Cronkhite-Canada Syndrome 

Updated: Feb 22, 2019
Author: Melba Estrella, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Cronkhite-Canada syndrome (CCS) is a rare, sporadically occurring, noninherited disorder reported for the first time in 1955 by Leonard W. Cronkhite, Jr, and Wilma J. Canada as a new distinct clinical entity in two female patients with generalized gastrointestinal polyps, cutaneous pigmentation, alopecia, and onychodystrophy.[1]

Pathophysiology

The etiology of Cronkhite-Canada syndrome (CCS) is unknown. No evidence exists to suggest a familial predisposition. The possibilities of asymptomatic offspring or afflicted patients have not been excluded. Reports suggest immune dysregulation as the basis of Cronkhite-Canada syndrome.[2, 3, 4, 5] Many patients with Cronkhite-Canada syndrome have positive antinuclear antibodies as well as a variety of autoimmune diseases such as systemic lupus erythematous, rheumatoid arthritis, scleroderma, polymyalgia rheumatica, or hypothyroidism.[6, 7] Cronkhite-Canada syndrome patients have also been found to have elevated serum IgG4 levels. Positive results for immune staining of IgG4 plasma cells in stomach and colonic polyps have been also reported from patients with Cronkhite-Canada syndrome.[8, 9] The autoimmune etiology is further supported by the excellent clinical response to systemic steroids and azathioprine.[2]

Negoro et al demonstrated that germlike mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue), located at 10q23.3, which is responsible for another gastrointestinal polyposis syndrome (Cowden disease), is not detected in persons with Cronkhite-Canada syndrome.[10] Boland et al performed whole exome sequencing on germline DNA from blood samples and polyp tissue from a gastric and a colonic polyp. The polyps did not share common nonsilent somatic mutations, suggesting distinct origin without a common molecular pathway. On germline analysis, they identified a rare variant affecting PRKDC, protein kinase DNA-activated catalytic polypeptide (DNA-PKcs).[11]

Senesse et al described Cronkhite-Canada syndrome in association with arsenic poisoning.[12]

Gastrointestinal lesions in Cronkhite-Canada syndrome are hamartomatous polyps generally involving the entire gastrointestinal tract except for the esophagus.[4, 5, 13] Histologically they reveal pseudopolypoid-inflammatory changes. One report describes an esophageal squamous cell papilloma.[14]

Cutaneous symptoms are believed to be due to malabsorption; however, ectodermal changes did not appear to parallel the disease activity and improved despite gut dysfunction in some reported cases. Multiple brownish macules and patches also preceded the onset of gastrointestinal symptoms in one of the first reported cases of Cronkhite-Canada syndrome.

Infantile Cronkhite-Canada syndrome (similar to typical Cronkhite-Canada syndrome) includes juvenile gastrointestinal polyps, alopecia, nail changes, and macrocephaly. Infantile Cronkhite-Canada syndrome is believed to be a special variant of juvenile gastrointestinal polyposis. Its mode of inheritance is assumed to be autosomal recessive; however, parental consanguinity was not present in either described case. This raises the question of whether infantile Cronkhite-Canada syndrome may be a sporadic condition.[15, 16]

Etiology

The pathogenesis of Cronkhite-Canada syndrome (CCS) is unknown.

The principal gastrointestinal symptoms, weight loss, and weakness probably are due to altered digestive, motive, absorptive, and secretory functions of the gut and bacterial overgrowth syndrome. (Clostridium difficile is isolated quite frequently in the stool.) The exact etiology of diarrhea is not clear. The symptom is likely related to the presence of polyps; however, the impaired bowel motility may cease without alteration of the size and number of polyps. Gastric polyps have been found to be infected with Helicobacter pylori.[17] Elevated gastric acid secretion also was found in one reported case.

