H. pylori - Commensal or Cause of Many Diseases? To be discussed:

Transcription

1 H. pylori - Commensal or Cause of Many Diseases? Functional Gastroenterology webinar series August 14, 2013 Steven Sandberg-Lewis, ND, DHANP To be discussed: Helicobacter pylori overgrowth- Epidemiology/pathophysiology Associated diseases/ cancers Inverse associations with disease Effect on acid secretion Effect on gastrin and ghrelin secretion Benefits and risks of therapy Options for therapy 1

2 Epidemiology of H. pylori overgrowth 50% of the world s population affected Discovered in 1982 by Warren and Marshall In 2005 Warren and Marshall received the Nobel Prize Rates are higher in developing nations Frequent consumption of fruits and vegetables and of vitamin C, may help treat and prevent infection with H. pylori Ingestion of sulforaphane-rich broccoli sprouts reduces H. pylori colonization in mice and decreases gastritis in infected mice and in humans 2

3 Evidence for H. pylori as a human commensal All mammals have helicobacters in their stomachs (Harper CMG, 2002, and Solnick JV, 2001) There is good evidence that H pylori has been a colonizer of the human stomach for over 58,000 years (Linz B, 2007) and has migrated with humans throughout the world. (Moodley Y, 2009) H. pylori variants The incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographical differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors in addition to host and environmental factors. (Shiota S, 2013) 3

4 H. pylori variants The high rate of East Asian-type caga, and virulent vaca genotypes, may underlie the high risk of gastric cancer in the region. (Wang MY, 2013) H. pylori risk factors Risk factors include: poor sanitation practices-water and soil contamination of food low social class crowded living conditions (familial and institutional clusters) high salt diet sodium chloride increases the cytotoxicity of H. pylori infection in vitro, risk of H. pylori infection and risk of H.pylori related stomach cancer World J Gastroenterol Apr 14;12(14): Asia Pac J Clin Nutr. 2008;17(4): Cancer Sci Jan;96(1):

5 Epidemiology of H. pylori overgrowth most likely mode of transmission is either the oral-oral route or the fecal-oral route. H. pylori DNA is detected in: vomitus saliva dental plaque gastric juice feces Epidemiology of H. pylori overgrowth clinical infection found with consumption of H. pylori-contaminated well water (U.S.) Non-Hispanic white = 29% of cases Hispanic = 60% of cases. African-American = up to a 5.2-fold increased odds of sero-positivity to H. pylori, primarily related to CagA sero-positive strains (Epplein M, 2011) 5

6 H. pylori associated diseases Overgrowth increases the risk of: Peptic ulcer Atrophic gastritis Gastric adenocarcinoma (intestinal type) Gastric lymphoma (Maltoma) Additional diseases associated with H. pylori Metabolic syndrome Coronary artery disease Atherosclerotic stroke Pancreatic adenocarcinoma Iron deficiency anemia 6

7 Additional diseases associated with H. pylori Immune thrombocytopenic purpura Chronic urticaria Hyperemesis gravidarum Ulcer healing/ early vs late Rx Ulcer healing is significantly faster in H. pylori + DU patients treated with allopathic triple therapy vs allopathic ulcer healing drugs but not in H. pylori + GU patients. Either type of treatment equally prevents recurrence of ulcer vs. no treatment (Ford AC, meta-analysis of 56 studies ) 7

8 Gastric cancer/early DU vs GU Rx Early treatment of H. pylori + DU patients decreases the risk of gastric cancer, but not so with H. pylori + GU patients (Ford AC, meta-analysis of 56 studies ) H. pylori and maltoma Lymphoma of the mucosal associated lymphatic tissue There is up to an 86% cure with triple therapy in H. pylori positive maltoma cases. (Sumida T, 2009) 8

