Chronic Gastritis Clinical Presentation
- Author: Akiva J Marcus, MD, PhD; Chief Editor: BS Anand, MD more...
Acute H pylori infection usually is not detected clinically, but persistence of the organism causes H pylori chronic gastritis, which is usually asymptomatic but may manifest as epigastric pain, nausea, vomiting, anorexia, early satiety or weight loss. Symptoms may occur with the development of complications of chronic H pylori gastritis, which include peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma.
The clinical manifestations of autoimmune gastritis are primarily related to the deficiency in cobalamin, which is not adequately absorbed because of intrinsic factor (IF) deficiency resulting from severe gastric parietal cell atrophy. The disease has an insidious onset and progresses slowly. Cobalamin deficiency affects the hematologic, gastrointestinal (GI), and neurologic systems.
The most significant hematologic manifestation is megaloblastic anemia, but on rare occasions, purpura due to thrombocytopenia may develop. Symptoms of anemia include weakness, light-headedness, vertigo, tinnitus, palpitations, angina and symptoms of congestive heart failure.
There are many gastrointestinal manifestations of cobalamin deficiency. Patients sometimes report having soreness of the tongue- called glossitis. Anorexia with moderate weight loss that is occasionally associated with diarrhea may result from malabsorption associated with megaloblastic changes of the small intestinal epithelial cells.
Neurologic manifestations result from demyelination, followed by axonal degeneration and neuronal death. Affected sites include the peripheral nerves, posterior and lateral columns of the spinal cord, and cerebrum. Signs and symptoms include numbness and paresthesias in the extremities, weakness, and ataxia. Sphincter disturbances may occur. Mental function disturbances range from mild irritability to severe dementia or psychosis. Neurologic disease may occur in a patient with hematocrit and red cell parameters within the reference range.
As previously mentioned, patients with pernicious anemia have an increased frequency of gastric polyps and gastric carcinoid, in addition to an increase in the frequency of gastric adenocarcinoma.[83, 84]
In multisystemic diseases, specific symptoms related to gastric involvement may be minor. Caseating granulomas secondary to tuberculosis may be found in the absence of lung disease in patients who are malnourished, immunosuppressed, or alcoholic.
Patients with Crohn disease and gastric involvement may report abdominal pain, nausea, and vomiting. Gastric involvement in Crohn disease is almost invariably associated with intestinal disease, and intestinal manifestations predominate.
Sarcoidosis of the stomach is usually associated with granulomatous inflammation in other locations, especially the lungs, hilar nodes, or salivary glands. About 10% of patients with sarcoid involvement of the stomach are asymptomatic. Patients who are symptomatic present with gastric ulcers, hemorrhage, pyloric stricture, and gastric outlet obstruction.
Idiopathic isolated granulomatous gastritis
The diagnosis of idiopathic isolated granulomatous gastritis is established only when known entities associated with granulomas are excluded. Patients who are symptomatic usually are older than 40 years at presentation and have epigastric pain, weight loss, and vomiting secondary to pyloric obstruction.
Lymphocytic gastritis mostly affects middle-aged or elderly patients. It may be associated with chronic H pylori infection, gluten-sensitive enteropathy, and Menetrier disease. It may represent a hypersensitivity reaction involving the gastric body. Lymphocytic gastritis has been described as complicating MALT lymphoma and gastric carcinoma.
Some patients with eosinophilic gastroenteritis have underlying connective tissue disorders. Those with predominant mucosal involvement may report nausea, vomiting, and abdominal pain related to the ingestion of specific foods. Those with involvement of the muscularis propria and resulting thickening and rigidity may present with outlet obstruction symptoms. Many patients have a history of allergy, peripheral eosinophilia, asthma, eczema, or food sensitivity. Some respond to removal of these items from the diet, and steroid treatment is often helpful.
Gastritis in graft versus host disease
Graft versus host disease (GVHD) follows allogeneic bone marrow transplantation or transfusions, especially in patients who are immunocompromised. Patients with isolated gastric GVHD have symptoms of nausea, vomiting, and upper abdominal pain without diarrhea.
The physical examination contributes relatively little to the assessment and management of chronic gastritis. However, some findings are specifically associated with the particular complications of H pylori–associated gastritis and autoimmune gastritis.
In uncomplicated H pylori–associated atrophic gastritis, clinical findings are few and nonspecific. Epigastric tenderness may exist. If gastric ulcers coexist, guaiac-positive stool may result from occult blood loss. Bad breath (ie, halitosis) and abdominal pain or discomfort may occur, with bloating associated with bacterial overgrowth syndrome.
