InternalMed_Harrison

InternalMed_Harrison. Crohn’s diseasea Drugs (binding or precipitating bile salts)—neomycin, cholestyramine, calcium carbonate Impaired mucosal absorption/mucosal loss or defect Intestinal resection or bypassa Inflammation, infiltration, or infection: Crohn’s diseasea Celiac disease Amyloidosis Collagenous sprue Sclerodermaa Whipple’s diseasea Lymphomaa Radiation enteritisa Eosinophilic enteritis Folate and vitamin B12 deficiency Mastocytosis Infections—giardiasis Tropical sprue Graft versus host disease Genetic disorders Disaccharidase deficiency Agammaglobulinemia Abetalipoproteinemia Hartnup’s disease Cystinuria Impaired nutrient delivery to and/or from intestine: Lymphatic obstruction Circulatory disorders Lymphomaa Congestive heart failure Lymphangiectasia Constrictive pericarditis Mesenteric artery atherosclerosis Vasculitis Endocrine and metabolic disorders Diabetesa Hypoparathyroidism Adrenal insufficiency Hyperthyroidism Carcinoid syndrome aMalabsorption caused by more than one mechanism.


InternalMed_Harrison

InternalMed_Harrison. Weight loss/malnutrition Anorexia, malabsorption of nutrients Diarrhea Impaired absorption or secretion of water and electrolytes; colonic fluid secretion secondary to unabsorbed dihydroxy bile acids and fatty acids Flatus Bacterial fermentation of unabsorbed carbohydrate Glossitis, cheilosis, stomatitis Deficiency of iron, vitamin B12, folate, and vitamin A Abdominal pain Bowel distention or inflammation, pancreatitis Bone pain Calcium, vitamin D malabsorption, protein deficiency, osteoporosis Tetany, paresthesia Calcium and magnesium malabsorption Weakness Anemia, electrolyte depletion Azotemia, hypotension Fluid and electrolyte depletion Amenorrhea, decreased libido Protein depletion, decreased calories, Anemia Impaired absorption of iron, folate, vitamin B12 Bleeding Vitamin K malabsorption, Dermatitis Deficiency of vitamin A, zinc, and essential


InternalMed_Harrison

InternalMed_Harrison. Anemia Impaired absorption of iron, folate, vitamin B12 Bleeding Vitamin K malabsorption, Dermatitis Deficiency of vitamin A, zinc, and essential The many conditions that can produce malabsorption are classified by their pathophysiology in Table 349-8. The pathophysiology of the various clinical manifestations of malabsorption is summarized in Table 349-9. The Schilling Test Henry J. Binder The Schilling test is performed to determine the cause of cobala-min malabsorption. Unfortunately, this test has not been available commercially in the United States for the last few years. Since an under-standing of the physiology and pathophysiology of cobalamin absorp-350e


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 350e The Schilling Test tion is very valuable in enhancing one’s understanding of aspects of gastric, pancreatic, and ileal function, discussion of the Schilling test is provided as supplemental information to Chap. 349. Because cobalamin absorption requires multiple steps, including gastric, pancreatic, and ileal processes, the Schilling test also can be used to assess the integrity of the organs involved in those processes (Chap. 128).


InternalMed_Harrison

InternalMed_Harrison. Cobalamin is present primarily in meat. Except in strict vegans, dietary cobalamin deficiency is exceedingly uncommon. Dietary cobalamin is bound in the stomach to a glycoprotein called R-binder protein, which is synthesized in both the stomach and the salivary glands. This cobalamin–R binder complex is formed in the acid milieu of the stomach. Cobalamin absorption has an absolute requirement for intrinsic factor, another glycoprotein synthesized and released by gastric parietal cells, to promote its uptake by specific cobalamin receptors on the brush border of ileal enterocytes. Pancreatic protease enzymes split the cobalamin–R binder complex to release cobalamin in the proximal small intestine, where cobalamin then is bound by intrinsic factor. As a consequence, cobalamin absorption may be abnormal in the following conditions: 1.


InternalMed_Harrison

InternalMed_Harrison. As a consequence, cobalamin absorption may be abnormal in the following conditions: 1. Pernicious anemia. In this disease, immunologically mediated atrophy of gastric parietal cells leads to an absence of both gastric acid and intrinsic factor secretion. 2. Chronic pancreatitis can result from a deficiency of pancreatic proteases to split the cobalamin–R binder complex. Although 50% of patients with chronic pancreatitis reportedly have an abnormal Schilling test that is corrected by pancreatic enzyme replacement, cobalamin-responsive macrocytic anemia in chronic pancreatitis is extremely rare. Although this probably reflects a difference in the digestion/absorption of cobalamin in food versus that in a crystalline form, the Schilling test still can be used to assess pancreatic exocrine function. 3.


InternalMed_Harrison

InternalMed_Harrison. 3. Achlorhydria is the absence of hydrochloric acid; intrinsic factor is also secreted with acid which is responsible for splitting cobalamin away from the proteins in food to which it is bound. Up to one-third of individuals >60 years of age have marginal vitamin B12 absorption because of an inability to release cobalamin from food; these people have no defects in the absorption of crystalline 350e-1 vitamin B12. 4. Bacterial overgrowth syndromes, which are most often secondary to stasis in the small intestine, lead to bacterial utilization of cobalamin (often referred to as stagnant bowel syndrome; see below). 5. Ileal dysfunction (as a result of either inflammation or prior intestinal resection) is due to impaired function of the mechanism of cobalamin–intrinsic factor uptake by ileal intestinal epithelial cells.


InternalMed_Harrison

InternalMed_Harrison. In the Schilling test, 58Co-labeled cobalamin is administered orally, and urine is collected for 24 h. The test is dependent on normal renal and bladder function. Urinary excretion of cobalamin reflects cobalamin absorption, provided that intrahepatic binding sites for cobalamin are fully occupied. To ensure saturation of these binding sites so that all absorbed radiolabeled cobalamin will be excreted in urine, 1 mg of cobalamin is administered intramuscularly 1 h after ingestion of the radiolabeled cobalamin. The Schilling test may yield an abnormal result (usually defined as <10% excretion in 24 h) in pernicious anemia, chronic pancreatitis, blind loop syndrome, and ileal disease (Table 350e-1). Therefore, whenever an abnormal Schilling result is obtained, 58Co-labeled cobalamin should be administered on another occasion, this time bound to intrinsic factor, with pancreatic enzymes, or after a 5-day course of antibiotic treatment (often with tetracycline). A variation of the


InternalMed_Harrison

InternalMed_Harrison. should be administered on another occasion, this time bound to intrinsic factor, with pancreatic enzymes, or after a 5-day course of antibiotic treatment (often with tetracycline). A variation of the Schilling test can detect failure to split cobalamin from food proteins. The labeled cobalamin is cooked together with a scrambled egg and administered orally. People with achlorydria excrete <10% of the labeled cobalamin in the urine. In addition to establishing the etiology for cobalamin deficiency, the Schilling test can help delineate the pathologic process responsible for steatorrhea by assessing ileal, pancreatic, and small-intestinal luminal function. Unfortunately, the Schilling test is performed infrequently because of the unavailability of human intrinsic factor.


InternalMed_Harrison

InternalMed_Harrison. With After 58Co-Labeled With Intrinsic Pancreatic 5 Days of Cobalamin Factor Enzymes Antibiotics inflammatory Bowel Disease Sonia Friedman, Richard S. Blumberg Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal condition. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major types of IBD. GLOBAL CONSIDERATIONS: EPIDEMIOLOGY 351


InternalMed_Harrison

InternalMed_Harrison. The incidence and prevalence of IBD are highest in Westernized nations, with UC incidence estimates ranging from 0.6 to 24.3 per 100,000 in Europe, 0 to 19.2 per 100,000 in North America, and 0.1 to 6.3 per 100,000 in the Middle East and Asia and CD estimates ranging from 0.3 to 12.7 per 100,000 in Europe, 0 to 20.2 per 100,000 in North America, and 0.04 to 5.0 per 100,000 in the Middle East and Asia (Table 351-1). For prevalence rates, the UC estimates range from 4.9 to 505 per 100,000 in Europe, 37.5 to 248.6 per 100,000 in North America, and 4.9 to 168.3 per 100,000 in the Middle East and Asia, and the CD estimates range from 0.6 to 322 per 100,000 in Europe, 16.7 to 318.5 per 100,000 in North America, and 0.88 to 67.9 per 100,000 in Asia and the Middle East. The highest reported incidence rates are in Canada (19.2 per 100,000 for UC and 20.2 per 100,000 for CD), with approximately 0.6% of the Canadian population having IBD. Countries in the Pacific, including New Zealand and


InternalMed_Harrison

InternalMed_Harrison. incidence rates are in Canada (19.2 per 100,000 for UC and 20.2 per 100,000 for CD), with approximately 0.6% of the Canadian population having IBD. Countries in the Pacific, including New Zealand and Australia, which share many possible environmental risk factors and similar genetic background as northwest Europe and North America, have high incidence rates of IBD.


InternalMed_Harrison

InternalMed_Harrison. In countries that are becoming more Westernized, including China, South Korea, India, Lebanon, Iran, Thailand, and countries in the French West Indies and North Africa, IBD appears to be emerging, emphasizing the importance of environmental factors in disease pathogenesis. In Japan, the prevalence of CD has risen rapidly from 2.9 cases per 100,000 in 1986 to 13.5 per 100,000 in 1998, whereas in South Korea, the prevalence of UC has quadrupled from 7.6 per 100,000 in 1997 to 30.9 per 100,000 in 2005. In Hong Kong, the prevalence of UC almost tripled from 2.3 in 1997 to 6.3 per 100,000 over a 9-year period. In Singapore, the prevalence of CD increased from 1.3 in 1990 to 7.2 per 100,000 in 2004. In China the number of cases of UC has increased by fourfold between 1981–1990 and 1991–2000. Increasing immigration to Western societies also has an impact on the incidence and prevalence of IBD. The prevalence of UC among southern Asians who immigrated to the United Kingdom (UK) was


InternalMed_Harrison

InternalMed_Harrison. Increasing immigration to Western societies also has an impact on the incidence and prevalence of IBD. The prevalence of UC among southern Asians who immigrated to the United Kingdom (UK) was Incidence (North 0–19.2 per 100,000 0–20.2 per 100,000 America) per person-years Age of onset Second to fourth decades Second to fourth and seventh to ninth decades and seventh decades to ninth decades Abbreviation: IBD, inflammatory bowel disease. higher in comparison to the European UK population (17 cases per 1947 100,000 persons vs 7 per 100,000). Spanish patients who emigrated within Europe, but not those who immigrated to Latin America, developed IBD more frequently than controls. Individuals who have immigrated to Westernized countries and then returned to their country of birth also continue to demonstrate an increased risk of developing IBD.


