Gastrointestinal and Hepatic Manifestations of Systemic Diseases

Rheumatoid Arthritis

RA has a prevalence of 0.5% to 1% in North America and Europe. GI symptoms are common and are largely due to medications, particularly NSAIDs. Oropharyngeal symptoms occur as a result of xerostomia and involvement of the temporomandibular joint, cervical spine, and larynx (particularly the cricoarytenoid joint). Atlantoaxial subluxation may result in dysphagia associated with other signs of spinal cord compression; endoscopy is a high-risk procedure in these patients. Esophageal dysmotility, characterized by low peristaltic pressure in the lower two thirds of the esophagus and reduced lower esophageal sphincter (LES) pressure, is associated with heartburn, dysphagia, and esophagitis. Associated rheumatoid vasculitis, Sjögren syndrome (SS), or amyloidosis (all discussed later) may also cause esophageal symptoms and dysmotility, and vasculitis may induce esophageal strictures from ischemia.

PUD may occur in relation to anti-inflammatory medications. Chronic superficial and chronic atrophic gastritis is seen in 30% and 65%, respectively, of biopsy specimens from patients with RA. About one third of patients with RA have hypochlorhydria or achlorhydria, predisposing them to small bowel bacterial overgrowth (SBBO). Hypergastrinemia may be associated with achlorhydria, antiparietal cell antibodies, vitamin B ₁₂ deficiency, or pernicious anemia.

RA is sometimes associated with ulcerative colitis, and rheumatoid vasculitis may mimic IBD. Unlike RA, IBD-related peripheral arthropathy is usually rheumatoid factor (RF)-negative, nondeforming, and nonerosive. RA may rarely be associated with pneumatosis cystoides intestinalis ( Fig. 37.1 ).

Rheumatoid vasculitis, an inflammatory condition of the small- and medium-sized vessels, affects about 1% to 5% of patients with RA, typically those with severe disease and high RF titers. About 10% to 38% of these cases have intestinal involvement, often associated with manifestations in the skin (digital gangrene, cutaneous ulcers) and peripheral nervous system (neuropathy, mononeuritis multiplex). Involvement of small vessels in the gut results in ischemia with ulcers, pain, and hemorrhage. Involvement of large vessels may lead to bowel infarction, stricture formation, bowel perforation, or hemoperitoneum. Therapy may include glucocorticoids and/or cyclophosphamide based on small uncontrolled studies. Notably, an increased rate of lower GI tract perforations has also been found in RA patients managed with tofacitinib or tocilizumab but not TNF inhibitors.

Adult-Onset Still Disease

Adult-onset Still disease (the adult form of juvenile RA) is an inflammatory disorder presenting with spiking fevers, pharyngitis, evanescent maculopapular rash, arthralgias/arthritis, and neutrophilic leukocytosis. Abdominal pain is usually mild and transient but may be severe. Occasionally, small bowel distention and air-fluid levels are found. Hepatosplenomegaly and lymphadenopathy are common. Ferritin is often extremely elevated ; C-reactive protein and ESR are high, whereas ANA and RF are negative or low titer. Abnormal liver chemistry tests occur in 50% to 75% of patients and are usually mild and transient, correlating with disease activity. Severe hepatitis and even fulminant hepatic failure occasionally occur, leading to death or liver transplantation. Liver histology may be normal, show portal mononuclear cell infiltration, or interface hepatitis with lymphoplasmacytic inflammation similar to AIH. Portal vein thrombosis has been described. Treatment may include NSAID(s), glucocorticoids, methotrexate, cyclosporine, and anakinra, with rare hepatotoxicity being reported with anakinra.

Systemic Sclerosis

Symptoms related to anywhere in the GI tract may be found in over 90% of patients with PSS, but esophageal symptoms may predominate. Patients most commonly complain of anorexia, reflux, dysphagia, early satiety, nausea, distension, diarrhea, constipation, fecal incontinence, and a decline in social and emotional well-being. Malnutrition is common, occasionally requiring parenteral nutrition. Among its causes are anorexia, delayed gastric emptying, malabsorption, SBBO, and slow small bowel transit.

