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, the frequency of malignant infiltration varies from less than 10% to nearly 100% depending on the nature of the underlying hematologic malignancy. In addition to histologic and biochemical abnormalities related to malignant infiltration, a variety of other hepatic abnormalities are observed in a significant fraction of such patients. Many of these abnormalities are related to toxicity of pharmacologic or radiation therapies or to the secondary opportunistic or transfusion-related infections commonly observed in such patients. In addition, a variety of nonspecific histologic abnormalities of uncertain etiology such as steatosis, fibrosis, hemosiderosis, and nonspecific portal lymphocytic infiltrates are observed commonly in treated as well as untreated patients. Other hepatic manifestations relatively unique to selected malignancies also may occur. Such notable paraneoplastic manifestations include granuloma formation or development of pronounced intrahepatic cholestasis in patients with Hodgkin’s disease and deposition of amyloid in patients with multiple myeloma.

Sickle Cell Disease

Sickle cell disease is an autosomal recessive disorder of hemoglobin structure that is characterized by chronic hemolytic anemia and recurrent episodes of vascular occlusion leading to ischemia and distal tissue infarction in multiple organs. Eight percent of African Americans are heterozygous for the hemoglobin S trait and homozygotes comprise 0.2% of African Americans. Patients with sickle cell anemia and other hemoglobinopathies may develop splenic infarction and liver disease (see following), likely from ischemic injury due to intrasinusoidal sickling and impairment of intrahepatic blood flow and delivery of oxygen to hepatocytes.^264,265 Chronic anemia due to hemolysis is typically present and predisposes to an indirect-reacting bilirubin elevation and to the formation of pigmented gallstones.²⁶⁶ Patients with other hereditary defects involving red blood cell cytoskeletal proteins, hereditary spherocytosis, and hereditary elliptocytosis, also have diminished red blood cell survival, leading to an increased incidence of pigmented gallstones. Transfusions are frequently used in the therapy for sickle cell anemia, and therefore such patients who were transfused prior to 1992 are at increased risk for hepatitis C.²⁶⁷ Multitransfused teenage and adult patients with sickle cell anemia also have been found to have degrees of excess hepatic iron stores that are comparable to that noted in thalassemia major.^268–270

Sickle cell crisis, an acute manifestation of this disease, is characterized by severe skeletal pain and fever. Abdominal pain is also commonly present, and it is important to distinguish vaso-occlusive crises from surgical conditions such as cholecystitis, bowel infarction, appendicitis, and pancreatitis. Abdominal pain from vaso-occlusive crises tends to be more diffuse and associated with remote pain such as limb and chest pain. The pain of vaso-occlusive crises is typically relieved with hydration and oxygen within 48 hours.²⁷¹ Sickle cell hepatopathy, a syndrome characterized by severe hyperbilirubinemia out of proportion to degree of ongoing hemolysis, is a rare complication of sickle cell anemia that can be associated with coagulaopthy and encephalopathy, leading to death from acute liver failure. Because treatment with exchange transfusions is associated with improved outcome,²⁷² it is important to distinguish this complication of sickle cell anemia from other causes of liver disease that are common in this patient population.²⁷³

When histologic evaluation of the liver has been performed in patients with sickle cell anemia at autopsy, cholecystectomy or diagnostic percutaneous liver biopsy, dilated sinusoids, erythrophagocytosis by Kupffer cells (Fig. 35-7), and varying degrees of parenchymal atrophy in the central zones of the liver have been observed frequently.^{265,274–277} In association with hepatic sinusoids engorged by phagocytosed, sickled red blood cells, adjacent areas of ischemic necrosis have been reported in patients with acute episodes of jaundice, right upper quadrant pain, fever, and leukocytosis thought to be secondary to intrahepatic sickle cell crises or sickle cell hepatopathy.^{264,265,274,276,278} Accumulation of collagen or thin basement membranes within the space of Disse,²⁷⁴ peri-sinusoidal fibrosis,²⁷⁶ and an apparently high incidence of cirrhosis in patients with sickle cell anemia²⁶⁴ has suggested that recurrent ischemic injury secondary to intrahepatic sickling may also be a cause of chronic liver disease.

Figure 35-7. Sickled red blood cells in a Kupffer cell (erythrophagocytosis) in a hepatic sinusoid of patient with sickle cell disease. (Hematoxylin and eosin, ×200.)