9 H. pylori and metabolic syndrome In a study of 7500 Japanese men and women H. pylori seropositivity significantly increased: with age in both men and women. with metabolic syndrome H. pylori seropositivity was significantly associated with: higher systolic blood pressure lower HDL higher LDL (Gunjj T, 2008) H. pylori and metabolic syndrome An Iranian study suggests that H. pylori positivity is actually a risk factor for insulin resistance and hyperinsulinemia Dig Dis Sci Sep;54(9):

10 H. pylori and atherosclerotic stroke Infection with H. pylori CagA-positive strains increases the risk of first ever and also recurrent atherosclerotic stroke. Serological testing (CagA) should be performed in order to identify high-risk patients. Helicobacter Dec;13(6): H. pylori and coronary artery disease Study - 73 patients with acute coronary syndrome and 79 patients with chronic stable angina and 22 control subjects. Seropositivity rates for HP were significantly higher in patients with coronary artery disease than in controls (80.2% versus 54.5%; P < 0.05). Tamer GS, et al Helicobacter pylori seropositivity in patients with acute coronary syndromes Dig Dis Sci Jun;54(6):

11 Pancreatic cancer Pancreatic adenocarcinoma is induced by N-nitrosamine carcinogens, which damage DNA through adduct formation. Human risk factors for pancreatic cancer include gastric colonization by H. pylori dietary intake N-nitrosamines or of nitrites which form N-nitrosamines in the stomach cigarette smoking which also contains N-nitrosamines. (Risch HA, 2012, Yeo TP, 2012) H. pylori, iron and B12 H. pylori reduces plasma levels of ghrelin H. pylori increases plasma levels of leptin and gastrin, affecting appetite and promoting dyspepsia. H. pylori eradication has been shown to improve serum level of iron and vitamin B12. (Vitale G, 2011) 11

12 H. pylori and iron deficiency anemia A meta-analysis revealed: risk for iron deficiency anemia OR 2.8 risk for iron deficiency OR 1.38 H. pylori and iron deficiency anemia At 6 months, 75% of patients had recovered from anemia Ferritin increased from 5.7+/-0.7 mcg/l to 24.5+/-5.2 mcg/l After 12 months, 91.7% of patients had recovered from anemia (Annibale B, 1999) 12

13 H. pylori and immune thrombocytopenic purpura Study Morimoto 2007 Asahi 2006 Inabi 2006 Takahashi 2004 Michel 2004 Ando 2004 Hino 2003 Tag HS, 2010 Payandeh M, 2012 Result 7/19 > / (24 wks) 11/ /15 > 20+ 1/15 At least 50 and double from baseline 10/17 count /21 significant incr. Average 100,000 in 44% Normalized in 57% H. pylori and ITP Overall response was 49.6% for H. pylori positive subjects. Overall response was 0% for H. pylori negative subjects. 13

14 H. pylori and hyperemesis gravidarum Ten studies showed a significant association between hyperemesis gravidarum and H pylori infection. Odds ratios were highly variable: From 0.55 to three results were less than 1.0 H. pylori and gastric secretion Effect on acid secretion Hypo/achlorhydria with chronic atrophic pangastritis (why?) Hyperchlorhydria with antral predominant dz (why?) Euchlorhydria in many asymptomatic carriers 14

15 Helicobacter pylori overgrowth Initial infection (3 mo) causes hypochlorhydria Chronic infection by location has various effects Antral infection hyperchlorhydria Asymptomatic carrier euchlorhydria Pangastritis Atrophy and hypo/achlorhydria H. pylori and gastric secretion Helicobacter pylori inhibits the transcriptional activity of HK-ATPase, the proton pump of the parietal cell. (Schubert ML, 2008) 15

16 H. pylori and gastrin Effect on gastrin secretion H. pylori overgrowth causes hypergastrinemia PPI induced hypergastrinemia is enhanced by H. pylori infection by % Do we really care? Why is this important? Hypergastrinemia risks colorectal carcinoma colorectal carcinoma 16

