RHEUMATOID ARTHRITIS

Approximately 0.8% of adults worldwide are affected with rheumatoid arthritis (RA), which is a chronic, inflammatory autoimmune disease primarily targeting the synovial tissues with systemic manifestations. Oropharyngeal symptoms may occur in patients with RA as a result of xerostomia, temporomandibular joint (TMJ) arthritis, cervical spine abnormalities, and laryngeal involvement.¹ Esophageal dysmotility, characterized by low-amplitude peristaltic waves, has been described in the proximal, middle, and distal esophagus with reduced lower esophageal sphincter (LES) pressure.^1,2 Rheumatoid vasculitis typically occurs in the setting of severe RA with rare gastrointestinal manifestations such as ischemic cholecystitis or appendicitis, ulceration, pancolitis, infarction, or intra-abdominal hemorrhage due to a ruptured visceral aneurysm.^3,4 Other gastrointestinal complications of RA include amyloidosis (discussed later) and malabsorption. Felty’s syndrome–RA, splenomegaly, and leukopenia have been associated with severe infections, portal hypertension, and variceal hemorrhage.⁵

ADULT-ONSET STILL’S DISEASE

Adult-onset Still’s disease, the adult form of juvenile RA, often has gastrointestinal manifestations such as weight loss, sore throat, hepatosplenomegaly, elevated aminotransferases, and abdominal pain, in addition to fever.⁴⁴ In contrast to the lack of significant hepatic dysfunction in classic rheumatoid arthritis, adults with Still’s disease present with features of mild hepatitis in the majority of cases and life-threatening acute liver failure in exceptional cases.^45–49 Variable degrees of aminotransferase and alkaline phosphatase elevations are typically observed in such patients during symptomatic disease flares. Liver biopsies usually reveal moderate portal mononuclear cell infiltration with occasional evidence of focal hepatocyte necrosis.⁴⁶ Biopsies obtained in patients with jaundice and biochemical evidence of severe hepatitis have been found to have interface and lobular hepatitis with lymphoplasmocytic inflammation reminiscent of autoimmune hepatitis.⁴⁹ Most cases of severe hepatitis have been observed in patients previously treated with salicylates or other NSAIDs,^46,49 but liver enzyme abnormalities are also commonly noted prior to therapy. Some patients with severe hepatitis have been reported to respond to immunosuppressive therapy,⁴⁹ whereas others required liver transplantation or have died of liver failure.^45,47–49 Although severe hepatitis is a rare complication of adult-onset Still’s disease, liver failure appears to be the most common cause of death related to this disease.⁴⁵

PROGRESSIVE SYSTEMIC SCLEROSIS

Progressive systemic sclerosis (PSS, scleroderma) is a multisystem disorder characterized by obliterative small vessel vasculitis and proliferation of connective tissue with fibrosis of multiple organs. Patients with limited cutaneous involvement frequently display findings of the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias).

Gastrointestinal manifestations occur in up to 90% of patients with PSS.⁵⁰ Gastrointestinal tract involvement can occur from the mouth to the anus. Atrophy and fibrosis of the perioral skin may limit mandibular motion. The periodontal ligament may become hypertrophic, and the gingivae, tongue papillae, and buccal mucosa may become friable and atrophic, resulting in impaired sensation and taste.