Although early reports suggested that viral hepatitis was an unusual cause of acute or chronic liver disease in such patients,^274,275 studies conducted in the 1980s and 1990s suggested that hepatitis B^276,277 and hepatitis C²⁶⁷ are common infections in patients with sickle cell anemia and may account for many episodes of acute or chronic liver disease previously attributed to sickle cell hepatopathy. More recent studies of adult sickle cell anemia patients presenting with acute hepatic dysfunction have found that viral or autoimmune hepatitis plays a role in about a third of such episodes.²⁷³ Of special note, intrasinusoidal sickling and Kupffer cell erythrophagocytosis (see Fig. 35-7) almost invariably are found in all patients with sickle cell disease irrespective of apparent cause of liver disease or degree of serum alanine aminotransferase (ALT) elevation.²⁷⁷ Intrasinusoidal sickling was also found in two liver biopsies performed after recovery from acute viral hepatitis. To some extent the presence of nonphagocytosed sickled red blood cells in hepatic sinusoids could be attributed to the fact that formalin fixation was noted to induce irreversible sickling of red blood cells in patients with hemoglobin SS or sickle cell disease.^277,279 In addition, Omata and colleagues²⁷⁷ have suggested that Kupffer cell erythrophagocytosis may reflect the role of Kupffer cells in clearance of sickled red cells in functionally asplenic patients with sickle cell disease. Thus, assessment of degree of intrasinusoidal sickling or even Kupffer cell erythrophagocytosis is a poor indicator of possible ischemic liver injury in patients with sickle cell disease. In contrast, other features of vascular insufficiency such as acute ischemic necrosis, sinusoidal dilatation and perisinusoidal fibrosis appear to be more specific markers of vascular injury in patients with symptomatic liver dysfunction in the absence of viral hepatitis or other causes for hepatocellular injury.²⁷⁶

Diggs²⁶⁵ reported in 1965 that 10% of patients presenting with acute sickle crises were jaundiced. More recent assessment of prevalence of liver disease in patients with sickle cell anemia have found persistent abnormalities of one or more liver enzyme tests in 24% of patients followed for sickle cell anemia.²⁷⁹ In addition, 48 of 72 (67%) patients without other biochemical evidence of liver disease had total serum bilirubin levels of greater than 2 mg/dL (greater than 34 µmol/L). Thus laboratory abnormalities suggesting possible liver disease are relatively common in patients with sickle cell disease and frequently lead to diagnostic evaluations as detailed in Figure 35-8. Of note, however, a high rate of complications has been reported in association with liver biopsies performed during acute sickling crises²⁸⁰ and thus invasive diagnostic procedures should be used judiciously in this patient population.

Figure 35-8. Algorithm for the evaluation of abnormal liver biochemical test levels in patients with sickle cell disease. ALT, alanine aminotransferase; ANA, anti-nuclear antibodies; AP, alkaline phosphatase; Dir Bil, direct bilirubin; Dx, diagnosis; Fe, iron; GGTP, gamma glutamyl transpeptidase; Indir Bili, indirect bilirubin; LDH, lactate dehydrogenase; LKM1, liver-kidney microsomal antibodies type 1; SMA, smooth muscle antibodies; TIBC, total iron binding capacity.

In sickle cell disease patients without liver disease, hyperbilirubinemia is exclusively unconjugated or indirect and only uncommonly exceeds levels of 4.5 mg/dL (77 µmol/L). In more severely jaundiced patients, higher serum lactic dehydrogenase levels are also seen and suggest higher rates of hemolysis.²⁷⁹ However, in the setting of acute viral hepatitis or other causes of liver dysfunction, extreme levels of hyperbilirubinemia consisting of relatively equal amounts of direct and indirect bilirubin are observed.^279,281 Although early reports suggested that a total serum bilirubin level of greater than 25 mg/dL (greater than 428 µmol/L) was a grave prognostic sign,^265,282 relatively benign courses have been noted in patients with extreme degrees of hyperbilirubinemia during the course of acute viral hepatitis or presumed intrahepatic sickle cell crises.^279,281,283 The degree of serum ALT or aspartate aminotransferase (AST) elevation in patients with sickle cell anemia and acute viral hepatitis is similar to that observed in other patients with acute viral hepatitis, with most symptomatic patients having elevations more than 10-fold the upper limit of normal.^275,281 However, among patients with jaundice and other symptoms such as fever, leukocytosis and intense right upper quadrant pain attributed to intrahepatic sickling or sickle cell hepatopathy, serum AST and ALT values often have been found to be only modestly elevated^{272,275,282,283} although in other cases, elevations in excess of 15 times the upper limit of normal have been noted.²⁷⁴ Thus, in patients with jaundice and prominent ALT elevations, both acute viral hepatitis and ischemic injury related to sickle cell disease itself must be considered as possible etiologies. In addition, coincidental causes of liver disease such as autoimmune hepatitis^284,285 have been reported in patients with sickle cell anemia and clinically apparent liver disease that was initially incorrectly ascribed to complications of sickle cell disease. Thus when evaluating liver disease in these patients, care must be taken to consider the full spectrum of possible etiologies.

