Patient 36: Glaucoma e Stomatopirosi

Author: Edoardo Manca
Date: 27/03/2012

Description

1) Definizione del paziente e della storia

Nome e Cognome: P. B.
Sesso: Femminile
Età: 33 anni

Attività Lavorativa: Impiegata

Peso: 64 Kg
Statura: 162 cm
BMI: 24.4

ANAMNESI FAMILIARE

ANAMNESI FISIOLOGICA

  • Normale sviluppo somato-psichico
  • Menarca a 13 anni; cicli mestruali regolari
  • Due gravidanze a termine (rispettivamente all'età di 22 e 26 anni)
  • Non fumatrice
  • Consumo abituale di bevande gasate, solo occasionale di alcolici
  • Assunzione di 3-4 tazzine di caffè al giorno
  • Alimentazione: quotidiana assunzione di frutta e verdura; privilegiato il consumo di pasta e carni bianche; elevata ingestione di dolci e zuccheri semplici
  • Attività fisica modesta (ginnastica in palestra circa 3-4 volte al mese)

ANAMNESI PATOLOGICA REMOTA

- A 6 anni :

  • Evento:
    • Addome acuto
  • Diagnosi:
    • Appendicite acuta (necessario ricovero ospedaliero)
  • Terapia:
    • Chirurgica: appendicectomia
  • Esami:
    • ***

- A 9 anni:

  • Evento:
  • Diagnosi:
    • Rinite allergica da graminacee, di carattere stagionale, complicata da eventi di asma allergica.
  • Terapia:
  • Esami:
    • Iniziale individuazione degli allergeni di interesse tramite test cutanei.
    • Successiva titolazione delle IgE specifiche.
    • Esami ematochimici
  • Note:
    • La paziente riferisce una graduale, ma significativa, attenuazione della sintomatologia rinitica dopo i 22-24 anni, ad andamento progressivo e con successiva assenza di ulteriori crisi asmatiche.

- A 22 anni:

  • Evento:
  • Diagnosi:
    • ***
  • Terapia:
    • ***
  • Esami:
    • ***

- A 24 anni:

  • Evento:
    • Riferiti primi episodi di crisi emicraniche senza aura della durata di 4-8 ore con intensità costante (mediamente 2 crisi/mese).
  • Diagnosi:
  • Terapia:
  • Esami:
    • Visita neurologica c/o Centro Cefalee
    • Esami ematochimici

- A 26 anni:

  • Note:
    • La paziente riferisce l’assenza pressoché totale durante la gestazione delle crisi emicraniche ricorrenti, ripresentatesi solo dopo alcuni mesi dal parto.

- A 29 anni:

  • Evento:
  • Diagnosi:
  • Terapia:
    • FANS al bisogno per os
  • Esami:
    • Visita neurologica - negativa
    • Elettromiografia arti superiori - nella norma
    • RM colonna cervico-dorsale - n.n.
    • Esami ematochimici

ANAMNESI PATOLOGICA PROSSIMA

- A 32 anni:

  • Evento:
    • Comparsa di disturbi visivi a rapida progressione, con riduzione della visione periferica.
  • Esami:
    • Visita oculistica
  • Diagnosi:
  • Terapia:
  • Commento personale:
    • All'atto di prescrivere il Timololo in gocce non è stata evidentemente eseguita una corretta anamnesi della paziente.
      Alla luce delle crisi asmatiche pregresse, seppure di tipo allergico e verificatesi in giovane età, sarebbe infatti risultato ovvio optare per una alternativa farmacologica, al fine di evitare ogni possibilie rischio di effetti avversi in tal senso.

  • Evento:
    • Peggioramento del bruciore orale (mai del tutto cessato dall’esordio verificatosi circa 3 anni addietro), di tipo urente e durata variabile, interessante la lingua e la mucosa orale, in assenza tuttavia di lesioni mucose visibili.
    • Vi si associa inoltre alitosi persistente.
    • Segnalata infine comparsa di saltuaria e modesta disgeusia.
    • Non riferita tuttavia alcuna sintomatologia compatibile con reflusso gastro-esofageo .
  • Esami:
    • Visita Stomatologica - nella norma (non protesi mobili)
    • Visita ORL - nella norma
    • Esami ematochimici
  • Diagnosi:
  • Terapia (sintomatica):

2) Le basi molecolari degli eventi descritti, tenendo conto di tutti i sintomi ed utilizzando i link alle informazioni pertinenti

I. Riflessioni :

  • Glaucoma e Stomatopirosi:
    Entrambe patologie con insorgenza indicata come solitamente post-menopausale .
    Il verificarsi dei due eventi appare perciò alquanto precoce alla luce dell’ età della paziente.
  • Cefalea, Iperestesie, Stomatopirosi:
    Tutte queste patologie potrebbero facilmente far pensare ad uno stato di sofferenza sistemica dei neuroni , in particolare sensitivi, riconducibile in ultima istanza a deficit della catena respiratoria e conseguentemente della produzione dell’ ATP necessario al corretto mantenimento dell’ omeostasi cellulare .
    Gli esami ematochimici disponibili evidenziano in diverse occasioni bassi livelli di transferrina circolante, quindi verosimilmente perduranti nel tempo.
    Anche i valori di ferro , vitamina B12 e folati appaiono spesso tendenti al basso e la necessità di una loro integrazione durante la gestazione avvalora la tesi di riserve sistemiche sempre a rischio di eccessivo impoverimento .
  • Indicatori di Malattia:
    Uno dei più noti modelli di competizione tra organismo umano e microrganismi patogeni riguarda proprio il ferro .
    Si potrebbe quindi supporre che la situazione di modesta carenza riscontrata dagli gli esami ematochimici sia conseguenza di una infezione cronica mai identificata.
    I valori sierici elevati di Proteina C Reattiva , alfa-2 globuline ed altri marker classici di infiammazione potrebbero avvalorare ulteriormente questa tesi.

II. Possibili spiegazioni del quadro clinico:

** N.B.: Si rimanda alla pagina di Flipper e Nuvola dal titolo Helicobacter Pylori - Virulence Factors per ulteriori dettagli ed approfondimenti sulle caratteristiche molecolari delle varie proteine e delle vie di segnalazione coinvolte. **

  • Helicobacter Pylori (Hp) and Iron

Helicobacter Pylori recently has also been associated with iron deficiency anemia.
During colonization of the stomach, a significant number of Hp (~20%) adhere to the host cell surface via various adhesins.
Hp can colonize and replicate directly while adhered to the epithelial surface, and can grow in this niche even in conditions where growth of the free-swimming bacteria is not supported.
The contact-dependent Hp virulence factor CagA, which is injected directly into host cells via the bacterium’s type IVsecretion system, plays an important role in enabling Hp colonization of the epithelium.
This occurs via a local perturbation of epithelial polarity, and can occur without gross disruption of epithelial integrity.
Since an important role of the epithelial barrier is to sequester and compartmentalize molecules that may be useful for colonizing microbes, Hp has evolved pecialized mechanisms to perturb cell polarity to acquire essential factors directly from the polarized epithelium.
However, the nature of the factors transferred from the host cells to the bacteria and the molecular mechanisms involved remain unclear.
Successful colonization of mucosal surfaces by bacteria implies an ability to extract essential micronutrients from their immediate environment, either from epithelial secretions near the cell surface, from the polarized host cells themselves, and/or from the interstitial side, across the epithelial cell layer.
Iron is a micronutrient critical for the survival and growth of many mucosal colonizers and its availability controls expression of bacterial virulence factors in Hp and several other pathogens.
In the host however, free iron exists in extremely limited quantities, since it is sequestered from the mucosal surface through various mechanisms, including the epithelial barrier blocking access to the interstitium, binding of interstitial iron by transferrin , sequestration of intracellular iron by ferritin , and chelation of mucosal iron by lactoferrin .
While Hp is known to possess several iron uptake systems, the sources of iron that Hp utilizes during colonization of the gastric mucosa remain unclear.
Unlike other mucosal colonizers that possess siderophore-mediated mechanisms for uptake of iron , Hp has not been shown to synthesize siderophores .
While the acidity of the gastric lumen releases iron from ingested food, Hp is not found in the gastric lumen but rather colonizes the neutral environment of the epithelial cell surface and the overlying mucus layer.
In this microenvironment, iron is complexed with lactoferrin or with other glycoproteins found in the mucus.
Hp is unable to compete with partially saturated lactoferrin for iron acquisition, and its ability to obtain iron complexed with mucus glycoproteins is unknown.
In the interstitium, iron is tightly bound to transferrin and Hp cannot compete with partially saturated transferrin for iron .
However, Hp is able to utilize iron from fully saturated transferrin, which is the major form endocytosed by epithelial cells.
CagA facilitates iron acquisition during Hp microcolony growth on the apical cell surface.