Physical findings may result from the development of pernicious anemia and neurologic complications in patients with autoimmune atrophic gastritis. With severe cobalamin deficiency, the patient is pale and has slightly icteric skin and eyes. The pulse is rapid, and the heart may be enlarged. Auscultation usually reveals a systolic flow murmur.
Szabo IL, Cseko K, Czimmer J, Mozsik G. Diagnosis of gastritis – Review from early pathological evaluation to present day management. Mozsik G, ed. Current Topics in Gastritis - 2012. Rijeka, Croatia: In Tech; 2012. Chap 1. [Full Text].
Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983 Jun 4. 1(8336):1273-5. [Medline].
Gao L, Weck MN, Stegmaier C, Rothenbacher D, Brenner H. Alcohol consumption and chronic atrophic gastritis: population-based study among 9,444 older adults from Germany. Int J Cancer. 2009 Dec 15. 125(12):2918-22. [Medline].
Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996 Oct. 20(10):1161-81. [Medline].
Sepulveda AR, Patil M. Practical approach to the pathologic diagnosis of gastritis. Arch Pathol Lab Med. 2008 Oct. 132(10):1586-93. [Medline].
Pounder RE, Ng D. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol Ther. 1995. 9 Suppl 2:33-9. [Medline].
McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med. 2010 Apr 29. 362(17):1597-604. [Medline].
NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 1994 Jul 6. 272(1):65-9. [Medline].
Shiotani A, Nurgalieva ZZ, Yamaoka Y, Graham DY. Helicobacter pylori. Med Clin North Am. 2000 Sep. 84(5):1125-36, viii. [Medline].
Wilson KT, Crabtree JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology. 2007 Jul. 133(1):288-308. [Medline].
Zalewska-Ziob M, Adamek B, Strzelczyk JK, et al. TNF-alpha expression in gastric mucosa of individuals infected with different virulent Helicobacter pylori strains. Med Sci Monit. 2009 Jun. 15(6):BR166-71. [Medline].
Wallace JL. Gastric ulceration: critical events at the neutrophil--endothelium interface. Can J Physiol Pharmacol. 1993 Jan. 71(1):98-102. [Medline].
Graham DY, Opekun A, Lew GM, Evans DJ Jr, Klein PD, Evans DG. Ablation of exaggerated meal-stimulated gastrin release in duodenal ulcer patients after clearance of Helicobacter (Campylobacter) pylori infection. Am J Gastroenterol. 1990 Apr. 85(4):394-8. [Medline].
Graham DY, Go MF, Lew GM, Genta RM, Rehfeld JF. Helicobacter pylori infection and exaggerated gastrin release. Effects of inflammation and progastrin processing. Scand J Gastroenterol. 1993 Aug. 28(8):690-4. [Medline].
Gao L, Weck MN, Nieters A, Brenner H. Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: enhanced elimination of the infection during disease progression?. Eur J Cancer. 2009 Nov. 45(16):2860-6. [Medline].
Wang SY, Shen XY, Wu CY, et al. Analysis of whole genomic expression profiles of Helicobacter pylori related chronic atrophic gastritis with IL-1B-31CC/-511TT genotypes. J Dig Dis. 2009 May. 10(2):99-106. [Medline].
Paniagua GL, Monroy E, Rodriguez R, et al. Frequency of vacA, cagA and babA2 virulence markers in Helicobacter pylori strains isolated from Mexican patients with chronic gastritis. Ann Clin Microbiol Antimicrob. 2009 Apr 30. 8:14. [Medline]. [Full Text].
Antonio-Rincon F, Lopez-Vidal Y, Castillo-Rojas G, et al. Pathogenicity island cag, vacA and IS605 genotypes in Mexican strains of Helicobacter pylori associated with peptic ulcers. Ann Clin Microbiol Antimicrob. 2011 May 13. 10:18. [Medline]. [Full Text].
Conteduca V, Sansonno D, Lauletta G, Russi S, Ingravallo G, Dammacco F. H pylori infection and gastric cancer: state of the art (review). Int J Oncol. 2013 Jan. 42(1):5-18. [Medline].
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001 Sep 13. 345(11):784-9. [Medline].
Zhao B, Zhao J, Cheng WF, et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia: a meta-analysis of randomized controlled studies with 12-month follow-up. J Clin Gastroenterol. 2014 Mar. 48(3):241-7. [Medline].
Delgado JS, Landa E, Ben-Dor D. Granulomatous gastritis and Helicobacter pylori infection. Isr Med Assoc J. 2013 Jun. 15(6):317-8. [Medline].
Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritis--pathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol. 2013 Sep. 10(9):529-41. [Medline].