Although the majority of patients with acute hepatocellular dysfunction thought secondary to either viral hepatitis or intrahepatic sickle cell crises recover following supportive care, cases of acute hepatic failure have been reported.^{264,275,278,286} Most such patients have presented with right upper quadrant pain, jaundice, modest aminotransferase elevations (less than 10-fold elevated) and progressive coagulopathy, and at postmortem examination have had histologic findings suggesting that the initiating cause of liver failure was centrilobular necrosis secondary to vascular complications of sickle cell disease. Recovery from severe cholestasis and coagulopathy has been reported after exchange transfusions.²⁸⁷ It also has been suggested that sickle cell disease may be a predisposing factor to the development of fulminant hepatic failure in children with acute viral hepatitis.²⁸⁶ Thus even in cases of liver failure with an apparent viral etiology, aggressive measures directed at reversal or prevention of intrahepatic sickling may be warranted.

In all sickle cell disease patients with direct hyperbilirubinemia and especially those with right upper quadrant pain, fever, or leukocytosis, acute cholecystitis with or without choledocholithiasis must be investigated as possible primary or contributing causes. A number of reports indicate that bile duct stones are found in a significant fraction of sickle cell disease patients undergoing cholecystectomy for symptomatic biliary tract disease.²⁸⁸ However, other studies have noted no objective evidence of choledocholithiasis or acute or chronic cholecystitis in many sickle cell disease patients undergoing cholecystectomy for presumed symptomatic biliary tract disease. This has led to speculation that events related to intrahepatic ischemia might better explain the signs and symptoms of liver disease in many of these patients.²⁷⁶

A significant rate of operative and anesthetic complications have been reported in patients with sickle cell disease.^276,288,289 Thus cholecystectomy is not recommended in asymptomatic patients with cholelithiasis. However, several reports have noted that in sickle cell patients with recurrent bouts of right upper quadrant pain and jaundice, a marked decrease in such symptomatic episodes is noted after cholecystectomy.^276,288,289 Thus in recurrently symptomatic patients with gallstones in whom there is difficulty in distinguishing between cholecystitis and intrahepatic crisis, cholecystectomy is recommended.²⁸⁹ However, in such patients special attention should be directed toward minimizing risks of anoxic injury during surgery by preoperative transfusion of red blood cells and expansion of intravascular volume and by intra- and postoperative oxygen therapy.

Chronic liver disease related to chronic viral hepatitis or to post-transfusional iron overload is being recognized with increased frequency in adult patients with sickle cell disease.^{267–269,290,291} Ferritin levels should be monitored in sickle cell patients who are recipients of multiple red cell transfusions and iron chelation therapy considered for those with evidence of significant iron overload.²⁶⁹ In recipients of chelation therapy and in the general sickle cell disease patient population, zinc deficiency related to excess renal losses is prevalent and via effects on ornithine transcarbamylase may potentiate hyperammonemia. Thus zinc therapy should be considered in sickle cell disease patients with evidence of hepatic encephalopathy.²⁹²

Thalassemia

Patients with thalassemia typically develop hepatomegaly from extramedullary hematopoiesis, with CT revealing well-defined hypodense lesions that enhance in the portovenous phase of contrast injection.²⁹³ These patients can also develop iron overload due to multiple transfusions, with the resulting end-organ dysfunction in the liver, gonads, and pancreas. The early parenteral use of the iron-chelating agent desferoxamine, in an amount proportional to the iron load, has been shown to be effective in halting the progression of fibrosis in patients with thalassemia major.²⁹⁴ However, deferiprone, an orally acting iron-chelating agent, has not been as effective in reducing the body iron burden and may worsen the fibrosis.²⁹⁵ Further studies are needed to better define the role of orally active iron chelators in thalassemic patients with iron overload.

DIABETES MELLITUS

Gastrointestinal symptoms are more prevalent in diabetic patients in comparison to the general population and have a negative effect on the quality of life.^296,297 These symptoms are independently associated with poor glycemic control and peripheral neuropathy.²⁹⁸ Autonomic dysfunction in diabetics (diabetic autonomic neuropathy [DAN]) can manifest itself in one or more organ systems. The pathogenesis of DAN is related to hyperglycemia, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency.²⁹⁹ In type 1 diabetes, enteric neurotransmission may be modulated by a functional IgG autoantibody that acts as an agonist at the L-type calcium channels of smooth muscle of the colon.³⁰⁰ Constipation, abdominal pain, nausea, vomiting, dysphagia, diarrhea, and fecal incontinence are symptoms of enteric DAN that are more commonly seen in older patients with long-standing type 1 diabetes, poor glucose control, and symptoms of cardiovascular or peripheral neuropathy.³⁰¹ Although motility disturbances are common in these patients, they do not correlate well with the presence or severity of symptoms. This suggests that other manifestations of DAN may play a role in the development of symptoms.

