Increased Serum Pepsinogen II Level as a Marker of Pangastritis and Corpus-Predominant Gastritis in Gastric Cancer Prevention.

Serum pepsinogen I and II are considered as indicators of changes in gastric morphology. Important publications from the last decades are reviewed with regard to the serum level of these biomarkers for the diagnosis of normal gastric mucosa, diffuse gastritis and its change to atrophic gastritis and intestinal metaplasia as well as gastric cancer. Due to the low sensitivity of serum biomarkers for diagnosis of gastric cancer, especially at its early stage and the poor prognosis of the tumor at the time of diagnosis, its prevention by eradication of H. pylori remains the mandatory strategy. On the other hand, the severity of regression and non-reversibility of precancerous lesions and intestinal metaplasia in gastric mucosa through eradication of H. pylori make it necessary to diagnose diffuse gastritis at its early stage. Increased serum pepsinogen II compared to normal serum pepsinogen I seems to indicate the presence of diffuse gastritis without precancerous lesions suitable for eradication of H. pylori infection, when it is serologically positive. A diagram illustrates the strategy of this therapeutic measure depending on the age of people and the level of serum biomarkers in areas with high gastric cancer prevalence.

The Presence of Autoantibodies to Cytoplasmic Rod and Ring Particles in the Serum of Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Chronic hepatitis C virus (HCV) is associated with extra hepatic autoimmune disorders, while peg-IFNa-2a/RBV combination therapy may exacerbate these conditions. Autoantibodies to cytoplasmic structures, called rod and ring particles (RR), have strong associations with these patients and are identified by HEp-2 cells. OBJECTIVES: Our purpose was to study the correlation of autoantibodies to cytoplasmic rod and ring particles in the serum of patients with chronic HCV infection with their response to standard therapy. METHODS: Serum samples were gathered from 120 patients with HCV infection (40 naive treatments, 40 with sustained virological response (SVR), and 40 with relapse response) during peg-IFNa-2a/RBV combination therapy and analyzed for the presence of RR antibodies by IIF on commercially available HEp-2 cell substrate slides from Euroimmun (Lu beck, Germany). RESULTS: Anti-rod and ring (anti-RR) autoantibodies were detected in only the serum of 1 out of 120 patients (0.8%), which belonged to a patient (out of 40) with relapse response (2.5%). No correlation was found between the types of response to peg-IFNa-2a/RBV combination therapy and the presence of anti-RR autoantibodies. CONCLUSIONS: The only HCV patient with RR autoantibodies previously had received IFN/ribavirin antiviral therapy. The presence of these autoantibodies is extremely rare in Iranian HCV patients. Further studies are warranted to determine the role of genetic background and geographical pattern in the prevalence of these novel autoantibodies worldwide.

Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients.

AIM: To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ (IFNL) polymorphisms. METHODS: This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 µg pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS: A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION: The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.

Detection of Specific Antibodies to HCV-ARF/CORE+1 Protein in Cirrhotic and Non-Cirrhotic Patients with Hepatitis C: A Possible Association with Progressive Fibrosis.

BACKGROUND: The role of different viral proteins in the progression of the disease to cirrhosis is not completely understood. The ARFP/F protein is a newly described protein synthesized from the +1 or -2 reading frames of the core protein gene, which its function remains unknown. The purpose of this study is to detect specific antibodies to HCV-ARF/Core+1 protein in cirrhotic and non-cirrhotic patients with HCV and investigate any possible association. METHODS: ARF/Core+1 recombinant proteins from HCV genotype 1a were expressed in Escherichia coli, and purified. Using an enzyme-linked immunosorbent assay, we assessed the prevalence of anti-ARF/Core+1 antibodies in 50 cirrhotic and 50 non-cirrhotic hepatitis C patients. RESULTS: All 50 cirrhotic patients were positive for anti-ARF/Core+1 antibody, while only 80% positive samples among non-cirrhotic patients were detected. The titer of anti-ARF/Core+1 antibody was also significantly higher in patients with cirrhosis than in non-cirrhotic patients. CONCLUSION: Compared to 80% positive samples among non-cirrhotic patients all 50 cirrhotic patients were positive for anti-ARF/Core+1 antibody and titer of anti-ARF/Core+1 antibody was significantly higher in patients with cirrhosis than in non-cirrhotic. These results suggest that ARF/Core+1 protein is associated with cirrhosis. A possible causative association between ARF/Core+1 and cirrhosis as well as the mechanism of this association needs to be further investigated.

