Dyspepsia Challenge in Primary Care Gastroenterology.

BACKGROUND: The purpose of this review is to take a deep dive into general problems and challenges of diagnosis and treatment of patients with symptoms of dyspepsia in primary care practice. SUMMARY: Primary care physicians become acquainted with a broad range of clinical problems and therefore require a wide span of knowledge in taking care of patients from their first medical examination within the health care system. Dyspepsia and Helicobacter pylori infection are two of the most frequent reasons of digestive-related health care issues, despite that in primary care practice, current recommendations for diagnosis and differential therapy are often not implemented. The "test-and-treat" strategy is the initial management of the condition, reserving gastroscopy for patients refractory to symptomatic treatment and for patients presenting with any of the following alarm signs: age of above 55, dysphagia, anemia, weight loss, frequent vomiting, family history of GI malignancy, or a physical examination with key pathological findings. KEY MESSAGES: Examination and treatment of dyspepsia symptoms is the diagnostic and therapeutic challenge dictated by organizational and economic potentials of the health system, professional resources, and primary health care capabilities to accept and treat patients with dyspepsia and to properly refer those with alarm symptoms and findings indicative of organic disease to a gastroenterologist.

Chronic Constipation: Gastroenterohepatologist's Approach.

BACKGROUND: Constipation is a common problem in gastroenterological practice. The prevalence of constipation is about 16%. Constipation can be primary or secondary. SUMMARY: The diagnostic and therapeutic approach to patients with constipation begins with a detailed history and physical examination. In selected cases, the use of additional diagnostic procedures is very important. This includes the use of laboratory, endoscopic, and radiological examinations, as well as advanced physiological testing (anorectal manometry, balloon expulsion test, colonic transit studies, and defecography). Constipation therapy can be both nonoperative and operative. Nonoperative therapy includes the application of a lifestyle measures, pharmacotherapy and biofeedback therapy. Key Messages: Two key things when taking a medical history and physical examination are to rule out the existence of alarm symptoms/signs and to rule out secondary constipation (primarily drug-induced). Therapy begins with lifestyle modification, and in case of failure, bulk or osmotic laxatives are used. In case of failure, the use of lubiprostone is indicated, as well as linaclotide. Surgical treatment of constipation is reserved for cases of refractory constipation, with delayed intestinal transit.

Abnormal Liver Blood Tests: Primary Care Approach.

BACKGROUND: According to recent epidemiological data, annual deaths due to liver disease have increased dramatically, while predictions show that trends will continue to rise in the upcoming years. SUMMARY: Abnormal liver blood tests are one of the most common challenges encountered in the primary care setting. The prevalence of mildly elevated transaminase levels is around 10-20% in the general population. The most common causes for the rising burden of liver disease are nonalcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ARLD), and viral hepatitis. With improvements in the management of viral hepatitis over the last decades, the causes for the rising burden of liver disease are shifting toward ARLD and NAFLD. It is well-known that liver disease usually progresses silently for years or decades until the complications of cirrhosis occur. The majority of patients will not require referral to a specialist but will need further assessment in primary care. They should be evaluated for the etiology of liver disease irrespective of the duration of abnormal liver blood tests or unmarked clinical presentation. The evaluation should include a history of alcohol use, a history of medicines or herbal supplements, testing for viral hepatitis, and assessment for NAFLD, especially in obese patients and patients with type 2 diabetes. Abdominal ultrasound should be performed. Key Messages: The general practitioner may contribute significantly by identifying and screening patients at risk for chronic liver disease, as well as prioritize individuals with symptoms or signs of advanced liver disease to the specialist clinic.

Jaundice as a Diagnostic and Therapeutic Problem: A General Practitioner's Approach.

BACKGROUND: Jaundice is a common clinical finding in clinical practice of hepatologists and general practitioners. It occurs when serum bilirubin levels exceed 3 mg/dL. SUMMARY: In this review, we summarize the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and laboratory and imaging techniques. Clinical presentation of jaundice manifests through yellow skin and sclera coloration. Evaluation of every patient includes detailed medical history and examination. In the laboratory, evaluation of enzymes of hepatic inflammation as well as cholestatic enzymes with serum bilirubin must be included. Additional laboratory analysis and imaging modalities are needed in order to differentiate jaundice etiology. Moreover, imaging is available and needed in further evaluation, and treatment is dependent on the underlying cause. KEY MESSAGES: In this review, we will outline the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and diagnostic and treatment approach to these patients.