The esophagus is the most frequently involved gastrointestinal organ.⁵⁰ On pathology, atrophy of smooth muscle layers and intimal proliferation of arterioles is seen in the distal esophagus.⁵¹ Dysphagia occurs as a result of impaired esophageal motility, and gastroesophageal reflux disease (GERD) is related to hypotensive LES pressures, impaired esophageal clearance of acid, and reduced acid-neutralizing capacity due to xerostomia with reduced saliva production.⁵² The incidence of esophagitis approaches 100% in patients with severe cutaneous involvement.⁵³ The extent of hypomotility varies from occasional uncoordinated contractions to complete paralysis.⁵⁴ The severity of esophageal dysmotility correlates with the development of interstitial lung disease.^55,56 Stricture formation from GERD may contribute to dysphagia, affecting approximately 8% of patients.⁵⁷ Upper gastrointestinal hemorrhage has been reported from esophageal ulcers, rare esophageoatrial fistulas, and esophageal telangiectasia.^58,59 An increased risk of infectious esophagitis with Candida (see Chapter 45) has been attributed to esophageal dysmotility and concomitant immunosuppressive therapy.⁶⁰ Severe esophagitis typically responds to proton pump inhibitors but may require higher doses for maximal effect.⁶¹ A neuropathic achalasia-like syndrome has also been reported.⁶² The prevalence of Barrett’s metaplasia of the esophagus in patients with PSS ranges between 7% and 38%.^63,64 A recent cohort study reported an increased incidence of carcinoma of the tongue and esophagus in patients with PSS.⁶⁵

Gastric involvement most commonly leads to gastroparesis but other manifestations may include dyspepsia, exacerbation of GERD, or gastric hemorrhage from gastric antral vascular ectasia (GAVE, watermelon stomach). Delayed gastric emptying has been shown using radionucleotide scintigraphy or radiopaque pellets, with cutaneous electrogastrography demonstrating bradygastria and decreased amplitude of electrical activity.^56,66,67 Prokinetic agents such as metoclopramide and erythromycin may increase LES pressures and improve gastric emptying in some patients with PSS.⁵⁷

The pathologic changes in the small bowel of PSS patients consist of smooth muscle atrophy and deposition of collagen in submucosal, muscular, and serosal layers. Small bowel hypomotility is present in as many as 88% of cases.⁶⁸ In the early stages of the disease, hypomotility is caused by neuropathic involvement, which may be more responsive to prokinetic agents. In advanced cases, hypomotility is more likely a result of “myopathic” and “fibrotic” changes.⁵⁷ The interdigestive migrating motor complex (IMMC) is frequently absent or markedly diminished in amplitude in PSS patients with symptoms of intestinal dysmotility.⁶⁹ Small bowel radiographic abnormalities are present in about 60% of PSS patients, but they may not correlate with symptoms. The duodenum is often dilated, especially in its second and third portions, often with prolonged retention of barium.⁷⁰ Typically the jejunum is dilated and foreshortened because of mural fibrosis, but valvulae conniventes of normal thickness give rise to an accordion-like appearance. Pneumatosis cystoides intestinalis, pseudo-obstruction, pseudodiverticula, sacculations, intussusception, acquired intestinal lymphangiectasia, and small bowel volvulus have been noted.^71–73

Symptoms of small intestinal PSS include bloating, borborygmi, anorexia, nausea, and vomiting. Rarely, thrombosis of large mesenteric arteries with extensive bowel necrosis may occur.⁷⁴ Malabsorption with steatorrhea is present in as many as a third of PSS patients⁶⁸ and is caused by bacterial overgrowth (see Chapters 101 and 102). Although antibiotic therapy can be effective in these patients, d-xylose malabsorption is often incompletely reversed, suggesting that collagen deposition in PSS may also contribute to malabsorption.⁷⁵ Although often disappointing, the use of prokinetic agents such as metoclopramide may be effective in some cases. Octreotide in low doses and erythromycin also may provide sustained relief from nausea, abdominal pain, and bloating in some patients with pseudo-obstruction.⁷⁶

Delayed colonic transit and impaired anal sphincter function are frequently found in constipated patients with PSS.^77,78 Cisapride (a drug no longer available in the United States) accelerates colonic transit,⁷⁹ but refractory cases may require surgery.⁸⁰ Colonic stricture, volvulus, and bleeding from mucosal telangiectasias have been reported.^81,82 Wide-necked diverticula can be seen, especially in the antimesenteric border of the transverse and descending colons. Rectal prolapse worsens anal sphincter function, aggravating fecal incontinence in patients with PSS.⁸³ Rectal bleeding can occur from vascular ectasia.⁸⁴

