on the underlying cause and severity of injury: Mucosal and mural infarctions by themselves may not be fatal. However, these may progress to more extensive, transmural infarction if the vascular supply is not restored by correction of the insult or, in chronic disease, by development of adequate collateral supplies. Chronic ischemia may masquerade as inflammatory bowel disease, with episodes of bloody diarrhea interspersed with periods of healing. Fig. 15.20 Ischemia.(A)Characteristicattenuatedandpartiallydetachedvillousepitheliuminacutejejunalischemia.Notethehyperchromaticnucleiofproliferatingcryptcells.(B)Chroniccolonicischemiawithatrophicsurfaceepitheliumandfibroticlaminapropria. Cytomegalovirus (CMV) infection causes ischemic gastrointestinal disease as a consequence of the viral tropism for and infection of endothelial cells. CMV infection can be a complication of immunosuppressive therapy (Chapter 9).


Pathology_Robbins

Pathology_Robbins. Radiation enterocolitis occurs when the gastrointestinal tract is irradiated. In addition to epithelial damage, radiation-induced vascular injury may be significant and produce changes that are similar to ischemic disease. Necrotizing enterocolitis is an idiopathic disorder of the small and large intestines that can result in transmural necrosis. It is the most common acquired gastrointestinal emergency of neonates, particularly those who are premature or of low birth weight. Its occurrence is often associated with initiation of oral feeding (Chapter 7). Although pathogenesis of necrotizing enterocolitis is not defined, ischemic injury is thought to contribute. Angiodysplasia, characterized by malformed submucosal and mucosal blood vessels, occurs most often in the cecum or right colon, and usually presents after the sixth decade of life. Although it affects less than 1% of the adult population, angiodysplasia accounts for 20% of major episodes of lower intestinal bleeding.


Pathology_Robbins

Pathology_Robbins. Hemorrhoids are dilated anal and perianal collateral vessels that connect the portal and caval venous systems to relieve elevated venous pressure within the hemorrhoid plexus. Thus, although hemorrhoids are less serious than esophageal varices, the pathogenesis of these lesions is similar. They are common, affecting about 5% of the general population. Common predisposing factors include constipation and associated straining, which increase intraabdominal and venous pressures, venous stasis of pregnancy, and portal hypertension.


Pathology_Robbins

Pathology_Robbins. Collateral vessels within the inferior hemorrhoidal plexus are located below the anorectal line and are termed external hemorrhoids, while those that result from dilation ofthesuperiorhemorrhoidalplexuswithinthedistalrectum are referred to as internal hemorrhoids. On histologic examination, hemorrhoids consist of thin-walled, dilated, submucosal vessels beneath anal or rectal mucosa. These vessels are subject to trauma, which leads to rectal bleeding. In addition, they can become thrombosed and inflamed. Hemorrhoids often manifest with pain and rectal bleeding, particularly bright red blood seen on toilet tissue. Hemorrhoids also may develop as a result of portal hypertension, where the implications are more ominous. Hemorrhoidal bleeding generally is not a medical emergency; treatment options include sclerotherapy, rubber band ligation, and infrared coagulation. In severe cases, hemorrhoids may be removed surgically by hemorrhoidectomy.


Pathology_Robbins

Pathology_Robbins. Intestinalischemiacanoccurasaresultofeitherarterial or venous obstruction. Ischemicboweldiseaseresultingfromhypoperfusionismostcommonatthesplenicflexure,sigmoidcolon,andrectum; http://ebooksmedicine.net thesearewatershed zones wheretwoarterialcirculationsterminate. Systemicvasculitidesandinfectiousdiseases(e.g.,CMVinfection)cancausevasculardiseasethatisnotconfinedtothegastrointestinaltract. Angiodysplasiaisacommoncauseoflowergastrointestinalbleedinginolderadults. Hemorrhoidsarecollateralvesselsthatforminresponsetovenoushypertension.


Pathology_Robbins

Pathology_Robbins. Angiodysplasiaisacommoncauseoflowergastrointestinalbleedinginolderadults. Hemorrhoidsarecollateralvesselsthatforminresponsetovenoushypertension. Diarrhea is defined as an increase in stool mass, frequency, or fluidity, typically to amounts greater than 200 grams per day. In severe cases, stool volume can exceed 14 L per day and, without fluid resuscitation, result in death. Worldwide, diarrheal diseases account for greater than 700,000 deaths of children under 5 years of age, making them the second leading cause of death in this age group. Painful, bloody, small-volume diarrhea is known as dysentery. Diarrhea is a common symptom of many intestinal diseases, including those due to infection, inflammation, ischemia, malabsorption, and nutritional deficiency. It can be classified into four major categories: Secretory diarrhea is characterized by isotonic stool and persists during fasting.


Pathology_Robbins

Pathology_Robbins. Secretory diarrhea is characterized by isotonic stool and persists during fasting. Osmotic diarrhea, such as that occurring with lactase deficiency, is due to osmotic forces exerted by unabsorbed luminal solutes. The diarrheal fluid is at least 50 mOsm more concentrated than plasma, and the condition abates with fasting. Malabsorptive diarrhea caused by inadequate nutrient absorption is associated with steatorrhea and is relieved by fasting. Exudative diarrhea is due to inflammatory disease and characterized by purulent, bloody stools that continue during fasting. Table 15.3 Defects in Malabsorptive and Diarrheal Disease We begin our discussion with malabsorptive diarrhea. Other disorders associated with secretory and exudative types of diarrhea (e.g., cholera and inflammatory bowel disease, respectively) are addressed in separate sections.