Ectodermal changes (ie, hyperpigmentation, alopecia, nail dystrophy) are believed to be due to protein loss and malabsorption; however, cutaneous manifestations preceded onset of diarrhea in many patients with Cronkhite-Canada syndrome. Authors suggest that ectodermal changes are an inherent part of the syndrome, not secondary to malabsorption, because similar ectodermal lesions do not appear in other protein-losing gastroenteropathies.[18] Moreover, based on the latest scalp biopsy histological findings, the hypothesis of an autoimmune causality for Cronkhite-Canada syndrome hair loss have been proposed.[19] Regrowth of hair was noted after treatment, during spontaneous remission, and even during active disease. Hyperpigmentation also was noted to be reversible after and without any specific therapy.

Presence of edema correlates well to hypoalbuminemia.

Neurologic or psychotic symptoms occurred as a cause of hypocalcemia, hypomagnesemia, and hypokalemia.

Mild-to-moderate anemia is secondary to malabsorption (ie, iron, vitamin B-12, folate deficiency), blood loss, or both. A case of Cronkhite-Canada syndrome concomitant with myelodysplastic syndrome has been diagnosed.[20]

Cataract progression likely is associated with hypoproteinemia and hypocalcemia. Low calcium levels in the aqueous humor were believed to promote changes in lens membrane permeability and subsequent membrane disruption. A flux of sodium ions was postulated to occur from the aqueous into the lens, resulting in overhydration and production of a cortical lens opacity.

The cause of macrocephaly, typically present in cases of the juvenile Cronkhite-Canada syndrome, is unknown. An increase of arachnoid cysts was demonstrated.

Epidemiology

Frequency

Cronkhite-Canada syndrome (CCS) has a worldwide distribution; over 500 cases have been reported.[21] The majority of these cases have been documented in Japan, including a large series of 180 patients.[22] Cronkhite-Canada syndrome is a rare disorder.[22, 23, 24, 25] Based on the large Japanese series, the estimated incidence of Cronkhite-Canada syndrome is about 1 case per million population.[22]

Race

No data are available on racial predisposition. Cronkhite-Canada syndrome has a worldwide distribution; however, most reported cases come from Japan.

Sex

Cronkhite-Canada syndrome does show a slight male predominance, with a male-to-female ratio of 3:2.[13]

Age

The typical onset of Cronkhite-Canada syndrome is during middle or old age. The average age is 59 years; the range is 31-86 years. Some reports suggest that the disease may remain asymptomatic, thus not being diagnosed for a long time.[26, 27]

Most patients are older than 50 years at the time of presentation.

The reported cases of infantile Cronkhite-Canada syndrome are scant (< 10).[15]

Prognosis

Cronkhite-Canada syndrome (CCS) is considered a relentlessly progressive disease with a variable course and poor prognosis depending mainly on control of protein and electrolyte balance. The mortality rate exceeds 50% regardless of therapy. The longest-surviving patients were alive 15 and 17.5 years after successful surgical treatment.

As reported in cases of Cronkhite-Canada syndrome, coexistent malignant changes in the polyps, gastrointestinal bleeding, and the possibility of intussusception or prolapse of gastric polyp–bearing mucosa increase the mortality.[28]

The first two described patients with Cronkhite-Canada syndrome died of starvation 7 and 8 months after the onset of symptoms.

Cases of spontaneous remission after nutritional support have been reported.

The prognosis in children is believed to be generally less optimistic than in adults.

Causes of death are attributable to severe cachexia, anemia, congestive heart failure, embolism, shock, bronchopneumonia, and postoperative complications. One third of patients die from intractable nutritional deficiency.

Appropriate corticosteroid therapy alongside nutritional support can alter the natural history of Cronkhite-Canada syndrome. Lasting polyp regression is associated with a markedly improved prognosis and decreased risk of cancer.[29]

 

Presentation

History

In most cases, symptoms of Cronkhite-Canada syndrome (CCS) appear in the sequence of gastrointestinal symptoms, weight loss, weakness, edema, and then ectodermal changes after a few weeks or a few months.

Patients' principal complaints start with a constant or episodic pain in the lower or upper abdomen. Intensity varies from mild and localized to severe and generalized. Pain is accompanied by chronic or recurrent watery diarrhea, sometimes melena. Watery bowel movements may occur 5-7 times per day, and stool volume as high as 4-6 L/d were reported. Progressive weight loss follows the diarrhea.