The long-standing theory is that a neuropathic process occurs first, followed by a myopathic process as the muscles atrophy and fibrosis develops. Only in the first stage would prokinetic agents be effective. Serum antimuscarinic-3 acetylcholine autoantibodies that may block neurotransmission may then lead to secondary tissue/muscle atrophy. Myositis-related antibodies may also be found in a subset of PSS patients.

Esophageal Involvement

Esophageal symptoms in PSS include heartburn, regurgitation, and dysphagia. Reflux is due to (1) low/absent esophageal peristalsis, (2) reduced LES pressure, (3) hiatal hernia (from a foreshortened esophagus), (4) gastroparesis, (5) autonomic nerve dysfunction, (6) sicca syndrome with loss of salivary bicarbonate, and (7) increased abdominal pressure from coughing and straining.

Patients with PSS develop Barrett esophagus, with an increased risk of esophageal adenocarcinoma, although the most common malignancy is probably lung cancer. Delayed esophageal transit, treatment with immunosuppressive drugs, and gastric acid suppression predispose to candidal esophagitis. Pill esophagitis may occur secondary to increased mucosal contact. PSS mainly affects the smooth muscle in the lower two thirds of the esophagus. The upper esophagus, composed mainly of striated muscle, is usually spared unless affected by proximal reflux. The dysmotility documented by esophageal manometry helps diagnose PSS. It classically shows low-amplitude contractions or aperistalsis in the lower two thirds of the esophagus, and low or absent LES pressure ( Fig. 37.2 ). These findings, however, are not universally seen nor specific to PSS and can be seen in other diseases, such as amyloidosis, diabetes, chronic alcoholism, esophageal candidiasis, severe reflux, hypothyroidism, and other connective tissue diseases. In 200 patients with scleroderma (117 limited, 83 diffuse) who underwent high-resolution manometry and had their findings classified according to the Chicago classification, the most common findings were absent contractility (56%), normal motility (26%), and ineffective motility (10%), irrespective of whether they had limited or diffuse disease. Classic scleroderma esophagus was observed in only 33%. Severe dysmotility was associated with disease duration, interstitial lung disease, and GI symptom scores. Moreover, in 111 patients with systemic sclerosis (89 women) who underwent high-resolution manometry that involved multiple rapid swallows, peristaltic amplification during multiple rapid swallows was much less frequent (18%) than in young healthy controls (100%). Abnormal peristaltic reserve was the most common manometric abnormality in patients with systemic sclerosis. Impedance studies show incomplete bolus clearance. Like achalasia, the esophagus may be dilated on imaging studies but in PSS there is no mechanical obstruction and, therefore, no air-fluid levels are seen unless a stricture is present. Endoscopy often shows abnormalities even without symptoms. Endoluminal ultrasonography shows hyperechoic abnormalities in the muscularis propria thought to represent fibrosis. Reflux may contribute to pulmonary disease by aspiration of gastric contents and/or vagal stimulation from gastric contents in the esophagus. Conversely, pulmonary disease may contribute to reflux by greater negative intrathoracic pressure required for ventilation and by the effect of bronchodilators lowering LES pressure.

Esophageal reflux is associated with interstitial lung disease in PSS ; these manifestations may evolve together. Although a cause-effect relationship has not been definitively proved, centrilobular fibrosis with a bronchocentric distribution is found in 21% of PSS patients with intraluminal basophilic content consistent with peptic necrosis, suggesting a pulmonary reaction to aspiration of gastric contents. Pulmonary disease is a major cause of death in PSS and responds poorly to treatment. Aspiration precautions and lifestyle modifications for reflux are essential.

PPIs may heal esophagitis and may even reverse esophageal fibrosis. Higher than standard doses of PPIs may be needed but likely do not prevent progression of dysmotility. Whether PPIs help pulmonary disease is not known. Prokinetic agents may help in the early stage of disease. Buspirone (a 5HT1 receptor agonist) may have a favorable effect on esophageal peristalsis and LES function. An open-label trial of buspirone 20 mg daily in 30 PPI—refractory patients with PSS showed a significant increase in resting LES pressure and significant reductions in heartburn and regurgitation scores at 4 weeks. Surgical therapy with fundoplication has a limited role due to concern that dysphagia could worsen in an aperistaltic esophagus. A Roux-en-Y gastric bypass is an alternative.

