Helicobacter pylori infection
1999; Elsevier BV; Volume: 5; Issue: 1 Linguagem: Inglês
10.1111/j.1469-0691.1999.tb00091.x
ISSN1469-0691
Autores Tópico(s)Gastrointestinal disorders and treatments
ResumoHelicobacter pylori has been for many years a forgotten bacterium, since the first reports on this spiral organism date from the nineteenth century [1Bizzozzero B Uber die sclauförmigen Drüsen des Magen-darmkanals und die Bezichuagen ihres Epithels zu dem Oberflächenepithel der Schleimhaut.Arch Mikr Anat. 1893; 23: 82-152Crossref Scopus (100) Google Scholar]. As early as 1906, an association between a spiral organism and gastric carcinoma was suggested [2Krienitz W Uber das Auftreten von Spirochaeten verschiedener Form im Mageninhalt bei Carcinoma ventriculi.Dtsch Med Wschr. 1906; 22: 872Crossref Scopus (106) Google Scholar]. Doenges reported in 1938 that, on autopsy, no fewer than 40% of human stomachs were found to be invaded by spiral organisms [3Doenges JL Spirochetes in the gastric glands of macacus rhesus and humans without definite history of related disease.Proc Soc Exp Med Biol. 1938; 38: 536-538Crossref Scopus (83) Google Scholar]. In 1940, the therapeutic effect of bismuth in patients with peptic ulcer disease in the presence of spiral bacteria in the stomach was reported [4Gorham F Editorial.Am J Dig Dis. 1940; 7: 445Google Scholar]. Interest in the bacterium then decreased. In 1982, two Australian researchers, Marshall and Warren, rediscovered the microbe [5Marshall BJ Warren JR Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983; 1: 1273-1275PubMed Google Scholar]. and called it first Campylobacter pylori, and later Helicobacter pylori. Today, the complete genome (1590 genes) of H. pylori has been unmasked [6Tomb JF White O Kerlavage AR The complete genome sequence of the gastric pathogen Helicobacter pylori.Nature. 1997; 388: 539-547Crossref PubMed Scopus (2869) Google Scholar] and published on the internet (http://www.tigr.org), probably paving the way for sequencing the genomes of other organisms, including that of humans within a few years [7Schlessinger D Genome sequencing projects.Nature Med. 1995; 1: 866-868Crossref PubMed Scopus (6) Google Scholar]. There is unequivocal evidence that H. pylori can be considered as a healthcare issue because of the mortality associated with the infection, due to the risk of ulcer bleeding and gastric cancer. Infection with H. pylori results in the development of gastritis in all infected humans, including children and adolescents [8Bourke B Jones N Sherman P Helicobacter pylori infection and peptic ulcer disease in children.Pediatr Infect Dis J. 1996; 15: 1-13Crossref PubMed Scopus (61) Google Scholar]. Worldwide, peptic ulcer disease is a major cause of morbidity and distal gastric adenocarcinoma, which is the second biggest cancer killer worldwide [9Atherton JC Helicobacter pylori unmasked—the complete genome sequence.Eur J Gastroenterol Hepatol. 1997; 9: 1137-1140PubMed Google Scholar]. However, the majority of infected individuals will remain free of symptoms throughout their lifetime; only a small minority will present with peptic ulcer disease (lifetime risk 15%), and an even smaller proportion will develop gastric neoplasms, including mucosa-associated lymphoid tissue lymphoma and adenocarcinoma (lifetime risk 0.1%) [10Fennerty MB Is the only good H. pylori a dead H. pylori.Gastroenterology. 1996; 111: 1773-1774Abstract Full Text PDF PubMed Scopus (18) Google Scholar]. Overall, H. pylori can be discovered in 92% of children with duodenal ulcers and in 25% of children with gastric ulcers [11Macarthur C Sauners N Feldman W Helicobacter pylori, gastroduodenal disease and recurrent abdominal pain in children.JAMA. 1995; 273: 729-734Crossref PubMed Scopus (221) Google Scholar]. H. pylori infection is contracted primarily in childhood, and infection from childhood appears to enhance the risk for carcinogenesis [12Blaser MJ Chyou PH Nomura A Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer and duodenal ulcer risk.Cancer Res. 1995; 55: 562-565PubMed Google Scholar]. The micro-aerophilic, Gram-negative, urease-producing H. pylori fulfills each of Koch's postulates [8Bourke B Jones N Sherman P Helicobacter pylori infection and peptic ulcer disease in children.Pediatr Infect Dis J. 1996; 15: 1-13Crossref PubMed Scopus (61) Google Scholar]. In its normal living form it is a spiral-shaped bacterium, but the coccoid form can also cause lesions. The bacterium colonizes the stomach of humans and induces severe mucosal inflammation and a local and systemic immune response. The bacterium is capable of changing its membrane potential at external pH levels from 3.0 to 7.0 in order to maintain a neutral internal pH [13Scott DR Weeks D Hong C Postius S Melchers K Sachs G The role of internal urease in acid resistance of Helicobacter pylori.Gastroenterology. 