Anemia as a Problem: GP Approach.

BACKGROUND: Anemia is a presentation of an underlying disease or deficiency. As stated by the WHO, anemia is defined as hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men. This review of clinical practice aimed to determine the diagnostic approach to anemia in primary care patients. SUMMARY: Nutritional deficiencies, medications, chronic inflammatory conditions, malignancy, renal dysfunction, and bone marrow and inherent disorders contribute to anemia development. Anemia is classified and diagnosed by the values of hematological parameters, underlying pathological mechanism, and patient history. The diagnostic approach of anemia in primary care settings is focused on history, physical examination, laboratory findings including complete blood cell count, reticulocyte count, and peripheral smear examination, fecal occult blood test, and ultrasound findings. KEY MESSAGES: Anemia is the most common hematological disorder that represents a major health burden worldwide. Hb levels alter with gender, ethnicity, and physiological status. Anemia is often multifactorial. The evaluation of a patient with anemia in primary care includes clinical history, physical examination, and laboratory findings with fecal occult blood test and abdominal ultrasound. The wide variations in general practice in European countries are based on different health care systems but also knowledge of GPs that reflect educational and research policy.

Abnormal Liver Blood Tests: Hepatologist Approach.

BACKGROUND: Available data suggest that the prevalence of chronic liver disease (CLD) and primary liver cancer is rising in Europe and represents a major public health problem. Predictions are showing that these trends will continue to rise in the upcoming years. SUMMARY: Alcohol-related liver disease, nonalcohol fatty liver disease, and viral hepatitis B and hepatitis C are the leading causes of liver cirrhosis and primary liver cancer in Europe. Drug-induced liver injury represents a major cause of acute hepatitis, while liver transplantation is the second most common solid organ transplantation in the world. Patients with CLD have increasing rates of hospitalization, longer hospital stays, and more adverse outcomes compared to the other chronic conditions. Direct targeting of risk factors can prevent complications of advanced liver disease and improve outcome. Patients with CLD should be referred to a hepatologist for assessment of the stage of liver disease, for specific treatment and screening for hepatocellular carcinoma. Moreover, patients with unknown etiology of abnormal liver blood tests should be referred to a hepatologist for assessment of liver disease, as well as for prevention and treatment of complications of cirrhosis and/or portal hypertension. Key Messages: CLD is amenable to prevention and treatment, while disease management strategies need to improve in order to reduce the burden of liver disease and deaths due to end-stage liver diseases.

General Aspects of Primary Cancer Prevention.

BACKGROUND: Cancer is the second leading cause of death worldwide next to cardiovascular diseases. Despite the advancement in screening, early diagnosis, and development in treatment technology in last several decades, cancer incidence overall, particularly that of gastrointestinal (GI) cancers, is far from being controlled, and is expected to increase worldwide. SUMMARY: Although numerous preclinical and population-based clinical studies have already made important progress in restraining the overall cancer incidence and mortality, the full potential of preventive strategy is still far from being realized, and remains at an early stage. There are several major challenges regarding this issue, and one of the crucial challenges is to maintain the balance between risks and benefits. As a result of past investments, primary prevention nowadays include the integration of various activities such as lifestyle changes to reduce risk, screening to detect early lesions, vaccines and preventive therapies aimed to actively interrupt the carcinogenic pathway. Long-term aspirin use seems to have the largest potential effect on the general population on cancer incidence and mortality overall, especially GI cancers. Helicobacter pylori eradication reduces the risk for gastric cancer and is advocated regardless of the symptoms and stage of disease. Metformin and statins are promising in cancer prevention in patients with type 2 diabetes. Vitamin D supplementation is promising in the prevention of colorectal adenoma recurrence. Key Message: However, additional studies are warranted to establish the potential of various agents and to identify more specific and highly targeted new agents for chemoprevention in digestive oncology.

