Meijers BK, Schalla S, Eerens F, Van Suylen RJ, Broers B, Cheriex EM, Smedema JP.
Protein-losing enteropathy in association with constrictive pericarditis.
Int J Cardiovasc Imaging. 2006 Jun-Aug;22(3-4):389-92. doi: 10.1007/s10554-005-9067-2. Epub 2006 Feb 25.
Abstract/Text
Although acute pericarditis is a common and usual benign disorder, sometimes evolution to constrictive pericarditis may occur. We present a case of constrictive pericarditis late after coronary bypass grafting, complicated by right sided heart failure. Edema formation was aggravated due to protein-losing enteropathy, resulting in hypoalbuminemia. Imaging of constrictive pericarditis was done by ultrasound as well as simultaneous pressure recording of the right and left ventricle. Imaging of intestinal protein loss was possible using intravenous Technetium-99m-labelled human serum albumin.
JEFFRIES GH, CHAPMAN A, SLEISENGER MH.
LOW-FAT DIET IN INTESTINAL LYMPHANGIECTASIA. ITS EFFECT ON ALBUMIN METABOLISM.
N Engl J Med. 1964 Apr 9;270:761-6. doi: 10.1056/NEJM196404092701503.
Abstract/Text
Aoyagi K, Iida M, Matsumoto T, Sakisaka S.
Enteral nutrition as a primary therapy for intestinal lymphangiectasia: value of elemental diet and polymeric diet compared with total parenteral nutrition.
Dig Dis Sci. 2005 Aug;50(8):1467-70. doi: 10.1007/s10620-005-2863-7.
Abstract/Text
Intestinal lymphangiectasia (IL) is a rare disease requiring oral fat restriction. The aim of this study was to evaluate the efficacy of enteral nutrition compared to that of total parenteral nutrition (TPN). We retrospectively reviewed nine patients with IL presenting with protein-losing enteropathy. Of these, seven patients not responding to a low-fat diet were treated with elemental diet (ED), polymeric diet (PD) containing medium-chain triglycerides, or TPN. Improvement in serum total protein was observed in two of three on ED and in one of two on PD, compared with three of three on TPN. Enteric protein loss was improved in two of two on ED, one of two on PD, and two of two on TPN. Outpatients who continued to receive enteral nutrition maintained a total protein level. Enteral nutirition appears to be as effective as TPN for patients with IL, and it may provide a valid and safe alternative therapy.
Ozen A, Comrie WA, Ardy RC, Domínguez Conde C, Dalgic B, Beser ÖF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ.
CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.
N Engl J Med. 2017 Jul 6;377(1):52-61. doi: 10.1056/NEJMoa1615887. Epub 2017 Jun 28.
Abstract/Text
BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55.
RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation.
CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Ozen A, Chongsrisawat V, Sefer AP, Kolukisa B, Jalbert JJ, Meagher KA, Brackin T, Feldman HB, Baris S, Karakoc-Aydiner E, Ergelen R, Fuss IJ, Moorman H, Suratannon N, Suphapeetiporn K, Perlee L, Harari OA, Yancopoulos GD, Lenardo MJ; Pozelimab CHAPLE Working Group.
Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study.
Lancet. 2024 Feb 17;403(10427):645-656. doi: 10.1016/S0140-6736(23)02358-9. Epub 2024 Jan 23.
Abstract/Text
BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5.
METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting.
FINDINGS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab.
INTERPRETATION: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab.
FUNDING: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Copyright © 2024 Elsevier Ltd. All rights reserved.
Yasunaga Y, Shinomura Y, Kanayama S, Yabu M, Nakanishi T, Miyazaki Y, Murayama Y, Bonilla-Palacios JJ, Matsuzawa Y.
Improved fold width and increased acid secretion after eradication of the organism in Helicobacter pylori associated enlarged fold gastritis.
Gut. 1994 Nov;35(11):1571-4. doi: 10.1136/gut.35.11.1571.
Abstract/Text
This study examined the effects of eradication of Helicobacter pylori (H pylori) infection on gastric mucosal morphology and acid secretion. Sixteen H pylori positive patients with enlarged gastric body folds were divided into two groups: (a) patients with moderate enlargement (fold width: 6 to 10 mm, n = 8) and (b) patients with severe enlargement (> 10 mm, n = 8). After successful treatment, gastric body fold width was reduced in both groups (p < 0.01) with an associated decrease in inflammatory infiltrates in the body mucosa (p < 0.01 and p < 0.05). Basal acid output and tetragastrin stimulated maximal acid output (mean (SEM)) in all 16 patients significantly increased from 1.1 (0.5) to 2.9 (0.9) mmol/h (p < 0.05) and from 5.4 (1.3) to 18.7 (2.3) mmol/h (p < 0.01), respectively, with a significant decrease in fasting serum gastrin concentrations, from 127.1 (16.1) to 59.6 (3.8) pg/ml (p < 0.01). The increase in acid secretion after eradication of H pylori was more noticeable in the severe group, who had shown lower acid secretion and higher serum gastrin concentrations (p < 0.05) before eradication, than the increase seen in the moderate group. The decreases in ammonia nitrogen content seen after eradication were significant in basal (from 0.91 (0.17) to 0.37 (0.08) mmol/h, p < 0.05) and stimulated gastric secretions (from 1.57 (0.19) to 0.37 (0.13) mmol/h, p < 0.01), although these changes were too small to explain the increases in basal acid output and maximal acid output. These results suggest that inflammation of the gastric body mucosa caused by H pylori infection is associated with enlarged gastric body folds and inhibition of acid secretion in H pylori positive patients with enlarged gastric body folds.