Pancreatic exocrine secretion is depressed in a third of patients with PSS, and idiopathic calcific pancreatitis has been reported.⁸⁵ In addition, arteritis resulting in ischemic pancreatic necrosis has been described in patients with PSS.^86,87 Gallbladder motility is not altered in PSS.⁸⁸

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is a multisystem disease characterized by immune system abnormalities and the production of autoantibodies with tissue damage. Gastrointestinal symptoms are common in patients with active SLE. Oral ulcers (one of the criteria used to diagnose SLE) are most commonly seen in the buccal mucosa, hard palate, and vermilion border.⁸⁹ In SLE, dysphagia (1% to 13% of patients) and GERD (11% to 50% of patients) poorly correlates with esophageal manometric abnormalities such as hypoperistalsis.⁹⁰ Dysphagia is typically related to GERD or peptic stricture, with one report of esophageal epidermolysis bullosa acquisita.⁹¹ Malabsorption of d-xylose, steatorrhea, hyperplastic gastropathy, and protein-losing enteropathy have been described (see Chapter 28); the latter can be steroid responsive.^92,93 Lupus peritonitis is a diagnosis that can be made only after other causes have been carefully excluded. Pneumatosis cystoides intestinalis may be an isolated benign condition or may accompany lupus vasculitis or necrotizing enterocolitis.^94,95

One of the most devastating complications of lupus is gastrointestinal vasculitis. Affecting only 2% of patients, it has a fatality rate of more than 50%.⁹⁶ Common sequelae include ulceration, hemorrhage, perforation, and infarction.^97–99 Pancreatitis,^100,101 gastritis, hemorrhagic ileocolitis resembling inflammatory bowel disease, and intussusception also have been reported. Although occasional case reports have documented polyarteritis-like changes on visceral arteriograms (described later), the typical pathologic changes are seen in the small vessels of the bowel wall rather than the medium-sized vessels of the bowel wall.⁹⁴ Computed tomography (CT) scan may help establish the diagnosis of ischemic bowel disease in SLE if there are at least three of the following five CT findings: (1) bowel wall thickening, (2) target sign (a thickened bowel wall with peripheral rim enhancement or an enhancing inner and outer rim with hypoattenuation in the center), (3) dilatation of intestinal segments, (4) engorgement of mesenteric vessels, and (5) increased attenuation of mesenteric fat.¹⁰² Because visceral angiography is not routinely helpful, the diagnosis is difficult to establish. The role of endoscopy or upper gastrointestinal series in the diagnosis of lupus vasculitis is not well defined. The diagnosis currently rests on clinical judgment, findings on CT scans, and occasionally from surgical specimens when exploratory laparotomy is undertaken to rule out acute surgical emergencies.¹⁰³ Treatment of abdominal lupus-induced vasculitis with glucocorticoids has been largely unsatisfactory. Although a controlled clinical trial comparing cyclophosphamide with glucocorticoids has not been performed, anecdotal reports of dramatic responses to intravenous cyclophosphamide are promising.⁹⁴ Some investigators have suggested that cyclophosphamide be considered early in patients who have not shown significant improvement shortly after high-dose glucocorticoids are started.

Patients with SLE have a 25% to 50% incidence of abnormal liver biochemical tests during the course of their disease, but clinically significant liver disease is rare.¹⁰⁴ Abnormal liver tests are commonly associated either with medication use or with mild, predominantly lobular hepatitis associated with periods of SLE activity.^104,105 Despite the shared association with antinuclear antibodies, the typical histologic and clinical features of autoimmune hepatitis are rarely observed in adult patients with SLE.^104,106 Concurrent SLE and autoimmune hepatitis occur more frequently in pediatric patients.¹⁰⁶ In addition, SLE patients with anticardiolipin antibodies or lupus anticoagulants may have thrombotic events in the liver leading to Budd-Chiari syndrome or nodular regenerative hyperplasia manifested by complications of portal hypertension.^104,107