** Hp utilizes the polarized epithelium as a filter for the extraction of iron

Host epithelial cells acquire iron largely via transferrin receptormediated endocytosis.
In the serum where transferrin is normally found, the population of transferrin molecules is 20% – 40% saturated with iron .
Since Hp is susceptible to iron chelation by transferrin, and because transferrin is the major chelator of iron in extracellular fluids of the interstitial space, it is suggested that CagA’s mechanism of action is not simply to injure the epithelium and provide paracellular diffusion of transferrin.
Hp utilizes the epithelial barrier as a shield from noxious macromolecules in the interstitial space, and can actively obtain nutrients from the epithelium.
Epithelial cells selectively acquire transferrin saturated with iron (holotransferrin) via endocytosis, as its affinity for the transferrin receptor is 2000X greater than iron-free transferrin.
Since Hp growing on the cell surface are protected from the toxic effects of partially saturated transferrin by the epithelial barrier, the bacteria can obtain iron from holotransferrin, the form of transferrin taken up into cells.

** Hp colonization of the apical cell surface increases internalized transferrin in a CagA-dependent manner

Since CagA has multiple effects on epithelial physiology and appears to aid Hp in iron acquisition from host cells, Hp colonization of the apical cell surface affects host cell transferrin recycling.
Once injected into the host cell, CagA is tyrosine phosphorylated by host Src- and Abl-family tyrosine kinases at several repeated sites in the C-terminal end containing EPIYA motifs.
CagA then acts as an adaptor protein that stimulates signaling downstream of growth factor receptor tyrosine kinases.
Growth factor signaling increases transferrin uptake.
CagA phosphorylation is necessary for its effects on transferrin internalization.
The ability of CagA to increase internalized transferrin depends on the presence of the EPIYA motifs.
CagA injected by Hp microcolonies on the apical cell surface increases transferrin internalization through receptor tyrosine kinase-like signaling, and suggest that this leads to an increased availability of iron for the colonizing bacteria.
Under normal conditions, transferrin should not be released to the apical side of an epithelium, since its recycling is confined to the basolateral membrane where the receptor is exclusively found.
This suggests that infecting bacteria perturb not just uptake, but also localization of the transferrin/transferrin receptor complex.

** Transferrin receptor is mislocalized to sites of Hp microcolony growth at the apical cell surface

Hp is known to affect host cell polarity and intracellular trafficking.
Perturbation of host cell polarity is involved in enhancing colonization of the polarized epithelium.
Hp colonization might lead to mis-sorting of the transferrin receptor , and hence transferrin and possibly iron, to sites of bacterial microcolony growth on the apical surface.
This mislocalization of the transferrin receptor near the Hp microcolonies does not occur immediately after bacterial attachment to the apical surface; Hp can affect host cell polarity locally to mislocalize basolateral proteins to sites of microcolony growth.
Hp microcolonies are associated with membrane patches containing basolateral proteins that were mis-sorted to the apical membrane.
Hp can induce mis-sorting of the transferrin receptor in multiple epithelial lines.
Not all basolateral proteins are mislocalized during Hp colonization.
CagA-deficient bacteria are less efficient but still able to recruit transferrin receptor to the sites of bacterial microcolonies: this ability suggest that other bacterial factor(s) may be involved in this phenomenon.
Another major virulence factor of Hp, vacuolating cytotoxin (VacA), has been reported to interfere with the endocytic pathway of host cells.
In monolayers infected with VacA deficient Hp mutant (vacA-), transferrin receptor was absent from the sites of bacterial microcolonies on the apical cell surface.
Both CagA and VacA are involved in disruption of polarity, and that the transferrin receptor is not the only molecule that is mislocalized apically.
Mutants deficient in both CagA and VacA (cagA- vacA-) are still able to mislocalize proteins to the sites of bacterial microcolonies.
CagA and VacA are not the only bacterial factors involved in this process, although they do appear to play major roles.
Together, these results indicate that Hp colonization of the apical cell surface leads to mislocalization of a subset of basolateral proteins to the apical cell membrane at sites of bacterial microcolony growth, with the Hp virulence factors CagA andVacA playing major roles in this process.
One of the proteins mislocalized to these sites is the transferrin receptor, and its mislocalization is primarily dependent on VacA.
Host cell transferrin receptor is functionally important in enabling Hp colonization of the apical surface of a polarized epithelium.
Hp colonization of the polarized epithelium leads to increased apical release of transferrin .
Hp colonization of the apical cell surface leads to mis-sorting of a subset of the transferrin/transferrin receptor complex and transcytosis of the complex from the basolateral to the apical surface at the sites of bacterial microcolony growth.

1
Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. - Tan, Noto, Romero-Gallo, Peek Jr, Amieva - PLoS Pathog., 2011
2
Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence. - DuBois, Kearney - Am J Gastroenterol., 2005
*
Iron deficiency anaemia can be improved after eradication of Helicobacter pylori. - Huang, Qu, Yan, Huang, Cai, Hu, Wu, Lin, Chen, Zhu, Lu L, Sun, Rong, Jiang, Sun, Zhong, Xiong - Postgrad Med J., 2010
Iron deficiency anemia in Helicobacter pylori infection: meta-analysis of randomized controlled trials. - Yuan, Li, Yang, Ma, Guan, Wang, Yang - Scand J Gastroenterol., 2010
Helicobacter pylori infection and iron stores: a systematic review and meta-analysis. - Muhsen, Cohen - Helicobacter., 2008
Does Helicobacter pylori infection play a role in iron deficiency anemia? A meta-analysis. - Qu, Huang, Xiong, Zhu, Huang, Lu, Sun, Rong, Zhong, Sun, Lin, Cai, Chen, Hu, Wu, Jiang, Yan - World J Gastroenterol., 2010
Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence. - DuBois, Kearney - Am J Gastroenterol., 2005
Unique Host Iron Utilization Mechanisms of Helicobacter pylori Revealed with Iron-Deficient Chemically Defined Media - Senkovich, Ceaser, McGee, Testerman - Infection and Immunity, 2010
NapA protects Helicobacter pylori from oxidative stress damage, and its production is influenced by the ferric uptake regulator. - Cooksley, Jenks, Green, Cockayne, Logan, Hardie – J Med Microbiol., 2003
The structure of the Helicobacter pylori ferric uptake regulator Fur reveals three functional metal binding sites. - Dian, Vitale, Leonard, Bahlawane, Fauquant, Leduc, Muller, de Reuse, Michaud-Soret, Terradot - Mol Microbiol., 2011
The role of the Ferric Uptake Regulator (Fur) in regulation of Helicobacter pylori iron uptake. - van Vliet, Stoof, Vlasblom, Wainwright, Hughes, Kelly, Bereswill, Bijlsma, Hoogenboezem, Vandenbroucke-Grauls CM, Kist M, Kuipers EJ, Kusters - Helicobacter., 2002
Proteomic analysis of a ferric uptake regulator mutant of Helicobacter pylori: regulation of Helicobacter pylori gene expression by ferric uptake regulator and iron. - Lee, Choe, Kim, Jung, Lee - Proteomics., 2004

  • Helicobacter Pylori (Hp) and Micronutrients (other than Iron)

H. pylori infection has been linked to some nongastric disorders, such as thrombocytopenic purpura , iron deficiency anemia , and atherosclerotic disease.
Studies have suggested that, beyond iron , H. pylori infection may affect the homeostasis of other micronutrients such as vitamins and trace elements including vitamin B12 , folic acid , vitamin C , alpha-tocopherol and beta-carotene .
Micronutrients are essential for life acting as cofactors of enzymes and as an organizer of the molecular structures of the cell.
Micronutrient deficiencies influence immune homeostasis, thus affecting infection-related morbidity and mortality.
Deficiency of hemopoietic micronutrients such as iron, cobalamin , or folate may lead to deleterious effects because of anemia and its clinical consequences including reduced work capacity, cognitive impairment, reduced resistance to infections , and negative effects on pregnancy and growth.
Micronutrients like vitamin C , alpha-tocopherol , beta-carotene, selenium, and others are powerful antioxidants and anticarcinogens.
Many micronutrients depend on a healthy stomach for their absorption.
Although the absorption process does not take place in the stomach, this organ contributes to the process by means of the secretion of hydrochloric acid and enzymes, which during the digestive process are necessary to release the micronutrients from the food matrix and, in the case of essential minerals, to render them soluble.
The chronic inflammatory response of the gastric mucosa to H. pylori infection may alter gastric physiology.
Impaired gastric acid secretion is a common consequence of H. pylori-induced gastritis: the chronic inflammatory injury of the corporal mucosa may lead to a functional inhibition of parietal cells by inflammatory products, which may finally provoke atrophy of gastric glands and hypochlorhydria.