1998; 114: 58-70Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar]. All H. pylori strains are not created equal [14Blaser MJ All Helicobacter pylori are not created equal: should all be eliminated.Lancet. 1997; 349: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar] and not all strains are associated with clinical symptoms. Some virulence factors such as urease and flagella are present in all strains and are necessary for pathogenesis and colonization. Flagella, and thus motility, are needed for persistent gastric colonization [15Eaton KA Suerbaum S Josenhans C Krakowka S Colonisation of gnotobiotic piglets by Helicobacter pylori deficient in 2 flagellin genes.Infect Immun. 1996; 64: 2445-2448Crossref PubMed Google Scholar]. The gene FlbA is needed for flagellar expression [16Schmitz A Josenhans C Suerbaum S Cloning and characterisation of the Helicobacter pylori flbA gene which codes for a membrane protein involved in coordinated expression of flagellar genes.J Bacteriol. 1997; 179: 987-997Crossref PubMed Google Scholar]. Enzymes produced by H. pylori have mostly metabolic, antioxidant and toxic properties [17Nilius M Malfertheiner P Helicobacter pylori enzymes.Aliment Pharmacol Ther. 1996; 10: 65-71Crossref PubMed Scopus (30) Google Scholar]; most of these are produced by all isolates tested. Urease is required to establish infection, and is located intra- and extra-cellularly [15Eaton KA Suerbaum S Josenhans C Krakowka S Colonisation of gnotobiotic piglets by Helicobacter pylori deficient in 2 flagellin genes.Infect Immun. 1996; 64: 2445-2448Crossref PubMed Google Scholar]. Urease is a nickel-containing metallo-enzyme, composed of two structural subunits, UreA and UreB [18Graham DY Klein PD What you should know about the methods, problems, interpretations and uses of urea breath tests.Am J Gastroenterol. 1991; 86: 1118-1122PubMed Google Scholar]. Urease is primarily a cytoplasmic enzyme [19Phadnies SH Parlow MH Levy M et al.Surface localization of Helicobacter pylori urease and a heat-shock protein homologue requires bacterial autolysis.Infect Immun. 1996; 64: 905-912PubMed Google Scholar], and hydrolyzes urea to bicarbonate and ammonia, resulting in a net increase in the ambient pH. Ammonia is a nutrient for the bacteria, and causes lesions of the gastric epithelium by many different mechanisms [20Figura N Are Helicobacter pylori differences important in the development of Helicobacter pylori-related diseases.Ital J Gastroenterol Hepatol. 1997; 29: 367-374PubMed Google Scholar]. Surface urease helps to protect against acid exposure, but it is as yet unclear why it is found on bacteria deep underneath gastric mucus, where the pH is thought to be neutral. Because there is no obvious urease export machinery, it has been suggested that some bacteria undergo autolysis, following which released proteins, including active urease, are absorbed onto the surface of remaining intact bacteria [19Phadnies SH Parlow MH Levy M et al.Surface localization of Helicobacter pylori urease and a heat-shock protein homologue requires bacterial autolysis.Infect Immun. 1996; 64: 905-912PubMed Google Scholar, 21Dunn BE Vakil NB Schneider BG Miller MM Zizer JB Peutz T Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.Infect Immun. 1997; 65: 1181-1188Crossref PubMed Google Scholar]. Urease might function as an adhesin, although this suggestion has also been contradicted [22Clyne M Drumm B The urease enzyme of Helicobacter pylori does not function as an adhesin.Infect Immun. 