Table 35-5 Gastrointestinal Manifestations of Endocrine Diseases

ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; GH, growth hormone; LES, lower esophageal sphincter; MCT, medullary carcinoma of the thyroid; MEN, multiple endocrine neoplasia; VIP, vasoactive intestinal polypeptide.

THYROID DISEASE

ADRENAL DISEASE

Adrenal insufficiency, or Addison’s disease, is associated with gastrointestinal symptoms or pathology in more than half of cases. A constellation of symptoms including anorexia, weight loss, nausea, vomiting, diarrhea, and abdominal pain may be present. Patients with Addison’s disease may also present with chronically elevated aminotransferase levels.³⁵⁶ Cyclical vomiting in children may rarely be due to adrenal insufficiency.³⁵⁷ Malabsorption and diarrhea seen in some patients with Addison’s disease are apparently due to functional defects in enterocytes that can be readily reversed with the administration of glucocorticoids. Atrophic gastritis, achlorhydria, and pernicious anemia may be present in association with autoimmune Addison’s disease.

Pheochromocytomas are tumors arising from the adrenal medulla and chromaffin tissue that secrete high levels of catecholamines, leading to hypertension. The humoral effects of high circulating levels of catecholamines may result in ileus or pseudo-obstruction.³⁵⁸ Gastrointestinal manifestations of pheochromocytoma also include ischemic colitis, diarrhea, acute abdominal pain, and, rarely, gastrointestinal bleeding.³⁵⁹ For unclear reasons, pheochromocytoma is associated with an increased incidence of cholelithiasis. Some patients also have MEN-IIA or MEN-IIB syndrome (see earlier).

PITUITARY DISEASE

Pituitary disorders infrequently affect the gastrointestinal tract, except in association with MEN-I syndrome (see Chapter 32). Hypercortisolism, caused by the inappropriate secretion of corticotropin in Cushing’s disease, may be associated with an increased incidence of gastric ulceration when concomitant NSAIDs are used.³⁶⁰ Panhypopituitarism may present with addisonian crisis, with hypotension, nausea, vomiting, abdominal pain, and diarrhea. The excessive secretion of pituitary growth hormone with concomitant elevation of insulin-like growth factor I results in acromegaly. The incidence of adenomatous colonic polyps may be increased in patients with acromegaly and the adenomas tend to be larger, multiple, and right-sided.³⁶¹ The risk of colon cancer is approximately two-fold higher in acromegaly, but screening recommendations have been contentious.³⁶²

PARATHYROID DISEASE

HYPERLIPOPROTEINEMIAS AND DYSLIPIDEMIAS

In familial hyperchylomicronemia (type I phenotype), the plasma is lactescent, with marked elevation of chylomicrons and triglycerides due to a deficiency of lipoprotein lipase. Manifestations can appear early in life and include recurrent episodes of abdominal pain, fever, peritonitis, and pancreatitis (see Chapter 58). In most patients the cause of recurrent attacks of pain is not known.³⁶⁹ Patients with familial hyperbetalipoproteinemia (type IV phenotype) suffer from premature atherosclerosis, hyperuricemia, and attacks of pancreatitis that generally occur when plasma triglyceride values are greater than 2000 mg/dL.³⁷⁰ The hyperlipidemia may mask elevated plasma amylase values. Type IV patients also have an increased incidence of cholelithiasis and cholecystitis.³⁷¹ Patients with familial hyperlipoproteinemia (type V phenotype) are prone to bouts of abdominal pain, with or without pancreatitis. Exacerbation of endogenous hypertriglyceridemia by diabetes, diet, alcohol, or medications can also cause pancreatitis.³⁷⁰

ABETALIPOPROTEINEMIA

Abetalipoproteinemia is an autosomal recessive disorder characterized by acanthotic erythrocytes, serum lipid abnormalities, ataxia, atypical retinitis pigmentosa, and steatorrhea.³⁷² The typical laboratory feature is complete absence in plasma of all lipoproteins containing apolipoprotein B: chylomicrons, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL). The histologic appearance of the small intestine after an overnight fast is marked by mucosal epithelial cells loaded with lipid droplets (Fig. 35-9).³⁷³ By contrast, the submucosa and lamina propria show practically no lipid, and the lymphatics are empty. The villi are normal in length and configuration. Mild steatorrhea with onset during the first 2 years of life is seen (see Chapter 101). Cholesterol malabsorption with increased endogenous cholesterol synthesis has also been reported.³⁷⁴ The intestinal mucosa may appear yellowish on endoscopy, reflecting the presence of mucosal lipid.³⁷⁵ Therapy consists of substituting medium-chain for long-chain triglycerides.

Figure 35-9. Small intestinal biopsy specimen obtained from a patient with abetalipoproteinemia. The biopsy specimen is notable for the accumulation of lipid droplets within the intestinal epithelial cells.