Systemic Lupus Erythematosus

SLE is a multisystemic autoimmune disorder. GI symptoms (e.g., nausea/vomiting, anorexia, abdominal pain) are common but usually mild. In adults, they are caused by diverse etiologies, sometimes unrelated to lupus, with wide ranges of severity. In children, abdominal pain is usually related to the SLE, most commonly from vasculitis, pancreatitis, and/or peritonitis/ascites.

Myopathies

The inflammatory myopathies—polymyositis, dermatomyositis, and inclusion body myositis—are diagnosed by a combination of muscle weakness, elevated muscle enzyme levels, electromyographic evidence of a myopathy, and typical muscle histology. Serum AST and ALT levels are roughly equal, because the greater release of AST is counteracted by its greater clearance. Often, an ALT of 100 U/L is accompanied by creatine phosphokinase levels of about 1000 U/L, although many exceptions occur. Of the drugs used in GI diseases, myositis can be caused by anti-TNF agents, interferon, and occasionally PPIs. Myositis can also be associated with IBD, celiac disease, infection with HBV or HCV, and PBC. Dermatomyositis may also be associated with a GI vasculopathy, a grave but rare manifestation, resulting in vascular ectasias, ulcers, and bowel perforation. Dermatomyositis and, less commonly, polymyositis may be paraneoplastic associated with malignancy involving the stomach, colon, pancreas, and other organs.

Involvement of the pharynx and upper esophageal sphincter (UES), both composed of skeletal muscle, results in nasal regurgitation, tracheal aspiration, tongue weakness, and dysphagia for both solids and liquids. Low-amplitude pharyngeal contractions and decreased UES pressure are found on esophageal motility studies. Smooth muscle may also be involved, with delayed esophageal and gastric emptying. Reduced LES pressure and nonperistaltic low-amplitude simultaneous esophageal contractions are associated with heartburn. Treatment of esophageal disease includes immunosuppressive therapy (e.g., glucocorticoids), intravenous immunoglobulin, cricopharyngeal myotomy, and pharyngeal dilatation, resulting in variable success rates.

Sjögren Syndrome

SS occurs alone (primary) or associated with an autoimmune disease (secondary). SS is characterized by lymphocytic infiltration of lacrimal and salivary glands with keratoconjunctivitis sicca and xerostomia. The mouth (discussed in Chapter 24 ) and esophagus are most commonly involved. Reduced salivary neutralization may increase esophageal acid exposure time and predispose to reflux symptoms and/or mucosal damage. Although salivary flow rates are reduced and a variety of motility disturbances may be found in the esophagus, neither of these abnormalities generally correlates with dysphagia. Although chronic atrophic gastritis is common, low vitamin B ₁₂ levels and/or pernicious anemia are rare. Whether the prevalence of Hp gastritis is increased in SS is controversial; treatment of Hp does not reduce gastric lymphocytic infiltration, atrophy, or dyspepsia. There is a well-known association with mucosa-associated lymphoid tissue lymphoma. Gastric lymphoma is the most common extraglandular site for lymphoma in SS. A risk for gastric adenocarcinoma has been suggested, which may parallel the disease severity association with inflammatory markers, IgA level and SS-B antibody. The role for gastric cancer screening or surveillance in SS is unclear. Associated celiac disease is found in up to 15% of SS patients.

Pancreatitis has been documented in up to 7% of patients with SS, often presenting as autoimmune pancreatitis or chronic pancreatitis. Chronic pancreatitis, with morphologic changes and/or an abnormal secretin test, may occur in about 25% of patients with SS but is usually clinically silent.

Abnormal liver chemistry tests, found in 10% to 49% of SS patients, are usually mild and have no definite pattern and little clinical significance. Hepatomegaly occurs in 11% to 21% of patients. The most common causes of liver disease are nonalcoholic fatty liver disease, PBC, AIH, and HCV. Sicca syndrome, abnormal salivary histology, and abnormal sialograms are common in PBC, whereas anti-SS-A/B antibodies are not. Although xerostomia, decreased salivary flow rates, and sialadenitis are seen in HCV, anti-Ro/SS-A/B antibodies are rare. The pathogenesis of HCV-related SS may be due to HCV infection of salivary glands, molecular mimicry, and/or the formation of immune complexes containing HCV.