1996; 64: 2817-2820Crossref PubMed Google Scholar]. Urease stimulates the release of a variety of inflammatory cytokines, including IL-β, IL-6, TNF-α, and chemokines such as IL-8 [23Harris PR Mobley HLT Perez-Perez GI Blaser MJ Smith PD Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production.Gastroenterology. 1996; 111: 419-425Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. Although the exact mechanism by which urease functions in the pathogenesis of gastric disease remains unclear, it is likely that urease is an important virulence factor. H. pylori can produce different kinds of phospholipases, weakening the hydrophobicity of the gastric mucus and mucosa. Phospholipase can also generate ulcerogenic substances [24Langton SR Cesareo SD Helicobacter pylori associated phospholipase A2 activity: a factor in peptic ulceration.J Clin Pathol. 1992; 45: 221-224Crossref PubMed Scopus (55) Google Scholar]. Many other enzymes, such as mucinase, neuraminidase, fucosidase and alcohol dehydrogenase, have been reported [20Figura N Are Helicobacter pylori differences important in the development of Helicobacter pylori-related diseases.Ital J Gastroenterol Hepatol. 1997; 29: 367-374PubMed Google Scholar]. The vacuolating cytotoxin A (vacA) gene is present in all strains, but is only expressed in 50% of H. pylori isolates [25Atherton JC Peek RM Tham KT Cover TL Blaser MJ Clinical and pathologic importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori.Gastroenterology. 1997; 112: 92-99Abstract Full Text PDF PubMed Scopus (563) Google Scholar]. The vacuolating activity of vacA is increased by exposure to acidic pH values [26De Bernard M Papini E De Filippis V Gottardi E Telfors J Manetti R Low pH activates the vacuolating toxin of Helicobacter pylori which becomes acid and pepsin resistant.J Biol Chem. 1995; 70: 23937-23940Crossref Scopus (168) Google Scholar]. The vacuoles are formed by merging of late endosomes, and the mechanism causing this has been determined [27Papini E Satin B Bucci C et al.The small GTP binding protein rab7 is essential for cellular vacuolating induced by Helicobacter pylori cytotoxin.EMBO J. 1997; 16: 15-24Crossref PubMed Scopus (190) Google Scholar]. The vacA gene exhibits different allelic combinations. Strains with the gene s1/m1 have the highest levels of cytotoxic activity, colonize the stomach more densely and are correlated with peptic ulcer, atrophic gastritis and gastric cancer; s2/m2 strains have no toxic activity [20Figura N Are Helicobacter pylori differences important in the development of Helicobacter pylori-related diseases.Ital J Gastroenterol Hepatol. 1997; 29: 367-374PubMed Google Scholar, 28Atherton JC Tham KT Peek RM Cover TL Blaser MJ Density of Helicobacter pylori infection in vivo as assessed by quantitative culture and histology.J Infect Dis. 1996; 174: 552-556Crossref PubMed Scopus (170) Google Scholar]. Other virulence factors, such as ‘cytotoxic-associated gene A’(cagA)-encoded proteins, are only found in a proportion of the strains. This might explain why not all strains are associated with clinical symptoms, although both cagA and the s1 vacA allele are unreliable as single markers in determining the risk of developing peptic ulcer disease [29Gunn MC Stephens JC Stewart JD Rathbone BJ Detection and typing of the virulence determinants cagA and vacA of Helicobacter pylori directly from biopsy DNA: are in vitro strains representative of in vivo strains.Eur J Gastroenterol Hepatol. 1998; 10: 683-687PubMed Google Scholar]. The cagA protein product is a cryptic 128-kDa immunodominant antigen produced by H. pylori. cagA is a marker for a larger cluster of genes (40 different genes [20Figura N Are Helicobacter pylori differences important in the development of Helicobacter pylori-related diseases.Ital J Gastroenterol Hepatol. 