Change in taste sensation and loss of smell, with or without hypogeusia, also were reported as early symptoms.[30]

Most patients lose more than 20 kg during the course of the disease.

Progressive anorexia has been reported in several patients.

Other gastrointestinal symptoms are nausea and vomiting, apparently more frequent in female patients.

A case of a patient with Cronkhite-Canada syndrome and severe recurrent acute pancreatitis owing to a polyp on the ampulla of Vater has been described.[31]

Swallowing difficulties are reported.

Ectodermal changes are present in nearly all patients. Generally, ectodermal changes follow gastrointestinal symptoms by weeks to months; however, cases have been reported in which the ectodermal findings are present years before the gastrointestinal pathology.[26] Patients typically experience hair loss. In most patients, hair loss takes place simultaneously from the scalp, eyebrows, face, axillae, pubic areas, and extremities. In some cases, only scalp hair loss is described. Alopecia usually occurs rapidly; total hair loss within a few days is reported. Hair loss was specially denied in one reported patient. Other ectodermal changes include skin hyperpigmentation, vitiligo, and nail dystrophy (discoloration, ragged fingernails) leading to onycholysis.

In some reported cases, not all of the symptoms described above were present.

Neurologic symptoms may include sensory neuropathy, seizures, syncope, and/or vestibular disturbances (ie, gaze-evoked nystagmus, dysequilibrium).[32] Two cases of Cronkhite-Canada syndrome have been described in association with peripheral neuropathy, one of which was diagnosed as mononeuritis multiplex.[8, 33]

Approximately four cases of Cronkhite-Canada syndrome  associated with membranous nephropathy have been reported in the literature. Within these cases, the first case of Cronkhite-Canada syndrome treated with rituximab was reported, with subsequent remission of both conditions (Cronkhite-Canada syndrome and membranous neuropathy).[34]

In two cases, Cronkhite-Canada syndrome was preceded by a blistering episode.[35] One case described subepidermal blisters and antibasement membrane zone antibodies on direct immunofluorescence, suggesting epidermolysis bullosa acquisita. The second case reported blistering eruption as a form of drug-induced erythema multiforme.

In another reported case, the characteristic changes of Cronkhite-Canada syndrome developed 2 months after hemicolectomy of the descending colon for a carcinoma and 3 neighboring polyps, followed by 4 weeks of chemotherapy.

Physical Examination

Physical examination in Cronkhite-Canada syndrome (CCS) typically reveals ectodermal and gastrointestinal changes.

Ectodermal lesions are as follows:

  • Skin - spotty (lentigolike macules ranging from a few millimeters to 10 cm in diameter) and diffuse hyperpigmentation notably localized on the dorsal surface of the hands, palms, arms, neck, face, scalp, anterior chest region, and body folds; ill-defined brown patches on the perioral and buccal areas; reported cases without hyperpigmentation; patchy vitiligo

  • Buccal mucosa - Brownish pigmentation and swollen tongue with loss of papillae

  • Fingernails and toenails[36] - Discoloration; proximal nail plate separation and shedding; soft and spongy look of proximal nails; ragged distal fingernails; often irregular regenerated distal plate; onychoschizia (splitting of nails into layers); onychomadesis (nail shedding staring at the base and extending forward)

  • Hair loss on the scalp and other body areas

Gastrointestinal symptoms are as follows:

  • Multiple sessile or semipedunculated polyps ranging from 0.5-2 cm in diameter located principally in the colon but also in the stomach ("carpetlike" polyposis) and small intestine

  • Rough granular changes of stomach mucosa with edematous giant rugae

  • Almost 40 cases of colorectal cancer have been reported in association with Cronkhite-Canada syndrome (adenocarcinoma arising from the mucosal hyperplasia). Cronkhite-Canada syndrome associated with colorectal cancer frequently (40%) includes polyps containing serrated adenoma lesions.[37]

Other findings are as follows:

  • Edema ranging from mild and peripheral edema to massive anasarca

  • Wasting of muscle

  • Streaks of tan pigment in the retina

  • Cataract[38]

  • Xanthelasmas, cheilosis papillary atrophy of the tongue

  • Positive Chvostek and Trousseau signs

  • Acute psychotic symptoms, possibly caused by electrolyte loss, and, possibly schizophrenia[39, 40]

  • Thrombosis and coagulation disorders[26]

  • Cardiac failure[26]

Children develop a symmetric desquamating rash on the lower back, buttocks, genital area, lips, and perioral region, similar to skin lesions in acrodermatitis enteropathica (zinc deficiency). Macrocephaly is a typical sign of infantile Cronkhite-Canada syndrome.

