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Peptic duodenal diseases
Clinical features
Peptic duodenitis and peptic ulcer disease (PUD) represent a continuum of the same disease process, namely acute and chronic inflammation of the duodenal mucosa resulting from the toxic effects of excess gastric acid. It is most common in Westernized countries and estimated to affect up to 10% of the population. Peptic disease is more common among patients who are older than 40 years and male.
Our current understanding of peptic duodenal diseases is that gastric peptic ulcers primarily result from altered mucosal defenses, whereas peptic duodenitis and peptic ulcers of the duodenum are associated with increased acid production. Chronic infection with Helicobacter pylori is highly correlated with peptic disease of the duodenum and is associated with greater than 80% of peptic ulcers in this region. Peptic disease of the duodenum is also commonly seen in patients who smoke, take nonsteroidal anti-inflammatory drugs (NSAIDs) chronically for other conditions, have renal insufficiency, or have duodenal immotility, which allows prolonged contact with gastric acid. Cystic fibrosis predisposes to ulcers resulting from decreased bicarbonate secretion.
The clinical features of peptic duodenitis are essentially the same as for PUD, with the most common symptom being burning epigastric pain relieved by eating. In severe cases, the pain may be constant and accompanied by nausea and vomiting.
Patients with multiple duodenal ulcers represent the most severe form of the disease; multiple duodenal ulcers most often accompany Zollinger-Ellison syndrome (ZES). Examples of ulcer disease in ZES include ulcers in the distal duodenum or jejunum, repeated perforating ulcers, or the presence of multiple ulcers. In the absence of ZES, refractory ulcers may be seen in patients with a prior intestinal wall perforation by the ulcer, smokers, chronic NSAID users, patients with gastric outlet obstruction/duodenal stenosis, or individuals who have had a gastric bypass procedure.
Pathologic features
Gross findings
Peptic duodenitis is most commonly seen in the duodenal bulb. The endoscopic appearance of peptic duodenitis varies from simple erythema to friability, erosions, and nodularity of the mucosa. Nodularity and frank polypoid lesions most often correspond to Brunner’s gland hyperplasia. In PUD, patients have symptoms that are similar to those of peptic duodenitis but also have evidence of mucosal ulceration. Duodenal ulcers resemble ulcers in other sites and show complete breakdown of the mucosa ( Fig. 5-1 ). The edges may show reactive and regenerative epithelial changes, acute inflammation, and granulation tissue formation. Most duodenal ulcers are circular and rarely exceed 3 cm in diameter. Ulcers located posteriorly in the duodenal bulb are more likely to bleed than those located elsewhere because of its proximity to the pancreaticoduodenal and gastroduodenal arteries. Penetration of a duodenal ulcer into one of these vessels may produce massive hemorrhage.
Microscopic findings
The microscopic findings characteristic of peptic duodenal disease include one or more of the following: inflammatory cells in the epithelium or lamina propria, damaged epithelium with or without gastric foveolar metaplasia, mucosal hemorrhage and edema, and Brunner’s gland hyperplasia with prominent ingrowth above the muscularis mucosae ( Figs. 5-2 through 5-4 ). Gastric foveolar metaplasia provides a definitive clue to the etiology of the mucosal injury and likely represents an adaptation to chronic exposure to hyperacidicity (see Fig. 5-4 ). In the most severe form, the villi are blunted and may be entirely lost. The superficial epithelium is damaged and shows reactive and regenerative changes, including mild nuclear atypia, as well as gastric foveolar metaplasia and erosions. Active inflammation is present within the villi and crypts ( Fig. 5-5 ). Lymphoid aggregates, vascular dilatation, and edema may all be present. When peptic duodenitis progresses to erosive peptic duodenitis, superficial loss of the duodenal mucosa occurs, leading to mucosal ulceration with associated acutely inflamed granulation tissue, necrosis, and hemorrhage. Often biopsy samples taken from the ulcer edges will show changes of peptic duodenitis (e.g., reactive epithelial changes, gastric foveolar metaplasia).