Hung OY, Maithel SK, Willingham FF, Farris AB 3rd, Kauh JS. Hypergastrinemia, type 1 gastric carcinoid tumors: diagnosis and management. J Clin Oncol. 2011 Sep 1. 29(25):e713-5. [Medline].
Gilligan CJ, Lawton GP, Tang LH, West AB, Modlin IM. Gastric carcinoid tumors: the biology and therapy of an enigmatic and controversial lesion. Am J Gastroenterol. 1995 Mar. 90(3):338-52. [Medline].
Conn DA. Detection of type I and type II antibodies to intrinsic factor. Med Lab Sci. 1986 Apr. 43(2):148-51. [Medline].
Ectors NL, Dixon MF, Geboes KJ, Rutgeerts PJ, Desmet VJ, Vantrappen GR. Granulomatous gastritis: a morphological and diagnostic approach. Histopathology. 1993 Jul. 23(1):55-61. [Medline].
Wu TT, Hamilton SR. Lymphocytic gastritis: association with etiology and topology. Am J Surg Pathol. 1999 Feb. 23(2):153-8. [Medline].
Wolber R, Owen D, DelBuono L, Appelman H, Freeman H. Lymphocytic gastritis in patients with celiac sprue or spruelike intestinal disease. Gastroenterology. 1990 Feb. 98(2):310-5. [Medline].
Lambert R, Andre C, Moulinier B, Bugnon B. Diffuse varioliform gastritis. Digestion. 1978. 17(2):159-67. [Medline].
Makinen JM, Niemela S, Kerola T, Lehtola J, Karttunen TJ. Epithelial cell proliferation and glandular atrophy in lymphocytic gastritis: effect of H pylori treatment. World J Gastroenterol. 2003 Dec. 9(12):2706-10. [Medline].
Ruget O, Burtin P, Cerez H, Cales P, Boyer J. Chronic diarrhea associated with villous atrophy and lymphocytic gastritis, caused by ticlopidine. Gastroenterol Clin Biol. 1992. 16(3):290. [Medline].
Sheikh RA, Prindiville TP, Pecha RE, Ruebner BH. Unusual presentations of eosinophilic gastroenteritis: case series and review of literature. World J Gastroenterol. 2009 May 7. 15(17):2156-61. [Medline]. [Full Text].
Sell A, Jensen TS. Acute gastric ulcers induced by radiation. Acta Radiol Ther Phys Biol. 1966 Aug. 4(4):289-97. [Medline].
Flobert C, Cellier C, Landi B, et al. [Severe hemorrhagic gastritis of radiation origin]. Gastroenterol Clin Biol. 1998 Feb. 22(2):232-4. [Medline].
Quentin V, Dib N, Thouveny F, L'Hoste P, Croue A, Boyer J. Chronic ischemic gastritis: case report of a difficult diagnosis and review of the literature. Endoscopy. 2006 May. 38(5):529-32. [Medline].
Chambon JP, Bianchini A, Massouille D, Perot C, Lancelevee J, Zerbib P. Ischemic gastritis: a rare but lethal consequence of celiac territory ischemic syndrome. Minerva Chir. 2012 Oct. 67(5):421-8. [Medline].
Singhal AV, Sepulveda AR. Helicobacter heilmannii gastritis: a case study with review of literature. Am J Surg Pathol. 2005 Nov. 29(11):1537-9. [Medline].
Hasegawa Y, Goto A, Nishimura S, Sukawa Y, Fujii K, Suzuki K. Cytomegalovirus gastritis after treatment with rituximab. Endoscopy. 2009 Jul. 41(S 02):E199. [Medline].
Genta RM. Differential diagnosis of reactive gastropathy. Semin Diagn Pathol. 2005 Nov. 22(4):273-83. [Medline].
Shapiro JL, Goldblum JR, Petras RE. A clinicopathologic study of 42 patients with granulomatous gastritis. Is there really an "idiopathic" granulomatous gastritis?. Am J Surg Pathol. 1996 Apr. 20(4):462-70. [Medline].
Maeng L, Lee A, Choi K, Kang CS, Kim KM. Granulomatous gastritis: a clinicopathologic analysis of 18 biopsy cases. Am J Surg Pathol. 2004 Jul. 28(7):941-5. [Medline].
Leung ST, Chandan VS, Murray JA, Wu TT. Collagenous gastritis: histopathologic features and association with other gastrointestinal diseases. Am J Surg Pathol. 2009 May. 33(5):788-98. [Medline].
Rosenberg JJ. Helicobacter pylori. Pediatr Rev. 2010 Feb. 31(2):85-6; discussion 86. [Medline].
