Helicobacter pylori infection: Beyond gastric manifestations

Table 1 Non-gastric manifestations of Helicobacter pylori and their suggested mechanisms of pathophysiology

Non-gastric manifestation	Mechanisms of pathology suggested to be correlated
Allergic diseases	Hygiene hypothesis[9,96]
Alzheimer’s disease	Vitamin B12 deficiency leading to increased concentrations of homocysteine[109]
	Anormal hyperphosphorylation of the TAU protein caused by H. pylori infection[109]
	ApoE polymorphism[110]
Asthma	Treg pattern, suppressing Th-2-mediated allergic response[94]
Atherosclerosis and myocardial infarction	Stimulation of foam production inside macrophages, contributing to the magnification of the atherosclerotic plaque and arterial dysfunction[122]
B12 deficiency	Still to be clarified, but proven to be independent of gastric atrophy and bleeding that impair their dietary absorption[49]
Cholelithiasis	Presence of H. pylori infected bile[43,44]
Coronary arterial disease/systemic arterial stiffness	Increased levels of homocysteine[132].
Gastroesophageal reflux disease	Hyperacidity[25]
Diabetes mellitus	Increased cytokine production; phosphorylation of serine residues from the insulin receptor substrate[136]
Hepatic carcinoma	Inflammatory, fibrotic and, consequently, necrotic process[37,38]
Idiopathic thrombocytopenic purpura (ITP)	CagA may stimulate the synthesis of anti-CagA antibodies that cross-react with platelet surface antigens causing ITP[74,75]
Inflammatory bowel disease	Reduced intestinal inflammation through release of IL-18 and development of FoxP3-positive regulatory T cells[16-18]
	Neutrophil-activating protein reducing inflammation through Toll-like receptor 2 and IL-10 stimulation[19,20]
Iron deficiency anemia	Still to be clarified, but proven to be independent of gastric atrophy and bleeding that impair their dietary absorption[49]
	Relationship with growth disorders in children[52,53]
Multiple sclerosis	Hygiene hypothesis[9]
	Inhibitory induction of H. pylori over the Th1 and Th17 immune response[103]
Non-alcoholic fatty liver disease	H. pylori induced insulin resistance[32]
	Reduced production of adiponectin[33]
	Liver inflammation[34,35]
Ophthalmic manifestations	Systemic inflammatory status; increased oxidative stress; mitochondrial dysfunction; damage to DNA[82]
Parkinson’s disease	Increased synthesis of 1-methyl-4-phenyl-1,2,36-tetrahydropyridine[118]
	Reduced levodopa absorption[118]

H. pylori: Helicobacter pylori; CagA: Cytotoxin-associated gene A.

Table 2 Levels of evidence of the risk relationship between Helicobacter pylori infection and each non-gastroduodenal manifestation

Manifestation	Year of publication1	Ref.1	Level of evidence
Alopecia areata	2017	Behrangi et al[72]	III
Alzheimer’s disease	2016	Shindler-Itskovitch et al[107]	II
	2020	Fu et al[108]	II
Arterial hypertension	2018	Wan et al[127]	III
Asthma	2013	Wang et al[90]	II
	2017	Chen et al[91]	III
Atherosclerosis	2019	Iwai et al[124]	III
B12 deficiency	2000	Kaptan et al[47]	I
	2018	Mwafy et al[48]	III
Central serous chorioretinopathy	2006	Cotticelli et al[88]	IV
Cholecystitis and cholelithiasis	2015	Guraya et al[43]	II
	2018	Tsuchiya et al[41]	III
	2018	Cen et al[44]	III
Coronary artery disease	2016	Sun et al[131]	II
Diabetes mellitus	2019	Chen et al[135]	III
Gastroesophageal reflux disease	2016	Wang et al[26]	II
Glaucoma	2018	Zeng et al[83]	III
	2002	Kountouras et al[84]	III
Guillain-Barré syndrome	2020	Dardiotis et al[120]	III
Halitosis	2017	HajiFattahi et al[29]	III
	2019	Anbari et al[30]	III
Hepatic carcinoma	2017	Huang et al[39]	III
Idiopathic thrombocytopenic purpura	2018	Kim et al[78]	II
Inflammatory bowel disease	2017	Castaño-Rodríguez et al[13]	III
	2019	Lin et al[14]	III
Iron deficiency anemia	2018	Mwafy et al[48]	III
Myocardial infarction	2015	Liu et al[125]	III
Multiple sclerosis	2007	Li et al[100]	III
	2016	Jaruvongvanich et al[101]	III
	2016	Yao et al[102]	III
Non-alcoholic fatty liver disease	2019	Liu et al[36]	II
Parkinson’s disease	2020	Wang et al[118]	III
Psoriasis	2019	Yu et al[67]	II
	2017	Mesquita et al[64]	III
Rosacea	2017	Saleh P et al[59]	III
	2017	Jørgensen et al[62]	III

Adapted from the American Society of Plastic Surgeons rating scale for risk studies, 2011[137].

¹Publications with the higher level of evidence found for the risk relationship between Helicobacter pylori infection and each non-gastroduodenal manifestation. Levels of evidence: I - High-quality, multi-centered or single-centered, prospective cohort or comparative study with adequate power, or a systematic review of these studies; II - Lesser-quality prospective cohort or comparative study, retrospective cohort or comparative study, untreated controls from a randomized controlled trial, or a systematic review of these studies; III - Case-control study, or systematic review of these studies; IV - Case series with pre/post test, or only post test; V - Expert opinion developed via consensus process; case report or clinical example; or evidence based on physiology, bench research or “first principles”.