Ancillary studies
Diff-Quik stains have utility in peptic duodenitis by demonstrating the presence of H. pylori organisms in association with the metaplastic gastric foveolar epithelium because these cells express the same surface receptors as normal gastric epithelium ( Fig. 5-6 ). A combination periodic acid-Schiff and alcian blue (PAS/AB) stain highlights the presence of neutral mucin characteristic of the gastric foveolar metaplasia (see Fig. 5-4 ). “Lipid hang-up” is physiologically normal vacuolization of the enterocyte cytoplasm resulting from a recent fatty meal ( Fig. 5-7 ). These vacuoles are PAS/AB negative ( Fig. 5-8 ); a similar finding is seen in abetalipoproteinemia.
Differential diagnosis
Other inflammatory disorders that affect the small bowel can enter into the differential diagnosis with peptic changes, including upper gastrointestinal (GI) tract Crohn’s disease and portal hypertensive duodenopathy. In both Crohn’s disease and portal hypertension, the inflammatory changes in this region may be nonspecific and include mild to moderate villous blunting and chronic inflammation, and gastric mucin cell metaplasia. Specific features to aid in the diagnosis of Crohn’s disease include granulomas, possible evidence of lower GI tract inflammatory disease, and the patchy nature of the acute and chronic changes. Gastric heterotopia may also be included in the differential diagnosis with peptic duodenitis resulting from the prominent gastric foveolar epithelium. However, unlike peptic duodenitis, gastric heterotopia can be recognized by normal-appearing oxyntic glands in association with the surface gastric mucinous epithelium.
Prognosis and therapy
The eradication of H. pylori and the use of acid-suppressive therapies improve symptoms in most patients with peptic duodenitis. Medical therapy is mainly intended to reduce gastric acid by small meals, antacids, and histamine-2 (H 2 ) blockers. Antibiotics may be added to the treatment regimen if H. pylori organisms are present. Avoidance of substances that promote gastric acid secretion, such as ethanol or aspirin is also recommended.
Bleeding ulcers are estimated to be responsible for up to 50% of all cases of acute hemorrhage from the upper GI tract. Up to 5% of patients may have bleeding that is brisk enough to cause hematochezia. Even if initially controlled, re-bleeding can affect up to one third of patients, most commonly patients in the seventh decade of life or beyond, or those with a visible vessel in the ulcer base. Refractory ulcers heal slowly or follow a relapsing and remitting course. Scarring of duodenal ulcers may lead to duodenal stricturing and obstruction.
Free perforation of a duodenal ulcer into the peritoneal cavity can be a catastrophic, life-threatening event. Most patients with this complication are elderly, and the perforations are associated with NSAID use in up to half of cases. However, in patients younger than 75 years, smoking may be a stronger risk factor for perforation than NSAIDs.
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Malabsorptive disorders
The term malabsorption is broadly used to describe any type or degree of dysfunction in the uptake of substances that are normally retained or absorbed by the small intestine. The underlying causes of malabsorption are broad and include luminal factors such as lactose deficiency and motility disorders, among others. In contrast, the malabsorption syndrome more specifically refers to the constellation of clinical findings that include diarrhea, steatorrhea, and associated secondary changes including weight loss and vitamin deficiencies from reduced absorption of nutrients.
Celiac disease
Clinical features
Once considered to be a rare childhood disorder, celiac disease (CD; also known as gluten-induced enteropathy, celiac sprue, or nontropical sprue) is now understood to be a multisystem autoimmune disorder that affects 1% of the population. In the most comprehensive U.S. study in which more than 13,000 adult and pediatric patients were screened, the overall prevalence of CD in a group with no risk factors was 1:133, while it was 1:22 in the first-degree relatives of an index case, 1:39 in second-degree relatives, and 1:56 in patients with either GI symptoms or an extragastrointestinal disorder associated with CD. The mean age of diagnosis is in middle adulthood.
According to the guidelines proposed by the European Society for Pediatric Gastroenterology and Nutrition and on recommendations from the National Institutes of Health Consensus Conference on Celiac Disease, unequivocal evidence of improvement on a gluten-free diet (GFD) is needed for definitive diagnosis of symptomatic CD. Celiac disease is present if histologic changes are found on small intestinal biopsy while the patient consumes a gluten-containing diet and unequivocal clinical improvement occurs while he or she maintains a GFD. A diagnosis of CD based solely on serologic markers (anti-transglutaminase II and anti-endomysial immunoglobulin A [IgA] is not accepted practice.