Stolte M, Bätz CH, Bayerdörffer E, Eidt S.
Helicobacter pylori eradication in the treatment and differential diagnosis of giant folds in the corpus and fundus of the stomach.
Z Gastroenterol. 1995 Apr;33(4):198-201.
Abstract/Text
In an earlier study, we were able to show that giant fold gastritis is probably a special form of Helicobacter pylori-associated gastritis. Proof of this contention, however--namely regression of the giant folds following eradication of the organism--in a large number of patients was not then possible. To rectify this, Helicobacter pylori (HP) eradication treatment with omeprazole and amoxicillin was applied to 47 patients with HP gastritis and giant folds (5 patients with giant folds localized in the anterior or posterior wall, 42 patients with generalised giant folds within the corpus and fundus). The results of treatment were investigated by endoscopy and histology at the earliest 4 weeks after termination of treatment. In 40 of the 47 patients (85.1%), HP eradication treatment was successful. In 7 patients in whom treatment was unsuccessful, follow-up examinations revealed no changes in the endoscopic or histological findings. In 2 out of 3 patients in whom the endoscopic findings were unchanged despite successful HP eradication, biopsy material revealed the cause of the giant folds to be a signet ring cell carcinoma; in the remaining patient the cause of giant fold persistence was unclear. In 36 patients, the endoscopic--findings normalised completely, while in one patient there was obvious regression of the giant folds. We conclude from this study that giant fold gastritis is indeed a special form of HP gastritis, and that eradicating the organism in patients with gastric giant folds may help to distinguish between inflammatory, hyperplastic and tumorous giant folds.
Bayerdörffer E, Ritter MM, Hatz R, Brooks W, Ruckdeschel G, Stolte M.
Healing of protein losing hypertrophic gastropathy by eradication of Helicobacter pylori--is Helicobacter pylori a pathogenic factor in Ménétrier's disease?
Gut. 1994 May;35(5):701-4. doi: 10.1136/gut.35.5.701.
Abstract/Text
Hypertrophic gastropathy--that is, Ménétrier's disease--was found, in a retrospective analysis, to be associated with Helicobacter pylori in more than 90% of patients. It is proposed that hypertrophic gastropathy represents a special form of H pylori gastritis in these patients. A case is described of a 28 year old woman with Ménétrier's disease associated with proved protein loss from the stomach. Treatment with cimetidine for more than three years had little benefit when colonisation by H pylori was detected. Density of H pylori colonisation and activity of gastritis, which was also present in the first biopsy specimens taken five years ago, were more pronounced in the body than in the antrum, which is in agreement with the characteristics of H pylori gastritis found in other cases with Ménétrier's disease. A 14 day antibacterial treatment course with 750 mg amoxicillin three times a day combined with 40 mg omeprazole three times a day was started in April 1991. This resulted in eradication of H pylori and the return to normal of giant folds and the mucosal histology. Serum protein concentrations returned to normal within six weeks and remained normal at two endoscopies during a two year follow up. This case report suggests that a subgroup of the patients with Ménétrier's disease may be healed by the eradication of H pylori.
Kawasaki M, Hizawa K, Aoyagi K, Nakamura S, Fujishima M.
Ménétrièr's disease associated with Helicobacter pylori infection: resolution of enlarged gastric folds and hypoproteinemia after antibacterial treatment.
Am J Gastroenterol. 1997 Oct;92(10):1909-12.
Abstract/Text
We herein report a case of a 46-yr-old female with Ménétrièr's disease associated with Helicobacter pylori (H. pylori) infection, in whom the appearance of enlarged gastric folds and hypoproteinemia were both successfully treated by antibacterial treatment. The patient had been treated with famotidine for 3 yr under a diagnosis of Ménétrièr's disease, which caused an increase in her serum protein concentration to a level at which she suffered no clinical problems; however, the concentration never reached a normal range, and the presence of enlarged gastric folds also remained unchanged. Because H. pylori colonization was detected in the stomach and was also retrospectively recognized in the initial histologic specimens, antibacterial treatment with omeprazole, clarithromycin, and metronidazole was thus attempted. As a result of the successful eradication of H. pylori, the enlarged gastric folds returned to normal and the serum protein concentration thus increased to a normal level after the treatment. The etiology of Ménétrièr's disease remains unknown; however, the above findings suggest that H. pylori infection may in some cases cause Ménétrièr's disease and should therefore be carefully treated in any patient with this condition.
Kaneko T, Akamatsu T, Gotoh A, Shimodaira K, Shimizu T, Kiyosawa K, Katsuyama T, Momose A.
Remission of Ménétrier's disease after a prolonged period with therapeutic eradication of Helicobacter pylori.
Am J Gastroenterol. 1999 Jan;94(1):272-3. doi: 10.1111/j.1572-0241.1999.00816.x.
Abstract/Text
We report here a case of Ménétrier's disease (MD) that required a prolonged period for remission after eradication therapy of Helicobacter pylori (HP). The appropriate time needed to judge the efficacy of the eradication therapy for HP infection in an MD case is discussed.