Everhart JE, Kruszon-Moran D, Perez-Perez GI, Tralka TS, McQuillan G. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000 Apr. 181(4):1359-63. [Medline].
Everhart JE. Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am. 2000 Sep. 29(3):559-78. [Medline].
Nabwera HM, Nguyen-Van-Tam JS, Logan RF, Logan RP. Prevalence of Helicobacter pylori infection in Kenyan schoolchildren aged 3-15 years and risk factors for infection. Eur J Gastroenterol Hepatol. 2000 May. 12(5):483-7. [Medline].
Sathar MA, Gouws E, Simjee AE, Mayat AM. Seroepidemiological study of Helicobacter pylori infection in South African children. Trans R Soc Trop Med Hyg. 1997 Jul-Aug. 91(4):393-5. [Medline].
Dattoli VC, Veiga RV, da Cunha SS, Pontes-de-Carvalho LC, Barreto ML, Alcantara-Neves NM. Seroprevalence and potential risk factors for Helicobacter pylori infection in Brazilian children. Helicobacter. 2010 Aug. 15(4):273-8. [Medline]. [Full Text].
Tsai CJ, Perry S, Sanchez L, Parsonnet J. Helicobacter pylori infection in different generations of Hispanics in the San Francisco Bay Area. Am J Epidemiol. 2005 Aug 15. 162(4):351-7. [Medline].
Lin DB, Lin JB, Chen CY, Chen SC, Chen WK. Seroprevalence of Helicobacter pylori infection among schoolchildren and teachers in Taiwan. Helicobacter. 2007 Jun. 12(3):258-64. [Medline].
Rubio CA, Befritz R, Eriksson B, Christensson B, Duvander A, Larsson B. The topographic distribution of lymphocytic gastritis in gastrectomy specimens. APMIS. 1991 Sep. 99(9):815-9. [Medline].
Jaskiewicz K, Price SK, Zak J, Louwrens HD. Lymphocytic gastritis in nonulcer dyspepsia. Dig Dis Sci. 1991 Aug. 36(8):1079-83. [Medline].
Tanih NF, Dube C, Green E, et al. An African perspective on Helicobacter pylori: prevalence of human infection, drug resistance, and alternative approaches to treatment. Ann Trop Med Parasitol. 2009 Apr. 103(3):189-204. [Medline].
Gao L, Weck MN, Raum E, Stegmaier C, Rothenbacher D, Brenner H. Sibship size, Helicobacter pylori infection and chronic atrophic gastritis: a population-based study among 9444 older adults from Germany. Int J Epidemiol. 2010 Feb. 39(1):129-34. [Medline].
Boelaert K, Newby PR, Simmonds MJ, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med. 2010 Feb. 123(2):183.e1-9. [Medline].
Laberge G, Mailloux CM, Gowan K, et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 2005 Aug. 18(4):300-5. [Medline].
de Vega Santos T, Zamarron Moreno A, Pascual de Pablo E, Lopez Lopez C. [Pernicious anemia and primary hyperparathyroidism]. Rev Clin Esp. 1995 Mar. 195(3):200-1. [Medline].
Asaka M, Kimura T, Kudo M, et al. Relationship of Helicobacter pylori to serum pepsinogens in an asymptomatic Japanese population. Gastroenterology. 1992 Mar. 102(3):760-6. [Medline].
Sugiyama T, Nishikawa K, Komatsu Y, et al. Attributable risk of H pylori in peptic ulcer disease: does declining prevalence of infection in general population explain increasing frequency of non-H pylori ulcers?. Dig Dis Sci. 2001 Feb. 46(2):307-10. [Medline].
O'Donohoe JM, Sullivan PB, Scott R, Rogers T, Brueton MJ, Barltrop D. Recurrent abdominal pain and Helicobacter pylori in a community-based sample of London children. Acta Paediatr. 1996 Aug. 85(8):961-4. [Medline].
Lindkvist P, Asrat D, Nilsson I, et al. Age at acquisition of Helicobacter pylori infection: comparison of a high and a low prevalence country. Scand J Infect Dis. 1996. 28(2):181-4. [Medline].
Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2000 Nov. 31(5):490-7. [Medline].
Hall CA, Beebe RT. Early onset of pernicious anaemia in two siblings: genetic and autoimmune aspects. Br J Haematol. 1973 Dec. 25(6):751-6. [Medline].
Annibale B, Lahner E, Fave GD. Diagnosis and management of pernicious anemia. Curr Gastroenterol Rep. 2011 Dec. 13(6):518-24. [Medline].
Min KU, Metcalfe DD. Eosinophilic gastroenteritis. Immunol Allergy Clin North Am. 1991. 11:799-813.