F protein increases CD4+CD25+ T cell population in patients with chronic hepatitis C.

HCV is a global health problem with an estimated 230 million chronically infected people worldwide. It has been reported that a 17-kd protein translated from core-encoding genomic region can contribute to immune-mediated mechanisms associated with the development of the chronic disease. Also, Treg cells can be contributed to an inadequate response against the viruses, leading to chronic infection. Here we evaluated the ability of protein F to modulate the frequency of CD4+CD25+FoxP3+T and IL-10+T cells in patients with chronic HCV infection. F gene was amplified and cloned in the expression vector. The protein was purified and used for stimulation of PBMCs in the HCV chronic patients and the control groups. The frequency of CD4+CD25+FoxP3+ T cell-like populations and IL-10-producing CD4+CD25+ T cells was assessed in the HCV-infected patients and in the healthy controls by flow cytometry, which showed an increase of both CD4+CD25+FoxP3+ T cell-like population and IL-10-producing CD4+CD25+ T cells in the HCV-infected patients positive for anti-F antibody. Our results suggest the potential involvement of F and core antigens in increasing the frequency of CD4+CD25+FoxP3+ T cell-like population and IL-10-producing CD4+CD25+ T cells which may be associated with HCV-persistent infection.

Pepsinogen II can be a potential surrogate marker of morphological changes in corpus before and after H. pylori eradication.

BACKGROUND: The aim of this investigation is to study the relationship between gastric morphology and serum biomarkers before and after Helicobacter pylori eradication. METHODS: First-degree relatives of gastric cancer patients underwent gastroscopy before and 2.5 years after H. pylori eradication. The morphological changes in two categories (normal to mild and moderate to severe) were compared with level of pepsinogens I and II before eradication (n = 369), after eradication (n = 115), and in those with persistent infection (n = 250). RESULTS: After eradication, pepsinogen I decreased to 70% and pepsinogen II to 45% of the previous values. Unlike pepsinogen II and pepsinogen I to II ratio that were affected by the severity of inflammation and atrophy in corpus in all groups, pepsinogen I generally did not change. After eradication, subjects with high mononuclear infiltration in corpus had lower pepsinogen I (54 versus 77.1 µ/mL), higher pepsinogen II (9.4 versus 6.9 µ/mL), and lower ratio (7.9 versus 11.6) than those without (P < 0.05). CONCLUSION: Pepsinogen II is a good marker of corpus morphological changes before and after H. pylori eradication.

Are the serum biomarkers pepsinogen I and II good predictors for the detection of subjects with atrophic gastritis in areas that have different gastric cancer incidence?

BACKGROUND: Northern Iran (Ardabil) is characterized by a high gastric cancer (GC) rate, whereas Southern Iran (Kerman and Yazd) has a low GC rate. The aim of this study is to verify the potential for pepsinogen I and II to detect atrophic gastritis (AG) in both high and low risk populations for GC. METHODS: Sera of blood donors and patients with GC from Ardebil, Kerman and Yazd were used to measure levels of pepsinogen I, II and H. pylori IgG antibody. GC rates in these cities were determined according to the Cancer Registry and upper gastrointestinal (GI) endoscopy results.  RESULTS: There were 449 subjects with an average age of 45 ± 15 years. The GC rate in the endoscopy units of the hospital in Ardabil was four times higher than Kerman or Yazd. The mean serum pepsinogen I levels did not differ between Ardabil (102 ± 42.6 µg/mL), Kerman (103.3 ± 49.8 µg/mL), and Yazd (111.7 ± 39 µg/mL). Pepsinogen II levels were: 8.1 ± 4.7 µg/mL (Ardabil), 7.5 ± 5.3 µg/mL (Kerman), and 7.6 ± 4.4 µg/mL (Yazd), which were not different. The H. pylori infection rates were: Ardabil (61%), Kerman (55%), and Yazd (73%). A low ratio of pepsinogen I to II (≤3) was seen in Ardabil (1.3%), Kerman (1.9%), and Yazd (0.0%), which was not significant. A total of 51.9% of GC patients from Ardabil had normal pepsinogen I (≥70 µg/mL) levels and pepsinogen I/II ratios that were >5.  CONCLUSION: Serum biomarkers pepsinogen I and II and their ratios are probably not sensitive predictors of AG in areas that have either a high or low GC prevalence. This finding is likely related to the lack of an association between GC and advanced AG.