Bradburn DM, Redwood NF, Venables CW, Gunn A.
Medical therapy of Ménétrier's disease with omeprazole.
Digestion. 1992;52(3-4):204-8. doi: 10.1159/000200954.
Abstract/Text
Medical therapy of Ménétrier's disease is often unsatisfactory and may lead to surgical treatment. Two cases, previously unresponsive to H2 antagonists, are presented showing a marked response to omeprazole.
Ladas SD, Tassios PS, Malamou HC, Protopapa DP, Raptis SA.
Omeprazole induces a long-term clinical remission of protein-losing gastropathy of Ménétrier's disease.
Eur J Gastroenterol Hepatol. 1997 Aug;9(8):811-3. doi: 10.1097/00042737-199708000-00014.
Abstract/Text
We report a patient with Ménétrier's disease presenting with extensive subcutaneous oedema, ascites and pleural effusion due to hypoalbuminaemia. Gastric secretory studies showed no free basal and stimulated acid secretion. The gastric juice contained significant amounts of albumin (0.2 g/dl) and immunoglobulin G (IgG) (1.11 mg/dl), corresponding to an estimated daily loss of 9.7 g and 45 mg, respectively. Protein-losing gastropathy was initially unsuccessfully treated with famotidine (80 mg/day) for 17 months, but a long-term (25 months) clinical remission was subsequently achieved with omeprazole (20 mg/day). We suggest that excellent clinical remission of Ménétrier's disease and the associated protein-losing gastropathy may be obtained with long-term omeprazole maintenance treatment, possibly due to Helicobacter pylori suppression.
Vendelboe M, Jespersen J.
Hypertrophic protein-losing gastritis (Ménétrier's disease) treated with cimetidine.
Acta Med Scand. 1981;209(1-2):125-7. doi: 10.1111/j.0954-6820.1981.tb11564.x.
Abstract/Text
A man aged 46 developed Ménétrier's disease with massive hypertrophic gastritis and significantly elevated gastrointestinal protein clearance. During treatment with cimetidine the protein loss decreased markedly and the gastric mucosa normalized.
Kang JY, Tang KF, Goh A, Sundram FX, Seah CS.
Remission of Ménétrier's disease associated with ranitidine administration.
Aust N Z J Med. 1990 Oct;20(5):716-7. doi: 10.1111/j.1445-5994.1990.tb00406.x.
Abstract/Text
We describe a patient with Ménétrier's disease in whom acute administration of ranitidine reduced gastric protein loss more effectively than cimetidine or propantheline. This patient went into remission following a course of ranitidine. We reviewed the literature on remissions in Ménétrier's disease occurring without surgery. More detailed studies of various anti-secretory agents on individual patients are required to determine whether or not they are truly efficacious.
Kondo M, Ikezaki M, Kato H, Masuda M.
Anti-fibrinolytic therapy of giant hypertrophic gastritis (Menetrier's disease).
Scand J Gastroenterol. 1978;13(7):851-6. doi: 10.3109/00365527809182202.
Abstract/Text
In five cases of giant hypertrophic gastritis (Menetrier's disease) biopsied gastric mucosa was examined for fibrinolytic activity; in all cases there was marked elevation of the activity due mainly to tissue plasminogen activator. The patients were given antifibrinolytic therapy with oral tranexamic acid (trans-4-aminomethyl cyclohexane carboxylic acid; trans-AMCHA), and four of the patients showed marked improvement of their hypoproteinemia as well as their mucosal disorders. One patient, who showed moderate increase of serum protein level but no reduction of the mucosal disorder, finally received gastrectomy. It was concluded that antifibrinolytic therapy seemed to block the vicious circle of 'membrane disorders', 'increased tissue fibrinolysis', 'increased vascular permeability' and 'hypoproteinemia' in Menetrier's disease.
Davis GE, O'Rourke MC, Metz JR, Kindig WV, Sweeney JG, Kane KN.
Hypertrophic gastropathy symptoms responsive to prednisone. A case report and a review of the literature.
J Clin Gastroenterol. 1991 Aug;13(4):436-41. doi: 10.1097/00004836-199108000-00014.
Abstract/Text
We describe a 33-year-old man with giant hypertrophic gastropathy (Menetrier's disease), which, on operative biopsy of the stomach, showed a significant inflammatory component. The patient was treated with prednisone and quickly responded. Although a review of the literature revealed only two cases similarly treated, with equivocal results, spontaneous remission, does occur. Symptoms associated with this disease may respond to corticosteroids, which may offer effective therapy while awaiting involution of the gastropathy. Thus total gastrectomy may be avoided.
Geist M, Fich A, Mogle P.
Menetrier's disease: evolution of disease under histamine-2 receptor antagonists.
Am J Gastroenterol. 1992 May;87(5):648-50.
Abstract/Text
A 33-yr-old man, with known peptic disease, developed giant thickening of the gastric mucosa and hypoproteinemia. Serial endoscopic and x-ray examinations of the upper gastrointestinal tract were available before and after the development of Menetrier's disease. In a 1-yr interval, erosive gastritis developed in a normal gastric mucosa, which was followed a few months later by hypoproteinemia. The patient developed the disease while being treated with histamine-2 receptor antagonists.