InternalMed_Harrison

InternalMed_Harrison. Peak incidence of UC and CD is in the second to fourth decades, with 78% of CD studies and 51% of UC studies reporting the highest incidence among those age 20–29 years old. A second modest rise in incidence occurs between the seventh and ninth decades of life. The female-to-male ratio ranges from 0.51 to 1.58 for UC studies and 0.34 to 1.65 for CD studies, suggesting that the diagnosis of IBD is not gender specific. The greatest incidence of IBD is among white and Jewish people, but the incidence of IBD in Hispanic and Asian people is increasing, as noted above. Urban areas have a higher prevalence of IBD than rural areas, and high socioeconomic classes have a higher prevalence than lower socioeconomic classes.


InternalMed_Harrison

InternalMed_Harrison. Epidemiologic studies have identified a number of potential envi ronmental factors that are associated with disease risk (Fig. 351-1). In Caucasian populations, smoking is an important risk factor in IBD with opposite effects on UC (odds ratio [OR] 0.58) and CD (OR 1.76), whereas in other ethnic groups with different genetic susceptibility, smoking may play a lesser role. There is a protective effect of previous appendectomy with confirmed appendicitis (reduction of 13–26%), particularly at a young age, on the development of UC across different geographical regions and populations. There is a modest association with the development of CD. Oral contraceptive use is associated with the risk of CD (OR 1.4). The association between oral contraceptive use and UC is limited to women with a history of smoking. There is an association between antibiotic use and the development of childhood IBD with children who received one or more dispensations of antibiotics during the first year of life


InternalMed_Harrison

InternalMed_Harrison. of smoking. There is an association between antibiotic use and the development of childhood IBD with children who received one or more dispensations of antibiotics during the first year of life having a 2.9-fold increase in the risk of developing IBD during childhood. Breastfeeding may also protect against the development of IBD. These factors are consistent with the rapid increase in IBD incidence recently noted during the first decade of life. Infectious gastroenteritis with pathogens (e.g., Salmonella, Shigella, Campylobacter spp., Clostridium difficile) increases IBD risk by twoto threefold. Diets high in animal protein, sugars, sweets, oils, fish and shellfish, and dietary fat, especially ω-6 fatty acids, and low in ω-3 fatty acids have been implicated in increasing the risk of IBD.


InternalMed_Harrison

InternalMed_Harrison. IBD is a familial disease in 5–10% of patients (Fig. 351-2). Some of these patients may exhibit early-onset disease during the first decade of life and, in CD, a concordance of anatomic site and clinical type within families. In the remainder of patients, IBD is observed in the absence of a family history (i.e., sporadic disease). If a patient has IBD, the lifetime risk that a first-degree relative will be affected is ∼10%. If two parents have IBD, each child has a 36% chance of being affected. In twin studies, 38–58% of monozygotic twins are concordant for CD and 6–18% are concordant for UC, whereas 4% of dizygotic twins are concordant for CD and 0–2% are concordant for UC in Swedish and Danish cohorts. The risks of developing IBD are higher in first-degree relatives of Jewish versus non-Jewish patients: 7.8% versus 5.2% for CD and 4.5% versus 1.6% for UC. GLOBAL CONSIDERATIONS: IBD PHENOTYPES


InternalMed_Harrison

InternalMed_Harrison. GLOBAL CONSIDERATIONS: IBD PHENOTYPES There are racial differences in IBD location and behavior that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. For example, African-American patients are more likely than non-Hispanic whites to develop esophagogastroduodenal CD, colorectal disease, and perianal disease and are less likely to have ileal involvement. They are also at higher risk for uveitis and sacroiliitis. Hispanics have a higher prevalence of perianal CD and erythema nodosum and a more proximal extent of disease. Fistulizing CD has been reported in nearly one-third of Hispanic patients, up to one-quarter of African-American patients, and up to one-half of Asian patients. Both African-American


InternalMed_Harrison

InternalMed_Harrison. Stress Microbial flora Enteropathogens Antibiotics Diet, hygiene NSAIDs, smoking Diet, hygiene Immune dysregulation IEC XBP1 NOD2 ATG16L1 TLR4 XBP1 DLG5 ECM1 ITLN1 SLC22A5 DMBT1 PTGER4 IL23R, IL12B, JAK2, STAT3, CCR6, NOD2,TLR4, CARD9, IRF5, ATG16L1, IRGM, LRRK2 TNFSF15,TNFRSF6B TNFAIP3, PTPN2/22 NLRP3, IL18RAP ICOSL,ARPC2, STAT3, IL10 FIGURE 351-1 Pathogenesis of inflammatory bowel disease (IBD). In IBD, the tridirectional relationship between the commensal flora (microbiota), intestinal epithelial cells (IEC), and mucosal immune system is dysregulated, leading to chronic inflammation. Each of these three factors is affected by genetic and environmental factors that determine risk for the disease. NSAIDs, nonsteroidal anti-inflammatory drugs.


InternalMed_Harrison

InternalMed_Harrison. (Adapted from A Kaser et al: Annu Rev Immunol 28:573, 2010.) and Hispanic CD patients, but not UC patients, had a lower prevalence of family history of IBD than their white counterparts. There are few data on all aspects of disease in Hispanics, in the incidence and prevalence of IBD in African Americans, and in Asians with IBD outside Asia. These ethnic variations implicate the importance of different genetic and/or environmental factors in the pathogenesis of this disorder. Environment Undiagnosedinfections?Early onset Genetics


InternalMed_Harrison

InternalMed_Harrison. Environment Undiagnosedinfections?Early onset Genetics FIGURE 351-2 A model for the syndromic nature of inflammatory bowel disease. Genetic and environmental factors variably influence the development and phenotypic manifestations of IBD. At the one extreme, IBD is a exemplified as a simple Mendelian disorder as observed in “early-onset IBD” due to single gene defects such as IL10, IL10RA, and IL10RB; and at the other extreme, it may be exemplified by as yet to be described emerging infectious diseases. (Adapted from A Kaser et al: Dig Dis 28:395, 2010.)


InternalMed_Harrison

InternalMed_Harrison. Under physiologic conditions, homeostasis normally exists between the commensal microbiota, epithelial cells that line the interior of the intestines (intestinal epithelial cells [IECs]) and immune cells within the tissues (Fig. 351-1). A consensus hypothesis is that each of these three major host compartments that function together as an integrated “supraorganism” (microbiota, IECs, and immune cells) are affected by specific environmental (e.g., smoking, antibiotics, enteropathogens) and genetic factors that, in a susceptible host, cumulatively and interactively disrupt homeostasis, which in so doing culminates in a chronic state of dysregulated inflammation; that is IBD. Although chronic activation of the mucosal immune system may represent an appropriate response to an infectious agent, a search for such an agent has thus far been unrewarding in IBD. As such, IBD is currently considered an inappropriate immune response to the endogenous (autocthonous) commensal microbiota within


InternalMed_Harrison

InternalMed_Harrison. a search for such an agent has thus far been unrewarding in IBD. As such, IBD is currently considered an inappropriate immune response to the endogenous (autocthonous) commensal microbiota within the intestines, with or without some component of autoimmunity. Importantly, the normal, uninflamed intestines contain a large number of immune cells that are in a unique state of activation, in which the gut is restrained from full immunologic responses to the commensal microbiota and dietary antigens by very powerful regulatory pathways that function within the immune system (e.g., T regulatory cells that express the FoxP3 transcription factor and suppress inflammation). During the course of infections or other environmental stimuli in the normal host, full activation of the gut-associated lymphoid tissues occurs but is rapidly superseded by dampening of the immune response and tissue repair. In IBD such processes may not be regulated normally.


InternalMed_Harrison

InternalMed_Harrison. The genetic underpinning of IBD is known from its occurrence in the context of several genetic syndromes and the development of severe, refractory IBD in early life in the setting of single gene defects that affect the immune system (Table 351-2). In addition, IBD has a familial origin in at least 10% of afflicted individuals (Fig. 351-2). In the majority of patients, IBD is considered to be a polygenic disorder that gives rise to multiple clinical subgroups within UC and CD. A variety of genetic approaches including candidate gene studies, linkage analysis, and genome-wide association studies (GWASs) that focus on the identification of disease-associated, single-nucleotide polymorphisms (SNPs) within the human genome and, more recently, whole-genome sequencing have elucidated many of the genetic factors that affect risk for these diseases. GWASs have, to date, identified 163 genetic loci with 100 of these loci observed to be associated with both disease phenotypes (Table 351-3). The


InternalMed_Harrison

InternalMed_Harrison. genetic factors that affect risk for these diseases. GWASs have, to date, identified 163 genetic loci with 100 of these loci observed to be associated with both disease phenotypes (Table 351-3). The remainder are specific for either CD (30 loci) or UC (20 loci). These genetic similarities account for the overlapping immunopathogenesis and consequently epidemiologic observations of both diseases in the same families and similarities in response to therapies. Because the specific causal variants for each identified gene or locus are largely unknown, it is not clear whether the similarities in the genetic risk factors associated with CD and UC that are observed are shared at structural or functional levels. The risk conferred by each identified gene or locus is unequal and generally small, such that only ∼20% of the genetic variance is considered to be explained by the current genetic information. Further, many of the genetic risk factors identified are also observed to be associated


InternalMed_Harrison

InternalMed_Harrison. such that only ∼20% of the genetic variance is considered to be explained by the current genetic information. Further, many of the genetic risk factors identified are also observed to be associated with risk for other immune-mediated diseases, suggesting that related immunogenetic pathways are involved in the pathogenesis of multiple different disorders accounting for the common responsiveness to similar types of biologic therapies (e.g., anti–tumor necrosis factor therapies) and possibly the simultaneous occurrence of these disorders. The diseases and the genetic risk factors that are shared with IBD include rheumatoid arthritis (TNFAIP3), psoriasis (IL23R, IL12B), ankylosing spondylitis (IL23R), type 1 diabetes mellitus (IL10, PTPN2), asthma (ORMDL3), and systemic lupus erythematosus (TNFAIP3, IL10) among others.


InternalMed_Harrison

InternalMed_Harrison. The genetic factors defined to date that are recognized to mediate risk for IBD have highlighted the importance of several common mechanisms of disease (Table 351-3). These include the following: those genes that are associated with fundamental cell biologic Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin; UC, ulcerative colitis.