Pathology_Robbins

Pathology_Robbins. Malabsorption manifests most commonly as chronic diarrhea and is characterized by defective absorption of fats, fatand water-soluble vitamins, proteins, carbohydrates, electrolytes, minerals, and water. Chronic malabsorption causes weight loss, anorexia, abdominal distention, borborygmi, and muscle wasting. A hallmark of malabsorption is steatorrhea, characterized by excessive fecal fat and bulky, frothy, greasy, yellow, or clay-colored stools. The chronic malabsorptive disorders most commonly encountered in Western countries are pancreatic insufficiency, celiac disease, and Crohn disease. Environmental enteric dysfunction, or environmental enteropathy, which has a malabsorptive component, is pervasive in some communities within developing countries. Malabsorption results from disturbance in at least one of the four phases of nutrient absorption: Intraluminal digestion, in which proteins, carbohydrates, and fats are broken down into absorbable forms


Pathology_Robbins

Pathology_Robbins. Intraluminal digestion, in which proteins, carbohydrates, and fats are broken down into absorbable forms Terminal digestion, which involves the hydrolysis of carbohydrates and peptides by disaccharidases and peptidases, respectively, in the brush border of the small-intestinal mucosa Transepithelial transport, in which nutrients, fluid, and electrolytes are transported across and processed within the small-intestinal epithelium Lymphatic transport of absorbed lipids In many malabsorptive disorders, a defect in one of these processes predominates, but more than one usually contributes ( Table 15.3 ). As a result, malabsorption syndromes resemble each other more than they differ. Signs and symptoms include diarrhea (from nutrient Mycobacterialinfection,Whippledisease +,Indicatesthattheprocesscanbeabnormalinthediseaseindicated.Otherprocessesarenottypicallyaffected.


Pathology_Robbins

Pathology_Robbins. Mycobacterialinfection,Whippledisease +,Indicatesthattheprocesscanbeabnormalinthediseaseindicated.Otherprocessesarenottypicallyaffected. http://ebooksmedicine.net malabsorption and excessive intestinal secretion), flatus, abdominal pain, and weight loss. Inadequate absorption of vitamins and minerals can result in anemia and mucositis due to pyridoxine, folate, or vitamin B12 deficiency; bleeding due to vitamin K deficiency; osteopenia and tetany due to calcium, magnesium, or vitamin D deficiency; or neuropathy due to vitamin A or B12 deficiency. A variety of endocrine and skin disturbances may also occur. Mycobacterial infection, which can be lead to lymphatic transport defects, is discussed with infectious causes of diarrhea in the next section.


Pathology_Robbins

Pathology_Robbins. Cystic fibrosis is discussed in greater detail elsewhere (Chapter 7). Only the malabsorption associated with cystic fibrosis is considered here. Owing to mutations of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR), individuals with cystic fibrosis have defects in intestinal and pancreatic ductal ion transport. This abnormality interferes with bicarbonate, sodium, and water secretion, ultimately resulting in inadequate luminal hydration. The viscous luminal contents may result in meconium ileus, which is present in up to 10% of newborns with cystic fibrosis. In the pancreas the ducts are plugged by thick mucus. This leads to obstruction, low-grade chronic autodigestion of the pancreas, and eventual exocrine pancreatic insufficiency in more than 80% of patients. The result is failure of the intraluminal phase of nutrient absorption, which can be effectively treated in most patients with oral enzyme supplementation.


Pathology_Robbins

Pathology_Robbins. Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, is an immune-mediated enteropathy triggered by the ingestion of gluten-containing cereals, such as wheat, rye, or barley, in genetically predisposed individuals. In countries whose populations consist predominantly of whites of European ancestry, celiac disease is a common disorder, with an estimated prevalence of 0.5% to 1%. The primary treatment for celiac disease is a gluten-free diet, which results in symptomatic improvement for most patients.


Pathology_Robbins

Pathology_Robbins. Celiac disease is an intestinal immune reaction to gluten, the major storage protein of wheat and similar grains. Gluten is digested by luminal and brush border enzymes into amino acids and peptides, including a 33–amino acid gliadin peptide that is resistant to degradation by gastric, pancreatic, and small-intestinal proteases (Fig. 15.21 ). Gliadin is deamidated by tissue transglutaminase and is then able to interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells and be presented to CD4+ T cells. These T cells in lamina propria produce cytokines that likely contribute to the tissue damage and characteristic mucosal histopathology. An antibody response follows: This includes production of antibodies against tissue transglutaminase, deamidated gliadin, and, perhaps as a result of cross-reactive epitopes, anti-endomysial antibodies, which can be diagnostically useful. They may also be used to monitor disease, as titers typically fall after 3 to 6 months of gluten-free diet.


Pathology_Robbins

Pathology_Robbins. of cross-reactive epitopes, anti-endomysial antibodies, which can be diagnostically useful. They may also be used to monitor disease, as titers typically fall after 3 to 6 months of gluten-free diet. However, whether these antibodies contribute to celiac disease pathogenesis or are merely markers of immune activation remains controversial. In addition to CD4+ cells, there is an accumulation of CD8+ cells that are not specific for gliadin but may play an ancillary role in causing tissue damage. It is thought that deamidated gliadin peptides induce epithelial cells to produce the cytokine IL-15, which in turn triggers activation and proliferation of CD8+ intraepithelial lymphocytes that become cytotoxic and kill


Pathology_Robbins

Pathology_Robbins. Loss of Fig. 15.21 The morphologic alterations that may be present in celiac disease, including varying degrees of villous atrophy, increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferation with crypt elongation (left). A model for the pathogenesis of celiac disease (right). Note that both innate and adaptive immune mechanisms are involved in the tissue responses to gliadin. CD4 T cells (producing IFNγ) are shown in lamina propria and CD8 T cells, expressing NKG2D receptor, in between epithelial cells. enterocytes that have been induced by various stressors to express surface MIC-A. This molecule is recognized by the NKG2D receptor on activated CD8+ T cells. The damage caused by these immune mechanisms may increase the movement of gliadin peptides across the epithelium, which are then deamidated by tissue transglutaminase, thus perpetuating the cycle of disease.


