Satya Vati Rana

Role of serotonin in gastrointestinal motility and irritable bowel syndrome.

Serotonin (5-HT) is an important signaling molecule in the gut targeting enterocytes, smooth muscles and enteric neurons. Most of the body serotonin is present in enterochromaffin cells. Serotonin activates both intrinsic and extrinsic primary afferent neurons to, respectively initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is inactivated by the serotonin reuptake transporter (SERT) in the enterocytes or neurons. Exogenous serotonin application evokes so many responses that it is difficult to determine which is physiologically relevant. This effect is largely due to the presence of multiple receptor subtypes, which appear to be present on several classes of myenteric neurons, on smooth muscle cells, and on epithelial cells. Irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion and sensation. Altered serotonin signaling may lead to both intestinal and extra intestinal systems in IBS. In this review, the literature related to role of serotonin signaling in pathophysiology of IBS has been searched and summarized. Therapeutic agents targeting altered serotonin signaling may provide new effective treatment for patients with IBS. Tegaserod, 5-HT(4) partial agonist is used in constipation predominant IBS while alosetron, a 5-HT(3) antagonist used in IBS with diarrhea. Other compounds such as tricyclic antidepressants and serotonin selective reuptake inhibitors have been used in some patients with IBS.

Serotonin transporter promoter variant: Analysis in Indian IBS patients and control population.

Background Studies of serotonin reuptake transporter (SERT-P) polymorphism and irritable bowel syndrome (IBS) have shown diverse results among different populations, which might be due to racial and ethnic difference. Aim This study was to investigate the potential association between the SERT-P polymorphism and clinical subtypes of IBS patients in the Indian population. Method This prospective case-control study included 151 IBS patients. Ninety-two patients were diarrhea-predominant IBS, 44 were constipation-predominant IBS (C-IBS), 15 were alternating diarrhea and constipation IBS, and 100 were healthy controls. SERT gene polymorphism was studied by polymerase chain reaction. Result A genotypic association was observed between SS genotype of SERT-P polymorphism and C-IBS (P<0.05). When the L/S and L/L genotypes were combined into one group, the frequency of the S/S genotype was significantly higher than that of the non-S/S genotype between C-IBS and the control group (P<0.05). There was no significant difference in the SERT-P genotype and allele frequency between c-ibs, alternating diarrhea and constipation IBS, all types of IBS cases, and controls. Conclusions A significant association was observed between the SS genotype of SERT-P polymorphism and C-IBS in the Indian population.

Relationship of cytokines, oxidative stress and GI motility with bacterial overgrowth in ulcerative colitis patients

BACKGROUND Ulcerative colitis (UC) is idiopathic, chronic and relapsing inflammatory bowel disease. Factors which initiate and perpetuate UC are not well understood. It is still unclear if any relationship exists between cytokines, oxidative stress, gastrointestinal (GI) motility, and small intestinal bacterial overgrowth (SIBO) in UC patients. GOALS To examine the relationship between these factors among UC patients. METHODS A total of 120 UC patients and 125 age and sex matched controls with no GI symptoms were enrolled. Plasma levels of IL-6, IL-8, TNF-α and IL-10 were measured in all subjects by using ELISA. Lipid peroxidation (LPO) and reduced glutathione (GSH) were measured by standard methods. Orocecal transit time (OCTT) and SIBO were measured by lactulose and glucose hydrogen breath tests respectively. RESULTS Out of the 120 UC patients, 74 were male with mean±SD age of 45.6±17.5years. Plasma levels of IL-6, IL-8, TNF-α and IL-10 in UC patients were significantly higher (p<0.01) as compared to controls. LPO in UC patients was significantly increased (p<0.01) while GSH was significantly decreased (p<0.01) as compared to controls. OCTT and SIBO were significantly higher in UC patients as compared to controls. UC patients with elevated inflammatory cytokines showed delayed OCTT and increased SIBO. It was also observed that there was a significant correlation between SIBO with IL-6, IL-8, TNF-α, and IL-10, LPO and GSH. CONCLUSION This study indicates that increase in cytokines and decrease in anti-oxidants in UC patients would have resulted in oxidative stress causing delayed GI motility leading to SIBO.

Breath tests and irritable bowel syndrome.