Bezafibrate for primary biliary cirrhosis.

BACKGROUND: Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet. OBJECTIVES: To assess the beneficial and harmful effects of bezafibrate in patients with primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. The searches in Chinese Bio-medical Literature Database, China Network Knowledge Information, Chinese Science Journal Database, Chinese Medical Citation Index, Wanfang Database, and full text searches were conducted until January 2011. Manufacturers and authors were contacted. SELECTION CRITERIA: All randomised clinical trials comparing bezafibrate at any dose or regimen in patients with primary biliary cirrhosis with placebo or no intervention, or with another drug. Any concomitant interventions were allowed if received equally by all treatment groups in a trial. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance). MAIN RESULTS: Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I² = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I² = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I² = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I² = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I² = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I² = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I² = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I² = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma-glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I² = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD -58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I² = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I² = 0%). AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.

Ursodeoxycholic acid for primary biliary cirrhosis.

BACKGROUND: Ursodeoxycholic acid is administered to patients with primary biliary cirrhosis, a chronic progressive inflammatory autoimmune-mediated liver disease with unknown aetiology. Despite its controversial effects, the U.S. Food and Drug Administration has approved its usage for primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of ursodeoxycholic acid in patients with primary biliary cirrhosis. SEARCH METHODS: We searched for eligible randomised trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform. The literature search was performed until January 2012. SELECTION CRITERIA: Randomised clinical trials assessing the beneficial and harmful effects of ursodeoxycholic acid versus placebo or 'no intervention' in patients with primary biliary cirrhosis. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Continuous data were analysed using mean difference (MD) and standardised mean difference (SMD). Dichotomous data were analysed using risk ratio (RR). Meta-analyses were conducted using both a random-effects model and a fixed-effect model, with 95% confidence intervals (CI). Random-effects model meta-regression was used to assess the effects of covariates across the trials. Trial sequential analysis was used to assess risk of random errors (play of chance). Risks of bias (systematic error) in the included trials were assessed according to Cochrane methodology bias domains. MAIN RESULTS: Sixteen randomised clinical trials with 1447 patients with primary biliary cirrhosis were included. One trial had low risk of bias, and the remaining fifteen had high risk of bias. Fourteen trials compared ursodeoxycholic acid with placebo and two trials compared ursodeoxycholic acid with 'no intervention'. The percentage of patients with advanced primary biliary cirrhosis at baseline varied from 15% to 83%, with a median of 51%. The duration of the trials varied from 3 to 92 months, with a median of 24 months. The results showed no significant difference in effect between ursodeoxycholic acid and placebo or 'no intervention' on all-cause mortality (45/699 (6.4%) versus 46/692 (6.6%); RR 0.97, 95% CI 0.67 to 1.42, I² = 0%; 14 trials); on all-cause mortality or liver transplantation (86/713 (12.1%) versus 89/706 (12.6%); RR 0.96, 95% CI 0.74 to 1.25, I² = 15%; 15 trials); on serious adverse events (94/695 (13.5%) versus 107/687 (15.6%); RR 0.87, 95% CI 0.68 to 1.12, I² = 23%; 14 trials); or on non-serious adverse events (27/643 (4.2%) versus 18/634 (2.8%); RR 1.46, 95% CI 0.83 to 2.56, I² = 0%; 12 trials). The random-effects model meta-regression showed that the risk of bias of the trials, disease severity of patients at entry, ursodeoxycholic acid dosage, and trial duration were not significantly associated with the intervention effects on all-cause mortality, or on all-cause mortality or liver transplantation. Ursodeoxycholic acid did not influence the number of patients with pruritus (168/321 (52.3%) versus 166/309 (53.7%); RR 0.96, 95% CI 0.84 to 1.09, I² = 0%; 6 trials) or with fatigue (170/252 (64.9%) versus 174/244 (71.3%); RR 0.90, 95% CI 0.81 to 1.00, I² = 62%; 4 trials). Two trials reported the number of patients with jaundice and showed a significant effect of ursodeoxycholic acid versus placebo or no intervention in a fixed-effect meta-analysis (5/99 (5.1%) versus 15/99 (15.2%); RR 0.35, 95% CI 0.14 to 0.90, I² = 51%; 2 trials). The result was not supported by the random-effects meta-analysis (RR 0.56, 95% CI 0.06 to 4.95). Portal pressure, varices, bleeding varices, ascites, and hepatic encephalopathy were not significantly affected by ursodeoxycholic acid. Ursodeoxycholic acid significantly decreased serum bilirubin concentration (MD -8.69 µmol/l, 95% CI -13.90 to -3.48, I² = 0%; 881 patients; 9 trials) and activity of serum alkaline phosphatases (MD -257.09 U/L, 95% CI -306.25 to -207.92, I² = 0%; 754 patients, 9 trials) compared with placebo or no intervention. These results were supported by trial sequential analysis. Ursodeoxycholic acid also seemed to improve serum levels of gamma-glutamyltransferase, aminotransferases, total cholesterol, and plasma immunoglobulin M concentration. Ursodeoxycholic acid seemed to have a beneficial effect on worsening of histological stage (random; 66/281 (23.5%) versus 103/270 (38.2%); RR 0.62, 95% CI 0.44 to 0.88, I² = 35%; 7 trials). AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any significant benefits of ursodeoxycholic acid on all-cause mortality, all-cause mortality or liver transplantation, pruritus, or fatigue in patients with primary biliary cirrhosis. Ursodeoxycholic acid seemed to have a beneficial effect on liver biochemistry measures and on histological progression compared with the control group. All but one of the included trials had high risk of bias, and there are risks of outcome reporting bias and risks of random errors as well. Randomised trials with low risk of bias and low risks of random errors examining the effects of ursodeoxycholic acid for primary biliary cirrhosis are needed.