Ndip RN, Malange AE, Akoachere JF, MacKay WG, Titanji VP, Weaver LT. Helicobacter pylori antigens in the faeces of asymptomatic children in the Buea and Limbe health districts of Cameroon: a pilot study. Trop Med Int Health. 2004 Sep. 9(9):1036-40. [Medline].
Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014 Apr 10. 345(2):196-202. [Medline].
Iacopini F, Consolazio A, Bosco D, et al. Oxidative damage of the gastric mucosa in Helicobacter pylori positive chronic atrophic and nonatrophic gastritis, before and after eradication. Helicobacter. 2003. 8(5):503-12. [Medline].
Warren JR. Gastric pathology associated with Helicobacter pylori. Gastroenterol Clin North Am. 2000 Sep. 29(3):705-51. [Medline].
Macintyre G, Kooi C, Wong F, Anderson R. On the membrane cytopathology of mouse hepatitis virus infection as probed by a semi-permeable translation-inhibiting drug. Adv Exp Med Biol. 1990. 276:67-72. [Medline].
Ito M, Takata S, Tatsugami M, et al. Clinical prevention of gastric cancer by Helicobacter pylori eradication therapy: a systematic review. J Gastroenterol. 2009. 44(5):365-71. [Medline].
Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008 Aug 2. 372(9636):392-7. [Medline].
Kamada T, Hata J, Sugiu K, et al. Clinical features of gastric cancer discovered after successful eradication of Helicobacter pylori: results from a 9-year prospective follow-up study in Japan. Aliment Pharmacol Ther. 2005 May 1. 21(9):1121-6. [Medline].
Yamamoto K, Kato M, Takahashi M, et al. Clinicopathological analysis of early-stage gastric cancers detected after successful eradication of Helicobacter pylori. Helicobacter. 2011 Jun. 16(3):210-6. [Medline].
Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997 Nov 13. 337(20):1441-8. [Medline].
Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10. 368(2):149-60. [Medline].
Arvanitakis C. Functional and morphological abnormalities of the small intestinal mucosa in pernicious anemia--a prospective study. Acta Hepatogastroenterol (Stuttg). 1978 Aug. 25(4):313-8. [Medline].
Kumar N. Neurologic aspects of cobalamin (B12) deficiency. Handb Clin Neurol. 2014. 120:915-26. [Medline].
Ross WA, Ghosh S, Dekovich AA, Liu S, Ayers GD, Cleary KR. Endoscopic biopsy diagnosis of acute gastrointestinal graft-versus-host disease: rectosigmoid biopsies are more sensitive than upper gastrointestinal biopsies. Am J Gastroenterol. 2008 Apr. 103(4):982-9. [Medline].
Tahara T, Shibata T, Nakamura M, et al. Gastric mucosal pattern by using magnifying narrow-band imaging endoscopy clearly distinguishes histological and serological severity of chronic gastritis. Gastrointest Endosc. 2009 Aug. 70(2):246-53. [Medline].
Anagnostopoulos GK, Ragunath K, Shonde A, Hawkey CJ, Yao K. Diagnosis of autoimmune gastritis by high resolution magnification endoscopy. World J Gastroenterol. 2006 Jul 28. 12(28):4586-7. [Medline].
Ford AC, Marwaha A, Lim A, Moayyedi P. What is the prevalence of clinically significant endoscopic findings in subjects with dyspepsia? Systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2010 Oct. 8(10):830-7, 837.e1-2. [Medline].
Graham DY, Belson G, Abudayyeh S, Osato MS, Dore MP, El-Zimaity HM. Twice daily (mid-day and evening) quadruple therapy for H pylori infection in the United States. Dig Liver Dis. 2004 Jun. 36(6):384-7. [Medline].
Malfertheiner P, Megraud F, O'Morain C, et al for the European Helicobacter Pylori Study Group (EHPSG). Current concepts in the management of Helicobacter pylori infection--the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther. 2002 Feb. 16(2):167-80. [Medline].
Oberhuber G, Hirsch M, Stolte M. High incidence of upper gastrointestinal tract involvement in Crohn's disease. Virchows Arch. 1998 Jan. 432(1):49-52. [Medline].
Shkolnik LE, Shin RD, Brabeck DM, Rothman RD. Symptomatic gastric sarcoidosis in a patient with pulmonary sarcoidosis in remission. BMJ Case Rep. 2012 Jul 13. 2012:[Medline].
Weck MN, Gao L, Brenner H. Helicobacter pylori infection and chronic atrophic gastritis: associations according to severity of disease. Epidemiology. 2009 Jul. 20(4):569-74. [Medline].