Pathology_Robbins

Pathology_Robbins. While nearly all individuals eat grain and are exposed to gluten and gliadin, most do not develop celiac disease. Thus, host factors determine whether disease develops. Among these, HLA proteins seem to be critical, since almost all individuals with celiac disease carry the class II HLA-DQ2 or HLA-DQ8 alleles. There is also an association of celiac disease with other immune diseases including type 1 diabetes, thyroiditis, and Sjögren syndrome. MORPHOLOGYBiopsyspecimensfromthesecondportionoftheduodenumorproximaljejunum,whichareexposedtothehighestconcentrationsofdietarygluten,aregenerallydiagnosticinceliacdisease.ThehistopathologyischaracterizedbyincreasednumbersofTlymphocytes,withintraepithelial lymphocytosis, crypt hyperplasia,andvillous atrophy (


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Pediatric celiac disease, which affects male and female children equally, may manifest with classic symptoms, typically between 6 and 24 months of age (after introduction of gluten to the diet) with irritability, abdominal distention, anorexia, diarrhea, failure to thrive, weight loss, or muscle wasting. Children with nonclassic symptoms tend to present at older ages with complaints of abdominal pain, nausea, vomiting, bloating, or constipation. A characteristic pruritic, blistering skin lesion, dermatitis herpetiformis, is also present in as many as 10% of patients, and the incidence of lymphocytic gastritis and lymphocytic colitis is increased as well.


Pathology_Robbins

Pathology_Robbins. In adults, celiac disease manifests most commonly between 30 and 60 years of age. However, many cases escape clinical attention for extended periods because of atypical presentations. Some patients have silent celiac disease, defined as positive serology and villous atrophy without symptoms, or latent celiac disease, in which positive serology is accompanied neither by villous atrophy nor symptoms. Symptomatic adult celiac disease is often associated with anemia (due to iron deficiency and, less commonly, B12 and folate deficiency), diarrhea, bloating, and fatigue. Fig. 15.22 Celiacdisease.(A)Advancedcasesofceliacdiseaseshowcom-pletelossofvilli,ortotalvillousatrophy.Notethedenseplasmacellinfil-tratesinthelaminapropria.(B)InfiltrationofthesurfaceepitheliumbyTlymphocytes,whichcanberecognizedbytheirdenselystainednuclei(labeledT).Comparewithelongated,pale-stainingepithelialnuclei(labeledE).


Pathology_Robbins

Pathology_Robbins. Noninvasive serologic tests are generally performed before biopsy. The most sensitive tests are the presence of IgA antibodies to tissue transglutaminase or IgA or IgG antibodies to deamidated gliadin. Anti-endomysial antibodies are highly specific but less sensitive than other antibodies.


Pathology_Robbins

Pathology_Robbins. Patients with celiac disease exhibit a higher than normal rate of malignancy. The most common celiac disease– associated cancer is enteropathy-associated T cell lymphoma, an aggressive tumor of intraepithelial T lymphocytes. Small-intestinal adenocarcinoma also is more frequent in individuals with celiac disease. Thus, when symptoms such as abdominal pain, diarrhea, and weight loss develop despite a strict gluten-free diet, cancer or refractory sprue, in which the response to a gluten-free diet is lost, must be considered. It is, however, important to recognize that failure to adhere to a gluten-free diet is the most common cause of recurrent symptoms, and that most individuals with celiac disease do well with dietary restrictions and die of unrelated causes.


Pathology_Robbins

Pathology_Robbins. The term environmental enteric dysfunction, or environmental enteropathy, refers to a syndrome of stunted growth and impaired intestinal function that is common in developing countries, including many parts of sub-Saharan Africa, such as Zambia; aboriginal populations within northern Australia; and some groups within South America and Asia, such as residents of impoverished communities within Brazil, Guatemala, India, and Pakistan. The impact of environmental enteric dysfunction, which was previously grouped under headings of tropical enteropathy or tropical sprue, cannot be overstated, as it is estimated to affect over 150 million children worldwide. Although malnutrition most likely contributes to the pathogenesis of this disorder, neither supplementary feeding nor vitamin and mineral supplementation are able to fully reverse the syndrome. Repeated bouts of diarrhea suffered within the first 2 or 3 years of life are most closely linked to environmental enteropathy, but no single


Pathology_Robbins

Pathology_Robbins. supplementation are able to fully reverse the syndrome. Repeated bouts of diarrhea suffered within the first 2 or 3 years of life are most closely linked to environmental enteropathy, but no single infectious agent has been established as causal in these diarrheal episodes. Intestinal biopsy specimens have been examined in only a small number of cases, and the reported histopathology has some overlap with severe celiac disease as well as infectious enteritis.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Lactase deficiency gives rise to osmotic diarrhea because, in its absence, osmotically active lactose remains in the lumen. The disaccharidases, including lactase, are located in the apical brush border membrane of villous absorptive epithelial cells. Because the defect is biochemical, biopsies are generally unremarkable. Lactase deficiency is of two types: Congenital lactase deficiency is an autosomal recessive disorder caused by mutations in the gene encoding lactase. The disease is rare and manifests as explosive diarrhea with watery, frothy stools and abdominal distention after milk ingestion. Symptoms abate when exposure to milk and milk products is terminated.


Pathology_Robbins

Pathology_Robbins. Acquired lactase deficiency is caused by downregulation of lactase gene expression and is particularly common among Native Americans, African Americans, and Chinese populations. Downregulation of lactase occurs in the gut after childhood, perhaps reflecting the fact that, before farming of dairy animals, lactase was unnecessary after children stopped drinking mother’s milk. Onset of acquired lactase deficiency is sometimes associated with enteric viral or bacterial infections.


Pathology_Robbins

Pathology_Robbins. Abetalipoproteinemia is an autosomal recessive disease characterized by an inability to secrete triglyceride-rich lipoproteins. Although rare, it is an example of a trans-epithelial transport defect leading to malabsorption. Mutation in the microsomal triglyceride transfer protein renders enterocytes unable to export lipoproteins and free fatty acids. As a result, monoglycerides and triglycerides accumulate within the epithelial cells. Abetalipoproteinemia manifests in infancy, and the clinical picture is dominated by failure to thrive, diarrhea, and steatorrhea. Failure to absorb essential fatty acids leads to deficiencies of fat-soluble vitamins, and lipid defects in plasma membranes often produce acanthocytic red blood cells (spur cells) in peripheral blood smears.