Precancerous conditions after H. pylori eradication: a randomized double blind study in first degree relatives of gastric cancer patients.

BACKGROUND: Regression of precancerous lesions after H. pylori eradication remains controversial. This study evaluates the change and topography in first degree relatives (FDR) of gastric cancer (GC) patients following H. pylori eradication. METHODS: Participants underwent endoscopy with antrum and corpus histological examinations. Subjects with pangastritis were randomly allocated to placebo or eradication therapy and followed over 4½ years.  RESULTS: Among 989 evaluated FDR, we excluded 468 patients as follows: 108 had macroscopic lesions, 243 had no evidence of any H. pylori infection, and 117 were excluded for other reasons. The remaining subjects (n = 521) were allocated to therapy (group A, n = 261) or placebo (group B, n = 260) groups. Interim analysis of 403 subjects (201 placebo, 202 therapy) showed regression of atrophy (60 out of 97 in the antrum and 37 out of 104 in the corpus) in H.pylori-eradicated versus regression of atrophy (57 out of 184 in the antrum and 23 out of 173 in the corpus) in non-H.pylori-eradicated cases over 2½ years (P < 0.0001). No regression of intestinal metaplasia (IM) occurred in the antrum and corpus of treated subjects over 4½ years. However, progression of IM occurred in the antrum in 17 out of 90 patients in the non-H. pylori-eradicated versus 4 out of 68 H. pylori-eradicated subjects after 4½ years (P < 0.05). CONCLUSION: Eradication of H. pylori is associated with regression of gastric atrophy but not IM, even in its early stages. Gastric atrophy and IM in the antrum have shown more rapid progression in cases not treated for H. pylori infection (over 4½ years follow-up) compared to H. pylori-eradicated cases.

Exacerbation of Skin Lesions in a 50 year old Man with Psoriasis during Treatment by Pegylated Interferon.

Chronic hepatitis C might lead to several immunological dysfunctions. Studies have shown a positive association between hepatitis C virus (HCV) infection and psoriasis. These results suggest that the infection may be one of the triggering factors for the development or exacerbation of psoriasis. Here, we present a case of chronic HCV infection with psoriasis who developed exacerbation of skin lesions during therapy with peginterferon alpha-2a plus ribavirin. We discuss the management, course and results of HCV treatment in this patient.

Serum pepsinogen I, pepsinogen II, and gastrin 17 in relatives of gastric cancer patients: comparative study with type and severity of gastritis.

BACKGROUND & AIMS: First-degree relatives of gastric cancer patients are at risk for developing precancerous conditions. The aim of this study was to investigate the potential of biomarkers pepsinogen I (PGI), pepsinogen II (PGII), their ratio (PG I:II), as well as gastrin 17 for screening of precancerous conditions and corpus predominant gastritis. METHODS: First-degree relatives of gastric cancer patients underwent endoscopy. Three biopsy specimens from the antrum and 3 from the corpus were evaluated according to the Sydney classification. Serum was taken for the measurement of fasting PGI, PGII, and gastrin 17 by enzyme-linked immunosorbent assay kits. RESULTS: A total of 481 patients were examined (age, 47.8 +/- 6.7 y). With the extension of gastritis, PGII was increased up to 2.5 times (6.6 +/- 2.8 microg/mL in normal mucosa, 9.5 +/- 6.7 microg/mL in antral gastritis, and 16.9 +/- 12.4 microg/mL in corpus-predominant gastritis; P < .01), PGI increased slightly (88.3 +/- 29.4 microg/mL in normal mucosa and 111.2 +/- 71.4 microg/mL in corpus-predominant gastritis), and gastrin 17 was increased substantially in corpus-predominant gastritis (15.3 +/- 19.5 pmol/mL vs 3.8 +/- 5.7 pmol/mL in normal mucosa). By using a cut-off value of 7.5 microg/mL for PGII, any type of gastritis from normal mucosa can be diagnosed with a sensitivity and specificity of 80%. The sensitivity and specificity of the PG I:II ratio (< or =3) and gastrin 17 (>17 pmol/mL) together were 9.4% and 99% for screening corpus-predominant gastritis and 14.8% and 97.8%, respectively, for screening intestinal metaplasia in the corpus. CONCLUSIONS: PGII is a suitable marker for screening any gastritis from normal mucosa, but neither PGI, the PG I:II ratio, gastrin 17, nor their combination were able to select those with precancerous conditions and corpus-predominant gastritis among the first-degree relatives of gastric cancer patients.