TANGIER DISEASE

Tangier disease is an autosomal recessive disorder characterized by accumulation of cholesterol esters in macrophages in tonsils, thymus, lymph nodes, marrow, liver, and the gut. Tangier disease is caused by a mutation in the adenosine triphosphate-binding cassette protein, ABCA1, which mediates the efflux of excess cellular sterol to apolipoprotein A-I (apo A-I), a step leading to the formation of beneficial high-density lipoprotein (HDL).³⁷⁶ These patients have very low levels of plasma cholesterol and HDLs, owing to a lack of apo A-I. The gene encoding apo A-I is normal in Tangier disease, but a defect in post-translational processing results in rapid degradation of apo A-I.³⁷⁶ The striking clinical findings include yellow-orange “streaked” tonsils in 80% of cases, hepatosplenomegaly, and peripheral neuropathy. Patients may have diarrhea without steatorrhea. Colonoscopy reveals orange-brown mucosal spots throughout the colon and rectum, and laparoscopy reveals similar yellow patches on the surface of the liver due to cholesterol esters in hepatic reticuloendothelial cells.³⁷⁷

NEUTRAL GLYCOSPHINGOLIPIDOSES

Fabry’s disease is an X-linked disorder of glycolipid metabolism due to the deficiency or absence of the enzyme α-galactosidase A, resulting in globotriaosylceramide deposition in many tissues and subsequent organ dysfunction. Impaired motility is the prominent gastrointestinal abnormality.³⁷⁸ Electron microsopic examination of biopsy specimens from the small intestine and rectum reveals large sphingolipid-filled vacuoles in the ganglion cells of Meissner’s plexus within smooth muscle cells of the muscularis mucosa and within endothelial cells lining the blood vessels. Mucosal enterocytes are normal.³⁷⁸ The prevalence of gastrointestinal symptoms was 52%, with abdominal pain and diarrhea being the most frequent symptoms.³⁷⁹ Delayed gastric emptying, bacterial overgrowth, increased fecal bile acid loss, cholelithiasis, and jejunal diverticulosis with perforation have been documented. Successful treatment of the gastrointestinal component of this disorder with metoclopramide and tetracycline has been reported. Glycolipid deposition in small vessels can induce severe vasculitis and thrombosis, resulting in ischemic bowel lesions. Ileal perforation also has been reported.³⁸⁰ Thirty percent to 60% of obligate carrier women and 60% of men have nonspecific gastrointestinal symptoms that can improve with agalsidase alfa enzyme replacement therapy.³⁸¹

Gaucher’s disease is a rare, usually autosomal recessive deficiency of the enzyme acid β-glucosidase resulting in the deposition of glucosylceramide in the cells of the reticuloendothelial system, including the liver and spleen. In the adult form of the disease gastrointestinal complications predominate, including hepatosplenomegaly, hepatic cirrhosis, ascites, and esophageal variceal hemorrhage.^382,383

Niemann-Pick disease is a rare autosomal-recessive disease with a predilection for Ashkenazi Jews. Types A and B result from defects in sphingomyelinase. In type C Niemann-Pick disease, mutation in Niemann-Pick protein C results in defective transport of cholesterol across the lysosomal membrane.³⁸⁴ Sphingomyelinase deficiency results in the deposition of sphingomyelin and cholesterol in the liver and spleen, the CNS, and the lungs and skin. Gastrointestinal complications include hepatosplenomegaly and liver failure. Rare adult survivors of Niemann-Pick disease have been reported.³⁸⁵

NEUROGENIC ABDOMINAL PAIN (see Chapters 10 and 11)

Neurogenic causes of abdominal pain originate in either the CNS or peripheral nervous system. Central neurogenic abdominal pain can result from abdominal migraines. Although classic migraine headaches are often associated with nausea and vomiting, abdominal migraine is a migraine variant characterized by recurrent gastrointestinal symptoms, including vomiting and epigastric pain.⁴⁰⁶ It is often seen in children and is not always associated with headache. The pathophysiology of the gastrointestinal symptoms is unclear, and some have questioned the validity of this controversial diagnosis. In one Greek study, most pediatric patients with abdominal migraine had evidence of esophagitis, gastritis, or duodenitis at endoscopy.⁴⁰⁷ A more recent study of 53 children with abdominal migraine and no underlying gastrointestinal pathology demonstrated symptomatic improvement or successful prophylaxis using standard antimigraine therapies such as propranolol or cyproheptadine.⁴⁰⁸ Adults with migraine do not tend to report abdominal pain,⁴⁰⁹ although some investigators believe that a subset of adult patients with recurrent nonorganic abdominal pain may suffer from abdominal migraine. Unfortunately, the lack of a precise definition of abdominal migraine has made research in this area difficult.