Bisphosphonates for osteoporosis in primary biliary cirrhosis.

BACKGROUND: Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis in patients with primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted for additional studies during the conductance of the review. SELECTION CRITERIA: All randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95% confidence intervals (CI). Methodological components were used to assess risk of systematic errors (bias). Trial sequential analysis was also used to control for random errors (play of chance). MAIN RESULTS: Six trials were included. Three trials with 106 participants, of which two trials with high risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95% CI -0.12 to 0.12, I² = 0%), fractures (RR 0.87; 95% CI 0.29 to 2.66, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04). Two trials with 62 participants with high risk of bias compared one bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95% CI -0.14 to 0.07, I² = 0%), fractures (RR 0.95; 95% CI 0.18 to 5.06, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04, I² = 0%). Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates had no significant effect on bone mineral density compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95% CI -23.77 to -10.10; 2 trials with 88 patients; I² = 0%) and serum osteocalcin (SMD -0.81; 95% CI -1.22 to -0.39; 3 trials with 100 patients; I² = 34 %) concentration. The former result was supported by trial sequential analysis, but not the latter. Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95% CI -9.41 to 2.18; 2 trials with 47 patients; I² = 82%) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95% CI -6.75 to -2.05; 2 trials with 47 patients; I² = 82%), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95% CI -15.96 to -1.63; 2 trials with 47 patients; I² = 38%), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95% CI -24.23 to -3.90; 2 trials with 46 patients; I²=0%) in a fixed-effect model. The latter two results were not supported by trial sequential analyses. There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95% CI -0.21 to 0.12; 2 trials with 46 patients; I² = 0%), or another bisphosphonate (RR 0.56; 95% CI 0.14 to 2.17; 2 trials with 62 patients; I² = 0%). One trial with 32 participants and with high risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or bone mineral density. Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration. AUTHORS' CONCLUSIONS: We did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis. The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error. There is need for more randomised clinical trials assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in primary biliary cirrhosis.

Hormone replacement for osteoporosis in women with primary biliary cirrhosis.