The classification and diagnosis of CD are based on GI manifestations; however, patients with extraintestinal complications are increasingly being recognized ( Table 5-1 ). The clinical presentation of CD ranges from asymptomatic to severe malnutrition. The most common manifestations of CD include abdominal pain, increased frequency of bowel movements, weight loss, bone disease, anemia, and weakness. CD may be divided into three clinical subtypes. In the classic, symptomatic form of the disease, patients exhibit chronic diarrhea, abdominal distension, pain, weakness, and, in advanced cases, malabsorption. In contrast, in the atypical form of the disease, GI symptoms may be less pronounced to absent. Instead, extraintestinal features such as anemia, osteoporosis, short stature, infertility, and neurologic problems are predominant. Finally, some patients have asymptomatic or silent CD; they lack classic or atypical symptoms but have unequivocal villous atrophy found incidentally for other reasons or following serologic screening.
| Endocrine disorders |
| Type 1 diabetes mellitus |
| Autoimmune thyroid disorders |
| Addison’s disease |
| Reproductive disorders (infertility, miscarriages) |
| Osteoporosis |
| Alopecia areata |
| Neurologic disorders |
| Cerebellar ataxia |
| Neuropathy |
| Epilepsy |
| Migraines |
| Cardiac disorders |
| Idiopathic dilated cardiomyopathy |
| Autoimmune myocarditis |
| Hepatic disorders |
| Primary biliary cirrhosis |
| Autoimmune hepatitis |
| Autoimmune cholangitis |
| Other |
| Dermatitis herpetiformis |
| Anemia |
| Selective IgA deficiency |
| Sjögren’s syndrome |
| Juvenile chronic arthritis |
| Turner’s syndrome |
| Down syndrome |
| Dental enamel defects |
The pathogenesis of CD involves environmental, genetic, and immunologic features, and can be viewed as both luminal events and cellular events leading to the eventual activation of immune cells and ensuing tissue damage.
Environmental
Enteric exposures to certain glutamine-rich proteins in the dietary grains wheat, rye, and barley are known to be essential for the development of CD. The actual proteins that can trigger the disease are the gliadins in wheat, the hordeins in barley, and the secalins in rye. Many of these peptides are poorly digested by the intestinal tract proteases and make their way intact through the epithelium into the lamina propria. Once in the lamina propria, intact peptides are deamidated by tissue transglutaminase converting the abundant glutamine residues to glutamic acid, thus rendering them negatively charged. The negative charged peptides are more efficiently bound to the specific HLA-DQ2 or HLA-DQ8 receptors on the surface of the antigen presenting cells. Intestinal DQ2- or DQ8-restricted CD4+ T cells then recognize the deamidated gliadin peptides and elaborate inflammatory cytokines.
Genetic
The major genetic risk factors for CD are the HLA class II genes HLA-DQ2 and HLA-DQ8 . Approximately 95% of all patients with CD have a DQ2 heterodimer, and almost all remaining patients with CD have a DQ8 heterodimer. Gene dosage correlates with the risk for developing CD, with patients homozygous for DQ2 carrying the greatest risk. CD is concordant in 70% to 80% of monozygotic twins, 30% to 40% of HLA-identical siblings, and less than 20% of dizygotic twins, a rate similar to that for all first-degree relatives. However, recent linkage studies suggest that non-HLA disease-associated genes may also play a role.
Immunologic
It is well accepted that DQ2- and DQ8-restricted CD4+ T-cell populations that recognize disease-activating peptides are present in the intestinal mucosa of CD patients. When activated, these cells elaborate cytokines such as interferon-γ that promote inflammation and intestinal injury. Nonspecific upregulation of the gut immune system may also play a role, as evidenced by the frequent overt clinical GI symptoms that develop in patients with clinically silent CD after viral gastroenteritis, traveler’s diarrhea, or GI surgery.