POLYMYOSITIS AND DERMATOMYOSITIS

Polymyositis is a syndrome characterized by weakness, high serum levels of striated muscle enzymes (creatine kinase, aldolase), and electromyographic (EMG) or biopsy evidence of an inflammatory myopathy. When accompanied by a characteristic violaceous rash on the extensor surfaces of the hands and periorbital regions, the disease is termed dermatomyositis. The primary gastrointestinal symptoms are due to involvement of the cricopharyngeus, resulting in nasal regurgitation, tracheal aspiration, and impaired deglutition.¹⁰⁸ Involvement is not limited to skeletal muscle fibers. Disordered esophageal motility, impaired gastric emptying, and poorly coordinated small intestinal peristalsis have been noted.¹⁰⁹ Malabsorption, malnutrition, and pseudo-obstruction rarely occur.¹¹⁰ Pathologically, edema of the bowel wall, muscle atrophy, fibrosis, and mucosal ulcerations or perforation due to vasculitis may be seen at any level of the gut. Symptoms include heartburn, bloating, constipation, and gastrointestinal hemorrhage. Pneumoperitoneum, pneumatosis intestinalis, colonic dilation, and pseudodiverticula also may be seen. Perforations of the esophagus and of duodenal diverticula have been described as rare complications.^111,112

In middle-aged to older adult patients, dermatomyositis and possibly polmyositis are associated with an increased prevalence of malignancy.¹¹³ The possibility that gastrointestinal symptoms may be the resultl of an underlying malignancy should be considered when evaluating these patients (see Chapter 22).

MIXED CONNECTIVE TISSUE DISEASE

Mixed connective tissue disease (MCTD) is a syndrome with overlapping features of PSS, polymyositis, and SLE, often in the presence of high levels of antibody directed against ribonucleoprotein. Upper gastrointestinal symptoms are seen in most patients.¹¹⁴ Abnormalities include diminished esophageal peristalsis (48%), esophageal stricture (6%), abnormal gastric emptying (6%), and gastric bezoar (2%).¹¹⁴ Small intestinal and colonic involvement includes dilation of proximal bowel, slow transit, intestinal pseudo-obstruction, diverticulosis, and, rarely, intestinal vasculitis. Pancreatitis also has been reported.¹¹⁴ Unlike PSS, the esophageal motility disturbances seen in MCTD appear to improve with the administration of glucocorticoids.

SJÖGREN’S SYNDROME

Sjögren’s syndrome (SS), occurring alone (primary SS) or in association with systemic autoimmune rheumatic diseases (secondary SS), is characterized by lymphocytic tissue infiltration of lacrimal and salivary glands with the clinical findings of keratoconjunctivitis sicca and xerostomia. As reviewed in Chapter 22, excessive dryness of the mouth and pharynx leads to oral symptoms of soreness, adherence of food to buccal surfaces, fissuring of the tongue, and periodontal disease.¹¹⁵ Dysphagia, reported by up to three quarters of patients with SS, can result from esophageal dysmotility and a lack of saliva; however, symptoms do not correlate with manometry or salivary secretion.^116–118 Mild atrophic antral gastritis can be seen in 25% of patients with primary SS, but 31% were infected with H. pylori.¹¹⁹ Older studies that reported higher rates and greater severity of gastritis did not control for H. pylori infection. GAVE can occur in patients with SS and is responsive to fulguration therapy.¹²⁰ A triad of sclerosing cholangitis, chronic pancreatitis, and SS has been reported in eight patients.¹²¹ Pancreatic exocrine function is frequently impaired.¹²² In primary SS, 7% of patients have positive antimitochondrial antibodies and among patients with primary biliary cirrhosis, clinical manifestations of SS are common (see Chapter 89).¹¹⁵