Pathology_Robbins

Pathology_Robbins. Microscopic colitis encompasses two entities, collagenous colitis and lymphocytic colitis. Both of these idiopathic diseases manifest with chronic, nonbloody, watery diarrhea without weight loss. Findings on radiologic and endoscopic studies typically are normal. Collagenous colitis, which occurs primarily in middle-aged and older women, is characterized by the presence of a dense subepithelial collagen layer, increased numbers of intraepithelial lymphocytes, and a mixed inflammatory infiltrate within the lamina propria. Lymphocytic colitis is histologically similar, but the subepithelial collagen layer is of normal thickness and the increase in intraepithelial, predominantly T lymphocytes, may be greater. Lymphocytic colitis is associated with celiac disease and autoimmune diseases, including thyroiditis, arthritis, and autoimmune or lymphocytic gastritis.


Pathology_Robbins

Pathology_Robbins. Graft-versus-host disease occurs after allogeneic hematopoietic stem cell transplantation. The small bowel and colon are involved in most cases. Although graft-versus-host disease is caused by donor T cell–mediated damage to the recipient’s epithelial cells, the lymphocytic infiltrate in the lamina propria is typically sparse, suggesting that cytokines secreted by T cells may be the major mediators of tissue injury. Epithelial apoptosis, particularly of crypt cells, is the most common histologic finding. Intestinal graft-versushost disease often manifests as watery diarrhea. Diarrheacanbecharacterizedassecretory, osmotic, malabsorptive, orexudative. Themalabsorptionassociatedwithcysticfibrosisistheresultofpancreatic insufficiency (i.e.,inadequatepancreaticdigestiveenzymes)anddeficient luminal breakdown ofnutrients.


Pathology_Robbins

Pathology_Robbins. Themalabsorptionassociatedwithcysticfibrosisistheresultofpancreatic insufficiency (i.e.,inadequatepancreaticdigestiveenzymes)anddeficient luminal breakdown ofnutrients. Celiac disease isanimmune-mediatedenteropathytriggeredbytheingestionofgluten-containinggrains.Themalabsorptivediarrheainceliacdiseaseisduetoloss of brush border surface area and,possibly,deficiententerocytematuration. Lactase deficiency causesanosmotic diarrhea owingtotheinabilitytobreakdownorabsorblactose. Abetalipoproteinemia ischaracterizedbyaninabilitytosecretetriglyceride-richlipoproteinsduetoaninheritedtransepithelialtransportdefect. Thetwoformsofmicroscopiccolitis,collagenous colitis andlymphocytic colitis, bothcausechronicwaterydiarrhea.Theintestinesaregrosslynormal,andthediseasesareidentifiedbytheirhistologicfeatures.


Pathology_Robbins

Pathology_Robbins. Thetwoformsofmicroscopiccolitis,collagenous colitis andlymphocytic colitis, bothcausechronicwaterydiarrhea.Theintestinesaregrosslynormal,andthediseasesareidentifiedbytheirhistologicfeatures. This global problem is responsible for more than 1 million deaths annually and greater than 10% of all deaths in patients younger than 5 years of age worldwide. Enterocolitis presents with a broad range of signs and symptoms, including diarrhea, abdominal pain, urgency, perianal discomfort, incontinence, and hemorrhage. Bacterial infections, such as enterotoxigenic Escherichia coli, are frequently responsible, but the most common pathogens vary with age, nutrition, and host immune status, as well as environment (


Pathology_Robbins

Pathology_Robbins. Table 15.4 ). For example, epidemics of cholera are common in areas with poor sanitation, as a result of inadequate public health measures, or as a consequence of natural disaster (e.g., the Haitian earthquake of 2010) or war. Pediatric infectious diarrhea, which may result in severe dehydration and metabolic acidosis, is commonly caused by enteric viruses. A summary of the epidemiology and clinical features of selected causes of bacterial enterocolitis is presented in Table 15.4. Representative bacterial, viral, and parasitic enterocolitides are discussed next. Vibrio cholerae organisms are comma-shaped, gram-negative bacteria that cause cholera, a disease that has http://ebooksmedicine.net Table 15.4 Features of Bacterial Enterocolitides CholeraIndia,AfricaShellfishFecal-oral,waterSporadic,endemic,SmallintestineSeverewateryDehydration,electrolyteepidemic


Pathology_Robbins

Pathology_Robbins. Table 15.4 Features of Bacterial Enterocolitides CholeraIndia,AfricaShellfishFecal-oral,waterSporadic,endemic,SmallintestineSeverewateryDehydration,electrolyteepidemic Campylobacter spp.DevelopedcountriesChickens,sheep,pigs,Poultry,milk,Sporadic;children,ColonWateryorbloodyArthritis,Guillain-Barrécattleotherfoodstravelers ShigellosisWorldwide,endemicHumansFecal-oral,food,Children,migrantLeftcolon,BloodydiarrheaReactivearthritis,urethritis,indeveloping waterworkers,travelers,ileum conjunctivitis,hemolytic-countries http://ebooksmedicine.net SalmonellosisWorldwidePoultry,farmanimals,Meat,poultry,eggs,Children,olderadultsColon,smallWateryorbloodySepsis,abscessreptilesmilk Enteric(typhoid)feverIndia,Mexico,HumansFecal-oral,waterChildren.adolescents,SmallintestineBloodydiarrhea,Chronicinfection,carrierstate,Philippines feverencephalopathy,myocarditis,intestinalperforation


Pathology_Robbins

Pathology_Robbins. PseudomembranousWorldwideHumans,hospitalsAntibioticsallowImmunosuppressed,ColonWaterydiarrhea,Relapse,toxicmegacoloncolitis(C. difficile) WhipplediseaseRural> urbanUnknownUnknownRareSmallintestineMalabsorptionArthritis,CNSdisease MycobacterialinfectionWorldwideUnknownUnknownImmunosuppressed,SmallintestineMalabsorptionPneumonia,infectionatotherendemic CNS, Centralnervoussystem;GI, gastrointestinal. been endemic in the Ganges Valley of India and Bangladesh for all of recorded history. V. cholerae is transmitted primarily by contaminated drinking water. However, it can also be present in food and causes rare cases of seafood-associated disease. There is a marked seasonal variation in most locales due to rapid growth of Vibrio bacteria at warm temperatures. The only animal reservoirs are shellfish and plankton.