High-risk groups to be screened for CD are those with the presence of other autoimmune diseases such as type 1 diabetes mellitus and autoimmune thyroiditis, a family history of CD, selective IgA deficiency, or dermatitis herpetiformis. CD is also more common in certain pediatric populations, including those with Down syndrome, where the frequency of CD is as high as 10%. In this group, CD is usually not detectable on the basis of GI symptoms.
Other manifestations may dominate the clinical picture, including failure to thrive, osteoporosis, refractory iron deficiency anemia, arthritis, peripheral neuropathies, cerebellar ataxia, dermatitis herpetiformis, and infertility.
Definition
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A multisystem autoimmune disorder caused by an immune response to dietary gluten and related proteins
Incidence
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1% of the U.S. population
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1 in 133 patients with no risk factors
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1 in 29 patients with at least one first-degree relative with CD
Morbidity and mortality
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20-fold higher risk for enteropathy-associated T-cell lymphoma
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30-fold higher risk for small intestinal adenocarcinomas
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2- to 4-fold higher risk for oropharyngeal and esophageal carcinomas
Gender, race, and age distribution
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Wide age range: children and adults
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Well known in Northern Europeans, rare in Southeast Asians, incidence unknown in Africans, common in pockets in the Middle East
Clinical features
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Variable: ranges from asymptomatic to severe malnutrition
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Most common presentation is weight loss, abdominal pain, diarrhea
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Extraintestinal manifestations include type 1 diabetes, osteoporosis, dermatitis herpetiformis, and various neuropathies
Prognosis and therapy
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Complete resolution of GI pathology with strict GFD
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Refractory CD refers to those patients on GFD without resolution of disease—up to 80% of cases associated with a clonal T-cell population.
Pathologic features
Gross findings
Typically the gross specimen consists of a tiny biopsy. If the specimen is assessed under a dissecting microscope (which is seldom done), delicate villi are attenuated to absent. Endoscopically, villous flattening can be suggested.
Microscopic findings
The hallmark features of CD are intraepithelial and lamina propria chronic inflammation leading to villous atrophy and malabsorption. The earliest change in CD is the presence of increased intraepithelial lymphocytes within the villi and throughout the villous epithelium with extension to the villous tips ( Fig. 5-9 ). With persistent disease, epithelial damage ensues with associated villous blunting, crypt hyperplasia, and increased chronic inflammation of the lamina propria ( Figs. 5-10 and 5-11 ). In severe CD, complete loss of villous architecture is seen with the bowel mucosa appearing atrophic. The patient may or may not have active inflammation, but it is usually focal. Because the disease may be patchy, up to six different biopsy samples must be taken. Such sampling will ensure that some sections will be oriented correctly to determine the degree of villous atrophy, as well as the degree of epithelial lymphocytosis, epithelial damage, and inflammation.
Upon initiation of a GFD, patients often report a marked improvement in symptoms. Microscopically, intestinal biopsies show diminished surface epithelial injury, a reduced number of intraepithelial lymphocytes, and partial return of villous architecture. Long-term changes on a GFD include return to normal villous architecture, normal mitotic proliferative activity, and clearance of chronic inflammation. If gluten is restored to the diet, a rapid return of all lesions and malabsorption will ensue.
Gross findings
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Attenuated to absent villi (as seen under a dissecting microscope)
Microscopic findings
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Variable degrees of villous atrophy
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Chronic inflammation
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Intraepithelial lymphocytes
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Epithelial damage
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Crypt hyperplasia
Differential diagnosis
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Bacterial overgrowth
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Colchicine toxicity
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Refractory sprue
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Lymphocytic enteritis
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Radiation enteritis
Ancillary studies
The histologic features of CD on routine stains are quite characteristic; thus, ancillary studies are not necessary for the diagnosis, although some observers have advocated immunophenotyping of intraepithelial lymphocytes (see Fig. 5-11 ).
Differential diagnosis
In the absence of an appropriate clinical history, a number of additional entities can enter into the differential diagnosis of CD based on the histologic features, including tropical sprue, bacterial overgrowth, and various drug toxicities such as colchicine. In tropical sprue, the characteristic histologic changes are resulting from a postinfectious enteritis. A travel history and appropriate serologic studies for infectious organisms may help determine this possibility. In bacterial overgrowth syndrome, in addition to the villous atrophy, the degree of active inflammation of the villi and crypts is often in excess of that expected for CD. A prior history of abdominal surgery or bypass procedure may be found in these patients and in some cases a prior antibiotic history. Finally, in some patients taking colchicine for gout or other indication, small bowel damage simulating CD may be found. The histologic clues are numerous ring mitoses and loss of goblet cell polarity.