POLYARTERITIS NODOSA AND OTHER VASCULITIDES

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small and medium-sized muscular arteries, frequently with visceral involvement (Fig. 35-1). A characteristic feature of this condition is the finding of aneurysmal dilatations up to 1 cm in size seen on visceral angiography (Fig. 35-2). Abdominal complications occur in up to 50% of patients and carries a poor prognosis.¹²³ Other clinical features of PAN include fever, myalgia, arthralgia of the large joints, mononeuritis multiplex, and livedo reticularis. Mesenteric visceral arteriograms are abnormal in up to 80% of patients with gastrointestinal involvement, with the superior mesenteric artery most commonly involved.¹²³ Organ damage resulting from ischemia frequently underlies symptoms. The most common gastrointestinal manifestation is abdominal pain with other common symptoms including nausea, vomiting, and gastrointestinal bleeding.¹²³ Bowel infarction and perforation, aneurysmal rupture, and acute cholecystitis are common causes of acute abdomen in PAN.¹²³ Rarely, PAN can present as acalculous cholecystitis secondary to isolated vasculitis of the gallbladder.¹²⁴ Pancreatitis,¹²⁵ appendicitis,¹²⁶ hemobilia,¹²⁷ solitary biliary strictures,¹²⁸ and hepatic infarcts¹²⁹ also have been reported to complicate PAN. The frequency of hepatitis B infection in PAN has declined from more than 30% to less than 10% because of improved screening of the blood supply and vaccination against hepatitis B.¹³⁰ Because of the frequent association with hepatitis B infection and potential association with hepatitis C infection (see Chapters 78 and 79), patients with clinical manifestations of PAN should be assessed for evidence of hepatitis B or C infection.

Figure 35-1. Sigmoidoscopic examination in an intravenous drug user who presented with a foot drop and fecal occult blood. Although not shown, the mucosa in the rectum and proximal sigmoid colon was entirely normal. A sural nerve biopsy confirmed the diagnosis of polyarteritis nodosa.

Figure 35-2. Celiac arteriogram in a patient with polyarteritis nodosa and hepatitis B surface antigenemia. Multiple saccular and fusiform aneurysms, as well as arterial tapering and beading, are seen throughout the celiac artery and its branches, especially the hepatic artery.

(Courtesy Connie Wofsy, MD.)

Churg-Strauss syndrome (CSS, allergic granulomatous angiitis) is a small to medium-sized vessel vasculitis characteristically associated with eosinophilia, asthma, sinusitis, and rhinitis. Abdominal pain is the most common gastrointestinal symptom.¹³¹ Preceding the vasculitic phase of CSS, patients may present with an eosinophilic gastroenteritis associated with abdominal pain, nausea, vomiting, diarrhea, and bleeding with an absolute eosinophil count of greater than 1500 cells/mm³ (see Chapter 27).¹³² Additional gastrointestinal manifestations of CSS include pancreatitis, cholecystitis, ascites, small intestinal ulcerations, and perforation.^131,133,134 Colonic involvement may present with multiple ulcers or obstruction.^134,135

Henoch-Schönlein purpura (HSP) is a systemic vasculitis characterized by nonthrombocytopenic purpura, arthralgias, renal disease, and colicky abdominal pain. Although the disease is frequently seen in children and adolescents, adults of any age may be affected. Colicky abdominal pain and gastrointestinal bleeding are seen in two thirds of cases.¹³⁶ Colonoscopic and endoscopic findings in bleeding patients include erosive duodenitis, small aphthous ulcerations, and petechial colonic lesions.¹³⁷ In patients who undergo CT scan, common findings include bowel-wall thickening, dilated intestinal segments, mesenteric vascular engorgement, and regional lymphadenopathy.¹³⁸ Other reported gastrointestinal complications of HSP include protein-losing enteropathy, esophageal and ileal structures, gastric and small bowel perforations, bowel infarction, pancreatitis, appendicitis, cholecystitis, intramural hematomas, and intussusception.¹³⁹

Malignant atrophic papulosis (Kohlmeier-Degos disease) is a rare vasculitis that causes nausea, vomiting, bleeding, malabsorption, bowel ischemia, and perforation.¹⁴⁰ Scattered on the skin are red papules that become hypopigmented atrophic scars (see Fig. 22-13).