Pathology_Robbins

Pathology_Robbins. Vibrio organisms are noninvasive but cause disease by producing a toxin that interferes with the absorptive function of enterocytes. Flagellar proteins, which are involved in motility and attachment, are necessary for efficient bacterial colonization, and a secreted metalloproteinase that also has hemagglutinin activity is important for bacterial detachment and shedding in the stool. However, it is the preformed enterotoxin, cholera toxin, which causes disease. The toxin, which is composed of five B subunits that direct endocytosis and a single active A subunit, is delivered to the endoplasmic reticulum by retrograde transport. A fragment of the A subunit is transported from the endoplasmic reticulum lumen into the cytosol, where it interacts with cytosolic ADP ribosylation factors to ribosylate and activate the G protein Gsα. This stimulates adenylate cyclase, and the resulting increases in intracellular cyclic adenosine monophosphate (cAMP) open the cystic fibrosis transmembrane


Pathology_Robbins

Pathology_Robbins. ribosylate and activate the G protein Gsα. This stimulates adenylate cyclase, and the resulting increases in intracellular cyclic adenosine monophosphate (cAMP) open the cystic fibrosis transmembrane conductance regulator (CFTR), which releases chloride ions into the lumen. This creates an osmotic gradient that draws water into the lumen, leading to massive secretory diarrhea. Remarkably, mucosal biopsy specimens show only minimal morphologic alterations.


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Pathology_Robbins. Most exposed individuals are asymptomatic or suffer only mild diarrhea. Those with severe disease have an abrupt onset of watery diarrhea and vomiting after an incubation period of 1 to 5 days. The volume of diarrhea may reach 1 L per hour, leading to dehydration, hypotension, electrolyte imbalances, muscular cramping, anuria, shock, loss of consciousness, and death. Most deaths occur within the first 24 hours of presentation. Although the mortality rate for severe cholera is 50% to 70% without treatment, fluid replacement can save more than 99% of patients. Campylobacter jejuni is the most common bacterial enteric pathogen in developed countries and is an important cause of traveler’s diarrhea. Most infections are associated with ingestion of improperly cooked chicken, but outbreaks also can be caused by unpasteurized milk or contaminated water.


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Pathology_Robbins. The pathogenesis of Campylobacter infection remains poorly defined, but four major virulence properties contribute: motility, adherence, toxin production, and invasion. Flagella allow Campylobacter to be motile. This facilitates adherence and colonization, which are also necessary for mucosal invasion. Cytotoxins that cause epithelial damage and a cholera toxin–like enterotoxin are also released by some C. jejuni isolates. Dysentery or bloody diarrhea, is generally associated with invasion and only occurs with a small minority of Campylobacter strains. Enteric fever occurs when bacteria proliferate within the lamina propria and mesenteric lymph nodes.


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Pathology_Robbins. Campylobacter infection can result in reactive arthritis, primarily in patients with HLA-B27. Other extraintestinal complications, including erythema nodosum and Guillain-Barré syndrome (Chapter 22), a flaccid paralysis caused by autoimmune-induced inflammation of peripheral nerves, are not HLA-linked. Fortunately, Guillain-Barré syndrome develops in 0.1% or less of individuals infected with Campylobacter. MORPHOLOGYCampylobacter, Shigella, Salmonella, andmanyotherbacterialinfections,includingYersinia andE. coli, allinduceasimilarmicroscopicpicture,termedacute self-limited colitis. Specificdiagnosisisprimarilybystoolculture.Thehistologyofacuteself-limitedcolitisincludesprominentlaminapropriaandintraepithelialneutrophilinfiltrates(


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Pathology_Robbins. Fig.15.23A );cryptitis (neutrophilinfiltrationofthecrypts)andcrypt abscesses (cryptswithaccumulationsofluminalneutrophils)alsomaybepresent.Thepreservationofcryptarchitectureinmostcasesofacuteself-limitedcolitisishelpfulindistinguishingtheseinfectionsfromchronicinflammatoryillnessessuchasinflammatoryboweldisease( Fig.15.23B Ingestion of as few as 500 C. jejuni organisms can cause disease after an incubation period of up to 8 days. Watery diarrhea, either acute or with onset after an influenza like prodrome, is the primary manifestation, and dysentery develops in 15% to 50% of patients. Patients may shed bacteria for 1 month or more after clinical resolution. The disease is self-limited, and antibiotic therapy generally is not required.


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Pathology_Robbins. Fig. 15.23 Bacterialenterocolitis.(A)Campylobacter jejuni infectionpro-ducesacute,self-limitedcolitis.Neutrophilscanbeseenwithinsurfaceandcryptepithelium,andacryptabscessispresent(lower right). (B)Enteroinva-siveEscherichia coli infectionissimilartootheracute,self-limitedcolitides.Notethemaintenanceofnormalcryptarchitectureandspacing,despiteabundantintraepithelialneutrophils. http://ebooksmedicine.net Shigella are gram-negative bacilli that are unencapsulated, nonmotile, facultative anaerobes responsible for one of the most common causes of bloody diarrhea. Shigellae are highly transmissible by the fecal-oral route or through ingestion of contaminated water and food; the infective dose is fewer than 100 organisms, and each gram of stool contains as many as 109 organisms during acute phases of the disease.


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Pathology_Robbins. In the United States and Europe, children in day care centers, migrant workers, travelers to developing countries, and residents of nursing homes are most commonly affected. Most Shigella-associated infections and deaths occur in children younger than 5 years of age; in countries in which Shigella is endemic, it is responsible for approximately 10% of all cases of pediatric diarrheal disease and as many as 75% of diarrheal deaths.


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Pathology_Robbins. Shigella organisms are resistant to the harsh acidic environment of the stomach, which partially explains the very low infective dose. Once in the intestine, organisms are taken up by M (microfold) epithelial cells, which are specialized for sampling and uptake of luminal antigens. After intracellular proliferation, the bacteria escape into the lamina propria. These bacteria then infect small-intestinal and colonic epithelial cells through the basolateral membranes, which express bacterial receptors. Alternatively, luminal shigellae can directly modulate epithelial tight junctions to expose basolateral bacterial receptors. The latter is partly mediated by virulence proteins, some of which are directly injected into the host cytoplasm by a type III secretion system. Some Shigella dysenteriae serotypes also release the Shiga toxin Stx, which inhibits eukaryotic protein synthesis and causes host cell death.