Complications

Principal complications in Cronkhite-Canada syndrome (CCS) are related to gastrointestinal involvement (number, size, location of polyps); other complications may include the following:

  • Water, protein, and electrolyte loss
  • Gastrointestinal bleeding (due to erosions on the surface of polyps)
  • Bacterial overgrowth syndrome
  • Small intestinal bacterial overgrowth
  • C difficile enterocolitis [7]
  • Intussusception
  • Prolapse of gastric polyp–bearing mucosa
  • Duodenal papillary prolapse [41]
  • Thromboembolic episodes due to dehydration
  • Cachexia
  • Heart failure

Nagata et al suggest that Cronkhite-Canada syndrome has definite malignant potential, although the rate of malignant transformation is thought to be low, observed in up to 15% of patients with Cronkhite-Canada syndrome; colon, gastric, and bile duct primary malignancies have been reported in Cronkhite-Canada syndrome, with rare cases of liver metastasis.[42, 43, 44]

Uncommon complications of Cronkhite-Canada syndrome with membranous neuropathy have been reported.[34, 45]

Diffuse polyposis in Cronkhite-Canada syndrome was identified as a rare cause of pouch outlet obstruction after a Roux-en-Y gastric bypass in one patient.[46]

A unique manifestation of flail chest in a Cronkhite-Canada syndrome patient with severe osteoporosis and osteomalacia secondary to vitamin D deficiency was reported.[47]

An unusual reported complication of Cronkhite-Canada syndrome is the occurrence of both arterial and venous thromboses, in the setting of elevated circulating factor VIIIc and fibrinogen.[48] Nemade et al reported a case of Cronkhite-Canada syndrome complicated by pulmonary embolism following surgery.[49] There is also a report of severe sepsis and disseminated intravascular coagulation successfully treated with recombinant human soluble thrombomodulin.[50]

 

DDx

Diagnostic Considerations

Also consider the following:

 

Workup

Laboratory Studies

Various laboratory studies may include the following:

  • Electrolyte and micronutrient determination - Hypokalemia; hypocalcemia; depressed serum levels of zinc, iron, copper, and magnesium; and vitamin B-12

  • Hematology - Depressed white blood cell count, hemoglobin, red blood cell count, and hematocrit

  • Serum proteins - Hypoproteinemia with hypoalbuminemia; increased in alpha1 globulin level

  • Raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

  • Elevated serum levels of gastrin, histamine-fast achlorhydria, hypochlorhydria.

  • Biochemical and hematologic tests - Total protein level; albumin level; glucose and lipids concentration; iron, magnesium, zinc, calcium, sodium, potassium, and copper concentrations; ESR; CRP

  • Decreased cholinesterase activity

  • Stool examination - Occult blood and Sudan III staining

  • H pylori infection test

Imaging Studies

Endoscopic (also wireless capsule endoscopy[52] ) procedures (ie, panendoscopy,[53] gastroscopy, colonoscopy, sigmoidoscopy) reveal polyp lesions of the sessile or semipedunculated type throughout the stomach, duodenum, ileum, and colon, sparing the esophagus. Ikeda et al found pedunculated polyps in patients with Cronkhite-Canada syndrome (CCS). A few reports have described selective sparing of the stomach, small intestine, and/or the colorectum.[54, 55] Lesion size has varied from a few millimeters to 2 cm in diameter.[56] Endoscopic findings in the stomach also include reddish and edematous granular lesions with mucoid exudate and giant folds.