InternalMed_Harrison

InternalMed_Harrison. processes such as endoplasmic reticulum (ER) and metabolic stress 1949 (e.g., XBP1, ORMDL3, OCTN), which serve to regulate the secretory activity of cells involved in responses to the commensal microbiota such as Paneth and goblet cells and the manner in which intestinal cells respond to the metabolic products of bacteria; those associated with innate immunity and autophagy (e.g., NOD2, ATG16L1, IRGM, JAK2, STAT3) that function in innate immune cells (both parenchymal and hematopoietic) to respond to and effectively clear bacteria, mycobacteria, and viruses; those that are associated with the regulation of adaptive immunity (e.g., IL23R, IL12B, IL10, PTPN2), which regulate the balance between inflammatory and anti-inflammatory (regulatory) cytokines; and, finally, those that are involved in the development and resolution of inflammation (e.g., MST1, CCR6, TNFAIP3, PTGER4) and ultimately leukocyte recruitment and inflammatory mediator production. Some of these loci are associated with


InternalMed_Harrison

InternalMed_Harrison. in the development and resolution of inflammation (e.g., MST1, CCR6, TNFAIP3, PTGER4) and ultimately leukocyte recruitment and inflammatory mediator production. Some of these loci are associated with specific subtypes of disease such as the association between NOD2 polymorphisms and fibrostenosing CD or ATG16L1 and fistulizing disease, especially within the ileum. However, the clinical utility of these genetic risk factors for the diagnosis or determination of prognosis and therapeutic responses remains to be defined.


InternalMed_Harrison

InternalMed_Harrison. The endogenous commensal microbiota within the intestines plays a central role in the pathogenesis of IBD. Humans are born sterile and acquire their commensal microbiota initially from the mother during egress through the birth canal and subsequently from environmental sources. A stable configuration of up to 1000 species of bacteria that achieves a biomass of approximately 1012 colony-forming units per gram of feces is achieved by 3 years of age, which likely persists into adult life, with each individual human possessing a unique combination of species. In addition, the intestines contain other microbial life forms including archae, viruses, and protists. The microbiota is thus considered as a critical and sustaining component of the organism. The establishment and maintenance of the intestinal microbiota composition and function is under the control of host (e.g., immune and epithelial responses), environmental (e.g., diet and antibiotics), and likely genetic (e.g., NOD2) factors


InternalMed_Harrison

InternalMed_Harrison. microbiota composition and function is under the control of host (e.g., immune and epithelial responses), environmental (e.g., diet and antibiotics), and likely genetic (e.g., NOD2) factors (Fig. 351-1). In turn, the microbiota, through its structural components and metabolic activity, has major influences on the epithelial and immune function of the host, which, through epigenetic effects, may have durable consequences. During early life when the commensal microbiota is being established, these microbial effects on the host may be particularly important in determining later life risk for IBD. Specific components of the microbiota can promote or protect from disease. The commensal microbiota in patients with both UC and CD is demonstrably different from nonafflicted individuals, a state of dysbiosis, suggesting the presence of microorganisms that drive disease (e.g., Proteobacteria such as enteroinvasive and adherent Escherichia coli) and to which the immune response is directed


InternalMed_Harrison

InternalMed_Harrison. of dysbiosis, suggesting the presence of microorganisms that drive disease (e.g., Proteobacteria such as enteroinvasive and adherent Escherichia coli) and to which the immune response is directed and/or the loss of microorganisms that hinder inflammation (e.g., Firmicutes such as Faecalibacterium prausnitzii). Many of the changes in the commensal microbiota occur as a consequence of the inflammation. In addition, agents that alter the intestinal microbiota such as metronidazole, ciprofloxacin, and elemental diets, may improve CD. CD may also respond to fecal diversion, demonstrating the ability of luminal contents to exacerbate disease.


InternalMed_Harrison

InternalMed_Harrison. The mucosal immune system is normally unreactive to luminal contents due to oral (mucosal) tolerance. When soluble antigens are administered orally rather than subcutaneously or intramuscularly, antigen-specific nonresponsiveness is induced. Multiple mechanisms are involved in the induction of oral tolerance and include deletion or anergy of antigen-reactive T cells or induction of CD4+ T cells that suppress gut inflammation (e.g., T regulatory cells expressing the FoxP3 transcription factor) that secrete anti-inflammatory cytokines such as interleukin (IL) 10, IL-35, and transforming growth factor β (TGF-β). Oral tolerance may be responsible for the lack of immune responsiveness to dietary antigens and the commensal microbiota + 5q33 IL12B Interleukin 12B IL-12 p40 chain of IL-12/IL-23 ++ 18p11 PTPN2 Protein tyrosine phosphatase, nonreceptor type 2 T cell regulation + Inflammation 3p21 MST1 Macrophage stimulating 1 Macrophage activation ++ 5p13 PTGER4 Prostaglandin E receptor 4 PGE2


InternalMed_Harrison

InternalMed_Harrison. 18p11 PTPN2 Protein tyrosine phosphatase, nonreceptor type 2 T cell regulation + Inflammation 3p21 MST1 Macrophage stimulating 1 Macrophage activation ++ 5p13 PTGER4 Prostaglandin E receptor 4 PGE2 receptor ++ 6q23 TNFAIP3 Tumor necrosis factor, alpha-induced protein 3 (A20) Toll-like receptor regulation + 6q27 CCR6 Chemokine (C-C motif ) receptor 6 Dendritic cell migration +


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: CD, Crohn’s disease; ER, endoplasmic reticulum; GTPase, guanosine triphosphatase; IL, interleukin; PGE2, prostaglandin E2; UC, ulcerative colitis. Source: Adapted from A Kaser et al: Ann Rev Immunol 28:573, 2010; B Khor et al: Nature 474:307, 2011; and L Jostins et al: Nature 491:119, 2012. in the intestinal lumen. In IBD this suppression of inflammation is altered, leading to uncontrolled inflammation. The mechanisms of this regulated immune suppression are incompletely known.


InternalMed_Harrison

InternalMed_Harrison. Gene knockout (–/–) or transgenic (Tg) mouse models of IBD, which include those that are directed at genes demonstrated to be associated with risk for the human disease, have revealed that deleting specific cytokines (e.g., IL-2, IL-10, TGF-β) or their receptors, deleting molecules associated with T cell antigen recognition (e.g., T cell antigen receptors), or interfering with IEC barrier function and the regulation of responses to commensal bacteria (e.g., XBP1, N-cadherin, mucus glycoprotein, or nuclear factor-κB [NF-κB]) leads to spontaneous colitis or enteritis. In the majority of circumstances, intestinal inflammation in these animal models requires the presence of the commensal microbiota. Thus, a variety of specific alterations can lead to immune activation by commensal microbiota and inflammation directed at the intestines in mice. How these relate to human IBD remains to be defined, but they are consistent with inappropriate responses of the genetically susceptible host to


InternalMed_Harrison

InternalMed_Harrison. and inflammation directed at the intestines in mice. How these relate to human IBD remains to be defined, but they are consistent with inappropriate responses of the genetically susceptible host to the commensal microbiota.


InternalMed_Harrison

InternalMed_Harrison. In both UC and CD, an inflammatory pathway thus likely emerges from the genetic predisposition that is associated with inappropriate innate immune and epithelial sensing and reactivity to commensal bacteria that secrete inflammatory mediators together with inadequate regulatory pathways that lead to activated CD4+ and CD8+ T cells within the epithelium and lamina propria that altogether secrete excessive quantities of inflammatory cytokines relative to anti-inflammatory cytokines. Some cytokines activate other inflammatory cells (macrophages and B cells), and others act indirectly to recruit other lymphocytes, inflammatory leukocytes, and mononuclear cells from the bloodstream into the gut through interactions between homing receptors on leukocytes (e.g., α4β7 integrin) and addressins on vascular endothelium (e.g., MadCAM1). Consistent with this, neutralization of tumor necrosis factor (TNF) or α4β7 integrin demonstrate therapeutic efficacy in IBD. CD4+ T helper (TH) cells that


InternalMed_Harrison

InternalMed_Harrison. on vascular endothelium (e.g., MadCAM1). Consistent with this, neutralization of tumor necrosis factor (TNF) or α4β7 integrin demonstrate therapeutic efficacy in IBD. CD4+ T helper (TH) cells that promote inflammation are of three major types, all of which may be associated with colitis in animal models and perhaps humans: TH1 cells (secrete interferon [IFN] γ), TH2 cells (secrete IL-4, IL-5, IL-13), and TH17 cells (secrete IL-17, IL-21). TH1 cells induce transmural granulomatous inflammation that resembles CD; TH2 cells, and related natural killer T cells that secrete IL-13, induce superficial mucosal inflammation resembling UC in animal models; and TH17 cells may be responsible for neutrophilic recruitment. However, neutralization of the cytokines produced by these cells, such as IFN-γ or IL-17, has yet to show efficacy in therapeutic trials. Each of these T cell subsets cross-regulate each other. The TH1 cytokine pathway is initiated by IL-12, a key cytokine in the pathogenesis of


InternalMed_Harrison

InternalMed_Harrison. or IL-17, has yet to show efficacy in therapeutic trials. Each of these T cell subsets cross-regulate each other. The TH1 cytokine pathway is initiated by IL-12, a key cytokine in the pathogenesis of experimental models of mucosal inflammation. IL-4 and IL-23, together with IL-6 and TGF-β, induce TH2 and TH17 cells, respectively, and IL-23 inhibits the suppressive function of regulatory T cells. Activated macrophages secrete TNF and IL-6. These characteristics of the immune response in IBD explain the beneficial therapeutic effects of antibodies to block proinflammatory cytokines or the signaling by their receptors (e.g., anti-TNF, anti-IL-12, anti-IL-23, anti-IL-6, or Janus kinase [JAK] inhibitors) or molecules associated with leukocyte recruitment (e.g., anti-α4β7), or the use of cytokines that inhibit inflammation and promote regulatory T cells (e.g., IL-10) or promote intestinal barrier function and may be beneficial to humans with intestinal inflammation.


InternalMed_Harrison

InternalMed_Harrison. Once initiated in IBD by abnormal innate immune sensing of bacteria by parenchymal cells (e.g., IECs) and hematopoietic cells (e.g., dendritic cells), the immune inflammatory response is perpetuated by T cell activation. A sequential cascade of inflammatory mediators extends the response; each step is a potential target for therapy. Inflammatory cytokines such as IL-1, IL-6, and TNF have diverse effects on tissues. They promote fibrogenesis, collagen production, activation of tissue metalloproteinases, and the production of other inflammatory mediators; they also activate the coagulation cascade in local blood vessels (e.g., increased production of von Willebrand’s factor). These cytokines are normally produced in response to infection but are usually turned off or inhibited at the appropriate time to limit tissue damage. In IBD their activity is not regulated, resulting in an imbalance between the proinflammatory and anti-inflammatory mediators. Therapies such as the 5-aminosalicylic


InternalMed_Harrison

InternalMed_Harrison. time to limit tissue damage. In IBD their activity is not regulated, resulting in an imbalance between the proinflammatory and anti-inflammatory mediators. Therapies such as the 5-aminosalicylic acid (5-ASA) compounds and glucocorticoids are potent inhibitors of these inflammatory mediators through inhibition of transcription factors such as NF-κB that regulate their expression.