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Pathology_Robbins. MORPHOLOGYShigella infections are most prominent in the left colon, but the ileum may also be involved, perhapsreflectingtheabundanceofMcellsintheepitheliumoverlyingPeyerpatches.Thehistologicappearanceinearlycasesissimilartothatinotheracuteself-limitedcolitides.Inmoreseverecases,themucosaishemorrhagicandulcerated,andpseudomembranesmaybepresent.PerhapsbecauseofthetropismforMcells,aphthousappearingulcerssimilartothoseseeninCrohndiseasealsomayoccur.Thepotentialforconfusionwithchronicinflammatoryboweldiseaseissubstantial,particularlyifthereisdistortionofcryptarchitecture. Shigella causes self-limited disease characterized by about 6 days of diarrhea, fever, and abdominal pain.


Pathology_Robbins

Pathology_Robbins. Shigella causes self-limited disease characterized by about 6 days of diarrhea, fever, and abdominal pain. After an incubation period of 1 to 7 days, the initial watery diarrhea progresses to a dysenteric phase in approximately 50% of patients, and constitutional symptoms can persist for as long as 1 month. A subacute presentation also can develop in a minority of adults. Antibiotic treatment shortens the clinical course and reduces the duration over which organisms are shed in the stool, but anti-diarrheal medications are contraindicated because they can prolong symptoms by delaying bacterial clearance.


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Pathology_Robbins. Complications of Shigella infection are uncommon and include reactive arthritis, a triad of sterile arthritis, urethritis, and conjunctivitis that preferentially affects HLA-B27– positive men between 20 and 40 years of age. Hemolytic uremic syndrome, which typically is associated with enterohemorrhagic Escherichia coli (EHEC), also may occur after infection with shigellae that secrete Shiga toxin. Escherichia coli are gram-negative bacilli that colonize the healthy gastrointestinal tract; most are nonpathogenic, but a subset cause human disease. The latter are classified according to morphology, mechanism of pathogenesis, and in vitro behavior (see Table 15.4 ). Here we summarize their pathogenic mechanisms:


Pathology_Robbins

Pathology_Robbins. Table 15.4 ). Here we summarize their pathogenic mechanisms: Enterotoxigenic E. coli (ETEC) organisms are the principal cause of traveler’s diarrhea, and are spread by the fecal-oral route. They express a heat-labile toxin (LT) that is similar to cholera toxin and a heat-stable toxin (ST) that increases intracellular cGMP with effects similar to the cAMP elevations caused by LT.


Pathology_Robbins

Pathology_Robbins. Enteropathogenic E. coli (EPEC) organisms are characterized by their ability to produce attaching and effacing (A/E) lesions in which bacteria attach tightly to the enterocyte apical membranes and cause local loss (i.e., effacement) of the microvilli. The proteins necessary for creating A/E lesions are all encoded by a large genomic pathogenicity island, the locus of enterocyte effacement (LEE). This locus also encodes a type III secretion system, similar to that in Shigella, that injects bacterial effector proteins into the epithelial cell cytoplasm. EPEC can cause endemic diarrhea as well as diarrheal outbreaks particularly in children younger than 2 years of age.


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Pathology_Robbins. Enterohemorrhagic E. coli (EHEC) organisms are categorized as O157:H7 and non-O157:H7 serotypes. Outbreaks of E. coli O157:H7 in developed countries have been associated with the consumption of inadequately cooked ground beef, milk, and vegetables. Both O157:H7 and non-O157:H7 serotypes produce Shiga-like toxins and can cause dysentery. They can also trigger hemolytic-uremic syndrome (Chapter 14). Enteroinvasive E. coli (EIEC) organisms resemble Shigella bacteriologically but do not produce toxins. They invade the gut epithelial cells and produce a bloody diarrhea. Enteroaggregative E. coli (EAEC) organisms attach to enterocytes by adherence fimbriae. Although they produce LT and Shiga-like toxins, histologic damage is minimal.


Pathology_Robbins

Pathology_Robbins. Enteroaggregative E. coli (EAEC) organisms attach to enterocytes by adherence fimbriae. Although they produce LT and Shiga-like toxins, histologic damage is minimal. Salmonella species, which are members of the Enterobacteriaceae family of gram-negative bacilli, are divided into Salmonella typhi, the causative agent of typhoid fever and nontyphoid Salmonella strains that cause gastroenteritis. Nontyphoid Salmonella infection usually is due to Salmonella enteritidis; more than 1 million cases occur each year in the United States, which result in 2000 deaths; the http://ebooksmedicine.net prevalence is greater in many other countries. Infection is most common in young children and older adults, with a peak incidence in summer and fall. Transmission usually is through contaminated food, particularly raw or undercooked meat, poultry, eggs, and milk.


Pathology_Robbins

Pathology_Robbins. Very few viable Salmonella organisms are necessary to cause infection, and the absence of gastric acid, as in individuals with atrophic gastritis or those on acid-suppressive therapy, further reduces the required inoculum. Salmonellae possess virulence genes that encode a type III secretion system capable of transferring bacterial proteins into M cells and enterocytes. The transferred proteins activate host cell Rho GTPases, thereby triggering actin rearrangement and bacterial uptake into phagosomes where the bacteria can grow. Salmonellae also secrete a molecule that induces epithelial release of a chemoattractant eicosanoid that draws neutrophils into the lumen and potentiates mucosal damage. Stool cultures are essential for diagnosis.