The findings of systematic reviews and meta-analyses support in adults the association between H. pylori infection and reduced levels of some micronutrients as ascorbic acid and cobalamin, which may be restored after cure of infection.
Sistematic reviews show a positive association between H. pylori positivity and low ascorbic acid levels in the plasma and in the gastric juice and a recovery after cure of infection in the gastric juice.
They also report for the first time meta-analytic data showing a positive association between H. pylori infection and cobalamin deficiency, which may be restored after eradication treatment.
The mechanisms by which H. pylori infection may compromise the homeostasis of some micronutrients have not been well established.
The observed positive association between H. pylori infection and ascorbic acid and cobalamin may plausibly be explained by a common mechanism that involves reduced gastric acid secretion leading to hypochlorhydria in the presence of a particular pattern of H. pylori gastritis involving the corporal acid-secreting mucosa.
Impaired gastric acid secretion is a common consequence of H. pylori induced gastritis: the chronic inflammatory injury of the corporal mucosa may lead to a functional inhibition of parietal cells by inflammatory products, which may finally provoke gastric gland atrophy and hypochlorhydria.
Gastric acidity seems to play a role in the homeostasis of ascorbic acid, the reduced form of vitamin C , because this compound is very unstable in the presence of an increased pH and is converted to the less active form of dehydroascorbic acid, as reported in the presence of H. pylori gastritis associated with corporal mucosa inflammation.
Thus, hypochlorhydria may decrease the stability and the bioavailability of this vitamin .
Moreover, ascorbic acid is an important promoter of iron absorption, and decreased bioavailability of this micronutrient may, in turn, have negative effects on iron absorption.
Also, the absorption of cobalamin from food requires the action of gastric acid for at least two steps of this complex process: to release in the stomach the strictly protein-bound dietary cobalamin and to increase the affinity of free, unbound cobalamin for salivary R proteins instead of intrinsic factor.
Thus, it is plausible that hypochlorhydria caused by H. pylori infection may contribute to food-cobalamin malabsorption.
Cobalamin deficiency may result also as a consequence of gastric atrophy of the corporal mucosa and consequent intrinsic factor deficiency, i.e., pernicious anemia , which in turn is a long-standing consequence of H. pylori infection.
The biological plausibility of the hypothesized link between impaired gastric acid secretion and reduced micronutrient levels is further supported by the observation that the long-term therapy with proton pump inhibitors may have negative effects on ascorbic acid and cobalamin levels.
The data of meta-analyses also support the association between H. pylori positivity and low folate levels, addressed in 21% of the selected studies.
A negative effect of H. pylori infection on folic acid absorption decrease may be explained as a consequence of a pH increase and⁄or a vitamin C concentration decrease in gastric juice, a situation frequently observed in H. pylori-infected patients.
Considering the worldwide high prevalence of H. pylori infection, its interference with micronutrient malnutrition may have important clinical implications: over 50% of people in the world are infected by H. pylori and in Africa, South America, and Central America, H. pylori infection reaches 70–90% of the population.
In developing and poorly industrialized regions, there is a concomitant high prevalence of both H. pylori infection and micronutrient malnutrition.

1
Micronutrients (Other than iron) and Helicobacter pylori Infection: A Systematic Review - Lahner, Persechino, Annibale - Helicobacter., 2011
*
Helicobacter pylori and vitamin B12 deficiency. - Kaptan K, Beyan C, Ifran - Haematologica., 2006
The influence of serum 25-hydroxy vitamin D levels on Helicobacter Pylori Infections in patients with end-stage renal failure on regular hemodialysis. - Nasri, Baradaran - Saudi J Kidney Dis transpl., 2007
Long-term effects of clearing Helicobacter pylori on growth in school-age children. - Mera, Bravo, Goodman, Yepez, Correa - Pediatr Infect Dis J., 2012

  • Helicobacter Pylori, Chronic Inflammation and C-Reactive Protein (CRP)

H. pylori eradication reduces the levels of pro-inflammatory cytokines such as migration inhibitory factor and hs-CRP and also results in a significant increase in anti-inflammatory markers such as fetuin-A.
Several epidemiologic studies have suggested associations between H. pylori seropositivity and atherosclerosis .
Atherosclerosis is defined as a metabolic and inflammatory disease, and several inflammatory and immunologic factors have been established to significantly contribute to atherogenesis.
Both humoral and cellular immune mechanisms play a major role in the onset and/or progression of atheromatous lesions.
MIF (macrophage migration inhibitory factor) is an important cytokine that regulates both adaptive and immune responses.
It is a potent pro-inflammatory cytokine that has been reported to stimulate TNF and IL-6 expression and an important downstream marker of inflammation .
C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation .
Anti-inflammatory cytokines produced during inflammation tend to modulate the inflammatory reaction.
One cytokine, fetuin-A, is considered to be a potent antiinflammatory cytokine.
Fetuin-A is an anti-inflammatory mediator that participates in macrophage deactivation, anti-fibrotic activity, and inhibition of apoptosis in vascular smooth muscle cells.
MIF and hs-CRP levels are significantly increased and fetuin-A levels are significantly decreased in H. pylori-infected patients.
Eradication of H. pylori are significantly associated with increased levels of fetuin-A and reduced levels of MIF and hs-CRP in patients free of classic cardiovascular (CV) risk factors.
However, eradication of the microorganism had no effect on the lipid profile.

Some infections, for example H. pylori , have also been presented as risk factors for cardiovascular diseases .
Observational studies have suggested that a chronic infection with Hp might be an independent, although weak, risk factor for CVD .
It has been hypothesized that there are indirect mechanisms that could link Hp with atherosclerosis .

One hypothesis postulates that the gastric damage induced by Hp-infection may affect atherogenesis by lower vitamin bioavailability and increased serum homocysteine levels.
As a sulfur-containing intermediate product in the metabolism of methionine , homocysteine is a highly reactive molecule.
It has been demonstrated that hyperhomocysteinemia is associated with endothelial dysfunction, alterations in vascular morphology and other atherogenetic mechanisms.

Because folic acid , vitamin B12 , and vitamin B6 are involved in the breakdown of homocysteine , it seems to be plausible that decreasing intestinal absorption of these B vitamins by Hp induced atrophic gastritis should elevate homocysteine levels, hence increasing the risk of CVD .
Manifestation of vitamin B12 deficiency occurs slowly over years due to the low requirement and the liver storages.

Beside the “homocysteine CVD connection”, infection with Hp may lead to a chronic low-grade systemic inflammation response, characterised by increased plasma levels of proinflammatory cytokines and acute-phase proteins such as CRP .
C-reactive protein (CRP) is an acute-phase protein which originates from the liver and has been identified as a marker of inflammation that can be used for diagnosis and follow-up of some inflammatory diseases.
CRP has many clinical and biological effects and can be used for the diagnosis and follow-up of various inflammatory and traumatic processes.
Moreover, CRP has been identified as an independent risk factor for cardiovascular disease and can also be regarded as a valuable tool for estimation of at risk populations.
There is strong evidence that CRP is a powerful predictor of incident cardiovascular events independent of levels of LDL cholesterol, all levels of the Framingham risk score, and the metabolic syndrome .
It has also been reported that measurement of serum levels of CRP using a high-sensitivity assay (hs-CRP) can reveal subclinical inflammatory states which may reflect vascular inflammation.
It is recently reported that serum levels of hs-CRP were significantly higher in patients with ischemic heart disease than in a healthy control group.
CRP is well recognized as an independent predictor of CVD .
Furthermore, CRP may directly promote atherosclerosis .
There are several mechanisms CRP could induce a proatherogenic environment in endothelial cells including the following: (I) decreasing prostacyclin and nitric oxide synthesis, (II) increasing endothelin-1 concentration and cell adhesion molecules such as monocyte chemoattractant protein.
Furthermore, in vascular smooth muscle cells CRP has been shown to (I) increase NF kappa B and (II) upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation .
H. pylori can elicit lifelong inflammatory and immune responses with release of various bacterial and host-dependent cytotoxic substances, resulting in chronic gastritis, peptic ulcer , and gastric cancer .
Epidemiological studies have suggested that H. pylori infection might be involved in the pathogenesis of coronary heart disease.
The suspicion about H. pylori involvement in the pathological lesions is based on the following: (I) local inflammation can have systemic effects; (II) H. pylori gastric infection is a chronic process that lasts for decades; and (III) persistent infection induces chronic inflammatory and immune responses that can induce lesions both local and remote sites from the primary infection site.
The manifestation may be caused by potential mechanisms with direct or indirect actions.
The direct effects on the vascular wall could include endothelial injury and dysfunction through circulating endotoxins, smooth muscle proliferation , and local inflammation .
The indirect effects are more often pronounced, including elevation of inflammatory mediators with proinflammatory, procoagulant, and atherogenic action, production of cross-reactive antibodies , as well as nutrient/vitamin malabsorption and metabolic disturbances such as overproduction of ammonia by the bacterium.

Although H. pylori infection is associated with coronary artery disease, the pathway to elevate the disease risk is not clear.
There are several possibilities for the mechanism underlying a causal role of H. pylori infection in endothelial dysfunction.
First, H. pylori may have the direct effect on the structure and function of vascular endothelial cells.
Extract of H. pylori has been reported to induce a disturbance of proliferation and apoptosis and to decrease viability of cultured vascular endothelial cells.
The second possibility is the nutritional effect of H. pylori .
An infection from H. pylori may cause malabsorption of folate , vitamin B6 , and vitamin B12 .
This nutritional defect could lead to failure of methylation by 5-methyl-tetrahydrofolic acid and subsequent hyperhomocysteinanemia , which is toxic to endothelial cells.
Serum folate and CRP are also candidate molecules.