Murata et al applied a prototype of a magnifying single-balloon enteroscope to observe the entire small bowel intestine in a patient with Cronkhite-Canada syndrome. Further analysis should be done to investigate its usefulness as a diagnostic tool.[57]

Abdominal CT scanning may reveal thickened gastric folds.

Regarding radiography, a barium enema and small intestine double-contrast radiology examination show polypoid lesions.

A CT endoscopy using a multidetector-row CT scan with 3-dimensional reconstruction has been shown to be useful for the detection of Cronkhite-Canada syndrome polyps and for the monitoring of effects of therapy.[42]

Magnified chromoendoscopy with crystal violet reveals sparsely distributed crypt openings with widening of the pericryptal space on the surface of the polyps and the intervening colonic mucosa.[58]

Fluoroscopic examination of the stomach may show rough granular changes of the mucosa with edematous giant rugae and polypoid lesions.

Scintigraphy using technetium Tc 99m–labeled human albumin may result in leakage to the gastrointestinal tract.

Consider intraoperative or postoperative examination of p55 immunoreactivity accumulation in the tissue suspected of having a carcinomatous component.

Other Tests

Other tests may include the following:

  • Presence of antinuclear antibodies, usually with a nucleolar pattern

  • Malignancy markers (carcinoembryonic antigen, alpha-fetoprotein)

  • D-xylose absorption test (impaired)

  • Glucose tolerance test (may be impaired)

  • Fecal fat excretion (increased)

  • Gastrointestinal clearance of alpha-1 antitrypsin (usually elevated)

  • Culture of nail scrapings for fungi (for differential diagnosis)

  • HIV testing (possibly)

  • Stool culture for C difficile, Salmonella, Shigella, Yersinia, and Campylobacter species and for parasites

  • ath tests - Bacterial overgrowth syndrome, small intestinal bacterial overgrowth[7]

Procedures

Procedures may include the following:

  • Endoscopic procedures (gastroscopic, duodenoscopic, and colonoscopic examinations)

  • X-ray procedures (eg, barium enema examination, small intestine double-contrast radiology after Sellink)

  • Fluoroscopic examination of the gastrointestinal tract

  • Abdominal computed tomographic scan

  • Endoscopic biopsy of the polypoid lesion

  • Histologic examination of polypoid lesions and, if necessary, the scalp lesion

Histologic Findings

Hyperpigmentation is related to an increase in melanin within the basal layer with or without the melanocyte proliferation, pigment incontinence, hyperkeratosis, and nonspecific perivascular inflammation.[59, 60]

Ong et al reported an increased number of telogen hair follicles, hair follicle miniaturization, presence of pigment casts and peribulbar lymphoid cell infiltrate. These findings point to alopecia areata incognito as the probable cause of hair loss in Cronkhite-Canada syndrome (CCS). This variant of alopecia areata is characterized by acute diffuse hair thinning.[61, 19]

Such results contrast those formerly reported by Watanabe-Okada et al in two patients with Cronkhite-Canada syndrome. They described a diffuse anagen-telogen conversion with increased telogen hair follicles in the absence of miniaturization or hair follicle inflammation, previously suggesting that acute telogen effluvium triggered by malnutrition was the preceding factor inducing hair loss in Cronkhite-Canada syndrome.[62] Given the complex spectrum of the syndrome, further research on scalp biopsies is required.

A case report presented the histologic evaluation of a nail matrix biopsy showing hypergranulosis. Matrix hypergranulosis is a common finding in numerous inflammatory nail diseases, suggesting that nail changes found in Cronkhite-Canada syndrome could be an inflammatory reaction, rather than a consequence of malnutrition as previously believed.[63]

Histologically, polyps in patients with Cronkhite-Canada syndrome are pseudopolypoid-inflammatory changes with cystic dilatation. Ikeda et al found that some of the colon polyps presented a histologic pattern of a tubulovillous adenoma and others exhibited that of a juvenile-type polyp.[56] The latter polyps were characterized by the presence of elongated and/or tortuous crypts with microcystic dilatation and inflamed edematous wide stroma. The areas of focal intestinal metaplasia were present. Even though cellular atypia was present, the adenomatous polyps showed histologic similarity to juvenile polyps with inflamed edematous stroma and occasional cystic glands. Extensive diffuse mucosal thickening has been reported instead of individual polyp growth. Often, this diffuse thickening, possibly an early active stage of disease, is seen in the upper gastrointestinal tract, leading to giant gastric and/or duodenal rugal folds.[26] Although rare, flat or atrophic mucosa has also been described in patients with Cronkhite-Canada syndrome.[55]