Abdominal epilepsy is an uncommon cause of central neurogenic abdominal pain. One retrospective study describes the spectrum and clinical course of 10 patients with abdominal epilepsy.⁴¹⁰ These patients, each with temporal lobe electroencephalographic (EEG) abnormalities, experienced a variety of paroxysmal gastrointestinal symptoms that included periumbilical and right upper quadrant pain, bloating, and diarrhea. All of the patients also experienced CNS symptoms such as headaches, confusion, dizziness, syncope, or blindness, occurring daily in association with the gastrointestinal complaints. Anticonvulsant therapy resulted in resolution of gastrointestinal and CNS disturbances. Even patients with classic epileptic seizure disorders may experience viscerosensory auras (vague epigastric sensations and nausea). Although they can occur in patients with temporal lobe mass lesions, epigastric auras are more frequently associated with hippocampal sclerosis. These epigastric auras can be unpleasant or even debilitating. Unfortunately, 25% of patients who are rendered seizure free after anteromedial temporal lobe resection continue to have persistent epigastric auras.⁴¹¹ Although epilepsy with gastrointestinal symptoms is uncommon, an EEG should be considered in the diagnostic workup of patients with unexplained paroxysmal gastrointestinal complaints associated with CNS symptoms.

Peripheral neurogenic abdominal pain emanating from peripheral nerves or spinal nerve roots is usually intermittent and sharp. It is not associated with food intake or abdominal distention and is usually easy to diagnose. Possible causes include infections such as herpes zoster (pain may precede the rash), and syphilis (gastric crisis in tabes dorsalis); inflammatory conditions such as PAN; metabolic disturbances such as diabetic neuropathy (see earlier); toxic ingestions such as lead poisoning; and nerve root impingement due to osteoarthritis, tumors, or herniated disks.

GASTROINTESTINAL COMPLICATIONS OF ACUTE HEAD INJURY AND STROKE

Increased intracranial pressure from any cause may lead to episodic projectile vomiting, which may precede other signs. In addition to direct effects of CNS injury on the control of oropharyngeal muscle movement during swallowing, acute head trauma and stroke (cerebrovascular accidents) are associated with a high incidence of upper gastrointestinal tract pathology.⁴¹² In one prospective study, acute gastrointestinal erosive lesions were found at endoscopy in 75% of patients. Erosive gastritis was seen in 69% of cases, gastric ulcer in 23%, esophagitis in 11%, and duodenal inflammation in 8%.⁴¹³ Most lesions were present within a week of injury. There was no correlation between glucocorticoid administration and development of upper gastrointestinal tract lesions. Although these lesions fall within the spectrum of stress gastropathy (see Chapters 52 and 53), an additional pathogenetic mechanism may play a role in their development. Serum gastrin levels are elevated in patients with head injury,⁴¹⁴ presumably through a direct neurogenic reflex, and gastric hypersecretion has been reported.⁴¹⁵ Because these injuries are largely preventable, patients with acute neurologic injury due to trauma, severe strokes, neurosurgery, or some other condition should receive prophylactic antiulcer therapy (see Chapter 53).

GASTROINTESTINAL PROBLEMS AFTER SPINAL CORD INJURY

The effect of spinal cord injuries on the gastrointestinal tract depends on the level of the lesion. Delayed gastric emptying is seen in patients with cervical spinal cord injuries.⁴¹⁶ In the early postinjury period, severe gastric stasis, gastric dilation, and ileus are often present.⁴¹⁷ Nasogastric suction is frequently required. Promotility agents such as metoclopramide can be effective because the enteric nervous system and smooth muscle layers are intact. A frequent problem in the first weeks after injury is peptic ulceration, although the mechanism is unclear. Upper gastrointestinal hemorrhage is more common with cervical cord injuries, with the use of oral anticoagulants, or when there is respiratory distress.⁴¹⁸ Ulcer perforation and peritonitis may not be detected initially because of myelopathy involving sensory fibers or because of concomitant glucocorticoid therapy. When ulcer surgery is required, gastric resection or simple closure of the perforation is sufficient; truncal vagotomy is not performed because of the risk of severe gastric retention.⁴¹⁹ Pancreatitis, another early complication of spinal injuries, also may be related to the effects of glucocorticoids.^417,420 Autonomic dysreflexia, a life-threatening condition, sometimes affects patients whose lesion lies above the fifth thoracic root, the upper level of greater splanchnic flow. The pathophysiology involves an abnormal autonomic reflex that is initiated by fecal impaction or bladder distention and leads to severe hypertension and tachycardia.⁴²¹ If untreated, seizures, subarachnoid hemorrhage, and stroke may result. Routine bladder catheterization and avoidance of constipation are preventive.