1997; 29: 367-374PubMed Google Scholar]) carried on a pathogenicity island that exhibits variability between strains [30Censini S Lange C Xiang Z et al.CagA, a pathogenic island of H. pylori encodes type I-specific and disease-associated virulence factors.Proc Natl Acad Sci USA. 1996; 93: 14684-14753Crossref Scopus (1586) Google Scholar]. CagA+ strains produce increased amounts of IL-8 [30Censini S Lange C Xiang Z et al.CagA, a pathogenic island of H. pylori encodes type I-specific and disease-associated virulence factors.Proc Natl Acad Sci USA. 1996; 93: 14684-14753Crossref Scopus (1586) Google Scholar]. Gastric atrophy, duodenal ulceration and gastric carcinoma are more common in patients infected with CagA+ than with CagA- strains [31Parsonnet J Friedman GD Orentreich N Vogelman H Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection.Gut. 1997; 40: 297-301Crossref PubMed Scopus (781) Google Scholar]. CagA- strains are very rare in some Far East countries such as China and Korea and frequent in others such as Hong Kong. However, allelic variations in CagA are found in different parts of the world. In Western countries, CagA+ strains are associated with gastric atrophy and peptic ulcer disease [32Beales ILP Crabtree JE Scunes D Covacci A Calam J Antibodies to CagA protein are associated with gastric atrophy in Helicobacter pylori infection.Eur J Gastroenterol Hepatol. 1996; 8: 645-649PubMed Google Scholar]. Other putative virulence determinants are being discovered, such as the neutrophil-activating protein (napA) gene, a gene ‘induced by contact with epithelium’(iceA1), etc. [20Figura N Are Helicobacter pylori differences important in the development of Helicobacter pylori-related diseases.Ital J Gastroenterol Hepatol. 1997; 29: 367-374PubMed Google Scholar]. However, according to recent data, it is suggested that there is no correlation between the degree of inflammation and the presence of the cag pathogenicity island, cytotoxin production, and vacA alleles associated with cytotoxin expression in children [33Celik J Su B Tiren U et al.Virulence and colonization-associated properties of Helicobacter pylori isolated from children and adolescents.J Infect Dis. 1998; 177: 247-252Crossref PubMed Scopus (25) Google Scholar]. Auto-immunity and host mimicry by expression of blood group antigens may be a relevant phenomenon. Adhesion of H. pylori is non-specific, although preferential to epithelial cells, and is enhanced at low pH, inducing epithelial cell reorganization and causing deep imagination of the apical membrane, explaining resistance to topical antibiotic treatment [34Corthsey-Theylaz I Porta N Pringault E et al.Adhesion of Helicobacter pylori to polarised T-84 human intestinal cell monolayers is pH dependent.Infect Immun. 1996; 64: 3827-3832PubMed Google Scholar]. One host receptor for adhesion appears to be a blood group O antigen, possibly explaining why ulcers are more common in people with this blood group [35Alkout AM Blackwell CC Weir DM et al.Isolation of a cell surface component of Helicobacter pylori that binds H type 2, Lewis (a) and Lewis (b) antigens.Gastroenterology. 1997; 112: 1179-1187Abstract Full Text PDF PubMed Scopus (58) Google Scholar]. The H. pylori lipopolysaccharide (LPS) or endotoxin is unusually biologically inert compared to that from other bacteria. However, the mechanisms by which H. pylori LPS stimulates cells appear to be similar to those of other types of bacterial LPS [36Kirkland T Viriyakosol S Perez-Perez GI Blaser MJ Helicobacter pylori lipopolysaccharide can activate 70Z/3 cells via CD14.Infect Immun. 1997; 65: 514-518PubMed Google Scholar]. H. pylori LPS often contains Lewis x and Lewis y blood group antigens that are identical to those occurring in the gastric mucosa [37Appelmelk BJ Negrini R Moran AP Kuipers EJ Molecular mimicry between Helicobacter pylori and the host.Trends Microbiol. 1997; 5: 70-73Abstract Full Text PDF PubMed Scopus (131) Google Scholar]. H. pylori presents bacterial epitopes to the host which are similar to the structure on host gastric epithelium; therefore, the host reacts with an auto-antibody response recognizing gastric mucosa, inducing atrophic gastritis [38Negrini R Savio A Poiesi C et al.Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis.Gastroenterology. 1996; 111: 655-665Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar]. Patients with a large parietal cell mass and high acid secretion will have predominantly antral gastritis, predisposing to duodenal ulcer [39Valle J Sipponen P Pajares JM Geographical variations in Helicobacter pylori gastritis and gastric cancer.Curr Opin Gastroenterol. 