Cogan’s syndrome is characterized by nonsyphilitic interstitial keratitis, audiovestibular symptoms, and large-vessel vasculitis that may involve the gut. Gastrointestinal manifestations include abdominal pain, diarrhea, hepatomegaly, and splenomegaly.¹⁴¹ Crohn’s disease has been reported in association with this rare condition.¹⁴²

Wegener’s granulomatosis, a systemic vasculitis characterized by pulmonary, sinus, and renal involvement, less commonly affects the gut.¹⁴³ Inflammatory ileocolitis with hemorrhage, gangrenous cholecystitis, and bowel infarction have been reported.¹⁴⁴ Wegener’s granulomatosis may mimic Crohn’s disease with granulomatous gastritis or ileitis.^145,146

Mixed immunoglobulin (IgG-IgM) cryoglobulinemia characterized by the triad of purpura, arthralgia, and asthenia may complicate chronic hepatitis C infection (see Chapter 79) and a variety of immune diseases, including inflammatory bowel disease, celiac disease, and postintestinal bypass syndrome. Cryoglobulinemia may cause severe visceral vasculitis with diarrhea, ischemia, and perforation of the small or large intestine.¹⁴⁷

BEHÇET’S DISEASE

Behçet’s disease is an idiopathic inflammatory disorder characterized by oral aphthous ulcers, genital ulcers, uveitis, and skin lesions, with gastrointestinal involvement occurring in up to 50% of patients.¹⁴⁸ As in Crohn’s disease, ulceration may occur throughout the alimentary tract, with the ileocecal region most commonly affected. Differentiating Behçet’s from Crohn’s disease can be difficult because of similarities in gastrointestinal symptoms, endoscopic findings, histology, and extraintestinal manifestations. Involvement of the esophagus includes ulcers (Fig. 35-3), varices, and perforation.¹⁴⁹ In the stomach, which is infrequently involved, aphthous ulcers may be seen. The typical intestinal involvement in Behçet’s disease includes “punched-out” ileocecal ulcerations, the most common finding on colonoscopy. Additional manifestations of Behçet’s disease include abdominal pain, diarrhea, bleeding, perforation, and fistulas (perianal, rectovaginal, and enteroenteric).¹⁵⁰ Hepatic or portal vein thrombosis may occur in patients with Behçet’s, and this syndrome should be included in the differential diagnosis of patients presenting with Budd-Chiari syndrome.^151,152 Medical therapy of the gastrointestinal lesions of Behçet’s disease includes mesalamine, glucocorticoids, immunomodulators such as azathioprine and 6-mercaptopurine, infliximab, and thalidomide.^153,154 Surgical intervention is associated with a high rate of recurrence, with nearly 50% requiring repeat surgery.¹⁵⁵

Figure 35-3. Aphthous ulcerations of the esophagus on an esophagogram in a patient with Behçet’s disease.

(Courtesy of the Radiology Learning Center, University of California School of Medicine, San Francisco, Calif.)

SERONEGATIVE SPONDYLOARTHROPATHIES (REACTIVE ARTHRITIDES)

The term seronegative spondyloarthropathy is used to describe an interrelated group of inflammatory disorders that include ankylosing spondylitis, reactive arthritis (formerly called Reiter’s syndrome), and psoriatic arthritis. The term has also been used to describe the enteropathic spondylitis associated with Crohn’s disease and ulcerative colitis.¹⁵⁶ These disorders are characterized by the absence of rheumatoid factor, an association with human leukocyte antigen-B27 (HLA-B27), and inflammation at the site of bony insertion of ligaments and tendons (enthesitis). There is a high prevalence of clinically silent inflammatory colon lesions in patients with these seronegative spondyloarthropathies.¹⁵⁷ Capsule endoscopy may yield more small bowel abnormalities than ileocolonoscopy.¹⁵⁸ Conversely, 22% of patients with inflammatory bowel disease have evidence of a seronegative spondyloarthropathy, with ankylosing spondylitis most commonly seen.¹⁵⁹ Although infliximab has been shown to induce remissions in some patients with ankylosing spondylitis as well as in Crohn’s disease, the effect of infliximab on gastrointestinal inflammatory lesions in typical seronegative spondyloarthropathies has not yet been studied.