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Pathology_Robbins. Typhoid fever, also referred to as enteric fever, is caused by Salmonella typhi and Salmonella paratyphi. It affects up to 30 million individuals worldwide each year. Infection by S. typhi is more common in endemic areas, where children and adolescents are most often affected. By contrast, S. paratyphi predominates in travelers and those living in developed countries. Humans are the sole reservoir for S. typhi and S. paratyphi, and transmission occurs from person to person or via contaminated food or water. Gallbladder colonization may be associated with gallstones and a chronic carrier state. Acute infection is associated with anorexia, abdominal pain, bloating, nausea, vomiting, and bloody diarrhea followed by a short asymptomatic phase that gives way to bacteremia and fever with flulike symptoms. It is during this phase that detection of organisms by blood culture may prompt antibiotic treatment and prevent further disease progression. Cultures are positive in 90% of cases during


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Pathology_Robbins. symptoms. It is during this phase that detection of organisms by blood culture may prompt antibiotic treatment and prevent further disease progression. Cultures are positive in 90% of cases during the febrile phase Without such treatment, the febrile phase is followed by up to 2 weeks of sustained high fevers with abdominal tenderness that may mimic appendicitis. Rose spots, small erythematous maculopapular lesions, are seen on the chest and abdomen. Systemic dissemination may cause extraintestinal complications including encephalopathy, meningitis, seizures, endocarditis, myocarditis, pneumonia, and cholecystitis. Patients with sickle cell disease are particularly susceptible to Salmonella osteomyelitis.


Pathology_Robbins

Pathology_Robbins. Like S. enteritidis, S. typhi and S. paratyphi are taken up by M cells and then engulfed by mononuclear cells in the underlying lymphoid tissue. Thus, infection causes Peyer patches in the terminal ileum to enlarge into plateau like elevations up to 8 cm in diameter. Mucosal shedding creates oval ulcers oriented along the long axis of the ileum. However, unlike S. enteritidis, S. typhi and S. paratyphi can disseminate via lymphatic and blood vessels. This causes reactive hyperplasia of draining lymph nodes, in which bacteria-containing phagocytes accumulate. In addition, the spleen is enlarged and soft with pale red pulp, obliterated follicular markings, and prominent phagocyte hyperplasia. Randomly scattered small foci of parenchymal necrosis with macrophage aggregates, termed typhoid nodules, can be found in the liver, bone marrow, and lymph nodes. Definitive diagnosis depends on positive blood cultures. Serologic tests are of limited utility, especially in endemic areas unless


Pathology_Robbins

Pathology_Robbins. nodules, can be found in the liver, bone marrow, and lymph nodes. Definitive diagnosis depends on positive blood cultures. Serologic tests are of limited utility, especially in endemic areas unless rising titers of antibodies can be demonstrated.


Pathology_Robbins

Pathology_Robbins. Pseudomembranous colitis, generally caused by C. difficile, also is referred to as antibiotic-associated colitis or antibiotic-associated diarrhea. While antibiotic-associated diarrhea also may be caused by other organisms such as Salmonella, C. perfringens type A, or Staphylococcus aureus, only C. difficile causes pseudomembranous colitis. It is likely that disruption of the normal colonic microbiota by antibiotics allows C. difficile overgrowth. Almost any antibiotic may be responsible; the most important determinants of the disease are frequency of use and the effect on colonic microbiota. Toxins released by C. difficile cause the ribosylation of small GTPases, such as Rho, and lead to disruption of the epithelial cytoskeleton, tight junction barrier loss, cytokine release, and apoptosis. MORPHOLOGYFullydevelopedC. difficile–associatedcolitisisaccompaniedbyformationofpseudomembranes (


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. In addition to antibiotic exposure, risk factors for C. difficile– associated colitis include advanced age, hospitalization, and immunosuppression. The organism is particularly prevalent in hospitals; as many as 20% of hospitalized adults are colonized with C. difficile (a rate 10 times higher than in the general population), but most colonized patients are free of disease. Individuals with C. difficile–associated colitis usually present with watery diarrhea and abdominal cramping; dehydration, fever, and leukocytosis may be seen in more severe cases. Fecal leukocytes and occult blood may be present, but grossly bloody diarrhea is rare. Diagnosis of C. difficile–associated colitis usually is accomplished by detection of C. difficile toxin, rather than culture, and is supported by the characteristic histopathologic findings. Regimens of metronidazole or vancomycin are generally effective treatments, but antibiotic-resistant and hypervirulent C. difficile strains are increasingly


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Pathology_Robbins. characteristic histopathologic findings. Regimens of metronidazole or vancomycin are generally effective treatments, but antibiotic-resistant and hypervirulent C. difficile strains are increasingly common, and the infection may recur in at-risk patients. Recent reports suggest that, particularly in patients with recurrent disease, fecal microbial transplantation may restore a normal microbiota and lead to lasting cure.


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Pathology_Robbins. Fig. 15.24 Clostridium difficile colitis.(A)Thecoloniscoatedbytanpseu-domembranescomposedofneutrophils,deadepithelialcells,andinflamma-torydebris(endoscopicview).(B)Typicalpatternofneutrophilsemanatingfromacryptisreminiscentofavolcaniceruption. http://ebooksmedicine.net Mycobacterial species, including M. tuberculosis, M. bovis, and M. avium species can involve the gastrointestinal tract primarily or be part of disseminated infection. Gastrointestinal tuberculosis is uncommon in Western countries, except in immunosuppressed individuals. In such cases, M. avium infection is most common. In endemic areas, including India and Pakistan, intestinal M. tuberculosis generally presents in the third and fourth decades of life and typically afflicts those of lower socioeconomic status. In such settings, primary intestinal infection is more common than disseminated disease. As the incidence of Crohn disease increases in these areas, differentiation between


Pathology_Robbins

Pathology_Robbins. M. tuberculosis and Crohn disease has become more difficult. M. avium tends to accumulate within the cytoplasm and distend lamina propria histiocytes. In some cases, this may result in a sheet-like expansion of histiocytes that fill the lamina propria and, in the small intestine, compress lympatic vessels leading to malabsorption. These cases can mimic Whipple disease clinically and morphologically. However, M. avium is positive by acid fast stain, while Tropheryma whippelii is not; both organisms are labelled by the periodic acid-Schiff (PAS) stain.


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Pathology_Robbins. M. tuberculosis can present with granulomatous disease. In contrast to Crohn disease, these granulomas, which are generally multiple, often have caseous necrosis, but this can be difficult to determine on biopsies. Because the granulomas can be present in all layers of the bowel wall, trans-mural disease with fibrosis, perforation, and stenoses, or strictures, can be present. Patients may also have peritoneal dissemination with ascites.