H. pylori infection may slightly elevate serum CRP , thereby increasing systemic disease risk.
CRP is an easily measurable substance in blood .
Increased levels of this protein indicate acute inflammation .
Many studies have shown that high levels of CRP also indicate an increased risk of suffering from a heart attack or stroke .
The CRP test is not specific, and the levels fluctuate daily and throughout the day.
The levels increase as a result of numerous factors including aging , alcohol use, smoking , eating a high protein diet, coffee consumption, low levels of physical activity, chronic fatigue, high blood pressure, BMI, high triglycerides , rheumatoid arthritis, rheumatic fever, insulin resistance and diabetes , as well as heart attack.
Medicines containing estrogen (oral contraceptive and hormone replacement therapy) may also elevate CRP levels.
If H. pylori has effects on the function of vascular endothelial cells, serum CRP could be one of the molecules to connect both.
H. pylori infection stimulates the production of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and IL-8.
H. pylori was detected not only in gastric mucosa but also in human atherosclerotic plaque, and the expression of intercellular adhension molecule-1 was higher in plaques containing H. pylori than in those without it.
The production of CRP is regulated by cytokines, principally interleukins, whose effects are modified by other cytokines and growth factors, as well as by hormones such as cortisol and insulin .
Production of cytokines and stress hormones may be altered in conditions other than inflammation or injury.
TNF is a potent inducer of IL-6 by various cells.
Therefore, the association of CRP concentration with H. pylori infection could be explained by the actions of cytokines, hormones, or both.

1
Serum levels of high-sensitivity C-reactive protein (hs-CRP) in Helicobacter pylori-infected peptic ulcer patients and its association with bacterial CagA virulence factor. - Jafarzadeh, Hassanshahi, Nemati - Dig Dis Sci., 2009
2
Association between Helicobacter pylori-infection, C-reactive protein and status of B vitamins - Stettin, Waldmann, Strohle, Hahn - Advance med.scien., 2008
3
Significant association between Helicobacter pylori infection and serum C-reactive protein. - Ishida, Suzuki, Taki, Niwa, Kurotsuchi, Ando, Iwase, Nishio, Wakai, Ito, Hamajima - Int J Med Sci., 2008
4
The effect of Helicobacter pylori eradication on macrophage migration inhibitory factor, C-reactive protein and fetuin-a levels. - Kebapcilar, Bilgir, Cetinkaya, Akyol, Bilgir, Bozkaya - Clinics (Sao Paulo)., 2010
*
A cross-sectional study to detect the prevalence of hyperhomocysteinemia in cases of deep vein thrombosis. - Kamat, Metgud, Pattanshetti, Godhi - Indian J Surg., 2010
The influence of serum 25-hydroxy vitamin D levels on Helicobacter Pylori Infections in patients with end-stage renal failure on regular hemodialysis. - Nasri, Baradaran - Saudi J Kidney Dis transpl., 2007

  • Helicobacter Pylori and Migraine (without aura)

Helicobacter pylori (H. pylori) infection has recently been associated with various extraintestinal pathologies and migraine without aura, in cases not affected by endogenous risk factors, like hereditary pattern or hormonal fluctuations.
Primary headache is a common and discomfort clinical event, which has been associated with vascular instability.
Although the molecular mechanisms of migraine have not yet been fully clarified, neurogenic inflammation and subsequent plasma extravasations in duramater have been suggested as the likely mechanism.
Furthermore, previous studies suggest the role of histamine (which liberates nitric oxide from the vascular endothelium), hypoxia and nitric oxide (NO) in migraine.
NO may function as a signalling molecule in controlling neuronal activity and as a major non-adrenergic, non-cholinergic neurotransmitter.
As a labile free radical with a half-life of only a few seconds, NO is rapidly oxidized by tissue oxygen to the stable end-products, nitrate, and nitrite.
Occurrence of migraine has been associated with clinically obvious or subclinical extracranial infection (herpes labialis, pharyngitis, cystitis, vaginitis, mycosis and gastrointestinal inflammation).
It has also been demonstrated that Helicobacter pylori infection has a possible role in precipitation of migraine, while other data support a simple co-occurrence of H. pylori infection and migraine.
H. pylori infection is the most common cause of gastritis and gastric and duodenal ulcers.
The association of H. pylori infection and various extraintestinal pathologies, such as coronary heart disease, primary Raynaud phenomenon, migraine, Alzheimer’s disease and mild cognitive impairment, has recently been addressed.
Migraine without aura seems to be caused by a combination of genetic and environmental factors, whereas migraine with aura is probably determined largely by genetic factors.
Literature data show higher frequency of H. pylori infection in migraineurs and consider that H. pylori should be examined in migrainous patients as a possible risk factor that can contribute to clinical improvement of duration and intensity of migraine attacks with its eradication.
A significantly higher prevalence of a specific type of H. pylori , the CagA-positive H. pylori strains, has been demonstrated only in migraine with aura patients.
A plausible mechanism underlying the association between CagA-positive H. pylori strains and vascular diseases may be linked to the significantly more intense chronic immuno-inflammatory response that follows colonisation of the gastric mucosa by these strains; cytokines (in particular, interleukin-1, -6 , -8 and interferon-gamma ) and other molecules endowed with proinflammatory, vasospastic and proalgogen properties conceivably may induce a systemic vasculopathy within various arterial districts.
A similar mechanism produces the association between H. pylori infection and migraine without aura.
Due to the fact that this bacterium can cause the secretion of serotonin from platelets , releasing PAF, it can play a role in creating migraine head-aches by increased secretion of serotonin .
Taking into account that hereditary pattern and hormonal fluctuations are known and well established endogenous risk factors for migraine, H. pylori infection could be a probable independent environmental risk factor for migraine without aura, especially in patients that are not genetically or hormonally susceptible to migraine.

1
Helicobacter pylori infection as an environmental risk factor for migraine without aura. - Yiannopoulou, Efthymiou, Karydakis, Arhimandritis, Bovaretos, Tzivras - J Headache Pain., 2007
2
Migraine, Helicobacter pylori, and oxidative stress. - Tunca, Ardiçoğlu, Kargil A, Adam - Helicobacter., 2007
3
Evaluation of Helicobacter pylori infection in patients with common migraine headache. - Hosseinzadeh , Khosravi, Saki, Ranjbar - Arch Med Sci., 2011

  • Helicobacter Pylori and Open-angle Glaucoma

H. pylori infection may influence the pathophysiology of glaucoma by releasing various proinflammatory and vasoactive substances, as well as by influencing the apoptotic process , parameters that may also exert their own effects in the induction and/or progression of glaucomatous neuropathy.
Systemic H. pylori-induced oxidative damage may be the mechanism which links oxidative stress, H. pylori infection and the damage to the trabecular meshwork and optical nerve head that results in glaucoma .
In recent years, a possible association between Helicobacter pylori (Hp) infection and eye diseases , including Sjögren syndrome , blepharitis, central serous chorioretinopathy and uveitis, has been proposed.
Recently, Hp infection has been proposed as an environmental familial clustering risk factor for primary open-angle glaucoma .
Hp infection may produce systemic disorders resulting from the release of vasoactive and proinflammatory substances; Hp infection may be related to atherosclerosis and increased platelet activation and aggregation.

** Hp and Oxidative Damage

Hp infection is responsible for inflammation , increased production of ROS and the induction of oxidative DNA damage in the gastric mucosa.
Hp infection locally induces a chronic inflammatory status consisting of neutrophil, polymorphonuclear (PMN) cells and lymphocyte recruitment at the infection site.
PMN cells attempt to damage bacterial structures by producing superoxide radical and other ROS , thus determining local oxidative stress.
Excessive and long-lasting ROS production in the gastric mucosa may damage cellular components, including polyunsaturated fatty acids , proteins and DNA.
Membrane lipid peroxidation results in the perturbation of various cellular and organellar membrane functions, including transport processes, the maintenance of ion and metabolite gradients, receptor mediated signal transduction, etc...
Accordingly, antioxidant reduced glutathione (GSH) in the gastric mucosa is significantly decreased in Hp-infected patients that may be associated with gastric carcinogenesis, since GSH is involved in the prevention and direct repair of oxidative DNA lesions .
Subjects infected by Hp also present lower levels of plasma ascorbic acid and plasma beta-carotene .
Beta-carotene and vitamins A , C and E are chain-breaking antioxidants , since decreased levels of antioxidants due to increased levels of lipid peroxidation create a state of oxidative stress.
Furthermore, many Hp virulence factors promote the release of variety emoattractants/inflammatory mediators triggering an intense leucocyte infiltration of the gastric mucosa, and neutrophil activation provides a major source of reactive oxygen species which can cause tissue damage mainly in the absence of antioxidants .