InternalMed_Harrison

InternalMed_Harrison. ULCERATIVE COLITIS: MACROSCOPIC FEATURES


InternalMed_Harrison

InternalMed_Harrison. UC is a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon. About 40–50% of patients have disease limited to the rectum and rectosigmoid, 30–40% have disease extending beyond the sigmoid but not involving the whole colon, and 20% have a total colitis. Proximal spread occurs in continuity without areas of uninvolved mucosa. When the whole colon is involved, the inflammation extends 2–3 cm into the terminal ileum in 10–20% of patients. The endoscopic changes of backwash ileitis are superficial and mild and are of little clinical significance. Although variations in macroscopic activity may suggest skip areas, biopsies from normal-appearing mucosa are usually abnormal. Thus, it is important to obtain multiple biopsies from apparently uninvolved mucosa, whether proximal or distal, during endoscopy. One caveat is that effective medical therapy can change the appearance of the mucosa such that either skip areas or the entire colon can


InternalMed_Harrison

InternalMed_Harrison. mucosa, whether proximal or distal, during endoscopy. One caveat is that effective medical therapy can change the appearance of the mucosa such that either skip areas or the entire colon can be microscopically normal.


InternalMed_Harrison

InternalMed_Harrison. With mild inflammation, the mucosa is erythematous and has a fine granular surface that resembles sandpaper. In more severe disease, the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 351-3). In long-standing disease, inflammatory polyps (pseudopolyps) may be present as a result of epithelial regeneration. The mucosa may appear normal in remission, but in patients with many years of disease it appears atrophic and featureless, and the entire colon becomes narrowed and shortened. Patients with fulminant disease can develop a toxic colitis or megacolon where the bowel wall thins and the mucosa is severely ulcerated; this may lead to perforation. ULCERATIVE COLITIS: MICROSCOPIC FEATURES


InternalMed_Harrison

InternalMed_Harrison. ULCERATIVE COLITIS: MICROSCOPIC FEATURES Histologic findings correlate well with the endoscopic appearance and clinical course of UC. The process is limited to the mucosa and superficial submucosa, with deeper layers unaffected except in fulminant disease. In UC, two major histologic features suggest chronicity and help distinguish it from infectious or acute self-limited colitis. First, the crypt architecture of the colon is distorted; crypts may be bifid and reduced in number, often with a gap between the crypt bases and the muscularis mucosae. Second, some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion, with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-4 Medium-power view of colonic mucosa in ulcerative colitis showing diffuse mixed inflammation, basal lymphoplasmacytosis, crypt atrophy and irregularity, and superficial erosion. These features are typical of chronic active ulcerative colitis. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) The neutrophils invade the epithelium, usually in the crypts, giving rise to cryptitis and, ultimately, to crypt abscesses (Fig. 351-4). Ileal changes in patients with backwash ileitis include villous atrophy and crypt regeneration with increased inflammation, increased neutrophil and mononuclear inflammation in the lamina propria, and patchy cryptitis and crypt abscesses. CROHN’S DISEASE: MACROSCOPIC FEATURES


InternalMed_Harrison

InternalMed_Harrison. CROHN’S DISEASE: MACROSCOPIC FEATURES CD can affect any part of the gastrointestinal (GI) tract from the mouth to the anus. Some 30–40% of patients have small bowel disease alone, 40–55% have disease involving both the small and large intestines, and 15–25% have colitis alone. In the 75% of patients with small intestinal disease, the terminal ileum is involved in 90%. Unlike UC, which almost always involves the rectum, the rectum is often spared in CD. CD is segmental with skip areas in the midst of diseased intestine (Fig. 351-5). Perirectal fistulas, fissures, abscesses, and anal stenosis are present in one-third of patients with CD, particularly those with


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-3 Ulcerative colitis. Diffuse (nonsegmental) mucosal disease, with broad areas of ulceration. The bowel wall is not thick-ened, and there is no cobblestoning. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) FIGURE 351-5 Crohn’s disease of the colon showing thickening of the wall, with stenosis, linear serpiginous ulcers and cobbleston-ing of the mucosa. (Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.)


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-6 Medium-power view of Crohn’s colitis showing mixed acute and chronic inflammation, crypt atrophy, and multiple small epithelioid granulomas in the mucosa. (Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) colonic involvement. Rarely, CD may also involve the liver and the pancreas. Unlike UC, CD is a transmural process. Endoscopically, aphthous or small superficial ulcerations characterize mild disease; in more active disease, stellate ulcerations fuse longitudinally and transversely to demarcate islands of mucosa that frequently are histologically normal. This “cobblestone” appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form in CD.


InternalMed_Harrison

InternalMed_Harrison. Active CD is characterized by focal inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel. The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel (“creeping fat”), and serosal and mesenteric inflammation promotes adhesions and fistula formation. CROHN’S DISEASE: MICROSCOPIC FEATURES


InternalMed_Harrison

InternalMed_Harrison. CROHN’S DISEASE: MICROSCOPIC FEATURES The earliest lesions are aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages, which form noncaseating granulomas in all layers of the bowel wall (Fig. 351-6). Granulomas can be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. Although granulomas are a pathognomonic feature of CD, they are rarely found on mucosal biopsies. Surgical resection reveals granulomas in about one-half of cases. Other histologic features of CD include submucosal or subserosal lymphoid aggregates, particularly away from areas of ulceration, gross and microscopic skip areas, and transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall and sometimes form fistulous tracts or local abscesses.


InternalMed_Harrison

InternalMed_Harrison. ULCERATIVE COLITIS Signs and Symptoms The major symptoms of UC are diarrhea, rectal bleeding, tenesmus, passage of mucus, and crampy abdominal pain. The severity of symptoms correlates with the extent of disease. Although UC can present acutely, symptoms usually have been present for weeks to months. Occasionally, diarrhea and bleeding are so intermittent and mild that the patient does not seek medical attention. Patients with proctitis usually pass fresh blood or blood-stained mucus, either mixed with stool or streaked onto the surface of a normal or hard stool. They also have tenesmus, or urgency with a feeling of incomplete evacuation, but rarely have abdominal pain. With proctitis or proctosigmoiditis, proximal transit slows, which may account for the constipation commonly seen in patients with distal disease.


InternalMed_Harrison

InternalMed_Harrison. When the disease extends beyond the rectum, blood is usually mixed with stool or grossly bloody diarrhea may be noted. Colonic motility is altered by inflammation with rapid transit through the inflamed intestine. When the disease is severe, patients pass a liquid stool containing blood, pus, and fecal matter. Diarrhea is often nocturnal and/or postprandial. Although severe pain is not a prominent symptom, some patients with active disease may experience vague lower abdominal discomfort or mild central abdominal cramping. Severe cramping and abdominal pain can occur with severe attacks of the disease. Other symptoms in moderate to severe disease include anorexia, nausea, vomiting, fever, and weight loss.


InternalMed_Harrison

InternalMed_Harrison. Physical signs of proctitis include a tender anal canal and blood on rectal examination. With more extensive disease, patients have tenderness to palpation directly over the colon. Patients with a toxic colitis have severe pain and bleeding, and those with megacolon have hepatic tympany. Both may have signs of peritonitis if a perforation has occurred. The classification of disease activity is shown in Table 351-4.


InternalMed_Harrison

InternalMed_Harrison. Laboratory, Endoscopic, and Radiographic Features Active disease can be associated with a rise in acute-phase reactants (C-reactive protein [CRP]), platelet count, and erythrocyte sedimentation rate (ESR), and a decrease in hemoglobin. Fecal lactoferrin is a highly sensitive and specific marker for detecting intestinal inflammation. Fecal calprotectin levels correlate well with histologic inflammation, predict relapses, and detect pouchitis. Both fecal lactoferrin and calprotectin are becoming an integral part of IBD management and are used frequently to rule out active inflammation versus symptoms of irritable bowel or bacterial overgrowth. In severely ill patients, the serum albumin level will fall rather quickly. Leukocytosis may be present but is not a specific indicator of disease activity. Proctitis or proctosigmoiditis rarely causes a rise in CRP. Diagnosis relies on the patient’s history; clinical symptoms; negative stool examination for bacteria, C. difficile toxin, and ova


InternalMed_Harrison

InternalMed_Harrison. Proctitis or proctosigmoiditis rarely causes a rise in CRP. Diagnosis relies on the patient’s history; clinical symptoms; negative stool examination for bacteria, C. difficile toxin, and ova and parasites; sigmoidoscopic appearance (see Fig. 345-4A); and histology of rectal or colonic biopsy specimens.


InternalMed_Harrison

InternalMed_Harrison. Sigmoidoscopy is used to assess disease activity and is usually performed before treatment. If the patient is not having an acute flare, colonoscopy is used to assess disease extent and activity (Fig. 351-7). Endoscopically mild disease is characterized by erythema, decreased vascular pattern, and mild friability. Moderate disease is characterized by marked erythema, absent vascular pattern, friability and erosions, and severe disease by spontaneous bleeding and ulcerations. Histologic features change more slowly than clinical features but can also be used to grade disease activity.


InternalMed_Harrison

InternalMed_Harrison. The earliest radiologic change of UC seen on single-contrast barium enema is a fine mucosal granularity. With increasing severity, the mucosa becomes thickened, and superficial ulcers are seen. Deep ulcerations can appear as “collar-button” ulcers, which indicate that the ulceration has penetrated the mucosa. Haustral folds may be normal in mild disease, but as activity progresses they become edematous and thickened. Loss of haustration can occur, especially in patients with long-standing disease. In addition, the colon becomes shortened and narrowed. Polyps in the colon may be postinflammatory polyps or pseudopolyps, adenomatous polyps, or carcinoma. FIGURE 351-7 Colonoscopy with acute ulcerative colitis: severe colon inflammation with erythema, friability, and exudates. (Courtesy of Dr. M. Hamilton, Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.)


InternalMed_Harrison

InternalMed_Harrison. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) is not as helpful as endoscopy in making the diagnosis of UC, but typical findings include mild mural thickening (<1.5 cm), inhomogeneous wall density, absence of small bowel thickening, increased perirectal and presacral fat, target appearance of the rectum, and adenopathy.