Mixed Connective Tissue Disease

MCTD is an overlap syndrome including characteristics of SLE, PSS, and polymyositis associated with antibodies to ribonucleoprotein. Patients can present with heartburn and dysphagia. Delayed esophageal transit, pathologic gastroesophageal reflux on 24-hour pH study, and reduced amplitude and coordination of esophageal peristalsis are found in the majority of patients. The diagnosis of MCTD is suggested if there is dysmotility of the entire esophagus, both upper and lower, similar to that seen in polymyositis and PSS, respectively. Like in PSS, esophageal abnormalities usually correlate with pulmonary abnormalities in MCTD. The role of glucocorticoid therapy in esophageal disease is uncertain.

Changes similar to those of PSS may be seen in the intestine. Occasionally patients may have a vasculitis, amyloidosis, or pancreatitis. There may be hepatomegaly, splenomegaly, AIH, idiopathic portal hypertension, or Budd-Chiari syndrome.

Polyarteritis Nodosa

PAN is a vasculitis affecting mainly medium-sized arteries; it causes necrotizing inflammation, fibrinoid necrosis, neutrophilic infiltration, and fibroblast proliferation of the vessel wall. Arterial aneurysms, stenosis, thrombosis, occlusion, and rupture of the artery occur. The result is impaired intestinal perfusion, ulcerations, bleeding, and ischemia if damage is limited to the mucosa or submucosa, and perforation if there is transmural involvement. The entire GI tract may be involved, but small bowel involvement is most common. Liver involvement, usually subclinical, includes necrotizing vasculitis leading to atrophy of a liver lobe, liver infarction, or nodular regenerative hyperplasia. Rarely, aneurysmal rupture occurs in the liver resulting in hemobilia, subcapsular hemorrhage, or intrahepatic hemorrhage. HBV-associated PAN, which generally occurs early in HBV infection, has a higher association with GI disease, more severe vasculitis, and a higher mortality rate than PAN without HBV. HBV-PAN is characterized by circulating immune complexes containing hepatitis B surface antigen and anti-hepatitis B surface antibodies, supporting the concept that it is mediated by deposition of viral Ag/Ab complexes. Hepatitis B is silent in most cases, with only mild increases in serum aminotransferases. HCV can occasionally be associated with PAN but unlike the early onset after HBV exposure, PAN usually occurs several years after viral exposure; like HBV-PAN, it usually manifests with severe vasculitis.

Pancreatic involvement occurs in 35% to 37% of autopsy cases, with acute pancreatitis, pancreatic infarcts, pseudocysts, pancreatic masses, or pancreatic insufficiency. Vasculitis of arteries supplying small bile ducts leads to intrahepatic sclerosing cholangitis, whereas cystic arteritis leads to acalculous gangrenous cholecystitis. Ascites due to vasculitis is rare.

Angiography, which is abnormal in more than 60% of patients, shows arterial aneurysms, irregularities, and thrombosis, all of which may progress to stenosis and occlusion of the vessels. Aneurysms are focal and segmental, in different stages of development, with a predilection for branch points of vessels. They tend to be multiple, intraparenchymal, and measure up to 1 centimeter in diameter. Rupture, especially in the presence of hypertension, occurs occasionally. Microaneurysms are sometimes seen as in other conditions (e.g., RA, SLE, granulomatosis with polyangiitis). A normal visceral angiogram does not exclude PAN; aneurysms may be thrombosed or healing. CT may show bowel wall thickening and the target sign. Three-dimensional CT angiography detects aneurysms with diameters as small as 3 mm, as well as early vasculitic changes such as increased wall thickness and calcification, not seen on routine angiography.

Biopsy sites include skin lesions, sural nerve, and muscle. Endoscopic biopsies are usually too superficial to make the diagnosis; deeper biopsies risk perforation.

Glucocorticoids, along with a potent immunosuppressive agent, particularly cyclophosphamide, dramatically decrease mortality. HBV-PAN or HCV-PAN are usually treated with immunosuppressive agents and an antiviral agent, sometimes with plasma exchanges (to remove immune complexes).