1997; 13: 35-39Google Scholar]. People with a small parietal mass and low acid output (or people receiving proton pump inhibitors (PPIs)) will be more prone to develop atrophic gastritis and gastric malignancy [39Valle J Sipponen P Pajares JM Geographical variations in Helicobacter pylori gastritis and gastric cancer.Curr Opin Gastroenterol. 1997; 13: 35-39Google Scholar]. The variability in occurrence of gastric cancer in different parts of the world can only partly be explained by the prevalence of H. pylori. Apoptosis of gastric epithelial cells is increased in H. pylori infection, stimulating crypt cell proliferation, and increasing the risk for mutagenesis [40Piotrowski J Piotrowski E Skrodzka D Slomiany A Slomiany BL Induction of acute gastritis and epithelial apoptosis by Helicobacter pylori lipopolysaccharide.Scand J Gastroenterol. 1997; 32: 203-211Crossref PubMed Scopus (97) Google Scholar]. Atrophic gastritis enhances the development of intestinal metaplasia, and is related to the intestinal type of gastric carcinoma but not to diffuse gastric carcinoma [41Solcia E Fiocca R Luinetti O et al.Intestinal and diffuse gastric cancers arise in a different background of Helicobacter pylori gastritis through different gene involvement.Am J Surg Pathol. 1996; 20: S8-22Crossref PubMed Scopus (154) Google Scholar]. Intestinal metaplasia is related to atrophic gastritis, which is, in turn, related to H. pylori infection. H. pylori gastritis, in the absence of duodenal ulcer, does not appear to be associated with specific symptoms [11Macarthur C Sauners N Feldman W Helicobacter pylori, gastroduodenal disease and recurrent abdominal pain in children.JAMA. 1995; 273: 729-734Crossref PubMed Scopus (221) Google Scholar,42Reifen R Rasooly I Sherman P Murphy K Drumm B Helicobacter pylori infection in children. Is there any specific symptomatology.Dig Dis Sci. 1994; 39: 1488-1492Crossref PubMed Scopus (60) Google Scholar, 43Gormally SM Prakash N Durnin MT Daly LE Clyne M Kierce BM Association of symptoms with Helicobacter pylori infection in children.J Pediatr. 1995; 126: 753-756Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 44Blecker U Hauser B Lanciers S Keymolen K Vandenplas Y Symptomatology of Helicobacter pylori infection in children.Acta Paediatr. 1996; 85: 1156-1158Crossref PubMed Scopus (35) Google Scholar]. After eradication of H. pylori infection, symptoms are improved only in those children with duodenal disease [43Gormally SM Prakash N Durnin MT Daly LE Clyne M Kierce BM Association of symptoms with Helicobacter pylori infection in children.J Pediatr. 1995; 126: 753-756Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Children with H. pylori gastritis cannot be distinguished from non-infected children on the basis of initial symptoms [42Reifen R Rasooly I Sherman P Murphy K Drumm B Helicobacter pylori infection in children. Is there any specific symptomatology.Dig Dis Sci. 1994; 39: 1488-1492Crossref PubMed Scopus (60) Google Scholar]. Many studies, however, have failed to demonstrate a difference in H. pylori infection rate between children with or without recurrent abdominal pain [11Macarthur C Sauners N Feldman W Helicobacter pylori, gastroduodenal disease and recurrent abdominal pain in children.JAMA. 1995; 273: 729-734Crossref PubMed Scopus (221) Google Scholar, 45Hardiker W Feekery C Smith A Oberklaid F Grimwood K Helicobacter pylori and recurrent abdominal pain in children.J Pediatr Gastroenterol Nutr. 1996; 22: 148-152Crossref PubMed Scopus (58) Google Scholar]. It is unclear whether children with recurrent abdominal pain with H. pylori represent a different entity to those without H. pylori. H. pylori-positive children might more often have pain related to meals than H. pylori-negative children. Ulcer-like symptoms may be more closely associated with the infection than other symptom complexes [46Armstrong D Helicobacter pylori infection and dyspepsia.Scand J Gastroenterol. 