InternalMed_Harrison

InternalMed_Harrison. Complications Only 15% of patients with UC present initially with catastrophic illness. Massive hemorrhage occurs with severe attacks of disease in 1% of patients, and treatment for the disease usually stops the bleeding. However, if a patient requires 6–8 units of blood within 24–48 h, colectomy is indicated. Toxic megacolon is defined as a transverse or right colon with a diameter of >6 cm, with loss of haustration in patients with severe attacks of UC. It occurs in about 5% of attacks and can be triggered by electrolyte abnormalities and narcotics. About 50% of acute dilations will resolve with medical therapy alone, but urgent colectomy is required for those that do not improve. Perforation is the most dangerous of the local complications, and the physical signs of peritonitis may not be obvious, especially if the patient is receiving glucocorticoids. Although perforation is rare, the mortality rate for perforation complicating a toxic megacolon is about 15%. In addition, patients


InternalMed_Harrison

InternalMed_Harrison. be obvious, especially if the patient is receiving glucocorticoids. Although perforation is rare, the mortality rate for perforation complicating a toxic megacolon is about 15%. In addition, patients can develop a toxic colitis and such severe ulcerations that the bowel may perforate without first dilating.


InternalMed_Harrison

InternalMed_Harrison. Strictures occur in 5–10% of patients and are always a concern in UC because of the possibility of underlying neoplasia. Although benign strictures can form from the inflammation and fibrosis of UC, strictures that are impassable with the colonoscope should be presumed malignant until proven otherwise. A stricture that prevents passage of the colonoscope is an indication for surgery. UC patients occasionally develop anal fissures, perianal abscesses, or hemorrhoids, but the occurrence of extensive perianal lesions should suggest CD. CROHN’S DISEASE Signs and Symptoms Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one of two patterns of disease: a fibrostenotic obstructing pattern or a penetrating fistulous pattern, each with different treatments and prognoses. The site of disease influences the clinical manifestations.


InternalMed_Harrison

InternalMed_Harrison. ileocolitis Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Sometimes the initial presentation mimics acute appendicitis with 1953 pronounced right lower quadrant pain, a palpable mass, fever, and leukocytosis. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests intraabdominal abscess formation. Weight loss is common—typically 10–20% of body weight—and develops as a consequence of diarrhea, anorexia, and fear of eating. An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes.


InternalMed_Harrison

InternalMed_Harrison. An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes. Extension of the mass can cause obstruction of the right ureter or bladder inflammation, manifested by dysuria and fever. Edema, bowel wall thickening, and fibrosis of the bowel wall within the mass account for the radiographic “string sign” of a narrowed intestinal lumen.


InternalMed_Harrison

InternalMed_Harrison. Bowel obstruction may take several forms. In the early stages of disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain. Over several years, persistent inflammation gradually progresses to fibrostenotic narrowing and stricture. Diarrhea will decrease and be replaced by chronic bowel obstruction. Acute episodes of obstruction occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food or medication. These episodes usually resolve with intravenous fluids and gastric decompression.


InternalMed_Harrison

InternalMed_Harrison. Severe inflammation of the ileocecal region may lead to localized wall thinning, with microperforation and fistula formation to the adjacent bowel, the skin, or the urinary bladder, or to an abscess cavity in the mesentery. Enterovesical fistulas typically present as dysuria or recurrent bladder infections or, less commonly, as pneumaturia or fecaluria. Enterocutaneous fistulas follow tissue planes of least resistance, usually draining through abdominal surgical scars. Enterovaginal fistulas are rare and present as dyspareunia or as a feculent or foul-smelling, often painful vaginal discharge. They are unlikely to develop without a prior hysterectomy.


InternalMed_Harrison

InternalMed_Harrison. JeJunoileitis Extensive inflammatory disease is associated with a loss of digestive and absorptive surface, resulting in malabsorption and steatorrhea. Nutritional deficiencies can also result from poor intake and enteric losses of protein and other nutrients. Intestinal malabsorption can cause anemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis in patients with an intact colon. Many patients need to take oral and often intravenous iron. Vertebral fractures are caused by a combination of vitamin D deficiency, hypocalcemia, and prolonged glucocorticoid use. Pellagra from niacin deficiency can occur in extensive small-bowel disease, and malabsorption of vitamin B12 can lead to megaloblastic anemia and neurologic symptoms. Other important nutrients to measure and replete if low are folate and vitamins A, E, and K. Levels of minerals such as zinc, selenium, copper, and magnesium are often low in patients with extensive small-bowel


InternalMed_Harrison

InternalMed_Harrison. nutrients to measure and replete if low are folate and vitamins A, E, and K. Levels of minerals such as zinc, selenium, copper, and magnesium are often low in patients with extensive small-bowel inflammation or resections, and these should be repleted as well. Most patients should take a daily multivitamin, calcium, and vitamin D supplements.


InternalMed_Harrison

InternalMed_Harrison. Diarrhea is characteristic of active disease; its causes include (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-acid malabsorption due to a diseased or resected terminal ileum, and (3) intestinal inflammation with decreased water absorption and increased secretion of electrolytes. colitis anD perianal Disease Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia. Gross bleeding is not as common as in UC and appears in about one-half of patients with exclusively colonic disease. Only 1–2% bleed massively. Pain is caused by passage of fecal material through narrowed and inflamed segments of the large bowel. Decreased rectal compliance is another cause for diarrhea in Crohn’s colitis patients. Toxic megacolon is rare but may be seen with severe inflammation and short duration disease.


InternalMed_Harrison

InternalMed_Harrison. Stricturing can occur in the colon in 4–16% of patients and produce symptoms of bowel obstruction. If the endoscopist is unable to traverse a stricture in Crohn’s colitis, surgical resection should be considered, especially if the patient has symptoms of chronic obstruction. 1954 Colonic disease may fistulize into the stomach or duodenum, causing feculent vomiting, or to the proximal or mid-small bowel, causing malabsorption by “short circuiting” and bacterial overgrowth. Ten percent of women with Crohn’s colitis will develop a rectovaginal fistula. Perianal disease affects about one-third of patients with Crohn’s colitis and is manifested by incontinence, large hemorrhoidal tags, anal strictures, anorectal fistulae, and perirectal abscesses. Not all patients with perianal fistula will have endoscopic evidence of colonic inflammation.


InternalMed_Harrison

InternalMed_Harrison. GastroDuoDenal Disease Symptoms and signs of upper GI tract disease include nausea, vomiting, and epigastric pain. Patients usually have an Helicobacter pylori–negative gastritis. The second portion of the duodenum is more commonly involved than the bulb. Fistulas involving the stomach or duodenum arise from the small or large bowel and do not necessarily signify the presence of upper GI tract involvement. Patients with advanced gastroduodenal CD may develop a chronic gastric outlet obstruction. Laboratory, Endoscopic, and Radiographic Features Laboratory abnormalities include elevated ESR and CRP. In more severe disease, findings include hypoalbuminemia, anemia, and leukocytosis.


InternalMed_Harrison

InternalMed_Harrison. Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Colonoscopy allows examination and biopsy of mass lesions or strictures and biopsy of the terminal ileum. Upper endoscopy is useful in diagnosing gastroduodenal involvement in patients with upper tract symptoms. Ileal or colonic strictures may be dilated with balloons introduced through the colonoscope. Strictures ≤4 cm and those at anastomotic sites respond better to endoscopic dilation. The perforation rate is as high as 10%. Most endoscopists dilate only fibrotic strictures and not those associated with active inflammation. Wireless capsule endoscopy (WCE) allows direct visualization of the entire small-bowel mucosa (Fig. 351-8). The diagnostic yield of detecting lesions suggestive of active CD is higher with WCE than CT or magnetic resonance (MR) enterography or small-bowel series. WCE cannot be used in the setting of a small-bowel stricture. Capsule retention occurs in <1% of


InternalMed_Harrison

InternalMed_Harrison. of active CD is higher with WCE than CT or magnetic resonance (MR) enterography or small-bowel series. WCE cannot be used in the setting of a small-bowel stricture. Capsule retention occurs in <1% of patients with suspected CD, but retention rates of 4–6% are seen in patients with established CD. It is helpful to give the patient with CD a patency capsule, which is made of barium and starts to dissolve 30 h after ingestion. An abdominal x-ray can be taken at around 30 h after ingestion to see if the capsule is still present in the small bowel, which would indicate a stricture.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-8 Wireless capsule endoscopy image in a patient with Crohn’s disease of the ileum shows ulcerations and narrow-ing of the intestinal lumen. (Courtesy of Dr. S. Reddy, Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) In CD, early radiographic findings in the small bowel include thickened folds and aphthous ulcerations. “Cobblestoning” from longitudinal and transverse ulcerations most frequently involves the small bowel. In more advanced disease, strictures, fistulas, inflammatory masses, and abscesses may be detected. The earliest macroscopic findings of colonic CD are aphthous ulcers. These small ulcers are often multiple and separated by normal intervening mucosa. As the disease progresses, aphthous ulcers become enlarged, deeper, and occasionally connected to one another, forming longitudinal stellate, serpiginous, and linear ulcers (see Fig. 345-4B).


InternalMed_Harrison

InternalMed_Harrison. The transmural inflammation of CD leads to decreased luminal diameter and limited distensibility. As ulcers progress deeper, they can lead to fistula formation. The radiographic “string sign” represents long areas of circumferential inflammation and fibrosis, resulting in long segments of luminal narrowing. The segmental nature of CD results in wide gaps of normal or dilated bowel between involved segments.


InternalMed_Harrison

InternalMed_Harrison. Both CT and MRI of the small bowel can be performed by enterography (CTE or MRE), using oral and IV contrast, as well as enteroclysis. Although institutional preference guides technique selection, CTE and MRE tend to be preferred over enteroclysis due to ease and patient preference. Although CTE, MRE, and small-bowel follow-through (SBFT) have been shown to be equally accurate in the identification of active small-bowel inflammation, CTE and MRE have been shown to be superior to SBFT in the detection of extraluminal complications, including fistulas, sinus tracts, and abscesses. Currently, the use of CT scans is more common than MRI due to institutional availability and expertise. However, MRI is thought to offer superior soft tissue contrast and has the added advantage of avoiding radiation exposure changes (Figs. 351-9 and 351-10). The lack of ionizing radiation is particularly appealing in younger patients and when monitoring response to therapy where serial images will be


InternalMed_Harrison

InternalMed_Harrison. radiation exposure changes (Figs. 351-9 and 351-10). The lack of ionizing radiation is particularly appealing in younger patients and when monitoring response to therapy where serial images will be obtained. Either CTE or MRE is the first-line test for the evaluation of suspected CD and its complications. Pelvic MRI is superior to CT for demonstrating pelvic lesions such as ischiorectal abscesses and perianal fistulae (Fig. 351-11).