Henoch-Schönlein Purpura

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in childhood, and occasionally affects young adults. HSP is clinically characterized by palpable purpura, arthritis, as well as renal and GI involvement. Adults typically have a more severe clinical syndrome with higher frequency of renal involvement. HSP is mediated by immune deposits (typically IgA), resulting in leukocytoclastic vasculitis that causes necrosis of small blood vessel walls. GI involvement occurs in the majority of patients and sometimes precedes the rash. The abdominal pain is usually colicky, periumbilical, or epigastric, sometimes worsening with eating. There is occult or, less commonly, overt, usually melenic bleeding, usually melena. The small intestine is most frequently involved, with the second portion of the duodenum involved more than the bulb. The main differential diagnosis is Crohn disease. Intussusception is usually ileoileal or ileocolic and due to an ileal lead-point (intramural hemorrhage or edema). It often resolves spontaneously or may be reduced with air or contrast enemas performed gently to minimize perforation risk. If intussusception is still present after 24 hours, surgery should be considered. Rarely, the patient may develop acute acalculous cholecystitis, ascites with serositis, or pancreatitis. Recurrences are usually stereotypic, milder, and shorter in duration than the first episode.

Endoscopic findings include petechiae, erosions and ulcers, hyperemia, and ecchymoses ( Fig. 37.3 ). Mucosal biopsies usually show IgA deposition and inflammation. Sampling of the submucosa may reveal vasculitis. Capsule endoscopy may determine the extent of disease and location of bleeding. CT shows thickened bowel walls with skip lesions, ileus, and bowel dilation. To avoid irradiation in children, abdominal ultrasonography is considered the study of choice by some and may help determine prognosis.

Glucocorticoids should be considered in those at high risk for renal involvement; their effects on GI disease are unknown, as more than 80% of cases resolve spontaneously. Other modalities (plasma exchange, dapsone, and intravenous immunoglobulins) have been tried.

Eosinophilic Granulomatosis With Polyangiitis

Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) is a small- and medium-vessel vasculitis with GI involvement in up to 59% of cases. Of the 3 phases of this disease (prodromal, eosinophilic, and vasculitic), the GI tract can be involved in the last 2. An eosinophilic gastroenteritis can occur with peripheral eosinophilia and an eosinophilic infiltrate in the GI mucosa. Abdominal pain, diarrhea, nausea/vomiting, and bleeding are the most common symptoms. Vasculitis may cause ulcerations, perforation, and rarely stenosis. The ulcers characteristically have an erythematous rim. Unusual complications include acalculous cholecystitis, pancreatitis, or eosinophilic ascites from involvement of the peritoneum. Intestinal resection specimens and submucosal biopsies reveal vasculitis with fibrinoid necrosis, eosinophilic infiltrates, and/or granulomas. Glucocorticoids achieve remission in 90%, but close monitoring for intestinal perforation is needed. Glucocorticoid–refractory disease may be treated with cyclophosphamide, intravenous immunoglobulin, or plasma exchange. Severe GI tract involvement is associated with a poor outcome.

Granulomatosis With Polyangiitis

Most of the GI tract can be involved in granulomatosis with polyangiitis, which is a necrotizing vasculitis affecting small- and medium-sized vessels. The incidence of GI involvement is difficult to determine as it is often asymptomatic. Oral involvement includes ulcers, lingual infarction, and the pathognomonic “strawberry gums,” representing gingival hyperplasia studded with petechiae like a ripe strawberry. Esophageal and gastric ulcers occur, with pathology showing necrotizing granulomatous inflammation. Vasculitis leads to intestinal ulcerations, ischemia, infarction, strictures, and perforation. It may resemble or be associated with IBD. Arteritis may lead to pancreatitis or a gangrenous gallbladder. Liver involvement is usually nonspecific, although unusual findings, such as incomplete septal fibrosis from ischemia, have been described. Superficial intestinal biopsies may reveal only nonspecific findings, and angiography may be normal. Perinuclear–staining antibody ANCA (p-ANCA) specific for myeloperoxidase may be positive but the cytoplasmic-staining antibody ANCA (c-ANCA) directed at the proteinase 3 antigen of myeloid lysosomes (PR3) is more specific. Most lesions respond to immunosuppression, such as with cyclophosphamide.