** Oxidative Damage and Glaucoma

Ascorbic acid is thought to be a primary substrate in eye protection on account of its high ocular concentration.
This molecule is highly concentrated in the aqueous humour, cornea and tear film.
Vitamin C is an important antioxidant, protecting cells from oxidative stress-induced death.
The trabecular meshwork ™ cells contain antioxidant enzymes , such as superoxide dismutase and catalase.
Glutathione is detectable in aqueous humour, while the ocular ciliary epithelium expresses genes coding for glutathione-S-transferases, glutathione peroxidases and other enzymes involved in the glutathione cycle.
Both glutathione peroxidase and glutathione reductase activities have been detected in TM cells.
Catalase has been suggested to protect ocular tissues when high H2O2 concentrations are present, whereas the GSH redox system is believed to protect ocular tissues from damage induced by low H2O2 concentrations.
The TM plays a fundamental role in the hydrodynamics of the aqueous humour.
Alterations in the aqueous outflow lead to IOP increase, elevated IOP being one of the main risk factors for the development of glaucomatous neuropathy.
The total reactive antioxidant potential of aqueous humour obtained from glaucoma patients is significantly decreased.
TM cells are in contact with high concentrations of H2O2, which can induce detrimental effects on aqueous humour outflow and the agerelated decrease in TM cellularity.
TM oxidative stress-related damage is likely to be manifested as an increase in IOP due to alterations in outflow facility, as outflow resistance increases in the presence of high H2O2 levels.
H2O2 damages the cytoskeleton, compromising TM integrity and influencing the biological reactions of the TM.
Increased oxidative damage in the TM could affect regulation of the extracellular matrix structure and the associated IOP regulation, leading to the clinical onset of
glaucoma .
Further support for this hypothesis is provided by the finding that timolol, a beta-blocking drug used to decrease IOP in glaucoma patients, exerts antioxidant activity which protects human endothelial cells from oxidative stress.
The permeability of the TM endothelium barrier is influenced by endothelins and nitric oxide (NO) .
These molecules also play an important role in the regulation of ocular blood flow.
Under normal conditions, the vasoconstricting effect of endothelin-1 is counterbalanced by the relaxing effect of NO .
In the presence of free radicals, NO generates toxic products that interact with oxygen, iron and copper , aggravating the metabolic conditions of the TM and altering its motility and function.
It is conceivable that oxidative stress plays an important pathological role in inducing damage both in TM endothelial cells and in the optic nerve head.
Glaucomatous neuropathy is characterised by a selective lost of retinal ganglion cells, which results in a loss of visual field corresponding to the nerve fibre layer pattern.
Glaucomatous visual-field defects and oxidative stress in the TM are correlated.
There are three major stimuli for retinal ganglion cell apoptotic death , that is hypoxia , neurotrophin withdrawal and glutamate-mediated toxicity.
In this context, oxidative stress seems to play an important role.
Ischaemia reperfusion injury produces free radicals responsible for oxidative damage to the axons. Moreover, the reuptake of glutamate is influenced by the concentration of free radicals, an increase in ROS levels leading to increased extracellular glutamate concentration.
Glutamate is a neurotransmitter whose hysiological role is to transmit synaptic pulses.
In pathological conditions it can potently stimulate target cells, causing death; this type of cellular damage is known as ‘‘excitotoxicity.’’
Activation of N-methyl-D-aspartate type (NMDA) membrane receptors by glutamate stimulates the production of large quantities of
nitric oxide .
Nitric oxide can react with superoxide (mostly produced in the mitochondria of the axons) leading to the formation of peroxynitrate and peroxynitrite anions, which are unstable and rapidly decompose to form the more toxic hydroxide radical, leading to neurotoxicity.
The peroxynitrite anion is particularly able to trigger cell death through apoptosis.
It has also been shown that large (magnocellular) retinal ganglion cells, the elements most sensitive to glaucomatous destruction, are more susceptible to NMDA and glutamate-mediated neurotoxicity than small ganglion cells.
Moreover, the astrocytes of the optic nerve head in glaucoma patients express the inducible form of nitric oxide synthase (NOS II) whose expression in glial cells can be induced in vitro by mechanical and hypoxic stress.
This finding further supports the possibility that free radicals may be a link between the vascular and mechanical theories of glaucoma pathogenesis.
Nitric oxide also appears to be involved in the pathogenesis of cellular damage in the lateral geniculate nucleus, as documented directly in glaucoma .

** Correlation between Hp infection and Open-angle Glaucoma

Oxidative stress has been implicated in the pathogenesis of several diseases, including both primary open-angle glaucoma and HP infection .
Upregulation of the genes involved in inflammation, which typically occurs in HP-infected gastric mucosa, and the acute-phase response might initiate and contribute to the progression of glaucoma .
Therefore, HP infection might influence the pathophysiology of glaucoma by releasing various proinflammatory and vasoactive substances, as well as by influencing the apoptotic process or TM omeostasis.
These parameters may also exert their own effects on the induction and/or progression of glaucomatous neuropathy.
What links HP infection and glaucoma may be oxidative damage, which has been shown to occur in cardiovascular diseases , inflammation and glaucoma .
HP infection affects the pathophysiology of glaucoma by producing systemic oxidative stress through the increase in circulating lipid peroxides.
Reactive oxygen species and circulating peroxides are apoptotic signals, apoptosis being the most important mechanism of cellular death during glaucoma.
Moreover, increased levels of HP-specific IgG antibodies have been found directly in the aqueous humour of glaucomatous patients.
Recently, it has been proposed that mitogen-activated protein kinases (MAPKs) present in the aqueous humour could be involved in glaucoma pathogenesis; mitogen-activated protein kinase networks are involved in the apoptotic process, which is a possible cellular response to oxidative stress.
Interestingly, HP has been shown to induce activation of the MAPKs extracellular signal-regulated protein kinase (ERK) 1/2, and MAPK/ERK kinase (MEK) 1/2, which are mediated at the level of the IL-8 promoter.
HP infection also induces IL-8 production, leading to neutrophil migration and activation, ROS generation and oxidative damage.
Gastric HP infection could result in the systemic release of proinflammatory and vasoactive substances, including endothelin-1, nitric oxide and inducible nitric oxide synthase .
Accordingly, glaucoma patients could display a higher susceptibility to oxidative damage in both the TM and optic nerve head.
Chronic oxidative stress in TM cells induced iROS production in mitochondria.
This increase in ROS may contribute to the pathogenesis of the TM in glaucoma by inducing the expression of inflammatory mediators and also has the potential to contribute by itself to pathophysiological changes in outflow pathway by increasing the levels of oxidative damage in the cells.
It has been hypothesised that eye problems in HP-infected patients may be related to the high concentration in exhaled air of volatile noxious compounds elaborated by the microorganism, including hydrogen nitrate and hydrogen cyanide.
The activation of inflammatory mediators by HP might be the pathogenetic mechanism underlying the association between ocular diseases and HP infection.
Similarly, an association between HP infection and respiratory diseases has been proposed on the basis of the genetic predisposition of the infected host, the presence of strain-specific virulence factors and the serum concentration of pro-inflammatory markers in HP-infected patients.
The notion that systemic oxidative damage induced by infective agents is related to the onset of chronic degenerative diseases has already been suggested by studies that have investigated this relationship with regard to cardiovascular diseases .
An association between Chlamydia pneumonieae or Cytomegalovirus infection and atherosclerosis has also been reported, suggesting that the underlying pathogenetic mechanism is the production of reactive oxygen species.

1
Helicobacter pylori infection and primary open-angle glaucoma: is there a connection? - Tsolaki, Gogaki, Sakkias, Skatharoudi, Lopatatzidi, Tsoulopoulos, Lampoura, Topouzis, Tsolaki, Kountouras - Clin Ophthalmol., 2012
2
Further data on the association between Helicobacter pylori infection and primary open-angle glaucoma. - Zavos, Kountouras - Clin Ophthalmol., 2012
3
Glaucoma and Helicobacter pylori infection: correlations and controversies. - Izzotti, Saccà, Bagnis, Recupero - Br J Ophthalmol., 2009
4
Mitochondrial damage in the trabecular meshwork of patients with glaucoma. - Izzotti, Saccà, Longobardi, Cartiglia - Arch Ophthalmol., 2010
*
Induction of apoptosis as a proposed pathophysiological link between glaucoma and Helicobacter pylori infection. - Kountouras, Zavos, Chatzopoulos - Med Hypotheses, 2004 )
Association between helicobacter pylori and open angle glaucoma: current perspective - Zaidi, Jilani, Gupta, Umair, Gupta - Nepal J Ophthalmol., 2009
Neuroprotection in glaucoma: is there a future role? - Baltmr, Duggan, Nizari, Salt, Cordeiro - Exp Eye Res., 2010
Neuroprotection in glaucoma: is there a future role of Helicobacter pylori eradication? - Kountouras, Zavos, Deretzi, Polyzos, Gavalas, Tsiaousi, Giartza-Taxidou, Chatzopoulos, Michael, Tsarouchas - Exp Eye Res., 2011
Helicobacter pylori infection as a risk factor for both primary open-angle glaucoma and pseudoexfoliative glaucoma in Thessaloniki Eye Study. - Kountouras, Zavos, Sakkias, Deretzi, Venizelos, Arapoglou, Polyzos - Am J Ophthalmol., 2011
Histological Presence of Helicobacter pylori Bacteria in the Trabeculum and Iris of Patients with Primary Open-Angle Glaucoma. - Zavos, Kountouras, Sakkias, Venizelos, Deretzi, Arapoglou - Ophthalmic Res., 2011