InternalMed_Harrison

InternalMed_Harrison. Complications Because CD is a transmural process, serosal adhesions develop that provide direct pathways for fistula formation and reduce the incidence of free perforation. Perforation occurs in 1–2% of patients, usually in the ileum but occasionally in the jejunum or as a complication of toxic megacolon. The peritonitis of free perforation, especially colonic, may be fatal. Intraabdominal and pelvic abscesses occur in 10–30% of patients with CD at some time in the course of their illness. CT-guided percutaneous drainage of the abscess is standard therapy. Despite adequate drainage, most patients need resection of the offending bowel segment. Percutaneous drainage has an especially high failure rate in abdominal wall abscesses. Systemic glucocorticoid therapy increases the risk of intraabdominal and pelvic abscesses in CD patients who have never had an operation. Other complications include intestinal obstruction in 40%, massive hemorrhage, malabsorption, and severe perianal disease.


InternalMed_Harrison

InternalMed_Harrison. Serologic Markers Patients with CD show a wide variation in the way they present and progress over time. Some patients present with mild disease activity and do well with generally safe and mild medications, but many others exhibit more severe disease and can develop serious complications that will require surgery. Current and developing biologic therapies can help halt progression of disease and give patients with moderate to severe CD a better quality of life. There are potential risks of biologic therapies such as infection and malignancy, and it would be optimal to determine at the time of diagnosis which patients will require more aggressive medical therapy. This same argument holds true for UC patients as well. Subsets of patients with differing immune responses to microbial antigens have been described, and serology is often tested for


InternalMed_Harrison

InternalMed_Harrison. Subsets of patients with differing immune responses to microbial antigens have been described, and serology is often tested for FIGURE 351-9 A coronal magnetic resonance image was obtained using a half Fourier single-shot T2-weighted acquisition with fat saturation in a 27-year-old pregnant (23 weeks’ gestation) woman. The patient had Crohn’s disease and was maintained on 6-mercaptopurine and prednisone. She presented with abdominal pain, distension, vomiting, and small-bowel obstruction. The image reveals a 7to 10-cm long stricture at the terminal ileum (white arrows) causing obstruction and significant dilatation of the proximal small bowel (white asterisk). A fetus is seen in the uterus (dashed white arrows). (Courtesy of Drs. J. F. B. Chick and


InternalMed_Harrison

InternalMed_Harrison. P. B. Shyn, Abdominal Imaging and Intervention, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; with permission.) perinuclear antineutrophil cytoplasmic antibodies (pANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCAs). Unfortunately, these serologic markers are only marginally useful in helping to make the diagnosis of UC or CD and in predicting the course of disease. For success in diagnosing IBD and in differentiating between CD and UC, the efficacy of these serologic tests depends on the prevalence of IBD in a specific population. pANCA positivity is found in about 60–70% of UC patients and 5–10% of CD patients; 5–15% of first-degree relatives of UC patients are pANCA positive, whereas only 2–3% of the general population is pANCA positive. Sixty to 70% of CD patients, 10–15% of UC patients, and up to 5% of non-IBD controls are ASCA positive. In a patient population with a combined prevalence of UC and CD of 62%,


InternalMed_Harrison

InternalMed_Harrison. is pANCA positive. Sixty to 70% of CD patients, 10–15% of UC patients, and up to 5% of non-IBD controls are ASCA positive. In a patient population with a combined prevalence of UC and CD of 62%, pANCA/ASCA serology showed a sensitivity of 64% and a specificity of 94%. Positive and negative predictive values (PPVs and NPVs) for pANCA/ASCA also vary based on the prevalence of IBD in a given population. For the patient population with a prevalence of IBD of 62%, the PPV is 94%, and the NPV is 63%.


InternalMed_Harrison

InternalMed_Harrison. Other serologic tests include antibodies to Escherichia coli outer membrane porin protein C (OmpC), which is found in 55% of CD patients; antibodies to I2, a homologue of the bacterial transcription factor families from a Pseudomonas fluorescens–associated sequence that is found in 50–54% of CD patients; and anti-flagellin (anti-CBir1) antibodies, which have been identified in approximately 50% of CD patients. Children with CD positive for all four immune responses (ASCA+, OmpC+, I2+, and anti-Cbir1+) may have more aggressive disease and a shorter time to progression to internal perforating


InternalMed_Harrison

InternalMed_Harrison. Children with CD positive for all four immune responses (ASCA+, OmpC+, I2+, and anti-Cbir1+) may have more aggressive disease and a shorter time to progression to internal perforating FIGURE 351-10 A coronal balanced, steady-state, free precession, T2-weighted image with fat saturation was obtained in a 32-year-old man with Crohn’s disease and prior episodes of bowel obstruction, fistulas, and abscesses. He was being treated with 6-mercaptopurine and presented with abdominal distention and diarrhea. The image demonstrates a new gastrocolic fistula (solid white arrows). Multifocal involvement of the small bowel and terminal ileum is also present (dashed white arrows). (Courtesy of Drs. J. F. B. Chick and P. B. Shyn, Abdominal Imaging and Intervention, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; with permission.)


InternalMed_Harrison

InternalMed_Harrison. FIGURE 351-11 Axial T2-weighted magnetic resonance image obtained in a 37-year-old man with Crohn’s disease shows a linear fluid-filled perianal fistula (arrow) in the right ischioanal fossa. (Courtesy of Dr. K. Mortele, Gastrointestinal Radiology, Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) 1956 and/or stricturing disease. However, larger prospective studies in both children and adults have not yet been performed and compared to CRP or other markers. Clinical factors described at diagnosis are more helpful than serologies at predicting the natural history of CD. The initial requirements for glucocorticoid use, an age at diagnosis below 40 years and the presence of perianal disease at diagnosis, have been shown to be independently associated with subsequent disabling CD after 5 years. Except in special circumstances (such as before consideration of an ileoanal pouch anastomosis [IPAA] in a patient with indeterminate colitis),


InternalMed_Harrison

InternalMed_Harrison. associated with subsequent disabling CD after 5 years. Except in special circumstances (such as before consideration of an ileoanal pouch anastomosis [IPAA] in a patient with indeterminate colitis), serologic markers have only minimal clinical utility.


InternalMed_Harrison

InternalMed_Harrison. UC and CD have similar features to many other diseases. In the absence of a key diagnostic test, a combination of features is used (Table 351-5). Once a diagnosis of IBD is made, distinguishing between UC and CD is impossible initially in up to 15% of cases. These are termed indeterminate colitis. Fortunately, in most cases, the true nature of the underlying colitis becomes evident later in the course of the patient’s disease. Approximately 5% (range 1–20%) of colon resection specimens are difficult to classify as either UC or CD because they exhibit overlapping histologic features.


InternalMed_Harrison

InternalMed_Harrison. Infections of the small intestines and colon can mimic CD or UC. They may be bacterial, fungal, viral, or protozoal in origin (Table 351-6). Campylobacter colitis can mimic the endoscopic appearance of severe UC and can cause a relapse of established UC. Salmonella can cause watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes watery diarrhea, abdominal pain, and fever followed by rectal tenesmus and by the passage of blood and mucus per rectum. All three are usually self-limited, but 1% of patients infected with Salmonella become asymptomatic carriers. Yersinia enterocolitica infection occurs mainly in the terminal ileum and causes mucosal ulceration, neutrophil invasion, and thickening of the ileal wall. Other bacterial infections that may mimic IBD include C. difficile, which presents with watery TABlE 351-5 DiffEREnT CliniCAl, EnDoSCoPiC, AnD RADioGRAPHiC fEATuRES Abbreviation: IBD, inflammatory bowel disease; NSAIDs, nonsteroidal anti-inflammatory drugs.


InternalMed_Harrison

InternalMed_Harrison. TABlE 351-5 DiffEREnT CliniCAl, EnDoSCoPiC, AnD RADioGRAPHiC fEATuRES Abbreviation: IBD, inflammatory bowel disease; NSAIDs, nonsteroidal anti-inflammatory drugs. diarrhea, tenesmus, nausea, and vomiting; and E. coli, three categories of which can cause colitis. These are enterohemorrhagic, enteroinvasive, and enteroadherent E. coli, all of which can cause bloody diarrhea and abdominal tenderness. Diagnosis of bacterial colitis is made by sending stool specimens for bacterial culture and C. difficile toxin analysis. Gonorrhea, Chlamydia, and syphilis can also cause proctitis.


InternalMed_Harrison

InternalMed_Harrison. GI involvement with mycobacterial infection occurs primarily in the immunosuppressed patient but may occur in patients with normal immunity. Distal ileal and cecal involvement predominates, and patients present with symptoms of small-bowel obstruction and a tender abdominal mass. The diagnosis is made most directly by colonoscopy with biopsy and culture. Mycobacterium avium-intracellulare complex infection occurs in advanced stages of HIV infection and in other immunocompromised states; it usually manifests as a systemic infection with diarrhea, abdominal pain, weight loss, fever, and malabsorption. Diagnosis is established by acid-fast smear and culture of mucosal biopsies.


InternalMed_Harrison

InternalMed_Harrison. Although most of the patients with viral colitis are immunosuppressed, cytomegalovirus (CMV) and herpes simplex proctitis may occur in immunocompetent individuals. CMV occurs most commonly in the esophagus, colon, and rectum but may also involve the small intestine. Symptoms include abdominal pain, bloody diarrhea, fever, and weight loss. With severe disease, necrosis and perforation can occur. Diagnosis is made by identification of characteristic intranuclear inclusions in mucosal cells on biopsy. Herpes simplex infection of the GI tract is limited to the oropharynx, anorectum, and perianal areas. Symptoms include anorectal pain, tenesmus, constipation, inguinal adenopathy, difficulty with urinary voiding, and sacral paresthesias. Diagnosis is made by rectal biopsy with identification of characteristic cellular inclusions and viral culture. HIV itself can cause diarrhea, nausea, vomiting, and anorexia. Small intestinal biopsies show partial villous atrophy; small bowel bacterial


InternalMed_Harrison

InternalMed_Harrison. of characteristic cellular inclusions and viral culture. HIV itself can cause diarrhea, nausea, vomiting, and anorexia. Small intestinal biopsies show partial villous atrophy; small bowel bacterial overgrowth and fat malabsorption may also be noted.


InternalMed_Harrison

InternalMed_Harrison. Protozoan parasites include Isospora belli, which can cause a self-limited infection in healthy hosts but causes a chronic profuse, watery diarrhea, and weight loss in AIDS patients. Entamoeba histolytica or related species infect about 10% of the world’s population; symptoms include abdominal pain, tenesmus, frequent loose stools containing blood and mucus, and abdominal tenderness. Colonoscopy reveals focal punctate ulcers with normal intervening mucosa; diagnosis is made by biopsy or serum amebic antibodies. Fulminant amebic colitis is rare but has a mortality rate of >50%. Other parasitic infections that may mimic IBD include hookworm (Necator americanus), whipworm (Trichuris trichiura), and Strongyloides stercoralis. In severely immunocompromised patients, Candida or Aspergillus can be identified in the submucosa. Disseminated histoplasmosis can involve the ileocecal area.