Scott HW Jr, Shull HJ, Law DH 4th, Burko H, Page DL.
Surgical management of Menetrier's disease with protein-losing gastropathy.
Ann Surg. 1975 May;181(5):765-77. doi: 10.1097/00000658-197505000-00036.
Abstract/Text
Three patients with Menetrier's disease and protein-losing gastropathy who were studied during a 12 year period have been presented. The characteristic findings which differentiate them from patients with hypertrophic hypersecretory gastropathy, including the Zollinger-Ellison syndrome, are: 1) hypertrophy of gastric mucosa with giant rugal folds involving the fundus, cardia and body of the stomach but sparing the antrum; 2) muscosal hypertrophy consisting of gastric mjcus-secreting cells while parietal cells and chief cells are diminished in number and may be absent from many microscopic sections; 3) gastric secretion of large volume containing excess mucus, low to absent hydrochloric acid and protein concentration 5 or 6 times normal (1.7 mg/ml); 4) hypoalbuminemia and hypoglobulinemia due to loss of serum proteins fron gastric mucosa into the gastric lumen; 5) rare association with gastric ulcer. Unlike the Zollinger-Ellison syndrome none of our patients had duodenal ucler or multiple endocrine adenomatosis or a family history of these conditions. We have found no authenticated reports in the literature which document a relationship of Menetrier's disease ( as defined above) with multiple endocrine adenomatosis. Menetrier's disease with protein-losing gastropathy is a potentially lethal disorder of unknown cause with no specific treatment. Resection of the site of gastric protein losses as first done by Waugh is logical and effective. One of our three patients died in hospital before gastrectomy was done. Two others have done well for 11 months and 12 years, respectively, after total gastrectomy with Roux-en-Y esophagojejunostomy and Hunt-Lawrence jejunal pouch.
Sundt TM 3rd, Compton CC, Malt RA.
Ménétrier's disease. A trivalent gastropathy.
Ann Surg. 1988 Dec;208(6):694-701. doi: 10.1097/00000658-198812000-00004.
Abstract/Text
Current conceptions of Ménétrier's disease only obliquely resemble those originally described. Bona-fide cases are so uncommon that, of 125 cases diagnosed as Ménétier's disease, hypertrophic gastritis, or protein-losing gastropathy treated at the Massachusetts General Hospital during the 26-year period of 1962-1987, only six cases merited an unequivocal anatomic diagnosis. Two other cases previously described proved on review to be nondiagnostic in one instance and Campylobacter pylori gastritis in the other. Because abnormalities in the secretion of gastric acid and in the loss of protein from the stomach may coexist, a representation of each case in semiquantitative terms can be described on triaxial coordinates. Three patients had a hypercoagulable state, one in association with gastric carcinoma. One other case of gastric carcinoma and one of esophageal carcinoma coexistant with Ménétrier's disease were identified. Administration of subcutaneous heparin during the perioperative period to patients with Ménétrier's disease is appropriate regardless of whether or not hypercoagulation or carcinoma is manifest. If treatment with anticholinergic drugs and inhibitors of gastric acid secretion fails, total gastrectomy is the best solution, because it stops protein loss, eliminates hyperchlorhydria, prevents development of gastric carcinoma, and permits anastomotic reconstruction between normal esophagus and normal small bowel.
Burdick JS, Chung E, Tanner G, Sun M, Paciga JE, Cheng JQ, Washington K, Goldenring JR, Coffey RJ.
Treatment of Ménétrier's disease with a monoclonal antibody against the epidermal growth factor receptor.
N Engl J Med. 2000 Dec 7;343(23):1697-701. doi: 10.1056/NEJM200012073432305.
Abstract/Text
Settle SH, Washington K, Lind C, Itzkowitz S, Fiske WH, Burdick JS, Jerome WG, Ray M, Weinstein W, Coffey RJ.
Chronic treatment of Ménétrier's disease with Erbitux: clinical efficacy and insight into pathophysiology.
Clin Gastroenterol Hepatol. 2005 Jul;3(7):654-9. doi: 10.1016/s1542-3565(05)00368-x.
Abstract/Text
BACKGROUND & AIMS: Ménétrier's disease is a rare premalignant hypertrophic gastropathy characterized by large rugal folds, foveolar hyperplasia with glandular atrophy, hypochlorhydria, and hypoalbuminemia. Patients with severe disease often exhibit refractory nausea and vomiting and require gastrectomy. Evidence from both mice and human beings suggests a critical role for epidermal growth factor receptor (EGFR) signaling in the pathogenesis of this disease. We previously reported significant clinical and biochemical improvement of a single patient treated for 1 month with Erbitux, a monoclonal antibody that blocks ligand binding to EGFR.
METHODS/RESULTS: We describe 2 patients who were given longer-term treatment with Erbitux as an alternative to gastrectomy. The first patient presented with nausea, hypoalbuminemia, and peripheral edema that required total parenteral nutrition (TPN) and infusions of albumin. On institution of Erbitux, there was rapid improvement in nausea and vomiting and stabilization of serum albumin with discontinuation of TPN and albumin infusions. Serum albumin remained stable during a 1-year course of Erbitux without supplemental protein. Application before and after Erbitux of the radiopaque dye ruthenium red to biopsies of the gastric oxyntic gland mucosa demonstrated prompt and persistent closure of tight junctions by electron microscopy. The second patient presented with chronic gastric bleeding that required bimonthly blood transfusions. During a 4-month course of Erbitux, his hematocrit stabilized, and transfusion requirements were eliminated.