Cryoglobulinemia

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37°C. Cryoglobulinemia may produce organ damage through hyperviscosity or vasculitis, the latter being the main mechanism for GI involvement. Although cryoglobulinemia is associated with infections, autoimmune diseases, and cancer, the most common cause is HCV. Up to 7% of patients with cryoglobulinemia have GI involvement, usually manifesting as mesenteric vasculitis (see RA, SLE, and PAN). Severe GI involvement is an independent factor associated with poor outcome in non–HCV related vasculitis. Treatment is aimed at the underlying disease and may include immunosuppressive drugs, apheresis, and/or rituximab.

Behçet Disease

This multisystemic vasculitis typically includes recurrent oral and genital ulcers, arthritis, and characteristic skin lesions. CNS symptoms, GI lesions, hypercoagulability, and visceral artery aneurysms may also be seen. Although Behçet disease (BD) is most common in the ancient Silk Road countries, GI involvement in this disease is most common in certain other countries (e.g., Japan, United Kingdom). Small vessel vasculitis primarily affecting veins and venules presents with mucosal inflammation causing ulcers; large vessel disease results in ischemia and infarction. This vasculitis mainly affects the ileocecal region resembling Crohn disease. Extraintestinal manifestations of oral aphthae, uveitis, arthritis, and erythema nodosum may mimic IBD. Several features distinguish BD from Crohn disease. Unlike Crohn disease, BD rarely causes strictures, perianal disease, or rectal ulcers and multisegmental or diffuse GI involvement is rare. BD frequently causes oral ulcers, mucosal edema, intestinal perforation, and venulitis (without bowel inflammation, fibrosis, or granulomas), and it often resolves spontaneously. Infectious processes may mimic or complicate BD. Endoscopic studies should be done with caution due to a risk of perforation, because the intestinal ulcers are often quite deep. There may be amyloidosis (discussed later), aneurysm formation, or hepatic or portal vein thrombosis. Thrombophlebitis, thought to be due to venulitis, may not benefit from anticoagulation. Acute pancreatitis, Budd-Chiari syndrome, multiple aseptic hepatic and splenic abscesses, and sclerosing cholangitis are reported in BD. Therapy of GI involvement includes mesalamine, immunomodulators, and TNF inhibitors. Whether glucocorticoids prolong the healing process and provoke perforation is unclear. A phase 2 study found that the oral phosphodiesterase inhibitor apremilast significantly reduced oral ulcer formation in patients with BD. However, the treatment was brief (12 to 24 weeks) and associated with diarrhea and with nausea and vomiting. Furthermore, effects of apremilast on other aspects of the disease, including the GI manifestations, remain to be elucidated. Recurrences after surgery, often at the anastomotic site, occur in 50%.

Spondyloarthropathies

Subclinical gut inflammation has been described in up to two thirds of patients with various spondyloarthopathies. The presence of ileitis may be associated with chronicity of the articular disease. The acute form of spondyloarthropathy (typically reactive arthritis) has gut inflammation that mimics bacterial enteritis with neutrophil infiltration but preserved gut architecture. The chronic form (typically ankylosing spondylitis) mimics Crohn disease, with a mononuclear cell infiltrate and disturbed architecture. Although it may be histologically indistinguishable from Crohn’s ileitis, spondyloarthropathy associated ileitis is usually asymptomatic, radiologically inapparent, and patients are usually HLA-B27 positive. Ankylosing spondylitis is found in up to 15% of IBD patients in general and in 50% of IBD patients with HLA-B27. For axial involvement, NSAIDs reduce joint pain and stiffness but may worsen underlying IBD. Glucocorticoids are rarely effective in spondyloarthropathies and decrease bone mineral density. Sulfasalazine and possibly methotrexate may have some efficacy in spondyloarthropathies, particularly in patients with appendicular involvement. TNF-α blocking agents, including etanercept, which is not used in IBD, are also quite effective.

Familial Mediterranean Fever

Familial Mediterranean fever (FMF), an autosomal recessive disease, is characterized by recurrent self-limited attacks of fever, joint pain, and abdominal pain, most commonly in people of Mediterranean origin. The gene responsible for FMF, MEFV on chromosome 16, encodes the protein pyrin. MEFV gene analysis assists in diagnosis.