InternalMed_Harrison

InternalMed_Harrison. Diverticulitis can be confused with CD clinically and radiographically. Both diseases cause fever, abdominal pain, tender abdominal mass, leukocytosis, elevated ESR, partial obstruction, and fistulas. Perianal disease or ileitis on small-bowel series favors the diagnosis of CD. Significant endoscopic mucosal abnormalities are more likely in CD than in diverticulitis. Endoscopic or clinical recurrence following segmental resection favors CD. Diverticular-associated colitis is similar to CD, but mucosal abnormalities are limited to the sigmoid and descending colon.


InternalMed_Harrison

InternalMed_Harrison. Ischemic colitis is commonly confused with IBD. The ischemic process can be chronic and diffuse, as in UC, or segmental, as in CD. Colonic inflammation due to ischemia may resolve quickly or may persist and result in transmural scarring and stricture formation. Ischemic bowel disease should be considered in the elderly following abdominal aortic aneurysm repair or when a patient has a hyper-coagulable state or a severe cardiac or peripheral vascular disorder. Patients usually present with sudden onset of left lower quadrant pain, urgency to defecate, and the passage of bright red blood per rectum. Endoscopic examination often demonstrates a normal-appearing rectum and a sharp transition to an area of inflammation in the descending colon and splenic flexure.


InternalMed_Harrison

InternalMed_Harrison. The effects of radiotherapy on the GI tract can be difficult to distinguish from IBD. Acute symptoms can occur within 1–2 weeks of starting radiotherapy. When the rectum and sigmoid are irradiated, patients develop bloody, mucoid diarrhea and tenesmus, as in distal UC. With small-bowel involvement, diarrhea is common. Late symptoms include malabsorption and weight loss. Stricturing with obstruction and bacterial overgrowth may occur. Fistulas can penetrate the bladder, vagina, or abdominal wall. Flexible sigmoidoscopy reveals mucosal granularity, friability, numerous telangiectasias, and occasionally discrete ulcerations. Biopsy can be diagnostic.


InternalMed_Harrison

InternalMed_Harrison. Solitary rectal ulcer syndrome is uncommon and can be confused with IBD. It occurs in persons of all ages and may be caused by impaired evacuation and failure of relaxation of the puborectalis muscle. Single or multiple ulcerations may arise from anal sphincter overactivity, higher intrarectal pressures during defecation, and digital removal of stool. Patients complain of constipation with straining and pass blood and mucus per rectum. Other symptoms include abdominal pain, diarrhea, tenesmus, and perineal pain. Ulceration as large as 5 cm in diameter is usually seen anteriorly or anterior-laterally 3–15 cm from the anal verge. Biopsies can be diagnostic.


InternalMed_Harrison

InternalMed_Harrison. Several types of colitis are associated with nonsteroidal anti-inflammatory drugs (NSAIDs), including de novo colitis, reactivation of IBD, and proctitis caused by use of suppositories. Most patients with NSAID-related colitis present with diarrhea and abdominal pain, and complications include stricture, bleeding, obstruction, perforation, and fistulization. Withdrawal of these agents is crucial, and in cases of reactivated IBD, standard therapies are indicated.


InternalMed_Harrison

InternalMed_Harrison. There are complications of two drugs used in a hospital setting that mimic IBD. The first is ipilimumab, a drug that targets cytotoxic T lymphocyte antigen 4 (CTLA-4) and reverses T cell inhibition and is used to treat metastatic melanoma; ipilimumab has an incidence of IBD in 0.0017 cases per 100 person-years. Ipilimumab-induced colitis is typically treated with glucocorticoids or infliximab. The 1957 second is mycophenolate mofetil (MMF), an immunosuppressive agent commonly used to prevent posttransplant rejection. The colitis associated with MMF is common and can occur in more than one-third of patients taking the drug. Treatment is dose reduction or cessation of the drug.


InternalMed_Harrison

InternalMed_Harrison. Two atypical colitides—collagenous colitis and lymphocytic colitis— have completely normal endoscopic appearances. Collagenous colitis has two main histologic components: increased subepithelial collagen deposition and colitis with increased intraepithelial lymphocytes. The female to male ratio is 9:1, and most patients present in the sixth or seventh decades of life. The main symptom is chronic watery diarrhea. Treatments range from sulfasalazine or mesalamine and diphenoxylate/atropine (Lomotil) to bismuth to budesonide to prednisone or azathioprine/6-mercaptopurine for refractory disease. Risk factors include smoking; use of NSAIDs, proton pump inhibitors, or beta blockers; and a history of autoimmune disease.


InternalMed_Harrison

InternalMed_Harrison. Lymphocytic colitis has features similar to collagenous colitis, including age at onset and clinical presentation, but it has almost equal incidence in men and women and no subepithelial collagen deposition on pathologic section. However, intraepithelial lymphocytes are increased. Use of sertraline (but not beta blockers) is an additional risk factor. The frequency of celiac disease is increased in lymphocytic colitis and ranges from 9 to 27%. Celiac disease should be excluded in all patients with lymphocytic colitis, particularly if diarrhea does not respond to conventional therapy. Treatment is similar to that of collagenous colitis with the exception of a gluten-free diet for those who have celiac disease.


InternalMed_Harrison

InternalMed_Harrison. Diversion colitis is an inflammatory process that arises in segments of the large intestine that are excluded from the fecal stream. It usually occurs in patients with ileostomy or colostomy when a mucus fistula or a Hartmann’s pouch has been created. Clinically, patients have mucus or bloody discharge from the rectum. Erythema, granularity, friability, and, in more severe cases, ulceration can be seen on endoscopy. Histopathology shows areas of active inflammation with foci of cryptitis and crypt abscesses. Crypt architecture is normal, which differentiates it from UC. It may be impossible to distinguish from CD. Short-chain fatty acid enemas may help in diversion colitis, but the definitive therapy is surgical reanastomosis. Up to one-third of IBD patients have at least one extraintestinal disease manifestation.


InternalMed_Harrison

InternalMed_Harrison. Up to one-third of IBD patients have at least one extraintestinal disease manifestation. Erythema nodosum (EN) occurs in up to 15% of CD patients and 10% of UC patients. Attacks usually correlate with bowel activity; skin lesions develop after the onset of bowel symptoms, and patients frequently have concomitant active peripheral arthritis. The lesions of EN are hot, red, tender nodules measuring 1–5 cm in diameter and are found on the anterior surface of the lower legs, ankles, calves, thighs, and arms. Therapy is directed toward the underlying bowel disease.


InternalMed_Harrison

InternalMed_Harrison. Pyoderma gangrenosum (PG) is seen in 1–12% of UC patients and less commonly in Crohn’s colitis. Although it usually presents after the diagnosis of IBD, PG may occur years before the onset of bowel symptoms, run a course independent of the bowel disease, respond poorly to colectomy, and even develop years after proctocolectomy. It is usually associated with severe disease. Lesions are commonly found on the dorsal surface of the feet and legs but may occur on the arms, chest, stoma, and even the face. PG usually begins as a pustule and then spreads concentrically to rapidly undermine healthy skin. Lesions then ulcerate, with violaceous edges surrounded by a margin of erythema. Centrally, they contain necrotic tissue with blood and exudates. Lesions may be single or multiple and grow as large as 30 cm. They are sometimes very difficult to treat and often require IV antibiotics, IV glucocorticoids, dapsone, azathioprine, thalidomide, IV cyclosporine, or infliximab.


InternalMed_Harrison

InternalMed_Harrison. 1958 Other dermatologic manifestations include pyoderma vegetans, which occurs in intertriginous areas; pyostomatitis vegetans, which involves the mucous membranes; Sweet syndrome, a neutrophilic dermatosis; and metastatic CD, a rare disorder defined by cutaneous granuloma formation. Psoriasis affects 5–10% of patients with IBD and is unrelated to bowel activity consistent with the potential shared immunogenetic basis of these diseases. Perianal skin tags are found in 75–80% of patients with CD, especially those with colon involvement. Oral mucosal lesions, seen often in CD and rarely in UC, include aphthous stomatitis and “cobblestone” lesions of the buccal mucosa.


InternalMed_Harrison

InternalMed_Harrison. Peripheral arthritis develops in 15–20% of IBD patients, is more common in CD, and worsens with exacerbations of bowel activity. It is asymmetric, polyarticular, and migratory and most often affects large joints of the upper and lower extremities. Treatment is directed at reducing bowel inflammation. In severe UC, colectomy frequently cures the arthritis. Ankylosing spondylitis (AS) occurs in about 10% of IBD patients and is more common in CD than UC. About two-thirds of IBD patients with AS express the HLA-B27 antigen. The AS activity is not related to bowel activity and does not remit with glucocorticoids or colectomy. It most often affects the spine and pelvis, producing symptoms of diffuse low-back pain, buttock pain, and morning stiffness. The course is continuous and progressive, leading to permanent skeletal damage and deformity. Anti-TNF therapy reduces spinal inflammation and improves functional status and quality of life.


InternalMed_Harrison

InternalMed_Harrison. Sacroiliitis is symmetric, occurs equally in UC and CD, is often asymptomatic, does not correlate with bowel activity, and does not always progress to AS. Other rheumatic manifestations include hyper-trophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing polychondritis. The incidence of ocular complications in IBD patients is 1–10%. The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis. Uveitis is associated with both UC and Crohn’s colitis, may be found during periods of remission, and may develop in patients following bowel resection. Symptoms include ocular pain, photophobia, blurred vision, and headache. Prompt intervention, sometimes with systemic glucocorticoids, is required to prevent scarring and visual impairment. Episcleritis is a benign disorder that presents with symptoms of mild ocular burning. It occurs in 3–4% of IBD patients, more commonly in Crohn’s colitis, and is treated with topical glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. Hepatic steatosis is detectable in about one-half of the abnormal liver biopsies from patients with CD and UC; patients usually present with hepatomegaly. Fatty liver usually results from a combination of chronic debilitating illness, malnutrition, and glucocorticoid therapy. Cholelithiasis occurs in 10–35% of CD patients with ileitis or ileal resection. Gallstone formation is caused by malabsorption of bile acids, resulting in depletion of the bile salt pool and the secretion of lithogenic bile.