CONCLUSIONS: The present report demonstrates the efficacy of prolonged Erbitux therapy in patients with different presentations of severe Ménétrier's disease and also provides insight into the pathophysiology of the protein-losing gastropathy.
Takahata J, Okubo K, Komeda T, Kono T, Fukui I.
Generalized gastrointestinal polyposis associated with ectodermal changes and protein-losing enteropathy with a dramatic response to prednisolone.
Digestion. 1972;5(3):153-61. doi: 10.1159/000197188.
Abstract/Text
Russell DM, Bhathal PS, St John DJ.
Complete remission in Cronkhite-Canada syndrome.
Gastroenterology. 1983 Jul;85(1):180-5.
Abstract/Text
A case of Cronkhite-Canada syndrome, where there was complete remission confirmed by radiology, endoscopy, and histology, is reported. On presentation, there was generalized gastrointestinal polyposis, hypoalbuminemia, skin pigmentation, onycho-dystrophy, and alopecia. Enteral nutrition alone was administered for 10 wk, with resolution of the ectodermal features and disappearance of the polyps within 4 mo of commencement of the treatment. This report of complete remission supports the generally accepted nonneoplastic and essentially inflammatory nature of the polyps in Cronkhite-Canada syndrome. Consideration needs to be given to nutritional deficiency as a cause of the syndrome.
Chadalavada R, Brown DK, Walker AN, Sedghi S.
Cronkhite-Canada syndrome: sustained remission after corticosteroid treatment.
Am J Gastroenterol. 2003 Jun;98(6):1444-6. doi: 10.1111/j.1572-0241.2003.07509.x.
Abstract/Text
Watanabe C, Komoto S, Tomita K, Hokari R, Tanaka M, Hirata I, Hibi T, Kaunitz JD, Miura S.
Endoscopic and clinical evaluation of treatment and prognosis of Cronkhite-Canada syndrome: a Japanese nationwide survey.
J Gastroenterol. 2016 Apr;51(4):327-36. doi: 10.1007/s00535-015-1107-7. Epub 2015 Jul 28.
Abstract/Text
BACKGROUND: First reported in 1955, Cronkhite-Canada syndrome (CCS), a rare syndrome characterized by ectodermal abnormalities and inflammatory changes of the gastrointestinal tract mucosa, has been associated with a poor prognosis and life-threatening malignant complications. In a large population survey, we endeavored to characterize the course and treatment outcome of CCS through clinical and endoscopic assessment, and to explore its optimal treatment and surveillance strategy.
METHODS: A retrospective analysis of 210 patients with CCS was conducted via a questionnaire-based nationwide survey of 983 teaching hospitals located throughout Japan. We assessed clinical features, endoscopic findings, treatments used, and short- and long-term outcomes.
RESULTS: The average age at diagnosis was 63.5 years. In all cases, upper or lower gastrointestinal tract polyposis was confirmed, accompanied by characteristic ectodermal abnormalities. Of the treatments used, oral corticosteroids (30-49 mg/day) were the most effective treatment for active disease, with adjunctive nutritional support considered beneficial. With corticosteroid treatment, abdominal symptoms were relieved within a few months, whereas polyp regression often required more than 6 months. Maintenance of endoscopic remission with or without steroids for 3 years significantly lowered the development of CCS-related cancer, compared with relapsers or nonresponders, underscoring the importance of sustained endoscopic remission for cancer prevention.
CONCLUSIONS: The prognosis of CCS has greatly improved through the use of improved medical treatment. Although CCS continues to be relentlessly progressive, carrying a high cancer risk, a sufficient dose and duration of corticosteroid therapy accompanied by nutritional support and periodic endoscopic surveillance appears to improve its natural history.
Okamoto K, Isomoto H, Shikuwa S, Nishiyama H, Ito M, Kohno S.
A case of Cronkhite-Canada syndrome: remission after treatment with anti-Helicobacter pylori regimen.
Digestion. 2008;78(2-3):82-7. doi: 10.1159/000165354. Epub 2008 Oct 24.
Abstract/Text
A 67-year-old man with nausea, appetite loss, frequent diarrhea and severe weight loss presented with alopecia, skin hyperpigmentation and onychodystrophy. Laboratory investigations showed mild anemia, hypoproteinemia and hypoalbuminemia. Colonoscopy identified the numerous, hyperemic and sessile polyps with mucous exudation of various sizes throughout the colorectum. The ileocecal valve was substantially swollen. Magnified chromoendoscopy revealed sparsely distributed crypt openings with widening of the preicryptal space without destruction in the affected lesions. Upper gastrointestinal endoscopy revealed multiple small, reddish, and sessile polyps in the duodenum and Helicobacter pylori-associated gastritis. Histopathological examination of the colonic polyps revealed cystic dilatation and elongation of scattered glands with epithelial hyperplasia and stromal edema and inflammatory cell infiltrates. Thus, a diagnosis of Cronkhite-Canada syndrome was made. The patient was given clarithromycin, amoxicillin and lansoprazole, resulting in negative (13)C-urea breath tests. Three months later, his clinical symptoms and edema of the legs resolved with normalization of serum total protein and albumin levels and return to his previous body. The ectodermal abnormalities were resolved 8 months later. On repeat colonoscopic examinations, there was progressive remission of the duodenal and colorectal polyposis, leaving scattered pedunculated polyps in the transverse and ascending colon and on the almost normal-appearing ileocecal valve. At the follow-up magnifying endoscopic examination 8 months later, small round or round-oval pits were densely and regularly distributed.