Patients develop what appears to be an acute abdomen due to peritonitis. Their severe abdominal pain is reduced by lying motionless with hips flexed. The abdomen is rigid with rebound tenderness, reduced bowel sounds, and abdominal distension. There may be multiple air-fluid levels, a leukocytosis with a left shift, an increased ESR, and elevated acute-phase reactants. The attack begins to subside after 24 hours. Peritonitis results in protein-rich sterile exudates with fibrin and neutrophils that, when organized, may lead to adhesions and small bowel obstruction, sometimes with strangulation and necrosis. Patients are asymptomatic between episodes, although acute-phase reactants may be elevated, indicating subclinical inflammation.

Serum amyloid concentration increases dramatically during febrile attacks (see Amyloidosis [under Infiltrative Diseases]). AA amyloidosis may develop independent of the frequency, duration, and intensity of flare-ups. Kidney impairment is the most clinically significant result, but amyloid can deposit in the GI tract and cause symptoms after many years. FMF is associated with other diseases such as IBD, some vasculitides, and irritable bowel syndrome. GI mucosal involvement may suggest IBD but mucosal healing can be achieved with colchicine alone.

Abnormal esophageal motility may occur regardless of amyloid status. Liver disease is usually from amyloid, and splenomegaly is from ongoing inflammation. Although there is no specific treatment for acute attacks, colchicine reduces the attack frequency, severity, and duration in most FMF patients. Because it can prevent, arrest, and even reverse renal amyloidosis, colchicine should be continued for life. Refractory cases may respond to the anti-IL-1 beta1 monoclonal antibody canakinumab.

Disorders of Connective Tissue

GI manifestations have been reported in a variety of connective tissue disorders. These may be classified as structural or functional abnormalities.

GI manifestations in Marfan syndrome are typically overshadowed by cardiac, ophthalmic, and musculoskeletal manifestations. Fibrillin-1 gene mutations lead to qualitative and/or quantitative alterations to the glycoprotein fibrillin-1, with subsequent myofibril deficiency and connective tissue instability. In the GI tract, this may lead to visceral herniation, abdominal wall hernias, diverticula/pseudodiverticula, and clinical events such as acute appendicitis or acute diverticulitis at unusually young ages. There also appears to be an increased frequency of hepatic cysts, renal cysts, and cholelithiasis. Functional GI disorders such as IBS may also be more common than in control groups.

In Ehlers Danlos syndrome (EDS), functional GI disorders predominate but epiphrenic diverticula, diaphragmatic eventration, megaesophagus, spontaneous GI perforations, and acute GI bleeding may occur. One large retrospective study found that 378 of 687 patients with EDS (56%) had associated GI manifestations in the classic, hypermobility, and vascular subtypes. The vascular subtypes all had frequent GI symptoms but such symptoms were somewhat less common than in the hypermobility variant. Typical symptoms included abdominal pain (56%), nausea (42%), constipation (39%), heartburn (38%), and IBS symptoms (28%). Gastric and colonic transit were delayed in 12% and 28%, respectively. All abdominal aneurysms occurred in the EDS vascular subtype.

The benign joint hypermobility syndrome may be found with increased frequency in unselected tertiary functional GI disorder patients when compared with a 10% to 20% frequency in normal individuals. Joint hypermobility incidence was evaluated in 129 unselected new tertiary referrals (97 female) to a neurogastrointestinal clinic and 63 (49%) had evidence of joint hypermobility; an unknown etiology of GI symptoms was more frequent in those with joint hypermobility than in those without it. A clinical impression of joint hypermobility was confirmed by a rheumatologist in 23 of 25 patients evaluated.

IgG4-Related Disease

This rare multisystem inflammatory and fibrotic disorder typically affects the pancreas (Type I or II autoimmune pancreatitis; see Chapter 59 ) or bile ducts and can mimic pancreatic cancer, cholangiocarcinoma, or PSC. Reports of other intra-abdominal involvement include retroperitoneal fibrosis, aortitis, sclerosing mesenteritis, inflammatory pseudo-tumor, hepatitis, enteritis, colitis, and pouchitis. Serum IgG4 is elevated in only 60% to 70% of patients; frequently, diagnostic biopsies of the affected organ are necessary and typically reveal a dense lymphoplasmacytic IgG4 staining infiltrate, storiform fibrosis, and obliterative phlebitis. Glucocorticoids are usually effective therapeutically and maintenance immunomodulators are sometimes required.