Breath tests are non-invasive tests and can detect H₂ and CH₄ gases which are produced by bacterial fermentation of unabsorbed intestinal carbohydrate and are excreted in the breath. These tests are used in the diagnosis of carbohydrate malabsorption, small intestinal bacterial overgrowth, and for measuring the orocecal transit time. Malabsorption of carbohydrates is a key trigger of irritable bowel syndrome (IBS)-type symptoms such as diarrhea and/or constipation, bloating, excess flatulence, headaches and lack of energy. Abdominal bloating is a common nonspecific symptom which can negatively impact quality of life. It may reflect dietary imbalance, such as excess fiber intake, or may be a manifestation of IBS. However, bloating may also represent small intestinal bacterial overgrowth. Patients with persistent symptoms of abdominal bloating and distension despite dietary interventions should be referred for H₂ breath testing to determine the presence or absence of bacterial overgrowth. If bacterial overgrowth is identified, patients are typically treated with antibiotics. Evaluation of IBS generally includes testing of other disorders that cause similar symptoms. Carbohydrate malabsorption (lactose, fructose, sorbitol) can cause abdominal fullness, bloating, nausea, abdominal pain, flatulence, and diarrhea, which are similar to the symptoms of IBS. However, it is unclear if these digestive disorders contribute to or cause the symptoms of IBS. Research studies show that a proper diagnosis and effective dietary intervention significantly reduces the severity and frequency of gastrointestinal symptoms in IBS. Thus, diagnosis of malabsorption of these carbohydrates in IBS using a breath test is very important to guide the clinician in the proper treatment of IBS patients.

Adenosine deaminase levels in cerebrospinal fluid as a diagnostic test for tuberculous meningitis in children.

Adenosine deaminase activity (ADA) was estimated in cerebrospinal fluid (CSF) of 30 patients of tuberculous meningitis (TBM) and 10 patients each of partially treated pyomeningitis (PTM), aseptic meningitis (AM) and pyogenic meningitis (PM). Mean ADA levels in CSF of TBM patients were higher (18.22 U/L) as compared to 6.28 U/L, 3.43 U/L and 7.98 U/L in PTM, AM and PM respectively. This difference of ADA values in CSF between TBM and other types of meningitis was statistically significant (p<0.01) different. Sensitivity and specificity of ADA levels in CSF of children to diagnose tuberculous meningitis was 66.6% and 90% respectively at 10 U/L cut off of ADA levels in CSF. ADA levels in CSF could also differentiate PTM, AM and PM from TBM with a specificity of 90%, 100% and 80% respectively.

Association of alpha 2A adrenergic receptor gene (ADRΑ2A) polymorphism with irritable bowel syndrome, microscopic and ulcerative colitis.

BACKGROUND Alpha 2 adrenergic receptors (alpha2 ARs) play a central role in the regulation of systemic sympathetic activity. Prejunctional alpha 2A adrenoceptor regulates through negative feedback at presynaptic nerve ending. A-1291 C>G polymorphism located in alpha2-adrenergic receptor gene (ADRAlpha2A) has been identified. We investigated the possible association between 1291 C>G polymorphism in the promoter region of ADRAlpha2A in clinical subtypes of IBS, ulcerative and microscopic colitis patients. METHODS This prospective case control study included 92 patients with diarrhea predominant IBS (D-IBS), 44 with constipation predominant IBS (C-IBS), 15 with alternating diarrhea and constipation IBS (M-IBS), 75 ulcerative colitis (UC), 41 microscopic colitis (MC) and 100 healthy controls. The subjects were genotyped by using PCR amplification of the promoter region of ADRAlpha2A gene followed by digestion with the restriction enzyme MspI. The study was approved by the institute ethical committee. RESULTS A strong genotypic association was observed between alpha2A-1291 C>G polymorphism and D-IBS (chi2=6.38, df=2, p<0.05). There was no significant difference in alpha2A-1291 C>G genotype and allele frequency between C-IBS, M-IBS, UC, MC cases and control subjects. CONCLUSIONS A significant association was observed between alpha2A-1291C>G polymorphism and D-IBS. Thus, alpha2 AR gene may be a potential candidate involved in the pathophysiology of D-IBS.

Hydrogen Breath Tests in Gastrointestinal Diseases

Hydrogen breath tests are widely used to explore pathophysiology of functional gastrointestinal (GI) disorders. Small intestinal bacterial overgrowth (SIBO) and carbohydrate malabsorption are disorders detected by these tests that have been proposed to be of great importance for symptoms of GI diseases. Glucose hydrogen breath test is more acceptable for diagnosis of SIBO whereas lactose and fructose hydrogen breath tests are used for detection of lactose and fructose maldigestion respectively. Lactulose hydrogen breath test is also used widely to measure the orocecal transit time for GI motility. These methods are noninvasive and inexpensive. Many patients with functional gut disorders are unaware of the relationship between diet and GI symptoms they present. In particular, patients with chronic symptoms may regard their condition as normal and may not be aware that their symptoms can be effectively managed following a proper diagnosis. Patients with symptoms of abdominal pain, bloating, flatulence and altered bowel movements (diarrhea and constipation), or with a medical diagnosis of irritable bowel syndrome or celiac disease, may have undiagnosed carbohydrate malabsorption or SIBO. Hydrogen breath tests are specific and sensitive diagnostic tests that can be used to either confirm or eliminate the possibility of carbohydrate malabsorption or SIBO in such patients. Breath tests, though valuable tools, are underutilized in evaluating dyspepsia and functional bloating and diarrhea as well as suspected malabsorption. However, because of their simplicity, reproducibility and safety of procedure they are now being substituted to more uncomfortable and expensive techniques that were traditionally used in gastroenterology.