Copyright 2008 S. Karger AG, Basel.
Frittoli RB, Vivaldo JF, Costallat LTL, Appenzeller S.
Gastrointestinal involvement in systemic lupus erythematosus: A systematic review.
J Transl Autoimmun. 2021;4:100106. doi: 10.1016/j.jtauto.2021.100106. Epub 2021 Jun 10.
Abstract/Text
INTRODUCTION: Gastrointestinal involvement is a common complain observed in 40-60% of systemic lupus erythematosus (SLE) patients. We performed a systematic review of clinically severe and potential life-threatening gastrointestinal manifestations and discuss clinical presentation, pathogenesis and treatment.
METHODS: We performed a literature search in English literature using PubMed and Embase from 2000 to December 2020. The following MeSH terms: systemic lupus erythematosus, protein-losing enteropathy, ascites, pancreatitis, vasculitis, intestinal vasculitis, enteritis and diarrhea published in the English literature.
RESULTS: We identified 141 studies (case reports, case series and cohort studies). The most frequent presenting symptoms are acute abdominal pain, nausea, and vomiting. Many of the manifestations were associated with disease activity. Histological features are rarely available, but both vasculitis and thrombosis have been described. There is no treatment guideline. The majority of patients were treated with corticosteroids and the most common immunososupressant were azathioprine, cyclophosphamide and mycophenolate.
CONCLUSION: Vasculitis and thrombosis may be responsible for severe life-threatening manifestations such as pancreatitis, protein loosing gastroenteritis, acalculous cholecistyitis and enteritis.
© 2021 The Authors. Published by Elsevier B.V.
Tian XP, Zhang X.
Gastrointestinal involvement in systemic lupus erythematosus: insight into pathogenesis, diagnosis and treatment.
World J Gastroenterol. 2010 Jun 28;16(24):2971-7. doi: 10.3748/wjg.v16.i24.2971.
Abstract/Text
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by the presence of a plethora of autoantibodies and immune complex formation. Virtually every system and organ can be affected by SLE. Gastrointestinal symptoms are common in SLE patients, and more than half of them are caused by adverse reactions to medications and viral or bacterial infections. Though not as common as lupus nephritis, SLE-related gastrointestinal involvement is clinically important because most cases can be life-threatening if not treated promptly. Lupus mesenteric vasculitis is the most common cause, followed by protein-losing enteropathy, intestinal pseudo-obstruction, acute pancreatitis and other rare complications such as celiac disease, inflammatory bowel diseases, etc. No specific autoantibody is identified as being associated with SLE-related gastroenteropathy. Imaging studies, particularly abdominal computed tomography scans, are helpful in diagnosing some SLE-related gastroenteropathies. Most of these complications have good therapeutic responses to corticosteroids and immunosuppressive agents. Supportive measures such as bowel rest, nutritional support, antibiotics and prokinetic medications are helpful in facilitating functional recovery and improving the outcome.
Amiot A.
[Protein-losing enteropathy].
Rev Med Interne. 2015 Jul;36(7):467-73. doi: 10.1016/j.revmed.2014.12.001. Epub 2015 Jan 21.
Abstract/Text
Protein-losing enteropathy is a rare syndrome of gastrointestinal protein loss. The primary causes can be classified into lymphatic leakage due to increased interstitial pressure and increased leakage of protein-rich fluids due to erosive or non-erosive gastrointestinal disorders. The diagnosis of protein-losing enteropathy should be considered in patients with chronic diarrhea and peripheral oedema. The diagnosis of protein-losing enteropathy is most commonly based on the determination of fecal alpha-1 antitrypsin clearance. Most protein-losing enteropathy cases are the result of either lymphatic obstruction or a variety of gastrointestinal disorders and cardiac diseases, while primary intestinal lymphangiectasia (Waldmann's disease) is less common. Treatment of protein-losing enteropathy targets the underlying disease but also includes dietary modification, such as high-protein and low-fat diet along with medium-chain triglyceride supplementation.
Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.
Feldt RH, Driscoll DJ, Offord KP, Cha RH, Perrault J, Schaff HV, Puga FJ, Danielson GK.
Protein-losing enteropathy after the Fontan operation.
J Thorac Cardiovasc Surg. 1996 Sep;112(3):672-80. doi: 10.1016/S0022-5223(96)70051-X.
Abstract/Text
Patients were observed after the Fontan operation to determine the frequency and severity of protein-losing enteropathy. A total of 427 patients who survived for 30 days after the Fontan operation, performed between 1973 and January 1987, were analyzed and, thus far, protein-losing enteropathy has developed in 47 of 427. The cumulative risk for the development of protein-losing enteropathy by 10 years was 13.4% among 30-day survivors, and 5-year survival after the diagnosis was 46%. Hemodynamic studies done coincident with the diagnosis of protein-losing enteropathy have shown increased systemic venous pressure, decreased cardiac index, increased pulmonary vascular resistance, and increased ventricular end-diastolic pressure. Medical management of protein-losing enteropathy was only partially successful. Statistical analysis has shown that factors related to protein-losing enteropathy were ventricular anatomy, increased preoperative ventricular end-diastolic pressure, longer operative bypass time, increased length of hospital stay, and postoperative renal failure. This study suggests that scrupulous selection of cases for the Fontan operation is mandatory and that certain perioperative factors may predispose to this serious complication of the Fontan procedure.