BACKGROUND: Women with primary biliary cirrhosis often suffer from postmenopausal osteoporosis due to their age, or osteoporosis secondary to their liver disease, or treatments provided for their liver disease. Hormone replacement increases bone mineral density and reduces fractures in postmenopausal women. On the other hand, hormone replacement increases the risk of various adverse events. We could not identify any meta-analyses or systematic reviews on hormone replacement in women with primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of hormone replacement for osteoporosis in women with primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted during the review conductance. SELECTION CRITERIA: All randomised clinical trials of hormone replacement in primary biliary cirrhosis administered by any route, or regimen, or dose compared with placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD), all with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance). MAIN RESULTS: Two trials with 49 participants were included. One trial had low risk of bias. The other trial had high risk of bias. Hormone replacement had no effect on all-cause mortality (RD 0.00; 95% CI -0.11 to 0.11, I² = 0%) and fractures (RD -0.08; 95% CI -0.24 to 0.07, I² = 0%). Hormone replacement significantly increased adverse events and number of patients having hormone replacement withdrawn due to adverse events (RR 5.26; 95% CI 1.26 to 22.04, I² = 0%). Hormone replacement had no significant effect on lumbar spine bone mineral density (MD 1.25 g/cm² yearÖ¿¹; 95% CI -0.91 to 3.42, I² = 0%). On the other hand, a significant increase in proximal femur bone mineral density was observed in the control group (MD 2.24 g/cm² yearÖ¿¹; 95% CI 0.74 to 3.74, I² = 0%). Hormone replacement had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity. Hormone replacement had no significant effect on serum bilirubin concentration (MD 4.60 µmol/L; 95% CI -3.42 to 12.62, I² = 0%). AUTHORS' CONCLUSIONS: We did not find evidence to support the use of hormone replacement for women with primary biliary cirrhosis. It seems that hormone replacement is connected with a significant increase in the occurrence of adverse events.

Capsule endoscopy is useful diagnostic tool for diagnosing Meckel's diverticulum.

OBJECTIVE: Meckel's diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract. Although a majority of patients remain asymptomatic, complications may occur in a subset of patients. MD is a rare cause of gastrointestinal bleeding (GIB) in adults. We aimed to clarify the possible role of capsule endoscopy (CE) in the identification of Meckel's diverticulum. PATIENTS AND METHODS: From October 2004 to December 2010, 157 CEs were performed (83 male individuals, mean age 51±20 years; range 3-83 years) for obscure GIB. Before CE, all patients underwent nonconclusive upper and lower endoscopy at least two times and barium follow-through. RESULTS: CE identified the source of bleeding in 70/157 patients (44.6%). MD was diagnosed in 13/70 (18.6%) patients (11 male individuals, mean age 35±20 years, range, 3-69 years) after CE. Nine patients presented with obscure overt and four with obscure occult bleeding. The mean duration of obscure GIB history was 13 months (range 1-72 months). The mean hemoglobin concentration at the time of the procedure was 115±12 g/l. The findings of MD on CE were double lumen sign (13/13), visible blood (7/13), and diaphragm sign (6/13). All patients were operated upon, and MD histologically verified in 11. In two patients CE was false-positive and in two patients, false-negative. Capsule endoscopy had a positive predictive value of 84.6% for the diagnosis of MD. CONCLUSION: MD should be considered in the differential diagnosis of obscure GIB in adults. CE is an effective and promising modality for diagnosing MD in patients with obscure GIB.

Assessment of depression and anxiety in patients with chronic liver disease.

BACKGROUND/AIM: In recent years mental health of patients including those with chronic liver disease (CLD), has become interesting because its disturbance leads to reduced quality of life, that is associated with worsening of clinical outcome, reduced compliance and increased mortality. The aim of the study was to determinate the frequency and severity of depression and frequency of anxiety in patients with CLD and to assess the contribution of selected socio-demographic, clinical and laboratory risk factors for depression and anxiety. METHODS: In this cross-sectional study, we used the Hamilton depression rating scale (HDRS) and Hamilton anxiety rating scale (HARS) in patients with CLD. RESULTS: The study included 54 male and 43 female patients. Depression was present in 62.9%, and anxiety in 13.4% of the patients. A higher HDRS was noted in the patients older than 50 years (p = 0.022) and unemployed patients (p = 0.043). The patients with at least one episode of gastrointestinal bleeding had a significantly higher frequency of anxiety than those without bleeding (p = 0.018). A higher HARS score was present in the women (p = 0.011), unemployed patients (p = 0.008) and those with non-alcoholic liver disease (p = 0.007). There was a significant correlation between the mean corpuscular volume (MCV) and the value of the HDRS score, and between serum potassium and sodium levels and HDRS score. CONCLUSION: Age and the mean corpuscular volume have significant influence on the HDRS score while unemployment, gastrointestinal bleeding, serum potassium and serum sodium have predictive value for HARS score.