17 Inverse H. pylori associations with disease GERD & Barrett esophagus (Thrift AP, 2011) Esophageal adenocarcinoma (Abe Y, 2011) Asthma, eczema, rhinitis (Chen Y, 2007) Fatal cardiovascular events (Schöttker B, 2011) Laryngeal carcinoma (Pirzadeh A, 2011) Crohn s disease (Keenan JI, 2011) Obesity ( Wu JC, 2011) Helicobacter pylori colonization is inversely associated with childhood asthma H. pylori seropositivity was inversely associated with: onset of asthma before 5 years of age (OR, 0.58; 95% CI, ). current asthma in children aged 3-13 years (OR, 0.41; 95% CI, ). H. pylori seropositivity also was inversely related to recent wheezing, allergic rhinitis, and dermatitis, eczema, or rash. (Chen Y, 2008) 17

18 CagA+ associated with asthma in adults The presence of caga(+) H pylori strains was inversely related to ever having asthma (OR, 0.79; 95% confidence interval [CI], The inverse association of caga positivity with childhood-onset (age </=15 years) asthma was stronger (OR, 0.63; 95% CI, Colonization with H pylori, especially with a caga(+) strain, was inversely associated with currently (OR, 0.77; 95% CI, ) or ever (OR, 0.77; 95% CI, ) having a diagnosis of allergic rhinitis, especially for childhood onset. (Chen Y, 2007) Inverse relationship with fatal cardiovascular events Point estimates of adjusted hazard ratios for myocardial infarction, stroke and cardiovascular mortality were all below 1 (0.71, 0.59 and 0.65, respectively) in a population-based German cohort of 9953 older adults (50-74 years). (Schöttker B, 2011) 18

19 Laryngeal carcinoma colonization of H. pylori only in the gastric body might have a protective effect against laryngeal cancer with decreasing gastric acid antral H. pylori, increasing gastric acid due to G cell hyperplasia, may be a predisposing factor for laryngeal cancer, with acid reflux as a possible underlying etiology. Pirzadeh A et al, Is there any association between Helicobacter Pylori infection and laryngeal carcinoma? Asian Pac J Cancer Prev.2011;12(4): (Iran) Crohn s disease Worldwide incidence of Crohn s disease (CD) is increasing Maori and Pacific Islanders living in New Zealand remain largely unaffected. This finding may be linked to emerging evidence suggesting a role for Campylobacter in the etiology of CD. Rates of campylobacteriosis are notably lower among Maori and Pacific Islanders and while this may reflect poorer access to primary care and diagnostic services, resulting in lower rates of notified disease, it may also reflect a level of protective immunity in Maori and Pacific Islanders as a result of chronic infection from an early age with the closely related gastric pathogen Helicobacter pylori. Keenan JI et al, Interactions between gastric and enteric infections: clues to the pathogenesis of inflammatory bowel disease? N Z Med J Apr 15;124(1332):

20 Why both pathogenic and protective? caga + and caga- mix may protect The prevalence of H. pylori is high in dyspeptic patients in Gambia and many strains are of the putatively more virulent caga(+), vacas1 and vacam1 genotypes. This study shows significantly lower disease burden (ulcer,etc.) in Gambians infected with a mixture of cagpositive and cag-negative strains, relative to those containing only cag-positive or only cag-negative strains, which suggests that harbouring both cag-positive and cag-negative strains is protective. Secka O et al, Mixed Infection with caga Positive and caga Negative Strains of Helicobacter pylori Lowers Disease Burden in The Gambia. Plos One. 2011;6(11):e Why is H. pylori both pathogenic and protective? Virulence genes In patients with peptic ulcers. caga-positive genotype was detected in most (81.5%) strains, and almost all of them harbored vaca s1 genotype. Strains with caga+/vaca s1a genotype were more common (80.6%) than the other genotypes (19.4%, P = ). These ulcer patients had more virulent strains than the non-ulcer patients (92.3% versus 75.4% for caga+, 100.0% versus 87.0% for vaca s1, 100% versus 84.0% for vaca s1a, and 92.3% versus 73.9% for caga+/vaca s1a, respectively The most common H. pylori genotype was caga+/vaca s1a. (Boyanova L, 2009) 20