  • Helicobacter Pylori and Oral Pathologies (Halitosis, Glossitis, BMS)

H. Pylori has recently been associated with burning sensations , acid taste, halitosis , lingual and papillary iperplasia on the mouth.
Eradication of H. pylori from the gastrointestinal tract is not an easy task.
This organism has been recently found in dental plaque, saliva, and at the lingual site.
This suggests that the oral cavity could be an adequate reservoir for this bacterium, and cause the reinoculation of gastric mucosa after treatment.
Therefore, the study of the oral cavity is of utmost importance for the detection of H. pylori .
Many patients with HP infection had burning, halitosis, and lingual dorsum hyperplasia (BHH) with self-reported burning; halitosis, detected with a halimeter, when the value was above 100 p.p.b.; and lingual papillary hyperplasia, which was detected by clinical examination.
Both the pathophysiologic mechanism and the etiologic agent of halitosis remain unclear.
In 1989, H. pylori was found in dental plaque by bacterial culture.
Cytobrush on the lingual dorsum of patients with atrophic glossitis, migratory glossitis, glossitis with burning mouth syndrome (BMS) found association with the presence of H.P.
These results suggest that H. pylori could be the etiologic agent of BHH and BMS .
Perinuclear vacuolization and papillomatosis found in the lingual biopsies of the BHH and BMS patients were not associated with other agents such as HPV .
On the contrary, these vacuolization and papillomatosis may be associated with CagA enzymes (cytotoxin associated gene) and VacA (vacuolization associated gene), which are coded in H. pylori genome and present vacuolizing properties.

  • Burning Mouth Syndrome (BMS) and Burning Mouth in Hypothyroidism (BMHT)

Burning mouth syndrome (BMS) is a common disorder frequently affecting women past the 5th decade of age.
It is characterized by oral burning, mainly involving the tongue, lip, and anterior palate, but without oral lesions or alteration showing in blood tests and/or instrumental findings.
Some patients report,in addition to oral burning, a sensation of a swollen lip and/or tongue in absence of clinical evidence.
Other BMS patients report, in addition, an alteration in the sense of taste and hypo or dysgeusia due to an increased bitter taste without receptorial stimulation.
Despite the large number of clinical and epidemiologic studies, the pathogenesis and etiology of BMS remain unclear.
Burning mouth syndrome is considered to be a psychosomatic pathology afflicting subjects of an anxious character and inclined to somatize.
On the basis of this knowledge, a certain diagnosis of BMS can be formulated only after excluding all possible conditions and pathologies which may be responsible for oral burning.
Several pathologies may be responsible for oral burning and recently it has been proposed that some oral burning cases belong to the diagnosis of BMS could be a symptomatic expression of hypothyroidism and should be identified as burning mouth in hypothyroidism (BMHT).
At present, the oral burning often reported by patients, affected by evident or undiagnosed thyroid pathology, is considered to be BMS .
Thyroid hypofunction or dysfunction may be responsible for the oral burning and dysgeusia sometimes reported by patients.
Patients with oral burning often show parenchymal inhomogeneity of the thyroid upon echographic examination with normal blood tests for thyroid function.
This contradiction (inhomogeneous thyroid parenchyma but with normal blood tests for thyroid function) may be explained by two hypotheses: either the presence of a structural anomaly of the receptor due to thyroxine or the secretion of reverse thyroxine (a poorly functioning thyroxine).
As a result, the thyroid parenchyma, to compensate for this functional anomaly, tries to increase its parenchyma and this leads to multifocal glandular hyperplasia (inhomogeneity).
This multifocal hyperplasia could, sometimes, be ineffective and to lead to the growth of thyroid nodules (latent hypothyroidism).
Several patients with oral burning often report dysgeusia at the same time, with taste phantoms (taste sensations in the absence of stimulation) regarding bitter or more rarely salty taste.
This trouble occurs more frequently when there is a thyroid dysfunction and it is bilieved that thyroid disorder could cause both oral burning and dysgeusia (taste phantoms).
The relationship between the thyroid and taste sensibility could be linked to the influence of thyroid hormones on the maturation and specialization of the taste buds; this happens particularly for the supertasters (subjects with a larger number of fungiform papillae on the tongue).
These subjects could be predisposed to taste phantoms and to idiopathic oral burning when a true sub-clinical or latent hypothyroidism occurs.
The oral burning represents a disturbance of somatic-sensorial sensitivity (tactile, thermal, and painful) of the trigeminal nerve.
There are connections between taste and oral pain in the central nervous system.
Taste stimulus normally inhibits the area of the brain that receives input from the trigeminal nerve through the chorda tympani.
It is possible that BMS patients and other oral pain phantoms can arise after damage to the taste system.
When a hypofunction of taste sensibility occurs owing to damage to the taste system, caused by traumatic lesions or infectious or inflammatory pathologies (otitis), altered activity of the taste receptors (drug-induced), illness of the maturation of fungiform papillae (reduction in thyroid hormone dosage), the inhibition, in the central nervous system, exercised on the somaticsensorial sensibility of the trigeminal nerve could be released, with the exaltation in the mouth of tactile (feeling of swelling), thermal (feelings of heat), and painful (burning feeling) sensitivity.
The exaltation of the somatic-sensorial sensitivity of the trigeminal nerve causes the same sensations cited in the clinical history of BMS patients.
Subjects more predisposed to this kind of sensitivity genetically have a larger number of taste papillae (supertasters).
Hypothyroidism could act as a negative factor for the maturation of fungiform papillae, with reduction in taste, the release of inhibition on the somatic-sensorial sensitivity of the trigeminal nerve in subjects with a larger number of taste papillae, and the subsequent onset of oral burning (tongue, palate, lip), a feeling of heat to the mouth, and a feeling of swelling to the lips and tongue.
It is necessary to distinguish patients with true BMS from BMHT, because they need a different therapeutic protocol.
For this reason, it could be essential for a correct BMS diagnosis to include tests for thyroid function and echography in the topical protocol.
The treatment of thyroid dysfunction improves taste disorders and reduces the somatic-sensorial sensitivity of the trigeminal nerve (oral burning).

1
Helicobacter pylori Associated with Glossitis and Halitosis - Adler, Denninghoff, Álvarez, Avagnina,Yoshida – Elsner – Helicobacter., 2005
2
Halitosis and Helicobacter pylori infection.Tangerman, Winkel, de Laat, van Oijen, de Boer - J Breath Res., 2012
3
Burning mouth syndrome and burning mouth in hypothyroidism: proposal for a diagnostic and therapeutic protocol - Femiano, Lanza, Buonaiuto, Gombos, Nunziata, Cuccurullo, Cirillo - Med Oral Pathol Oral Radiol Endod., 2008

3) Eventuali proposte di terapia, volta al ripristino delle condizioni ottimali

  • Per HP:
    • Sulla base dell’ipotesi diagnostica di possibile coinvolgimento di un’ infezione cronica da Helicobacter Pylori nella genesi della variegata sintomatologia clinica, la paziente è stata inizialmente sottoposta a Breath-Test all’urea (per ricerca HP), risultato POSITIVO.
    • E’ stato inoltre effettuato in seguito un esame EGDScopico con riscontro di “GASTROPATIA CRONICA EROSIVA DELL’ANTRO” – Referto Istologico su Biopsie Gastriche: GASTRITE CRONICA ATTIVA H.P. POSITIVA (+++).
    • E’ stata dunque prescritta terapia eradicante per l’HP (OMEPRAZOLOCLARITROMICINA TINIDAZOLO per una durata di 10 giorni).
    • Il successivo controllo del Breath-test dopo 3 mesi risulta NEGATIVO con conferma dell’avvenuta eradicazione dell’ HP.
  • Per BMHT:
    • Viene effettuata una ECOGRAFIA TIROIDEA.
      Il referto dell’esame riporta: “ Tiroide ai limiti superiori della norma con parenchima di aspetto diffusamente disomogeno, secondario ad iperplasia multifocale ghiandolare senza evidenti formazioni nodulari. - Quadro ecografico compatibile con ipotiroidismo latente in presenza di normale funzionalità tiroidea”.
    • Si procede quindi a prescrizione di terapia con acido alfa-lipoico (TIOBEC 800 1 c/die).
  • ESITO DELLA TERAPIA:
    • La paziente ad oggi presenta pressochè totale scomparsa della sintomatologia orale, con notevole diminuzione delle crisi emicraniche, sia in frequenza sia in intensità.
    • Si rileva inoltre successiva assenza post-terapia di dolori ed iperestesie , ad eccezione di un episodio di dolore acuto di tipo trafittivo al braccio dx della durata di 1-2 ore, verosimilmente associabile ad un movimento scorretto durante lo svolgimento della normale attività fisica.
    • La paziente riferisce inoltre di un sonno tornato regolare, non interrotto da risvegli notturni né crisi di panico.
    • La terapia antiipertensiva topica adottata per il trattamento del glaucoma si è infine dimostrata efficace nella stabilizzazione delle condizioni oculari .
    • Da segnalare tuttavia una improvvisa e discreta ripresa della sintomatologia rinitica da allergia stagionale (i cui ultimi episodi riportati risalivano ai tempi dell’adolescenza), associata ad un episodio asmatico .
    • Esami ematochimici successivamente eseguiti mostrano un incremento del numero assoluto e percentuale degli eosinofili e dei basofili, in analogia con quanto evidenziato dagli esami effettuati dalla paziente all'età di 9 anni.