MARFAN’S AND EHLERS-DANLOS SYNDROMES

Owing to defective collagen synthesis, patients with Marfan’s or Ehlers-Danlos syndrome develop skin fragility, megaesophagus, small intestine hypomotility, giant jejunal diverticula, bacterial overgrowth, and megacolon.¹⁶⁰ Mesenteric arterial rupture and intestinal perforation also can occur.¹⁶¹

FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease characterized by recurrent self-limiting attacks of fever, joint pain, and abdominal pain. Acute attacks typically last three to five days. FMF is most commonly seen in people of Mediterranean origin including Sephardic Jews, Arabs, Turks, Greeks, Italians, and Armenians, although FMF has been described in Cubans, and Belgians. The gene responsible for FMF in Mediterranean patients, designated MEFV, has been mapped to chromosome 16, which encodes a 781-amino acid protein called pyrin or marenostrin.¹⁶²

Gastrointestinal symptoms, typically manifest as episodic abdominal pain, are seen in 95% of patients, and this may be the presenting symptom in as many as 50% of cases.¹⁶³ Abdominal pain may be diffuse or localized and may range from mild bloating to acute peritonitis with boardlike rigidity, rebound tenderness, and air-fluid levels on upright radiographs. The acute presentation may be confused with acute appendicitis, cholecystitis, or pelvic inflammatory disease, whereas relapsing and remitting attacks may be confused with other diseases such as porphyrias. Small bowel obstruction from adhesions may occur as a consequence of recurrent sterile peritonitis or as a result of previous exploratory surgery. In patients with obstruction due to adhesions, abdominal attacks without other typical symptoms (arthralgias, fever) should tip off the clinician to consider an obstruction.¹⁶⁴ The diagnosis of FMF is based on validated clinical criteria including fever, serositis, location of pain, and response to colchicine.¹⁶⁵

In FMF, the long-term prognosis is poor in patients who develop nephrotic syndrome and chronic kidney disease from amyloid A deposition¹⁶³ (amyloidosis is discussed later in this chapter). Prophylactic colchicine has been shown to reduce the frequency of attacks, prevent amyloidosis, and avoid renal failure.¹⁶⁶ Vasculitis in the form of HSP, PAN, protracted febrile myalgia, or Behçet’s is encountered in 3% of FMF patients.¹⁶³

METASTASES

Metastasis to the gut can occur by direct invasion from adjacent organs, by intraperitoneal seeding, or by hematogenous or lymphatic spread. About 20% of all patients with nongastrointestinal malignancies have metastases to the gastrointestinal tract, the most common of which are breast, lung, and ovarian cancers and melanoma (Fig. 35-4).¹⁶⁷ Patterns of metastases are not random but reflect the location and histologic type of the primary tumor. The esophagus is most frequently affected by direct extension from tumors arising from adjacent structures (bronchus and stomach). The stomach is a particularly common site of breast cancer metastases, and the small intestine can be involved by tumor extension from the stomach, pancreas, biliary system, kidney, or retroperitoneum. The pancreas is usually an asymptomatic site of metastasis, with the most common primary tumors being lung, gastrointestinal, and renal.¹⁶⁸ The ileum may be affected by cancers arising in the colon or pelvis. Metastases to the gut typically begin in the serosa or submucosa and produce intraluminal lesions that can lead to obstruction, submucosal polypoid masses that can result in intussusception or ulcerated mucosal lesions. The most common presenting clinical condition in patients with metastatic lesions to the gut is small bowel obstruction. Lobular breast cancer, malignant melanoma, and non–small cell lung cancer are the most common neoplasms to cause small bowel obstruction from isolated metastases.¹⁶⁹ In addition, pain, fever, ascites, gastrointestinal bleeding, and perforation have been described.