John AS, Johnson JA, Khan M, Driscoll DJ, Warnes CA, Cetta F.
Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation.
J Am Coll Cardiol. 2014 Jul 8;64(1):54-62. doi: 10.1016/j.jacc.2014.04.025.
Abstract/Text
BACKGROUND: Patients with protein-losing enteropathy (PLE) following the Fontan operation have a reported 50% mortality at 5 years after diagnosis.
OBJECTIVES: The aim of this study was to review outcomes in patients with PLE following the Fontan operation.
METHODS: From 1992 to 2010, 42 patients (55% male) with PLE following the Fontan operation were identified from clinical databases at the Mayo Clinic. Data were collected retrospectively.
RESULTS: Mean age at PLE diagnosis was 18.9 ± 11.0 years. Initial Fontan operation was performed at 10.1 ± 10.8 years of age. Mean time from Fontan operation to PLE diagnosis was 8.4 ± 14.2 years. Survival was 88% at 5 years. Decreased survival was seen in patients with high Fontan pressure (mean >15 mm Hg; p = 0.04), decreased ventricular function (ejection fraction <55%; p = 0.03), and New York Heart Association functional class >2 at diagnosis (p = 0.04). Patients who died had higher pulmonary vascular resistance (3.8 ± 1.6 Wood units [WU] vs. 2.1 ± 1.1 WU; p = 0.017), lower cardiac index (1.6 ± 0.4 l/min/m(2) vs. 2.7 ± 0.7 l/min/m(2); p < 0.0001), and lower mixed venous saturation (53% vs. 66%; p = 0.01), compared with survivors. Factors were assessed at the time of PLE diagnosis. Treatments used more frequently in survivors with PLE included spironolactone (21 [68%]), octreotide (7 [21%]), sildenafil (6 [19%]), fenestration creation (15 [48%]), and relief of Fontan obstruction (7 [23%]).
CONCLUSIONS: PLE remains difficult to treat; however, in the current era, survival has improved with advances in treatment. Further study is needed to better understand the mechanism of disease and ideal treatment strategy.
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Yoon JK, Kim GB, Song MK, Lee SY, Kim SH, Jang SI, Kim WH, Lee CH, Ahn KJ, Bae EJ.
Long-term Outcome of Fontan-Associated Protein-Losing Enteropathy: Treatment Modality and Predictive Factor of Mortality.
Korean Circ J. 2022 Aug;52(8):606-620. doi: 10.4070/kcj.2021.0309. Epub 2022 Mar 16.
Abstract/Text
BACKGROUND AND OBJECTIVES: Protein-losing enteropathy (PLE) is a devastating complication after the Fontan operation. This study aimed to investigate the clinical characteristics, treatment response, and outcomes of Fontan-associated PLE.
METHODS: We reviewed the medical records of 38 patients with Fontan-associated PLE from 1992 to 2018 in 2 institutions in Korea.
RESULTS: PLE occurred in 4.6% of the total 832 patients after the Fontan operation. After a mean period of 7.7 years after Fontan operation, PLE was diagnosed at a mean age of 11.6 years. The mean follow-up period was 8.9 years. The survival rates were 81.6% at 5 years and 76.5% at 10 years. In the multivariate analysis, New York Heart Association Functional classification III or IV (p=0.002), low aortic oxygen saturation (<90%) (p=0.003), and ventricular dysfunction (p=0.032) at the time of PLE diagnosis were found as predictors of mortality. PLE was resolved in 10 of the 38 patients after treatment. Among medical managements, an initial heparin response was associated with survival (p=0.043). Heparin treatment resulted in resolution in 4 patients. We found no evidence on pulmonary vasodilator therapy alone. PLE was also resolved after surgical Fontan fenestration (2/6), aortopulmonary collateral ligation (1/1), and transplantation (1/1).
CONCLUSIONS: The survival rate of patients with Fontan-associated PLE has improved with the advancement of conservative care. Although there is no definitive method, some treatments led to the resolution of PLE in one-fourth of the patients. Further investigations are needed to develop the best prevention and therapeutic strategies for PLE.
Copyright © 2022. The Korean Society of Cardiology.
John AS, Driscoll DJ, Warnes CA, Phillips SD, Cetta F.
The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation.
Ann Thorac Surg. 2011 Oct;92(4):1451-6. doi: 10.1016/j.athoracsur.2011.03.103. Epub 2011 Jul 23.
Abstract/Text
BACKGROUND: Approximately 5% to 15% of patients develop protein-losing enteropathy (PLE) after the Fontan operation. Oral controlled release (CR) budesonide has been used as a treatment strategy, but its use in the older Fontan population has not been described.
METHODS: Seven patients with refractory PLE after the Fontan operation were started on oral CR-budesonide at 9 mg. After 3 to 9 months, the dose was weaned to 3 mg. Response to treatment was assessed by clinical evaluation, serum albumin levels, and fecal α-1 antitrypsin clearance when available.