Patients often face a different set of problems in the months to years following permanent spinal cord damage. With chronic loss of function, patients with quadriplegia are more likely to have gut complications than are patients with paraplegia. The incidence of gastroesophageal reflux is increased.⁴¹⁷ There may be decreased bioavailability of orally administered drugs owing to impaired gastric emptying.⁴²² Secondary amyloidosis involving the gastrointestinal tract is more common (see later), especially when chronic pyelonephritis and renal failure complicate spinal cord disease.^417,423 Other complications include cholelithiasis, the superior mesenteric artery syndrome (see Chapters 14 and 36), hemorrhage due to solitary colonic ulcer, and the precocious appearance of diverticulosis.^78,417 Many patients with spinal cord injury have marked impairment of their bowel function. Fecal incontinence and urgency can have a significant effect on quality of life.^424,425

Chronic constipation plagues many patients with spinal cord injury. Damage to neurons in the spinal cord eliminates the sensation of rectal fullness and the voluntary control of defecation. There may be decreased splanchnic outflow, impairing the coordination of intestinal and colonic motility. Prolonged transit time may be explained by decreased colonic activity, colonic contractions, and intraluminal pressure. Further, the gastrocolic reflex after feeding may be regionally diminished in the rectosigmoid.⁴²⁶ Fortunately, the lower motor neurons of the second, third, and fourth sacral roots, which provide the sensory and motor fibers for the defecation reflex, are usually intact.

Rehabilitation of bowel function is individualized to each patient’s disability. Physical exercise, adequate fluid intake, and stool softeners are prescribed, as for constipation of any origin. Most patients can learn to distend the rectum digitally on a regular schedule to initiate the defecation reflex. Stimulatory laxatives such as bisacodyl suppositories occasionally are necessary. It is not clear which patients, if any, may benefit from promotility agents. In the setting of major bowel dysfunction, colostomy may be a viable option.⁴²⁷ Patients with spinal cord injuries often have subtle symptoms and signs of colorectal emergencies that may lead to a delayed diagnosis and increased morbidity and mortality.⁴²⁸

DISEASES OF THE AUTONOMIC NERVOUS SYSTEM

Congenital and neurodegenerative diseases of the autonomic nervous system may affect the gastrointestinal tract and are listed in Table 35-6. These include familial dysautonomia, or the Riley-Day syndrome. Patients present at birth with feeding difficulties, poor temperature control, and motor incoordination. Common gastrointestinal symptoms include dysphagia, gastroesophageal reflux, and abnormal swallowing reflexes. A large percentage of patients require feeding gastrostomy or fundoplication. Lower gastrointestinal tract symptoms are less common, but patients may develop diarrhea as a result of decreased motility and bacterial overgrowth.⁴²⁹

Idiopathic autonomic neuropathy is a relatively uncommon acquired cause of autonomic neuropathy.⁴²⁹ It can affect sympathetic as well as parasympathetic function (pandysautonomia), or it may be limited to a parasympathetic deficit (cholinergic dysautonomia). The onset of symptoms can be acute or subacute. Cholinergic dysautonomia usually affects patients in their teens, whereas pandysautonomia manifests in early middle age.⁴³⁰ The etiology of this condition is unknown, but most cases develop after nonspecific viral infections. The syndrome also has been seen in association with mononucleosis,⁴³¹ Stevens-Johnson syndrome,⁴³² and herpes zoster or herpes simplex infections.⁴³³ In nearly 70% of cases, the initial manifestation of the disease is in the gastrointestinal tract. The most common symptoms are due to excessive cholinergic activity, such as diarrhea, hyperhidrosis, and hypersalivation. Although a large proportion of these patients has manometric abnormalities, complications of motility disorders such as bacterial overgrowth are usually not seen.⁴²⁹

A poorly understood autonomic condition is postprandial orthostatic hypotension, which occurs commonly in older adults and in patients with autonomic dysfunction. Direct gastrointestinal symptoms are infrequent, but abdominal pain and nausea may occur after meals. Other clinical manifestations include postprandial presyncope and syncope. The diagnosis is established by demonstrating a 20-mm Hg or more decrease in systolic blood pressure after a standardized test meal.⁴³⁴

Secondary causes of autonomic neuropathy include the porphyrias (variegate, acute intermittent, hereditary coproporphyria), discussed in Chapter 76, diabetes mellitus (discussed earlier), paraneoplastic autonomic neuropathy, amyloidosis (discussed following), and Chagas’ disease (see Chapter 109).

EXTRAPYRAMIDAL DISORDERS

Huntington’s chorea is a hereditary neurodegenerative basal ganglia disease characterized by chorea, dementia, and emotional changes. Dysphagia is a common symptom that may lead to fatal complications from aspiration pneumonia.⁴³⁵ Gastroparesis and constipation have been reported.