1996; 31: 38-47Crossref PubMed Scopus (164) Google Scholar]. In adults, a significantly lower H. pylori prevalence is reported in patients with gastro-esophageal reflux disease [47Werdmuller BF Loffeld RJ Helicobacter pylori infection has no role in the pathogenesis of reflux oesophagitis.Dig Dis Sci. 1997; 42: 103-105Crossref PubMed Scopus (189) Google Scholar]. The role of H. pylori in duodenogastric reflux is unclear. Decreased mean acid output in subjects with H. pylori gastritis might explain the inverse relationship between reflux and H. pylori. Heartburn and epigastric pain might be more frequent in H. pylori-infected patients. Pooled data from 18 studies suggest that the prevalence of H. pylori is greater in patients with dyspepsia than in controls [46Armstrong D Helicobacter pylori infection and dyspepsia.Scand J Gastroenterol. 1996; 31: 38-47Crossref PubMed Scopus (164) Google Scholar]. It is unclear whether H. pylori changes gastric emptying rate or not, although most data suggest that gastric emptying is normal [48Maconi G Lazzoaroni M Sangaletti O Barriggia S Vago L Porro GB Effect of Helicobacter pylori eradication on gastric histology, serum gastrin and pepsinogen I levels, and gastric emptying in patients with gastric ulcer.Am J Gastroenterol. 1997; 92: 1844-1848PubMed Google Scholar, 49Fock KM Khoo TK Chia KS Sim CS Helicobacter pylori infection and gastric emptying of indigestible solids in patients with dysmotility-like dyspepsia.Scand J Gastroenterol. 1997; 32: 676-680Crossref PubMed Scopus (37) Google Scholar, 50Chang CS Chen GH Kao CH Wang SJ Peng SN Huang CK The effect of Helicobacter pylori infection on gastric emptying of digestible and indigestible solids in patients with nonulcer dyspepsia.Am J Gastroenterol. 1996; 91: 474-479PubMed Google Scholar]. Similarly to other chronic inflammatory conditions, infection with H. pylori has been linked to reduced growth [51Patel P Mendall MA Khulusi S Northfield TC Strachan DP Helicobacter pylori infection in childhood: risk factors and effect on growth.Br Med J. 1994; 309: 1119-1123Crossref PubMed Scopus (228) Google Scholar, 52Raymond J Bergeret M Benhamou PH Mensah K Dupont C A 2-year study of Helicobacter pylori in children.J Clin Microbiol. 1994; 32: 461-465PubMed Google Scholar, 53Perri F Pastore M Leandro G et al.Helicobacter pylori infection is associated with growth delay in older children.Arch Dis Child. 1997; 77: 46-49Crossref PubMed Scopus (110) Google Scholar, 54Dale A Thomas JE Darboe MK Coward WA Harding M Weaver LT Helicobacter pylori in children, gastric acid secretion, and infant growth.J Pediatr Gastroenterol Nutr. 1998; 26: 393-397Crossref PubMed Scopus (99) Google Scholar], although socio-economic factors confuse the issue. TNF-α is inversely correlated with growth, and is increased in H. pylori [55Mendall M Patel P Ballam L et al.Relation of serum cytokine concentration to cardiovascular risk factors and coronary heart disease.Heart. 1998; 78: 273-277Crossref Scopus (340) Google Scholar]. However, studies have also failed to find differences in hemoglobin, leukocytes, thrombocytes, weight and height [45Hardiker W Feekery C Smith A Oberklaid F Grimwood K Helicobacter pylori and recurrent abdominal pain in children.J Pediatr Gastroenterol Nutr. 1996; 22: 148-152Crossref PubMed Scopus (58) Google Scholar]. Differences in growth seem to be limited to developing countries [54Dale A Thomas JE Darboe MK Coward WA Harding M Weaver LT Helicobacter pylori in children, gastric acid secretion, and infant growth.J Pediatr Gastroenterol Nutr. 1998; 26: 393-397Crossref PubMed Scopus (99) Google Scholar]. After controlling for socioeconomic status, there is no difference between the height of adults with and without H. pylori. H. pylori seropositivity is related to a late menarche [56Rosenstock SJ Anderson LP Bonevie O Jorgensen T Serum lipids, body indices, age of menarche and Helicobacter pylori infection in 1756 Danish women.Gut. 1996; 39: A62Google Scholar, 57Pretolani S Bonvicini F Arienti V et al.Late onset of menstrual cycle in H. pylori infected females in the general population.Int J Gastroenterol. 1996; 28: 200-201Google Scholar]. Socio-economic status and malnutrition do not explain late menarche, since elevated body mass index is also independently associated with H. pylori in the same population [57Pretolani S Bonvicini F Arienti V et al.Late onset of menstrual cycle in H. pylori infected females in the general population.Int J Gastroenterol. 