According to Burke and Sobin,[64] Cronkhite-Canada syndrome polyps are characterized by their broad sessile base, expanded edematous lamina propria, and cystic glands. The only reliable distinction between Cronkhite-Canada syndrome and colonic juvenile polyposis is the pedunculated growth of the latter with the exception of the gastric polyps. Gastric polyps in Cronkhite-Canada syndrome are sessile and composed of focally dilated irregular foveolar glands within a lamina propria expanded by edema and often an inflammatory infiltrate. Most polyps contain smooth muscle fibers in the lamina propria, and a minority has surface erosions. Gastric Cronkhite-Canada syndrome polyps are quite similar to juvenile or hyperplastic polyps. Prominent mast cells, eosinophils, and IgG4 plasma cell infiltration have all been reported as well.[5, 65]

The most constant features of Cronkhite-Canada syndrome polyps are a sessile base, an expanded edematous lamina propria, and dilated glands. Other features, including inflammation, a small number of smooth muscle fibers, and a complex contour, are variable.

 

Treatment

Medical Care

Because of the unknown etiology, treatment for Cronkhite-Canada syndrome (CCS) remains predominantly symptomatic. Controlled therapeutic trials have not been possible because of the rarity of the disease. Remissions may occur spontaneously.

The primary goal of the treatment is to correct fluid, electrolyte, and protein loss, and to regulate stool frequency. These measures help improve the patient's general condition. Most patients need symptomatic treatment for abdominal pain.

The most effective treatment is combination therapy composed of systemic corticosteroids together with an antiplasmin, an elemental diet, and hyperalimentation (nutritional supplements). Antibiotics are used to correct intestinal bacterial overgrowth syndrome. The indication for corticosteroids is gastrointestinal inflammation; however, its origin is not clear. Yamakawa et al reported two cases of steroid-resistant Cronkhite-Canada syndrome that were effectively treated with cyclosporine. Dramatic improvement of clinical symptoms and endoscopic findings were observed in both cases.[20] Another case in which multiple treatments, including steroids, azathioprine, adalimumab, and cyclosporine, failed was treated with sirolimus, with apparent clinical and endoscopic remission of the disease.[66] One case has been reported to be treated with rituximab.[34]

Reports describe clinical response in Cronkhite-Canada syndrome to tumor necrosis factor (TNF) inhibitors, with improvement of symptoms, weight gain, and polyp regression. These findings reinforce the theory of this syndrome’s inflammatory etiology.[11, 29, 67, 68, 69] Immunosuppression in Cronkhite-Canada syndrome patients should be cautiously performed, owing to the potential accelerated malignancy risk.

Nutritional supplementation includes oral and/or intravenous fluids, electrolytes, vitamins, minerals, amino acids, albumins, and lipids.

Transfusions are sometimes required for severe anemia or acute blood loss.

In one reported case with elevated gastric acid secretion, the patient responded very well to ranitidine therapy.[70] Other medications used are sulfasalazine and metronidazole.

After H pylori eradication, gastric polypectomy can be of value.[17]

Emergent re-admission of patients with Cronkhite-Canada syndrome may occur because of significant diarrhea, gastrointestinal bleeding, intussusception, prolapse of gastric polyp-bearing mucosa, and thromboembolic episodes due to dehydration.

Surgical Care

At present, surgery is needed only for complications of Cronkhite-Canada syndrome (CCS), such us prolapse, bowel obstruction, and malignancy. Other authors suggest that surgical intervention should also be reserved for patients who are not responsive to conservative methods.

Surgical intervention carries a significant risk in weakened patients with Cronkhite-Canada syndrome. Careful consideration must be given to the clinical course of Cronkhite-Canada syndrome before administration of systemic corticosteroids.