Figure 35-4. Endoscopic view of an ulcerated metastatic melanoma lesion involving the second portion of the duodenum in a young man who presented with upper gastrointestinal bleeding.

Metastases to the gastrointestinal tract may be difficult to diagnose. Barium contrast studies may reveal extramural masses, mucosal ulcerations, or a rigid stomach with the appearance of linitis plastica. CT may be helpful in determining the primary tumor, in tumor staging, and in detecting large serosal implants. Small bowel metastases, however, are detectable radiographically in only 50% of cases.¹⁷⁰

When feasible, surgical resection should be used to treat gastrointestinal metastases that result in obstruction, perforation, or significant hemorrhage. If a solitary bowel metastasis is the only evident site of disseminated malignancy, segmental bowel resection should be performed, offering a small chance for cure. In aggressive resections of melanoma metastases, the mesenteric nodes draining the involved segment of bowel should be resected because they frequently contain tumors.¹⁷¹

PARANEOPLASTIC SYNDROMES

Paraneoplastic syndromes affecting the gut include the hormonal effects of carcinoid tumors, vasoactive intestinal polypeptide-secreting tumors (VIPomas), gastrinomas, and somatostatinomas (see Chapters 31 and 32), as well as the gastrointestinal effects of hypercalcemia (constipation, nausea, and vomiting). A watery diarrhea syndrome with elevated serum immunoreactive VIP has been described accompanying nonpancreatic tumors such as bronchogenic carcinomas, ganglioneuromas, pheochromocytomas, and a rare mastocytoma.¹⁷² Elevated serum levels of somatostatin, calcitonin, gastrin, and corticotropin also have been reported in pheochromocytoma.¹⁷³

Paraneoplastic gastrointestinal dysmotility may occur in some patients with occult or established malignancy and specific serum antibodies. Clinically the patient may present with pseudoachalasia, gastroparesis, intestinal pseudo-obstruction, or constipation. Intestinal pseudo-obstruction (see Chapter 120) is most frequently associated with small cell carcinoma of the lung but has been described with other tumors such as squamous cell lung carcinoma, lymphoma, melanoma, and cancers of the kidney, breast, and prostate.^174–176 Patients with paraneoplastic intestinal pseudo-obstruction characteristically suffer from constipation and obstipation and from symptoms of intestinal obstruction. In addition, dysphagia, gastroparesis, early satiety, autonomic insufficiency, and peripheral neuropathy have been described.¹⁷⁷ The onset of symptoms may precede the discovery of the primary tumor by several years. The gastrointestinal pathology in this syndrome is confined to the myenteric plexus, in which an inflammatory lymphocytic infiltrate is variably seen accompanying neuronal degeneration.¹⁷⁸ Cross-reacting autoantibodies found in the sera of these patients bind to the primary tumor cells and to neural cells in the myenteric plexus, resulting in inflammation and destruction of the myenteric plexus.¹⁷⁹ In the setting of pseudo-obstruction, detection in the serum of circulating antineuronal nuclear antibodies (ANNA-1 or anti-Hu), type 1 Purkinje cell antibodies (PCA-1), or N-type calcium channel binding antibodies should suggest a paraneoplastic process and prompt further evaluation for an underlying malignancy.¹⁷⁷ ANNA-1 are postulated to induce neuronal apoptosis leading to gut dysmotility.¹⁸⁰ Although the symptoms of paraneoplastic pseudo-obstruction may resolve with successful treatment of the primary tumor, persistence of gastrointestinal symptoms despite effective anticancer treatment is more common. Attempts to alleviate the symptoms of pseudo-obstruction with prokinetic agents have been disappointing.

HEMATOLOGIC MALIGNANCIES

Liver involvement during hematologic malignancies is only rarely life threatening or a source of great morbidity. Nevertheless, the liver is a major component of the reticuloendothelial system, and thus it is not surprising that malignant infiltration of the liver commonly occurs in such diseases.¹⁸¹ As detailed in Table 35-2