RESULTS: Median age at last evaluation was 20 years (range, 16 to 32 years). Six patients had increases in serum albumin levels but only 4 patients had symptomatic improvement. Systemic side effects included: cushingoid features (5), adrenal insufficiency (4), and new-onset type 2 diabetes mellitus (2). One patient had improvement in cushingoid features after weaning CR-budesonide to 3 mg. Older patients (ages 27 to 32 years) had the worst side effect profiles and were the most refractory to treatment. These patients had sonographic evidence of hepatic cirrhosis but normal serum liver function tests. Two deaths occurred: 1 from sepsis 1 month after CR-budesonide initiation and 1 from respiratory arrest 5 months after CR-budesonide discontinuation.
CONCLUSIONS: CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well.
Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
Itkin M, Piccoli DA, Nadolski G, Rychik J, DeWitt A, Pinto E, Rome J, Dori Y.
Protein-Losing Enteropathy in Patients With Congenital Heart Disease.
J Am Coll Cardiol. 2017 Jun 20;69(24):2929-2937. doi: 10.1016/j.jacc.2017.04.023.
Abstract/Text
BACKGROUND: Protein-losing enteropathy (PLE), characterized by loss of proteins in the intestine, is a devastating complication in patients with congenital heart disease. The cause of PLE is unknown, but lymphatic involvement has been suspected.
OBJECTIVES: The authors evaluated the use of lymphangiographic imaging and liver lymphatic embolization as a treatment for PLE.
METHODS: This was a single-center, retrospective review of imaging and interventions used in 8 consecutive patients with liver lymphatic embolization and congenital heart disease with elevated central venous pressure complicated by PLE.
RESULTS: Liver lymphangiography was performed in 8 patients (5 males, 3 females; median age, 21 years), 7 of whom demonstrated leakage of liver lymph into the duodenum through abnormal hepatoduodenal lymphatic communications. This was confirmed by duodenoscopy with simultaneous injection of isosulfan blue dye into the liver lymphatics in 6 of 7 patients. Liver lymphatic embolization with ethiodized oil in 2 patients resulted in a temporary increase in albumin blood level and symptom improvement in 1 patient, but was complicated by duodenal bleeding in both patients. Of the remaining 6 patients, liver lymphatic embolization with n-butyl cyanoacrylate glue resulted in sustained improvement of the serum albumin level and symptoms in 3 patients, temporary improvement in 2 patients, and no change in 1 patient with median follow-up of 135 days (range, 84 to 1,005 days).
CONCLUSIONS: The authors demonstrated liver lymph leakage as a cause of PLE in patients with congenital heart disease and elevated central venous pressure. Lymphatic embolization led to improved albumin levels and relief of symptoms. Further experience with the technique is needed to determine long-term outcome of this procedure.
Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Gartenberg AJ, Krishnamurthy G, Srinivasan A, Escobar FA, Brownell JN, Mamula P, O'Byrne ML, Dori Y, Smith CL.
Intrahepatic and Periduodenal Embolization for Protein-Losing Enteropathy Patients With Congenital Heart Disease.
J Am Coll Cardiol. 2023 Jun 27;81(25):2476-2478. doi: 10.1016/j.jacc.2023.04.033.
Abstract/Text
Vyas H, Driscoll DJ, Cabalka AK, Cetta F, Hagler DJ.
Results of transcatheter Fontan fenestration to treat protein losing enteropathy.
Catheter Cardiovasc Interv. 2007 Mar 1;69(4):584-9. doi: 10.1002/ccd.21045.
Abstract/Text
Transcatheter fenestration to create an interatrial communication has been used to treat patients with protein losing enteropathy (PLE) after Fontan operation. No systematic data have been reported assessing the results of this procedure. Our institutional database was queried to identify patients after Fontan operation who had transcatheter fenestration to treat PLE. Clinical notes, laboratory data, echocardiograms, and cardiac catheterization data were reviewed. From 1995 to 2005, 16 transcatheter fenestration procedures were performed in seven patients. Median age at fenestration was 18 years (range 13-41 years). Median duration of follow-up was 3.6 years (range 0.2-10.4 years). Techniques for fenestration included blade/balloon septostomy, stent placement, Amplatzer-fenestrated ASD device, and balloon dilation of previous stent. Size of the fenestration created was 5.2 +/- 1.1 mm. Systemic venous pressure remained unchanged after fenestration. Cardiac index increased significantly. Reduction of ascites and edema was noted after 9 of the 16 procedures. Ten of 16 (63%) of fenestrations spontaneously occluded. Three patients are free of ascites although recurrence of PLE occurred in all. One patient with a patent fenestration continues to have ascites. Two patients had Fontan takedown. One patient had conversion to a fenestrated extracardiac conduit Fontan and died postoperatively. The results of transcatheter Fontan fenestration are often disappointing. Maintaining fenestration patency is difficult. Even after "successful" fenestration, resolution of PLE may be incomplete and recurrences have occurred in all. Early consideration should be given to Fontan takedown or cardiac transplant in severely symptomatic patients with PLE who do not respond to fenestration. Transcatheter fenestration may be a bridge to a definitive procedure.
(c) 2007 Wiley-Liss, Inc.