1996; 28: 200-201Google Scholar]. Incidentally, anemia, hemoptysis and vertigo have been reported [58Blecker U Hauser B Vandenplas Y Hemoptysis as an expression of Helicobacter pylori infection.J Pediatr Gastroenterol Nutr. 1994; 18: 116-117PubMed Google Scholar]. The association of H. pylori with extra-digestive diseases, such as functional vascular diseases and skin and endocrine autoimmune diseases, has been described [59Whincup PH Mendall MA Perry IJ Strachan DP Walker M Prospective relations between Helicobacter pylori infection, coronary heart disease and stroke in middle aged men.Heart. 1996; 75: 568-572Crossref PubMed Scopus (176) Google Scholar, 60Gasbarrini A Franceschi F Gasbarrini G Pola P Extraintestinal pathology associated with Helicobacter pylori.Eur J Gastroenterol Hepatol. 1997; 9: 23-28Google Scholar, 61Figura N Tabaqchali S Bacterial pathogenic factors.Curr Opin Gastroenterol. 1996; 12: 33-36Google Scholar, 62Kolibasova K Tothova I Baumgartner I Filo V Eradication of Helicobacter pylori as the only successful treatment in rosacca.Arch Dermatol. 1996; 132: 1393Crossref PubMed Scopus (47) Google Scholar]. An interesting relationship between seropositivity to H. pylori, serum glucose and noninsulin-dependent diabetes mellitus is worthy of further attention. Recent studies suggest that the association between H. pylori and coronary heart disease is rather weak [59Whincup PH Mendall MA Perry IJ Strachan DP Walker M Prospective relations between Helicobacter pylori infection, coronary heart disease and stroke in middle aged men.Heart. 1996; 75: 568-572Crossref PubMed Scopus (176) Google Scholar]. Primary Raynaud's phenomenon, observed in young women, which is defined by intermittent vasospasm of the arterioles of the distal limbs that occurs mostly following exposure to cold or emotional stimuli, may be related to H. pylori in some cases [60Gasbarrini A Franceschi F Gasbarrini G Pola P Extraintestinal pathology associated with Helicobacter pylori.Eur J Gastroenterol Hepatol. 1997; 9: 23-28Google Scholar]. H. pylori may in addition cause headache [60Gasbarrini A Franceschi F Gasbarrini G Pola P Extraintestinal pathology associated with Helicobacter pylori.Eur J Gastroenterol Hepatol. 1997; 9: 23-28Google Scholar]. Vasoactive substances, such as cytokines (interleukins, IFN-γ, TNF-α), prostaglandins, leukotrienes, oxyradicals, C-reactive protein and fibrinogen, are released in chronic infection [60Gasbarrini A Franceschi F Gasbarrini G Pola P Extraintestinal pathology associated with Helicobacter pylori.Eur J Gastroenterol Hepatol. 1997; 9: 23-28Google Scholar]. Henoch-Schönlein purpura and Sjögren's syndrome have been correlated with the presence of the bacterium. Many patients with auto-immune thyroid diseases are infected with type I cytotoxic CagA+ strains [61Figura N Tabaqchali S Bacterial pathogenic factors.Curr Opin Gastroenterol. 1996; 12: 33-36Google Scholar]. Rosacea and recurrent urticaria may also be associated with H. pylori infection [62Kolibasova K Tothova I Baumgartner I Filo V Eradication of Helicobacter pylori as the only successful treatment in rosacca.Arch Dermatol. 1996; 132: 1393Crossref PubMed Scopus (47) Google Scholar]. Alopecia areata is associated with atrophic gastritis and pernicious anemia, and thus with H. pylori [60Gasbarrini A Franceschi F Gasbarrini G Pola P Extraintestinal pathology associated with Helicobacter pylori.Eur J Gastroenterol Hepatol. 1997; 9: 23-28Google Scholar]. Until now, H. pylori has not yet been reported to cause hepatitis in humans although a mouse Helicobacter species has been reported to cause hepatitis in germfree mice, and H. pylori has been identified in the gallbladders of humans [63Fox JG Yan L Shames B Campbell J Murphy JC Li X Persistent hepatitis and enterocolitis in germfiee mice infected with Helicobacter hepaticus.Infect Immun. 1996; 40: 3673-3681Google Scholar, 64Fox JG Dewhirst FE Shen Z et al.Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis.Gastroenterology. 1998; 114: 755-763Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar]. Independent risk factors for H. pylori infection in infants and children include living in developing countries, lower socio-economic status, living in overcrowded circumstances and sharing a bed with a parent. Human lactoferrin can supp
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