Consultations

Gastroenterologist consultation always is required to establish number, localization, and size of polypoid lesions.

Consultation with a surgeon can help determine if surgical intervention is necessary.

Acute brain syndrome requires psychiatrist consultation.

Long-Term Monitoring

Some Cronkhite-Canada syndrome (CCS) patients remain asymptomatic after the hospital treatment and do not require further therapy. Prolonged corticosteroid therapy is necessary in other patients.

Controlling the macronutrient and micronutrient balance, periodically performing endoscopic examination of the gastrointestinal tract, and testing for occult blood presence in the stool are recommended.

It is essential to explain that patients must be reliable with follow-up care and regular examination of the gastrointestinal tract. Large polyps (>1 cm in diameter) require biopsy and pathologic examination.

 

Medication

Medication Summary

In described cases of Cronkhite-Canada syndrome (CCS), drugs used include corticosteroids, mesalamine (also known as mesalazine or 5-aminosalicylic acid),[71] tumor necrosis factor (TNF) inhibitors (infliximab), and antibiotics (ie, tetracycline, metronidazole). Immunosuppressive treatment with azathioprine, sirolimus, and calcineurin inhibitors, such as cyclosporine, should be considered for patients with steroid-resistant Cronkhite-Canada syndrome.[20, 66]

H1- and H2-receptor blockers have been used. Therapy with antiplasmin agents has also been reported. These agents interfere with fibrinolysis in the gastrointestinal tract, thereby reducing the loss of proteins.

Corticosteroids

Class Summary

Corticosteroids inhibit inflammation within gastrointestinal mucosa.

Prednisone (Deltasone)

Prednisone is used as an immunosuppressant to treat immune disorders. It decreases inflammatory reactions by reversing increased capillary permeability and inhibits antigen-antibody binding.

Antibiotics

Class Summary

Antibiotics are used for the concomitant bacterial overgrowth syndrome within gastrointestinal mucosa.

Tetracycline (Sumycin)

Tetracycline treats gram-positive and gram-negative organisms and mycoplasmal, chlamydial, and rickettsial infections. It inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunit(s).

Metronidazole (Flagyl)

Metronidazole is used to inhibit the concomitant bacterial overgrowth syndrome within gastrointestinal mucosa. It is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Metronidazole is used in combination with other antimicrobial agents (except for C difficile enterocolitis).

DMARDs, TNF Inhibitors

Class Summary

The use of biologic response modifiers that target TNF and other cytokines represents an advance in the treatment of several diseases involving autoimmune mechanisms. TNF inhibitors help stop inflammation.

Infliximab (Inflectra, Infliximab-abda, Infliximab-dyyb)

This is off-label use. Infliximab is a recombinant humanized monoclonal anti-TNF-alfa antibody; it prevents synovial and intestinal inflammation.

Anti-inflammatories

Class Summary

Anti-inflammatories inhibit inflammatory lesions within gastrointestinal mucosa.

Mesalamine (Rowasa, Asacol, Pentasa)

Mesalamine reduces the production of nitric oxide and superoxides, and the regulatory effect on leukotriene B4 results in inhibition of inflammation in the gastrointestinal tract. Mesalamine treats mildly to moderately active ulcerative colitis. The usual course of therapy in adults is 3-6 weeks. Some patients may need concurrent rectal and oral therapy.

Proton pump inhibitors

Class Summary

Proton pump inhibitors inhibit gastric acid secretion by inhibition of the H+/K+/ATP-ase enzyme system in the gastric parietal cells.

Omeprazole (Prilosec)

Omeprazole decreases gastric acid secretion by inhibiting the parietal cell H+/K+ -ATPase pump. It is indicated for gastric ulcers, duodenal ulcers, GERD, erosive esophagitis, and eradication of H pylori when combined with other medications.

Histamine H2 blockers

Class Summary

An increased gastric acid secretion is found in some patients with Cronkhite-Canada syndrome.

Ranitidine (Zantac)

Ranitidine inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and hydrogen concentrations.