21 H. pylori, Ghrelin and GERD Epidemiological evidence shows a rising trend of GERD is coincident with declining prevalence of H. pylori and peptic ulcer disease in Asia. Most case-controlled and population-based studies suggest a negative association between H. pylori infection and GERD. It is generally believed that the preponderance of caga+ and vaca+ virulent strains increase the risk of hypochlohydria and protects against the development of GERD in the Asian population. (Wu JC, 2011) H. pylori, Grehlin and GERD Recovery of gastric acid secretion and emergence of reflux esophagitis has been reported after H. pylori eradication in patients with corpus gastritis and atrophic gastritis. Recent studies have also reported that H. pylori eradication leads to recovery of ghrelin secreting cells in the gastric corpus and a rise in plasma ghrelin levels, which may contribute to obesity through its appetitestimulating action and predispose to GERD. (Wu JC,2011) 21

22 Lab testing H. pylori Serum IgG H. pylori Salivary IgG H. pylori breath test H. pylori stool antigen H. pylori stool DNA H. pylori eradication Benefits of therapy Decreased peptic ulcer recurrence Decreased ulcer complications Decreased risk of gastric cancer in duodenal ulcer patients Regression of maltoma Cure for ITP, iron deficiency anemia, chronic urticaria, hyperemesis gravidarum, etc. Possible reduced risk for pancreatic cancer Possible reduced risk for CHD and stroke 22

23 H. pylori eradication Risks of therapy Increase incidence of: GERD and its complications Barrett esophagitis esophageal adenocarcinoma antibiotic resistance dysbiosis asthma seasonal allergies H. pylori eradication Possible risks of therapy increased incidence of: fatal heart attacks laryngeal cancer Crohn s disease Obesity Delayed NSAID ulcer healing 23

24 Best Practice currently 1) Follow-up DNA or salivary H.pylori positives with a standard test Breath test Stool antigen 2) Don t treat H. pylori in a patient who does not have an H. pylori related disorder eg. don t treat GERD with H. pylori Rx 3) In the future virulence testing may become standard to aid your decision H. pylori eradication - combined Tx If prescription Rx is desired, I recommend: OCAL (first choice regimen) for 7 days omeprazole 20 mg BID clarithromycin-500 mg BID amoxicillin 1000 mg BID lactoferrin 900 mg HS probiotic OCML(first choice in a penicillin allergic pt) for 7 days omeprazole 20 mg BID clarithromycin-500 mg BID metronidazole or tinidazole 500 mg BID Lactoferrin 900 mg HS Probiotic (89+% eradication) (91+% eradication) 24

25 Drug resistant cases Add N-acetyl cysteine Helps to break down the biofilm essential to manintenance of H. pylori drug resistance Pretreatment with NAC lead to a 13/20 success rate vs 4/20 in resistant H. pylori. (Cammarota G, 2010) One day treatment A one day protocol has been used: omeprazole (40 mg) bismuth subcitrate (240 mg 4) amoxicillin suspension (2000 mg 4) metronidazole (500 mg 4) All were taken for only one day. Endoscopy, histology, culture, and susceptibility studies were done at entry and 30 and 90 days after the treatment day. Successful eradication was obtained in 23/32 (72%) patients and gastritis had resolved in 95% of these. Tucci et al Dig Dis Sci Sept 1993 Volume 38, Number

26 Why use a proton pump inhibitor? PPIs increase activity of antibiotics PPIs have in vitro antibacterial activity PPIs inhibit urease production by H. pylori *Dr. Thad Jacob s protocol Mastica (resin) 1000 mg tid Garlic Extract (whole herb) 300 mg tid Lactoferrin 100mg tid Probiotics (L. acidophilus and B. bifidum ) 5 B. tid (N-acetyl cysteine 600 mg bid) 6 cases eradicated based on pre and post stool antigen or serum H. pylori IgG 26