InternalMed_Harrison

InternalMed_Harrison. Primary sclerosing cholangitis (PSC) is a disorder characterized by both intrahepatic and extrahepatic bile duct inflammation and fibrosis, frequently leading to biliary cirrhosis and hepatic failure; approximately 5% of patients with UC have PSC, but 50–75% of patients with PSC have IBD. PSC occurs less often in patients with CD. Although it can be recognized after the diagnosis of IBD, PSC can be detected earlier or even years after proctocolectomy. Consistent with this, the immunogenetic basis for PSC appears to be overlapping but distinct from UC based on GWAS, although both IBD and PSC are commonly pANCA positive. Most patients have no symptoms at the time of diagnosis; when symptoms are present, they consist of fatigue, jaundice, abdominal pain, fever, anorexia, and malaise. The traditional gold standard diagnostic test is endoscopic retrograde cholangiopancreatography (ERCP), but magnetic resonance cholangiopancreatography (MRCP) is also sensitive and specific. MRCP is


InternalMed_Harrison

InternalMed_Harrison. The traditional gold standard diagnostic test is endoscopic retrograde cholangiopancreatography (ERCP), but magnetic resonance cholangiopancreatography (MRCP) is also sensitive and specific. MRCP is reasonable as an initial diagnostic test in children and can visualize irregularities, multifocal strictures, and dilatations of all levels of the biliary tree. In patients with PSC, both ERCP and MRCP demonstrate multiple bile duct strictures alternating with relatively normal segments.


InternalMed_Harrison

InternalMed_Harrison. The bile acid ursodeoxycholic acid (ursodiol) may reduce alkaline phosphatase and serum aminotransferase levels, but histologic improvement has been marginal. High doses (25–30 mg/kg per day) may decrease the risk of colorectal dysplasia and cancer in patients with UC and PSC. Endoscopic stenting may be palliative for cholestasis secondary to bile duct obstruction. Patients with symptomatic disease develop cirrhosis and liver failure over 5–10 years and eventually require liver transplantation. PSC patients have a 10–15% lifetime risk of developing cholangiocarcinoma and then cannot be transplanted. Patients with IBD and PSC are at increased risk of colon cancer and should be surveyed yearly by colonoscopy and biopsy.


InternalMed_Harrison

InternalMed_Harrison. In addition, cholangiography is normal in a small percentage of patients who have a variant of PSC known as small duct primary sclerosing cholangitis. This variant (sometimes referred to as “pericholangitis”) is probably a form of PSC involving small-caliber bile ducts. It has similar biochemical and histologic features to classic PSC. It appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSC. Granulomatous hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD.


InternalMed_Harrison

InternalMed_Harrison. The most frequent genitourinary complications are calculi, ureteral obstruction, and ileal bladder fistulas. The highest frequency of nephrolithiasis (10–20%) occurs in patients with CD following small bowel resection. Calcium oxalate stones develop secondary to hyperoxaluria, which results from increased absorption of dietary oxalate. Normally, dietary calcium combines with luminal oxalate to form insoluble calcium oxalate, which is eliminated in the stool. In patients with ileal dysfunction, however, nonabsorbed fatty acids bind calcium and leave oxalate unbound. The unbound oxalate is then delivered to the colon, where it is readily absorbed, especially in the presence of inflammation.


InternalMed_Harrison

InternalMed_Harrison. Low bone mass occurs in 3–30% of IBD patients. The risk is increased by glucocorticoids, cyclosporine, methotrexate, and total parenteral nutrition (TPN). Malabsorption and inflammation mediated by IL-1, IL-6, TNF, and other inflammatory mediators also contribute to low bone density. An increased incidence of hip, spine, wrist, and rib fractures has been noted: 36% in CD and 45% in UC. The absolute risk of an osteoporotic fracture is about 1% per person per year. Fracture rates, particularly in the spine and hip, are highest among the elderly (age >60). One study noted an OR of 1.72 for vertebral fracture and an OR of 1.59 for hip fracture. The disease severity predicted the risk of a fracture. Only 13% of IBD patients who had a fracture were on any kind of antifracture treatment. Up to 20% of bone mass can be lost per year with chronic glucocorticoid use. The effect is dosage-dependent. Budesonide may also suppress the pituitary-adrenal axis and thus carries a risk of causing


InternalMed_Harrison

InternalMed_Harrison. Up to 20% of bone mass can be lost per year with chronic glucocorticoid use. The effect is dosage-dependent. Budesonide may also suppress the pituitary-adrenal axis and thus carries a risk of causing osteoporosis.


InternalMed_Harrison

InternalMed_Harrison. Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse. The pain is aggravated by motion and swelling of the joints. It affects the hips more often than knees and shoulders, and in one series, 4.3% of patients developed osteonecrosis within 6 months of starting glucocorticoids. Diagnosis is made by bone scan or MRI, and treatment consists of pain control, cord decompression, osteotomy, and joint replacement.


InternalMed_Harrison

InternalMed_Harrison. Patients with IBD have an increased risk of both venous and arterial thrombosis even if the disease is not active. Factors responsible for the hypercoagulable state have included abnormalities of the platelet-endothelial interaction, hyperhomocysteinemia, alterations in the coagulation cascade, impaired fibrinolysis, involvement of tissue factor-bearing microvesicles, disruption of the normal coagulation system by autoantibodies, and a genetic predisposition. A spectrum of vasculitides involving small, medium, and large vessels has also been observed.


InternalMed_Harrison

InternalMed_Harrison. More common cardiopulmonary manifestations include endocarditis, myocarditis, pleuropericarditis, and interstitial lung disease. A secondary or reactive amyloidosis can occur in patients with long-standing IBD, especially in patients with CD. Amyloid material is deposited systemically and can cause diarrhea, constipation, and renal failure. The renal disease can be successfully treated with colchicine. Pancreatitis is a rare extraintestinal manifestation of IBD and results from duodenal fistulas; ampullary CD; gallstones; PSC; drugs such as 6-mercaptopurine, azathioprine, or, very rarely, 5-ASA agents; autoimmune pancreatitis; and primary CD of the pancreas.


InternalMed_Harrison

InternalMed_Harrison. The mainstay of therapy for mild to moderate UC is sulfasalazine and the other 5-ASA agents. These agents are effective at inducing and maintaining remission in UC. They may have a limited role in inducing remission in CD but no clear role in maintenance of CD. Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. Peroxisome proliferator activated receptor γ (PPAR-γ) may mediate 5-ASA therapeutic action by decreasing nuclear localization of NF-κB. Sulfa-free aminosalicylate formulations include alternative azo-bonded carriers, 5-ASA dimers, and delayed-release and controlled-release preparations. Each has the same efficacy as sulfasalazine when equimolar concentrations are used.


InternalMed_Harrison

InternalMed_Harrison. Sulfasalazine was originally developed to deliver both antibacterial (sulfapyridine) and anti-inflammatory (5-ASA) therapy into the connective tissues of joints and the colonic mucosa. The molecular structure provides a convenient delivery system to the colon by allowing the intact molecule to pass through the small intestine after only partial absorption and to be broken down in the colon by bacterial azo reductases that cleave the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine is effective treatment for mild to moderate UC and is occasionally used in Crohn’s colitis, but its high rate of side effects limits its use. Although sulfasalazine is more effective at higher doses, at 6 or 8 g/d up to 30% of patients experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis,


InternalMed_Harrison

InternalMed_Harrison. such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities. Sulfasalazine can also impair folate absorption, and patients should be given folic acid supplements.


InternalMed_Harrison

InternalMed_Harrison. Balsalazide contains an azo bond binding mesalamine to the car-1959 rier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon. Olsalazine is composed of two 5-ASA radicals linked by an azo bond, which is split in the colon by bacterial reduction, and two 5-ASA molecules are released. Olsalazine is similar in effectiveness to sulfasalazine in treating UC, but up to 17% of patients experience nonbloody diarrhea caused by increased secretion of fluid in the small bowel.


InternalMed_Harrison

InternalMed_Harrison. Delzicol and Asacol HD (high dose) are enteric-coated forms of mesalamine with the 5-ASA being released at pH >7. They disinte grate with complete breakup of the tablet occurring in many different parts of the gut ranging from the small intestine to the splenic flexure; they have increased gastric residence when taken with a meal. Asacol has recently been discontinued and replaced with Delzicol, which lacks dibutyl phthalate (DBP), an inactive ingredient in Asacol’s enteric coating. DBP has been associated with adverse effects on the male reproductive system in animals at very high doses. Asacol HD with the same chemical in its coating is still on the market, but the human doses of DBP are within acceptable limits of toxicity.


InternalMed_Harrison

InternalMed_Harrison. Lialda is a once-a-day formulation of mesalamine (Multi-Matrix System [MMX]) designed to release mesalamine in the colon. The MMX technology incorporates mesalamine into a lipophilic matrix within a hydrophilic matrix encapsulated in a polymer resistant to degradation at a low pH (<7) to delay release throughout the colon. The safety profile appears to be comparable to other 5-ASA formulations. Apriso is a formulation containing encapsulated mesalamine granules that delivers mesalamine to the terminal ileum and colon via a proprietary extended-release mechanism (Intellicor). The outer coating (Eudragit L) dissolves at a pH >6. In addition, there is a polymer matrix core that aids in sustained release throughout the colon. Because Lialda and Apriso are given once daily, an anticipated benefit is improved compliance compared with two to four daily doses required for other mesalamine preparations.


InternalMed_Harrison

InternalMed_Harrison. Pentasa is another mesalamine formulation that uses an ethylcellulose coating to allow water absorption into small beads containing the mesalamine. Water dissolves the 5-ASA, which then diffuses out of the bead into the lumen. Disintegration of the capsule occurs in the stomach. The microspheres then disperse throughout the entire GI tract from the small intestine through the distal colon in both fasted and fed conditions. Salofalk® Granu-Stix, an unencapsulated version of mesalamine, has been in use in Europe for induction and maintenance of remission for several years.


InternalMed_Harrison

InternalMed_Harrison. Appropriate doses of the 5-ASA compounds are shown in Table 351-7. Some 50–75% of patients with mild to moderate UC improve when treated with 5-ASA doses equivalent to 2 g/d of 1960 mesalamine; the dose response continues up to at least 4.8 g/d. As a general rule, 5-ASA agents act within 2–4 weeks. 5-ASA doses equivalent to 1.5–4 g/d of mesalamine maintain remission in 50–75% of patients with UC. More common side effects of the 5-ASA medications include headaches, nausea, hair loss, and abdominal pain. Rare side effects of the 5-ASA medications include renal impairment, hematuria, pancreatitis, and paradoxical worsening of colitis. Renal function tests and urinalysis should be checked yearly. Topical Rowasa enemas are composed of mesalamine and are effective in mild-to-moderate distal UC. Clinical response occurs in up to 80% of UC patients with colitis distal to the splenic flexure. Combination therapy with mesalamine in both oral and enema form is more effective than either


InternalMed_Harrison

InternalMed_Harrison. UC. Clinical response occurs in up to 80% of UC patients with colitis distal to the splenic flexure. Combination therapy with mesalamine in both oral and enema form is more effective than either treatment alone for both distal and extensive UC. Canasa suppositories composed of mesalamine are effective in treating proctitis.