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Pathology_Robbins. Norovirus, previously known as Norwalk-like virus, causes approximately half of all gastroenteritis outbreaks worldwide and is a common cause of sporadic gastroenteritis in developed countries. Local outbreaks are usually related to contaminated food or water, but person-toperson transmission underlies most sporadic cases. Infections spread easily within schools, hospitals, nursing homes and, on other densely populated communities including cruise ships. After a short incubation period, affected individuals develop nausea, vomiting, watery diarrhea, and abdominal pain. Biopsy morphology is nonspecific. The disease is self-limited.


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Pathology_Robbins. The encapsulated rotavirus infects 140 million individuals and causes 1 million deaths each year, making rota-virus the most common cause of severe childhood diarrhea and diarrhea-related deaths worldwide. Children between 6 and 24 months of age are most vulnerable. Protection in the first 6 months of life is probably due to the presence of antibodies to rotavirus in breast milk, while protection beyond 2 years of age is due to immunity that develops after the first infection. Outbreaks in hospitals and day care centers are common, and infection spreads easily; the estimated minimal infective inoculum is only 10 viral particles. Rotavirus selectively infects and destroys mature (absorptive) enterocytes in the small intestine, and the villus surface is repopulated by immature secretory cells. This change in functional capacity results in loss of absorptive function and net secretion of water and electrolytes, compounded by an osmotic diarrhea from incompletely absorbed nutrients. Like


Pathology_Robbins

Pathology_Robbins. This change in functional capacity results in loss of absorptive function and net secretion of water and electrolytes, compounded by an osmotic diarrhea from incompletely absorbed nutrients. Like norovirus, rotavirus infection becomes symptomatic after a short incubation period and manifests as several days of vomiting and watery diarrhea. Vaccines are now available, and their use is beginning to change the epidemiology of rotavirus infection. Unfortunately, oral rotavirus vaccines have been less effective in developing countries where they are most needed.


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Pathology_Robbins. Parasitic disease and protozoal infections affect over half of the world’s population on a chronic or recurrent basis. The small intestine can harbor as many as 20 species of parasites, including nematodes, such as the roundworms Ascaris and Strongyloides; hookworms and pinworms; cestodes, including flatworms and tapeworms; trematodes (flukes); and protozoa. Ascaris lumbricoides. This nematode infects more than 1 billion individuals worldwide as a result of human fecal-oral contamination. Ingested eggs hatch in the intestine, and larvae penetrate the intestinal mucosa. From there, the larvae migrate via the splanchnic circulation to the liver, creating hepatic abscesses, and then through the systemic circulation to the lung, where they can cause Ascaris pneumonitis. In the latter case, larvae migrate up the trachea, are swallowed, and arrive again in the intestine to mature into adult worms. Diagnosis is made by detection of eggs in the stools.


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Pathology_Robbins. Strongyloides. The larvae of Strongyloides live in fecally contaminated ground soil and can penetrate unbroken skin. They migrate through the lungs to the trachea from where they are swallowed and then mature into adult worms in the intestines. Unlike other intestinal worms, which require an ovum or larval stage outside the human, the eggs of Strongyloides can hatch within the intestine and release larvae that penetrate the mucosa, creating a vicious cycle referred to as autoinfection. Hence, Strongyloides infection can persist for life, http://ebooksmedicine.net and immunosuppressed individuals can develop overwhelming infections.


Pathology_Robbins

Pathology_Robbins. Necator americanus and Ancylostoma duodenale. These hookworms infect 1 billion individuals worldwide and cause significant morbidity. Infection is initiated by larval penetration through the skin. After further development in the lungs, the larvae migrate up the trachea and are swallowed. Once in the duodenum, the larvae mature and the adult worms attach to the mucosa, suck blood, and reproduce. Hookworms are a leading cause of iron-deficiency anemia in the developing world. Detection of eggs in the stools is used for diagnosis.


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Pathology_Robbins. Giardia lamblia. This flagellated protozoan, also referred to as Giardia duodenalis or Giardia intestinalis, is the most common pathogenic parasite in humans and is spread by fecally contaminated water or food. Infection may occur after ingestion of as few as 10 cysts and is characterized by acute or chronic malabsorptive diarrhea. Because cysts are resistant to chlorine, Giardia organisms are endemic in unfiltered public and rural water supplies. In the acidic environment of the stomach, excystation occurs and trophozoites are released. Secretory IgA and mucosal IL-6 responses are important for clearance of Giardia infections, and immunosuppressed, agammaglobulinemic, or malnourished individuals often are severely affected. Giardia evades immune clearance through continuous modification of the major surface antigen, variant surface protein, and can persist for months or years while causing intermittent symptoms. Giardia infection reduces expression of brush border enzymes, including


Pathology_Robbins

Pathology_Robbins. of the major surface antigen, variant surface protein, and can persist for months or years while causing intermittent symptoms. Giardia infection reduces expression of brush border enzymes, including lactase, and causes microvillous damage and apoptosis of small-intestinal epithelial cells. Giardia trophozoites are noninvasive and can be identified in duodenal biopsy specimens by their characteristic pear shape. The availability of a stool antigen assay for Giardia has simplified the diagnosis of Giardia infection.


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Pathology_Robbins. • Entamoeba histolytica. This protozoan causes amebiasis and is spread by fecal-oral transmission. E. histolytica infects approximately 500 million people in countries such as India, Mexico, and Colombia, and causes 40 million cases of dysentery and liver abscess annually. While amebiasis affects the cecum and ascending colon most often, the sigmoid colon, rectum, and appendix can also be involved. Dysentery develops when the amebae attach to the colonic epithelium, induce apoptosis, invade crypts, and burrow laterally into the lamina propria. This recruits neutrophils, causes tissue damage, and creates a flask-shaped ulcer with a narrow neck and broad base. Parasites may penetrate splanchnic vessels and embolize to the liver to produce abscesses in about 40% of patients with amebic dysentery. Amebic liver abscesses, which can exceed 10 cm in diameter, have a scant inflammatory reaction at their margins and a shaggy fibrin lining. The abscesses persist after the acute intestinal