Effect of different oral doses of isoniazid-rifampicin in rats

Hepatotoxicity is one of the most serious adverse effects of antituberculosis drugs. The aim of this study was to produce a rat model of isoniazid-rifampicin (INH-RIF) induced hepatotoxicity. Materials and Methods: Wistar rats (100–150 g) were treated with different doses of INH i.e. 25, 50 and 75 mg/kg/day with a fixed dose of RIF i.e. 50 mg/kg/day intragastrically for a period of 28 days. Serum glutamate oxaloacetate aminotransferase (SGOT), glutamate pyruvate aminotransferase (SGPT), bilirubin (Bil) and alkaline phosphatase (ALP) were estimated at 0,14, 21 and 28 days in rats. Histological analysis was carried out to assess the liver. Results: Treatment of rats with INH–RIF (50 mg/kg/day each) induced hepatotoxicity as judged by elevated serum SGPT, SGOT, Bil and ALP as compared with their base line. Histological evaluation of INH–RIF induced hepatotoxicity also showed liver damage. Conclusion: The present study suggests that 50 mg/kg/day each of INH–RIF was selected as hepatotoxic dose (i.e. minimum dose with maximum hepatotoxicity) in wistar rats.

Prolonged orocecal transit time enhances serum bile acids through bacterial overgrowth, contributing factor to gallstone disease.

Background: Gallstones (GS) are associated with slow intestinal transit but the effect of altered transit time on physiological changes in gastrointestinal tract among GS patients is poorly understood. Goals: To investigate the association of gallstone disease with change in intestinal motility and how motility alters serum bile acid (SBA) levels. Study: A total of 333 subjects were enrolled, of which 183 were GS patients and 150 age-matched and sex-matched controls. Intestinal transit time was assessed by measuring orocecal transit time (OCTT). Breath tests were used to evaluate OCTT and small intestinal bacterial overgrowth (SIBO). Total SBA levels were measured by enzymatic colorimetric assay. A linear regression analysis was performed to look for interrelationship between OCTT and SBA levels. Results: Orocecal transit time was significantly delayed (P<0.001) in GS patients (134.8±30.64 min) compared with controls (85.35±19.81 min). SIBO was observed to be significantly higher (P<0.01) in patients (15%) compared with controls (0.7%). OCTT was further delayed significantly (P<0.01) in GS patients with SIBO (165.6±33.9 min) compared with patients lacking SIBO. Total SBA levels were found to be significantly higher (P<0.05) in GS patients (5.3±2.7 &mgr;mol/L) compared with controls (3.7±1.8 &mgr;mol/L). SBA levels were also significantly higher (P<0.05) in SIBO-positive GS patients (6.4±2.8 &mgr;mol/L) compared with SIBO-negative patients (4.8±2.4 &mgr;mol/L). There was positive correlation between OCTT and SBA levels in SIBO-positive patients. Conclusions: The findings indicate that delayed OCTT leads to SIBO and thus enhance SBA levels in etiology underlying GSs.

CA 19-9 as a serum marker in urothelial carcinoma.

Introduction: CA 19-9 is a carbohydrate antigen related to Lewis A blood group antigen. It is well-known marker for pancreatic carcinoma and is being investigated for other malignancies including carcinoma bladder. We evaluated the role of serum CA 19-9 as a tumor marker and correlated its level with tumor stage and grade. Materials and Methods: Seventy-five patients with histologically proven urothelial carcinoma were included in this study as case and 25 healthy volunteers as control. Preoperative 5 ml blood sample was collected. Serum level of CA 19-9 was measured using solid-phase enzyme-linked immunosorbent assay kit. The value of CA19-9 was expressed in U/ml and 37 U/ml was taken as cut-off upper value of normal. Results: The range of CA19-9 in patients of urothelial carcinoma was 2 to 122 U/ml with a mean of 26.33±29.28, while in control, it was 8.48±5.01 U/ml (P<0.001). The sensitivity of CA19-9 was 29%. Serum CA19-9 was significantly elevated in invasive disease in comparison with superficial disease (47.17±34.43 vs 16.53±20.13) (P<0.001). Significantly high proportion of patients with invasive disease had value ≥37 U/ml (14/24 [58.3%] vs 8/51 [15.7%]) with P value <0.001. High proportion of high-grade tumor had raised value, 14/34 (41.25%); all patients with metastatic disease had value more than 37 U/ml. Conclusions: Serum CA19-9 is a marker of aggressiveness of urothelial carcinoma and is almost invariably raised in patients with metastatic disease. Thus, it may be used as a prognostic marker but not as a screening tool due to its low sensitivity.