Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study.

BACKGROUND AND OBJECTIVES: Long-term proton pump inhibitor (PPI) use is frequently encountered in primary care. Its effect on micronutrient absorption is known, as vitamin B12, calcium or vitamin D insufficiency may occur in such patients. MATERIALS AND METHODS: We recruited patients using a PPI (pantoprazole) for >12 months. The control group was represented by subjects attending the general practitioner not taking any PPI in the last 12 months. We excluded subjects using nutritional supplements or with diseases interfering with micronutrient blood levels. All subjects underwent blood sampling with full blood count, iron, ferritin, vitamin D, calcium, sodium, potassium, phosphate, zinc and folate. RESULTS: We recruited 66 subjects: 30 in the PPI group and 36 in the control group. Long-term pantoprazole users had lower red blood cell count but similar hemoglobin. We did not find any significant difference in blood iron, ferritin, vitamin B12 and folate. Vitamin D deficit was observed more frequently in the PPI group (100%) than in controls (30%, p < 0.001), with blood levels lower in pantoprazole consumers. No differences in calcium, sodium and magnesium were observed. Pantoprazole users had lower phosphate levels than controls. Finally, a non-significant trend for zinc deficiency was found in PPI users. CONCLUSIONS: Our study confirms that chronic PPI users may encounter alterations in some micronutrients involved in bone mineral homeostasis. The effect on zinc levels deserves further investigation.

Curcumin and Colorectal Cancer: From Basic to Clinical Evidences.

Curcumin diffuses through cell membranes into the endoplasmic reticulum, mitochondria, and nucleus, where it exerts actions, as an antioxidant property. Therefore, its use has been advocated for chemopreventive, antimetastatic, and anti-angiogenic purposes. We conducted a literature review to summarize studies investigating the relationship between curcumin and colorectal cancer (CRC). In vitro studies, performed on human colon cancer cell lines, showed that curcumin inhibited cellular growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis by interacting with multiple molecular targets. In vivo studies have been performed in inflammatory and genetic CRC animal models with a chemopreventive effect. To improve curcumin bioavailability, it has been associated with small particles that increase its absorption when orally administered with excellent results on both inflammation and carcinogenesis. Curcumin has been used, moreover, as a component of dietetic formulations for CRC chemoprevention. These combinations showed in vitro and in vivo anticarcinogenetic properties in inflammation-related and genetic CRC. A synergic effect was suggested using an individual constituent dosage, which was lower than that experimentally used "in vivo" for single components. In conclusion, curcumin falls within the category of plant origin substances able to prevent CRC in animals. This property offers promising expectations in humans.

Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma.

BACKGROUND: Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs. AIM: To elucidate the role of ARBs and ACE-Is in HCC. METHODS: We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms "angiotensin-converting enzyme inhibitors" OR "ACE inhibitors" OR "ACE-I" AND "hepatocarcinoma*" OR "hepatocellular carcinoma; moreover "angiotensin II type 1 receptor blockers" OR "ARBs" AND "hepatocarcinoma*" OR "hepatocellular carcinoma". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals. RESULTS: Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs. CONCLUSION: In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.

Noninvasive molecular analysis of Helicobacter pylori: Is it time for tailored first-line therapy?

The main problem of Helicobacter pylori (H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction (PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.

Helicobacter pylori DNA isolation in the stool: an essential pre-requisite for bacterial noninvasive molecular analysis.

PURPOSE: Real-time polymerase chain reaction (RT-PCR) is a widely used technique for bacterial and viral infection diagnosis. Herein, we report our preliminary experience in retrieving H. pylori genetic sequences in stools and analyzing genotypic clarithromycin resistance by RT-PCR (noninvasive), with the aim of comparing this procedure with that performed on biopsy samples (invasive). MATERIALS AND METHODS: After 'in vitro' demonstration of H. pylori DNA detection from pure and stool-mixed bacteria, 52 consecutive patients at the first diagnosis of infection were investigated. DNA was extracted from biopsy tissue and stool samples (THD® Fecal Test, Italy). RT-PCR was performed to detect 23S rRNA encoding bacterial subunit gene and search A2143G, A2142C, A2142G point mutations for clarithromycin resistance assessment. RESULTS: RT-PCR showed H. pylori positive DNA in all infected patients with full concordance between tissue and stool detection (100%). We found A2143G mutation in 10 (19.2%), A2142G in 4 (7.7%) and A2142C in 5 (9.6%) patients; there was a full agreement between biopsy and fecal samples. A2143G was found in all the four A2142G positive cases and in three out of the five A2142C positive strains. Overall clarithromycin resistance rate in our series was 23%. CONCLUSIONS: Despite the need of confirmation on large sample, stool RT-PCR analysis could represent a feasible tool to detect H. pylori DNA sequences and antibiotic resistance point mutations. As compared to tissue molecular analysis, this technique is noninvasive, with potential advantages such as improvement of patient compliance, reduction of diagnostic procedure time/cost and improvement of therapeutic outcome.

Ulcerative colitis: from inflammation to cancer. Do estrogen receptors have a role?

Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.