Prognosis and therapy
A lifelong adherence to a GFD is the mainstay of safe and effective treatment of CD. Commonly substituted grains in the GFD include rice, corn, quinoa, and buckwheat. Serum antiendomysial, anti-transglutaminase II, and antigliadin antibodies are used to screen and check the effectiveness of a GFD. Patients whose disease does not respond to dietary therapy should undergo a systematic evaluation including review of the patients’ diet by an expert dietician and review of the original biopsy slides. Associated conditions that must be ruled out include pancreatic insufficiency, lymphocytic colitis, bacterial overgrowth, and true refractory sprue with a clonal T-cell population.
The most frequent malignant complication of CD is a high-grade T-cell non-Hodgkin’s lymphoma (NHL) of the upper small intestine defined as enteropathy-associated T-cell lymphoma (EATL). This rare T-cell disorder is 20 times more common in patients with CD. The EATL immunophenotype is consistent with a derivation from a clonal proliferation of intraepithelial lymphocytes (IELs). In some cases, EATL represents the end-stage evolution of refractory CD unresponsive to a GFD. In 80% of cases of refractory CD, an abnormal clonal population of IELs can be demonstrated characterized by T-cell receptor gene rearrangement. This is the precursor lesion to EATL, and it is associated with a high risk for ulcerative jejunitis and lymphomatous transformation characterized clinically by weight loss, diarrhea, abdominal pain, fever, lymphadenopathy, hepatomegaly, and at times a palpable abdominal mass. Approximately 50% of patients require laparotomy for complications of hemorrhage, perforation, or obstruction. In previous studies, the 5-year survival rate was 10%.
Patients with CD have more than a 30-fold increased risk for small bowel adenocarcinoma as compared with the general population, and 13% of patients with a small bowel adenocarcinoma have underlying CD. Other malignancies potentially associated with CD include papillary thyroid carcinoma and malignant melanoma.
The question of whether the early diagnosis and treatment of CD reduces the risk for developing other autoimmune diseases is still under debate. There are several lines of evidence that support the notion that CD is a causative factor in the development of other autoimmune diseases. The presence of autoimmune disease is closely related to the duration of gluten exposure and the age of initiation of a GFD, with children diagnosed and treated before 2 years of age having little subsequent increased risk. Older children diagnosed with CD have a higher than expected frequency of organ-specific autoantibodies that tend to disappear after starting a GFD.
Uncommon causes of malabsorption
A rare but important disorder related to CD is tropical sprue (postinfective tropical malabsorption), defined as intestinal malabsorption of unknown etiology, occurring among residents in or visitors to the tropics. No single etiologic agent has been identified to account for tropical sprue. However, evidence in favor of an infectious etiology is that an infection often initiates and sustains tropical sprue; tropical sprue occurs in specific geographic areas (West Indies and the Indian subcontinent) where enteric infections are common; in some areas tropical sprue is endemic; aerobic bacteria colonize the patient’s small intestine and may be toxic producing; and recovery from tropical sprue with antibiotics is usually rapid and dramatic. Protozoan infections such as with Cyclospora have been suggested to play a role. Other factors such as epithelial damage may also contribute to the condition because folate and vitamin B 12 deficiencies are commonly present in these patients. In severe tropical sprue there can be resulting diminution in epithelial mitosis accompanied by nuclear enlargement, changes that are the epithelial counterpart to maturational derangements in the marrow and macrocytic anemia (megaloblastic changes). Genetic or ethnic predispositions have also been suggested.
The mucosal lesion in tropical sprue is nonspecific, with epithelial blunting, chronic inflammation, and focal neutrophil infiltrates in the epithelium and lamina propria ( Fig. 5-12 ). A completely flat biopsy finding like that seen in CD is rare in tropical sprue, but epithelial dysfunction, as in CD, is central to its pathogenesis. Unlike CD, in which mucosal changes are greatest in the proximal small bowel, lesions in the ileum are as prominent as in the proximal small bowel in tropical sprue. This fits well with the resulting secondary vitamin B 12 and folate deficiency states that are uncommon in CD. Intraepithelial lymphocytes are increased in tropical sprue but are often more numerous in the crypts than in the villi.