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MeSH
Blood, Blood Coagulation Disorders, Inherited, Blood Coagulation, Mitochondria, Heart, Hemeproteins, Iron, Dietary, Iron Metabolism Disorders, Vitamin D, Diabetes Mellitus, Type 2, Calcium, Thyroid Gland, Haptoglobins, Stomatitis, Blood Cells, Macrophages, Iron, Myocardial Infarction, Antioxidants, Thrombosis, Nitric Oxide, Hypothyroidism, Hypoxia-Inducible Factor 1, Cell Hypoxia, Apoptosis, Carcinoma, Proton Pumps, Homocysteine, Platelet Aggregation Inhibitors, Inflammatory Bowel Diseases, Cell Adhesion Molecules, Disease, Cardiomyopathies, Heart, Ascorbic Acid, Ascorbic Acid Deficiency, Signs and Symptoms, Cortisone, Panic, Ferritins, Free Radicals, Mitochondria, Diet Therapy, Vitamin D Response Element, Purpura, Platelet Activation, Platelet Aggregation, Glaucoma, Cyclooxygenase 2 Inhibitors, Cyclooxygenase 2, Blood Circulation, Asthma, Sodium, Glucocorticoids, Lymphocytes, Intestinal Secretions, Phosphates, Cyclic AMP, Antibodies, Potassium, Vitamin D Deficiency, Blood-Brain Barrier, Erythrocytes, Molecular Chaperones, Hormones, Nitric Oxide Synthase, Fibrosis, Glutathione, Membranes, Anemia, Inflammation, Inflammation Mediators, Folic Acid, Cell Differentiation, Helicobacter Infections, Helicobacter pylori, Cytokines, Intestinal Absorption, T-Lymphocyte Subsets, Signal Transduction, Venous Thrombosis, Dyspepsia, Cardiovascular Diseases, Cell Cycle Proteins, Cell Cycle, Mitochondrial Diseases, Iron Overload, Vitamin K 1, Periodontitis, Vitamin K Deficiency, Metalloproteases, Sleep Disorders, Endocarditis, Atherosclerosis, Anti-Inflammatory Agents, Mucins, Vitamin B 12, Vitamin B 12 Deficiency, Eosinophilia, Oxygen Compounds, Mouth, Anticoagulants, Nonheme Iron Proteins, Antibiosis, Heme Oxygenase-1, Immunoglobulin E, Oxygen, Vascular Diseases, Prothrombin, Restless Legs Syndrome, ATP-Binding Cassette Transporters, Ischemia, Bradykinin, Sepsis, Extracellular Matrix, Extracellular Matrix Proteins, Food Habits, Tongue Diseases, Blood Coagulation Factors, Blood Coagulation Factor Inhibitors, Erythropoietin, Aspirin, Causality, Hemopexin, Embolism and Thrombosis, Gastrointestinal Hormones, Gastrins, Gastrin-Releasing Peptide, Gastrin-Secreting Cells, Bacteria, Disinfectants, Food, Granulocytes, Eosinophils, Oxygen Consumption, Infection, Cyclooxygenase 1, Drug Toxicity, Cytoskeletal Proteins, Vitamin D-Binding Protein, Gastrointestinal Diseases, Genome, Gap Junctions, C-Reactive Protein, Gene Expression Profiling, Mutation, Metabolism, Gene Expression, Heart Diseases, Pregnancy, Diarrhea, Irritable Bowel Syndrome, Gastrointestinal Hemorrhage, Caffeine, Vitamin B Complex, Anti-Bacterial Agents, Peptic Ulcer Perforation, Benzodiazepines, Thromboembolism, Protein C, Dental Plaque, Vasculitis, Myocardial Ischemia, Molecular Mimicry, Drug Compounding
Comments
2012-03-31T23:52:45 - Edoardo Manca

UNA SUGGESTIVA IPOTESI SUL PERCHE' DELLA RICOMPARSA DELL' ASMA ALLERGICA DOPO LA TERAPIA

The prevalence of airway allergic disease such as asthma has over the years increased in developed countries.
The causes of this increase remain largely unknown.
Proposed associations include changes in smoking habits, exposure to food-borne and orofecal infections,types of dwellings, ownership of furry animals number of siblings, family income/education level, and the presence of particulates in diesel exhaust.
The inverse association between family size and manifestations of allergy has been consistently found, and there is also a much-published potential link between allergy and childhood infection, especially with Helicobacter pylori .
Until the late 1980s, interest in the role of infections in allergic diseases focused principally upon the process of primary allergic sensitization.
The literature of the time contained several observations which argued for a role for infections, including the ability of bacterial-derived immunostimulants such as pertussigen to selectively improve priming for immunoglobulin (Ig)E antibody production, and the potential of lipopolysaccharide to bypass tolerance to mucosally applied allergens.
Also, other studies reported that respiratory viral infections such as influenza could subvert the generation of protective “inhalation tolerance” to aeroallergens.
More recently, signals such as enterotoxins from skin-dwelling bacteria have been invoked as important contributors to the pathogenesis of atopic dermatitis . However, it was also clear from other observations that microbial exposure per se could not be considered in generic terms as “pro-atopic”.
For example, other microbial-derived agents exemplified by the components of Freund’s adjuvant displayed atopy-antagonistic activity, and stimuli derived from normal gut flora were demonstrated to be necessary to facilitate the expression of oral tolerance to fed allergens, and also inhalation tolerance to aeroallergens.
These observations suggested that microbial-derived stimuli had potential to modulate the etiology and pathogenesis of atopic diseases in dichotomous ways, their ultimate effects perhaps being context-dependent.

In 1989, Strachan proposed the “hygiene hypothesis”, stating that the exposure to infectious agents and living in an unhygienic environment might “educate” the immune system and thus protect against the development of allergic diseases.
The idea originated from epidemiological observations suggesting a general hypothesis that infections in early childhood acquired from older siblings might confer protection against the development of atopic diseases such as atopic eczema , allergic rhinoconjunctivitis, and asthma .
The T helper (Th)-1/Th-2 paradigm of adaptive immune responses provided the initial immunological backbone for the hygiene hypothesis.
On the basis of the cytokine production patterns, T cell responses may be divided into counter-regulatory Th-1 and Th-2 subtypes.
Th-2 responder phenotype is associated with atopic sensitization and atopic disease.
Indeed, inflammation of the Th-2 type appears to be active in the initial stage of the pathogenesis of atopic eczema , allergic rhinoconjunctivitis,and asthma .
In detail, the histopathological characteristics of bronchial asthma, even a mild one, are represented by inflammatory infiltrates consisting of T lymphocytes and accumulation of activated eosinophils, epithelial shedding, and basal membrane thickening.
Immunological and molecular studies of bronchial biopsies and bronchoalveolar lavage samples obtained in baseline disease or taken after natural or “experimentally” induced asthma exacerbations have shown that a complex and fascinating inflammatory mechanism sustains the pathogenesis of bronchial asthma, including the participation of different types of Th cells and peculiar cytokine and chemokine networks.
In allergic asthmatic patients, allergen exposure induces a predominant activation of Th-2
lymphocytes in the airways, able to over-express several Th-2 cytokines, such as interleukin (IL)-4 and IL-5.
Moreover, the degree of IL-5 expression at the bronchial level is associated with the disease severity both in atopic and in nonatopic asthma
IL-5 and granulocyte macrophage colony-stimulating factor (GM-CSF) can be considered the most important cytokines for eosinophil accumulation in asthmatic inflammation.
Th-2 cytokines in bronchial asthma are produced not only by CD4+ but also by CD8+ T cells, which contribute to the genesis of asthma and to the clinical expression of the disease.
In H. pylori infection, a predominant activation of Th-1 cells, with the production of interferon (IFN)-γ , IL-12 , IL-18 , IL-23, and tumor necrosis factor (TNF)-α , occurs in vivo in the stomach of humans and in animal models, and the inhibition of the allergic Th-2 inflammation by Th-1 responses can explain the inverse relationship between H. pylori and asthma .