Validation of the chronic liver disease questionnaire in Serbian patients.

AIM: To translate into Serbian and to investigate the validity of the cross-culturally adapted the chronic liver disease questionnaire (CLDQ). METHODS: The questionnaire was validated in 103 consecutive CLD patients treated between October 2009 and October 2010 at the Clinic for Gastroenterology, Clinical Centre of Serbia, Belgrade (Serbia). Exclusion criteria were: age < 18 years, psychiatric disorders, acute complications of CLD (acute liver failure, variceal bleeding, and spontaneous bacterial peritonitis), hepatic encephalopathy (grade > 2) and liver transplantation. Evaluation of the CLDQ was done based on the following parameters: (1) acceptance is shown by the proportion of missing items; (2) internal reliabilities were assessed for multiple item scales by using Cronbach alpha coefficient; and (3) in order to assess whether the allocation of items in the domain corresponds to their distribution in the original questionnaire (construction validity), an exploratory factor analysis was conducted. Discriminatory validity was determined by comparing the corresponding CLDQ score/sub-score in patients with different severity of the diseases. RESULTS: The Serbian version of CLDQ questionnaire completed 98% patients. Proportion of missing items was 0.06%. The total time needed to fill the questionnaire was ranged from 8 to 15 min. Assistance in completing the questionnaire required 4.8% patients, while 2.9% needed help in reading, and 1.9% involved writing assistance. The mean age of the selected patients was 53.8 ± 12.9 years and 54.4% were men. Average CLDQ score was 4.62 ± 1.11. Cronbach's alpha for the whole scale was 0.93. Reliability for all domains was above 0.70, except for the domain "Activity" (0.49). The exploratory factor analysis model revealed 6 factors with eigenvalue of greater than 1, explaining 69.7% of cumulative variance. The majority of the items (66%) in the Serbian version of the CLDQ presented the highest loading weight in the domain assigned by the CLDQ developers: "Fatigue" (5/5), "Emotional function" (6/8), "Worry" (5/5), "Abdominal symptoms" (0/3), "Activity" (0/3), "Systemic symptoms" (3/5). The scales "Fatigue" and "Worry" fully corresponded to the original. The factor analysis also revealed that the factors "Activity" and "Abdominal symptoms" could not be replicated, and two new domains "Sleep" and "Nutrition" were established. Analysis of the CLDQ score/sub-score distribution according to disease severity demonstrated that patients without cirrhosis had lower total CLDQ score (4.86 ± 1.05) than those with cirrhosis Child's C (4.31 ± 0.97). Statistically significant difference was detected for the domains "Abdominal symptoms" [F (3) = 5.818, P = 0.001] and "Fatigue" [F (3) = 3.39, P = 0.021]. Post hoc analysis revealed that patients with liver cirrhosis Child's C had significantly lower sub-score "Abdominal symptoms" than patients without cirrhosis or liver cirrhosis Child's A or B. For domain "Fatigue", patients with cirrhosis Child's C had significantly lower score, than non-cirrhotic patients. CONCLUSION: The Serbian version of CLDQ is well accepted and represents a valid and reliable instrument in Serbian sample of CLD patients.

Nutritional status in patients with active inflammatory bowel disease: prevalence of malnutrition and methods for routine nutritional assessment.