Bacterial overgrowth is another cause of malabsorption. All causes of bacterial overgrowth are related to stasis; thus, these disorders are also known as stasis syndrome. Causes of stasis in the small bowel include motor/neural disorders such as diabetic neuropathy and scleroderma, as well as structural lesions, such as diverticula and surgical anastomoses. The pathophysiology of stasis is largely caused by anaerobic bacteria that deconjugate bile salts, deplete vitamin B 12 , and damage surface epithelium. Stasis in the small bowel, regardless of the etiology, may result in abnormal inflammatory changes in the mucosa. As with most small bowel disorders, the histologic features are nonspecific and include mild to moderate villous blunting, which may be accompanied by an increase in lamina propria mononuclear cells and focal neutrophilic infiltrates in the epithelium. At low power these changes may mimic partially developed or treated CD, although bacterial overgrowth typically lacks the intense intraepithelial lymphocytosis of CD, and the findings may be focal.
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Microvillus inclusion disease
Microvillus inclusion disease is one of several causes of intractable diarrhea in infancy.
Clinical features
Babies with intractable diarrhea of infancy have a clinical presentation including the presence of diarrhea for more than 2 weeks, severe nutritional malabsorption, and negative stool cultures. Their condition is life-threatening and can require total parenteral nutrition. When a baby has such a presentation, the clinical differential diagnosis is mostly among autoimmune enteropathy and lesions displaying primary enterocyte abnormalities. These are rare conditions and are considered once causes of protracted diarrhea (which responds to bowel rest in contrast to intractable diarrhea) are excluded (Bruton’s agammaglobulinemia, allergic enteropathy, and severe infection).
Microvillus inclusion disease is an uncommon congenital enteropathy, producing intractable secretory diarrhea in early infancy. It is an inherited disease in an autosomal-recessive genetic trait pattern and, not surprisingly, more common among highly inbred populations. Synonyms used for this disease include Davidson’s disease, familial microvillus atrophy, congenital microvillus atrophy, and intestinal microvillus dystrophy (a variant of microvillus inclusion disease). The outcome is typically poor, with most patients requiring small bowel transplantation. Rare cases have resolved.
Definition
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A primary enterocyte anomaly that results in intractable diarrhea of infancy
Incidence and location
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Rare
Morbidity and mortality
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High morbidity and mortality
Gender, race, and age distribution
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No gender predominance, affects infants, autosomal recessive, common in populations prone to consanguinity (tribal Saudis, Native Americans)
Clinical features
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Intractable diarrhea of infancy requiring total parenteral nutrition
Prognosis and therapy
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Invariably fatal without surgical intervention (small bowel transplantation) or total parenteral nutrition
Pathologic features
Gross findings
Microvillus inclusion disease usually results in biopsy specimens rather than specific gross specimens.
Microscopic findings
Biopsy samples of duodenal mucosa show moderate villous blunting with no active inflammatory reaction or intraepithelial lymphocytosis. The optimal specimen is a small intestinal sample; duodenal biopsy is most commonly used. Architecturally, diffuse intestinal villous atrophy without inflammation is a characteristic feature. Because of increased crypt cell apoptosis, either crypt hypoplasia or hyperplasia can be found. The characteristic histologic changes in the enterocytes are confined to the villous tips and distal villous lateral borders. Changes are difficult to discern at the base of the villus and in the crypt epithelium; the enterocytes appear normal in these regions. Cytologically, a bubbly vacuolated appearance of the apical cytoplasm with extensive or patchy absence of the brush border is a specific sign for the diagnosis ( Fig. 5-13 ). Typical targetoid cytoplasmic inclusions are occasionally identified in the surface enterocytes. Instead of a sharp linear brush border that stains with PAS or alkaline phosphatase histochemically, a bright apical cytoplasmic blush is present and is the most easily recognized change of microvillus inclusion disease ( Fig. 5-14 ).