** Mechanism of action of Hp

Like many human commensal bacteria, H.pylori has evolved specific mechanisms to avoid stimulating the immune response .
For example, innate immune recognition by several Toll-like receptors (TLRs) is attenuated for H.pylori .
Despite this, colonization is associated with inflammatory and mucosa infiltration of polymorphonuclear leukocytes, macrophages, and Th-1 lymphocytes, with active production of IL-12 and IFN-gamma .
Such an immune response is expected to play a role in the pathogenesis of H. pylori-associated diseases in humans.
Accordingly, a Th-1-directed immune response, induced by H. pylori infection, increases gastric inflammation and atrophy, whereas Th-2 redirection reduces them.
Different pathways are responsible for the predominant H. pylori-induced mucosal Th-1 response.
Stimulation of human neutrophils, monocytes, and dendritic cells with H. pylori neutrophil-activating protein strongly upregulates both IL-12 and IL-23 production, via TLR2 activation.
In the gastric mucosa of H. pylori-infected patients, a considerable proportion of Th cells is specific for different H. pylori antigens, including HP-NAP, CagA, urease, VacA, and heat shock proteins , and HP-NAP drives the production of high levels of IFN-gamma and TNF-alfa by gastric Th cells, thus promoting a polarized Th-1 response.

** Protective properties of Helicobacter pylori on Asthma and Allergies

Asthma , a chronic inflammatory disease of the airways is a multifaceted disorder characterized by airway hyperresponsiveness to a multiplicity of specific and nonspecific stimuli, and mucus hypersecretion by goblet cells.
The severity and incidence of asthma have increased drastically in the developed nations over recent decades.
Although the underlying reason is still unknown, clinical, epidemiological, and experimental evidence indicate that infectious diseases can influence the development of allergic disorders. Accordingly, an inverse correlation has been demonstrated between the onset of allergic disorders and the incidence of infections.
This may be the result of an inhibition of allergic Th-2 inflammation exerted by Th-1 responses; the latter are elicited by infectious agents and are able to induce the production of IFN , IL-12 , IL-18, and IL-23.
This view is supported by studies showing that development of asthma can be prevented in animals by administering live or killed bacteria or their components, which induce Th-1 responses.
H. pylori inhibit Th-2 responses in asthmatic patients.
Interestingly, on the basis of large epidemiological studies, recently, a consistent negative association between H. pylori infection and the presence of allergic disorders, such as asthma and rhinitis, has been proposed.
Addition of HP-NAP (a dodecamer formed by four-helix bundled subunits with a hollow central part) to allergen-induced T-cell lines derived from allergic asthmatic patients led to a drastic increase in IFN-γ-producing T cells and to a decrease in IL-4-secreting cells, thus resulting in a redirection of the immune response from a Th-2 to a Th-1 phenotype.
Furthermore, in the gastric mucosa of H. pylori-infected patients a remarkable proportion of Th-cells showed significant proliferation to different H. pylori antigens, including HP-NAP ; upon HP-NAP stimulation, Ag-specific gastric Th cells produced large amounts of IFN and TNF , and displayed a powerful cytotoxic activity, thus showing a polarizing Th-1 effector phenotype.
Likewise, HP-NAP stimulation of neutrophils, monocytes,and dendritic cells resulted in a remarkable upregulation of cytokines, including IL-12 and IL-23, contributing to the induction of an IL-12 and IL-23-enriched milieu, which has the potential to drive the differentiation of antigen-stimulated T cells towards a polarized Th-1 phenotype.
Another hypothetical explanation for the inverse association between H. pylori and asthma is that the high levels of regulatory T cells (Tregs) associated with H. pylori infection may contribute to prevention of allergic diseases, and H. pylori-free humans are thus more susceptible to these diseases.
In support of this, H. pylori positive people have higher levels of gastric Tregs than those without the organism, and more importantly also, circulating Tregs are increased in number.
In addition, in mice experimentally infected with H. pylori , systemic Tregs are increased, and these suppress other immune responses, one effect of which is to facilitate H. pylori colonization.
The excess Tregs may have immunosuppressive activity in humans as well: among H. pylori-positive persons, those with fewer Tregs are more likely to have peptic ulcers and so presumably have more intense gastritis.
In vivo administration of HP-NAP prevents the typical eosinophil accumulation in the lung, as well as the increase of serum IgE .
These results suggest the possibility that HP-NAP might be a part of the molecular mechanism underlying the negative association between H. pylori infection and allergy, corroborating the epidemiology.
Both systemic and mucosal administration of HP-NAP strongly inhibited the development of airway eosinophilia and bronchial inflammation.
Likewise, HP-NAP treatment strongly affected the lung cytokine release, reducing the production of IL-4, IL-5, and GM-CSF.
Systemic HP-NAP also significantly resulted in both the reduction of total serum IgE and an increase of IL-12 plasma levels studies suggest that TLR2 ligand HP-NAP might be the key element responsible for the decrement of allergy frequency in H. pylori-infected patients.
Several studies were devoted to the definition of new immune modulating factors able to inhibit Th-2 responses, and different compounds have been proposed for the treatment and prevention of asthma and atopic diseases, including several TLR ligands mimicking the effects of microbial components.
The increased prevalence and severity of asthma and allergy in Western countries may be related, at least in part, to the decline of H. pylori infection, which is able to induce a long-lasting Th-1 background, and suggest also that H. pylori compounds such as HP-NAP could be important candidates for novel strategies of the prevention and treatment of asthma and allergic diseases.

1
Helicobacter pylori, asthma and allergy - D’Elios, Codolo, Amedei, Mazzi, Berton, Zanotti, Del Prete, de Bernard - FEMS Immunol Med Microbiol, 2009
2
Th1 and Th2 cells
3
The effect of Helicobacter pylori on asthma and allergy - Amedei, Codolo, Del Prete, de Bernard, D'Elios - J Asthma Allergy, 2010
4
The immune modulating activity of the Helicobacter pylori HP-NAP: Friend or foe? - de Bernard, D’Elios - Toxicon, 2010
5
The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immunemodulating agent - D’Elios, Amedei, Cappon, Del Prete, Marina de Bernard - FEMS Immunol Med Microbiol, 2007
6
Association Between Helicobacter pylori Infection and Inflammatory Bowel Disease: A Meta-analysis and Systematic Review of the Literature - Luther, Dave, Higgins, Kao - Inflamm Bowel Dis, 2010

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Si rimanda inoltre alla pagina di Flipper e Nuvola dal titolo Helicobacter Pylori - Virulence Factors per ulteriori approfondimenti sull'HP-NAP, il suo ipotetico funzionamento ed il sinergismo d'azione con altri fattori di virulenza di Hp

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Inverse association between Helicobacter pylori and pediatric asthma in a high-prevalence population. - Zevit, Balicer, Cohen, Karsh, Niv, Shamir - Helicobacter., 2012
DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. - Oertli, Sundquist , Hitzler, Engler, Arnold, Reuter, Maxeiner, Hansson, Taube, Quiding-Järbrink, Müller - J Clin Invest. 2012
To treat or not to treat Helicobacter pylori to benefit asthma patients. – D'Elios, de Bernard - Expert Rev Respir Med., 2010
Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. - Arnold, Dehzad, Reuter, Martin, Becher, Taube, Müller - J Clin Invest., 2011
Does Helicobacter pylori protect against asthma and allergy? - Blaser, Chen, Reibman - Gut., 2008
Helicobacter pylori neutrophil-activating protein promotes myeloperoxidase release from human neutrophils. - Wang, Liu, Du, Lin, Fu - Biochem Biophys Res Commun., 2008
The neutrophil-activating protein of Helicobacter pylori (HP-NAP) activates the MAPK pathway in human neutrophils. -Nishioka, Baesso, Semenzato, Trentin, Rappuoli, Del Giudice, Montecucco - Eur J Immunol., 2003
Helicobacter pylori-derived neutrophil-activating protein increases the lifespan of monocytes and neutrophils. - Cappon, Babolin, Segat, Cancian, Amedei, Calzetti, Cassatella, D'Elios, de Bernard - Cell Microbiol., 2010
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The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a potent stimulant of mast cells. - Montemurro, Nishioka, Dundon, de Bernard, Del Giudice, Rappuoli, Montecucco - Eur J Immunol., 2002
The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. - Amedei, Cappon, Codolo, Cabrelle, Polenghi, Benagiano, Tasca, Azzurri, D'Elios, Del Prete, de Bernard - J Clin Invest., 2006
The neutrophil-activating protein of Helicobacter pylori. - Dundon, Nishioka, Polenghi, Papinutto, Zanotti, Montemurro, Del, Rappuoli, Montecucco - Int J Med Microbiol., 2002
The neutrophil-activating protein of Helicobacter pylori crosses endothelia to promote neutrophil adhesion in vivo. - Polenghi, Bossi, Fischetti, Durigutto, Cabrelle, Tamassia, Cassatella, Montecucco, Tedesco, de Bernard - J Immunol., 2007
The neutrophil-activating protein of Helicobacter pylori down-modulates Th2 inflammation in ovalbumin-induced allergic asthma. - Codolo, Mazzi, Amedei, Del Prete, Berton, D'Elios, de Bernard - Cell Microbiol., 2008
Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP. - Brisslert, Enarsson, Lundin, Karlsson, Kusters, Svennerholm, Backert, Quiding-Järbrink - FEMS Microbiol Lett., 2005

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