Parkinson’s disease is frequently associated with gastrointestinal symptoms. Oropharyngeal dysphagia and drooling can be particularly distressing. Abnormalities are found in the oral, pharyngeal, and esophageal stages of deglutition. Poor voluntary control of the tongue results in lingual hesitancy, poor bolus formation, and delayed transit into the pharynx. This defect in bolus propulsion persists in the poorly contracting pharynx. Food is often retained in the valleculae, and tracheal aspiration frequently occurs even in asymptomatic patients. Incomplete upper esophageal sphincter relaxation can be seen in 21% of patients.⁴³⁶ Manometric studies suggest that between 61% and 73% of patients have abnormal esophageal function, including aperistalsis, simultaneous or ineffective contractions, and decreased LES tone.⁴³⁷ Treatment of swallowing difficulties in patients with Parkinson’s disease should include optimization of therapy directed at the tremor and associated depression and treatment of underlying gastroesophageal reflux if it exists. Levodopa has beneficial effects on the oral and pharyngeal aspects of swallowing and should be taken at mealtimes. Anticholinergics may impair esophageal motility, and excessive dosing of levodopa itself may cause nausea. Botulinum toxin injection of the cricopharyngeal muscle leads to significant short-term improvement in swallowing and weight gain.⁴³⁸ Finally, smaller and more frequent meals of soft food and posterior spoon placement may help in the oral phase of swallowing. Delayed gastric emptying, constipation due to delayed colonic transit, and external sphincter dysfunction also can be seen in Parkinson’s disease.⁴³⁷

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is associated with fecal incontinence and constipation in up to 70% of patients (see Chapters 17 and 18).⁴³⁹ Impaired external and internal anal sphincter function contributes to fecal incontinence in MS.⁴⁴⁰ Defecography in MS patients with intractable constipation can demonstrate rectal intussusception, rectal outlet obstruction, and failure of the puborectalis and anal sphincter muscles to relax appropriately.^441,442 Biofeedback training may be beneficial in patients with limited disability and a nonprogressive disease course.⁴⁴³ Cranial nerve involvement in MS may lead to oropharyngeal dysphagia.

NEUROMUSCULAR DISORDERS

Degenerative diseases of peripheral motor neurons can present with gastrointestinal symptoms. In amyotrophic lateral sclerosis, bulbar dysfunction leads to oropharyngeal dysphagia with complications of malnutrition and aspiration. Patients often need gastrostomy or jejunostomy placement; a forced vital capacity of less than 50% is associated increased postprocedural mortality.⁴⁴⁴ Charcot-Marie-Tooth degenerative peripheral neuropathy also has been reported to cause pharyngeal dysphagia and abnormal gastrointestinal motility with delayed gastric emptying and disordered motility of the esophageal body.⁴⁴⁵

Motor end-plate disorders such as myasthenia gravis, an autoimmune disorder of the neuromuscular junction, are frequently associated with oropharyngeal dysphagia. Autoimmune hepatitis and primary biliary cirrhosis also may be associated with myasthenia gravis.^446,447

Inherited muscular dystrophies, including myotonic dystrophies (see later), are generally believed to involve only skeletal muscles. However, several muscular (and neuromuscular) disorders have been associated with motor disturbances of the gastrointestinal system. Duchenne’s muscular dystrophy (DMD) is an X-linked recessive disease that is the most common neuromuscular disease of childhood. Patients with DMD may experience nausea and vomiting, as well as abdominal distention, constipation, pseudo-obstruction, and gastric dilation. Even when gastrointestinal symptoms are absent, dysfunction of smooth muscle in the upper gastrointestinal tract is detectable.⁴⁴⁸ Patients with DMD as well as those with oculopharyngeal muscular dystrophy may experience cervical dysphagia. Also, gastroparesis and intestinal pseudo-obstruction have been reported in DMD.⁴⁴⁹

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive mitochondrial myopathy defined by the constellation of peripheral neuropathy, opthalmoparesis, and gastrointestinal dysmotility; muscle biopsy reveals histologic features of a mitochondrial myopathy.⁴⁵⁰ Gastrointestinal symptoms include dysmotility, diarrhea, pseudo-obstruction, achalasia, and malabsorption. A possible variant of MNGIE may be the “3-A” syndrome of familial achalasia, alacrima, and ACTH (corticotropin) sensitivity, characterized by postural hypotension, achalasia, decreased sweating and tears, and denervation hypersensitivity of the pupils.⁴⁵¹

Stiff-man syndrome manifests as symmetrical stiffness and painful spasm of the axial musculature. Dysphagia, perhaps due to spasm of the cricopharyngeus and upper esophagus, and delayed gastric emptying have been reported.⁴⁵² Myotonic dystrophy, an autosomal dominant disease of striated and smooth muscle, is considered a rare cause of gastrointestinal dilation and abnormal peristalsis. Gastrointestinal problems can be the presenting feature in 28% of patients with common symptoms including abdominal pain, dysphagia, emesis, diarrhea, and fecal incontinence.⁴⁴⁹