BACKGROUND AND AIM: Malnutrition is a common feature of inflammatory bowel disease (IBD). There are numerous methods for the assessment of nutritional status, but the gold standard has not yet been established. The aims of the study were to estimate the prevalence of undernutrition and to evaluate methods for routine nutritional assessment of active IBD patients. MATERIAL AND METHODS: Twenty-three patients with active Crohn disease, 53 patients with active ulcerative colitis and 30 controls were included in the study. The nutritional status was assessed by extensive anthropometric measurements, percentage of weight loss in the past 1-6 months and biochemical markers of nutrition. RESULTS: All investigated nutritional parameters were significantly different in IBD patients compared to control subjects, except MCV, tryglicerides and serum total protein level. Serum albumin level and body mass index (BMI) were the most predictive parameters of malnutrition. According to different assessment methods the prevalence of undernutrition and severe undernutrition in patients with active IBD were 25.0%-69.7% and 1.3%-31.6%, respectively, while in the control subjects no abnormalities have been detected. There was no statistically significant difference of nutritional parameters between UC and CD patients except lower mid-arm muscle circumference in UC group. CONCLUSIONS: Malnutrition is common in IBD patients. BMI and serum albumin are simple and convenient methods for the assessment of the nutritional status in IBD patients. Further studies with larger group of patients are necessary to elucidate the prevalence of malnutrition and the most accurate assessment methods in IBD patients.

Role of serotonin in development of esophageal and gastric fundal varices.

AIM: to determine the effect of free serotonin concentrations in plasma on development of esophageal and gastric fundal varices. METHODS: this prospective study included 33 patients with liver cirrhosis and 24 healthy controls. Ultrasonography and measurement of serotonin concentration in plasma were carried out in both groups of subjects. The upper fiber panendoscopy was performed only in patients with liver cirrhosis. RESULTS: the mean plasma free serotonin levels were much higher in liver cirrhosis patients than in healthy controls (219.0 ± 24.2 nmol/L vs 65.4 ± 18.7 nmol/L, P < 0.0001). There was no significant correlation between serotonin concentration in plasma and the size of the esophageal varices according to Spearman coefficient of correlation (r(s) = -0.217, P > 0.05). However, the correlation of plasma serotonin concentration and gastric fundal varices was highly significant (r(s) = -0.601, P < 0.01). CONCLUSION: free serotonin is significant in pathogenesis of portal hypertension especially in development of fundal varices, indicating the clinical value of serotonergic receptor blockers in these patients.

CARD15 gene polymorphisms in Serbian patients with Crohn's disease: genotype-phenotype analysis.

OBJECTIVE: Genetic heterogeneity and incomplete phenotype penetrance complicate genetic analysis of Crohn's disease (CD). Studies in western Europe have shown that CARD15 polymorphisms increase susceptibility to CD, but frequencies vary within different European populations. The aim here was to evaluate the prevalence of CARD15 mutations and their phenotypic correlation in a Serbian population. MATERIALS AND METHODS: 131 patients with CD, 65 patients with ulcerative colitis, and 88 healthy controls were genotyped for three common mutations (R702W, G908R, Leu1007insC) by PCR-restriction fragment length polymorphism. chi and Student's t-test were used for statistical assessment. RESULTS: At least one CARD15 disease-associated allele was found in 35.11% patients with CD, 14.77% of healthy controls (P=0.001), and 7.69% patients with ulcerative colitis (P=0.0001). The L1007fs mutation showed a significant association with CD (P<0.0001). The frequency of R702W mutant allele was almost equal in the control group and CD patients Univariate analyses established that CARD15 carriers had a significantly higher risk of isolated ileal location [P=0.042; odds ratio (OR) 2.30; 95% confidence interval (CI): 1.02-5.19], fibrostenotic behavior (P<0.0001; OR 9.86; 95% CI: 4.29-22.62), surgical resection (P=0.036; OR 2.2; CI, 1.046-4.626), and earlier onset of disease (P=0.026). CONCLUSION: This study confirms that CARD15 carriers, especially L1007fs mutants, in central Europeans have an increased risk of CD and it is associated with earlier onset, ileal, fibrostenotic disease and a higher risk of surgery. Any influence of latitude is not matched by an east-west divide on the genotype frequency and phenotype of CD within Europe.