The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease.

The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.

Quality of care in inflammatory bowel disease: actual health service experiences fall short of the standards.

BACKGROUND: Quality of care in inflammatory bowel disease (IBD) has received much attention internationally; however, the available surveys focus on health professionals rather than patients. AIMS: To assess the experiences of healthcare for people living with IBD against established Australian IBD Standards. METHODS: An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics and the Royal Flying Doctor Service. Participants completed a questionnaire incorporating items addressing the Australian IBD Standards 2016, the Picker Patient Experience Questionnaire, IBD Control Survey and the Manitoba Index. RESULTS: Complete data were provided by 731 respondents (71.5% female, median age 46 years, ranging from 16 to 84 years). While the majority (74.8%) were satisfied with their IBD healthcare, the care reported did not meet the Australian IBD Standards. Overall, 32.4% had access to IBD nurses, 30.9% to a dietician and 12% to a psychologist in their treating team. Participants managed by public IBD clinics were most likely to have access to an IBD nurse (83.7%), helpline (80.7%) and research trials (37%). One third of respondents reported waiting >14 days to see a specialist when their IBD flared. Participants received enough information, mostly from medical specialists (88.8%) and IBD nurses (79.4%). However, 51% wanted to be more involved in their healthcare. CONCLUSIONS: These data show discordance between expectations of patients and national standards with current levels of service provision, which fail to deliver equitable and comprehensive IBD care.

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease.

The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease.

Crohn's & Colitis Australia inflammatory bowel disease audit: measuring the quality of care in Australia.

BACKGROUND: Australia has among the highest prevalence of Crohn disease and ulcerative colitis in the world. Management of the chronic gastrointestinal disorders results in significant societal costs and the standard of care is inconsistent across Australia. AIM: To audit the quality of care received by patients admitted for inflammatory bowel disease (IBD) across Australia against national IBD standards. METHODS: A retrospective cross-sectional survey and clinical audit was undertaken assessing organisational resources, clinical processes and outcome measures. This study was conducted in Australian hospitals that care for inpatients with Crohn disease or ulcerative colitis. The main outcome measures were adherence to national IBD standards and comparison of quality of care between hospitals with and without multidisciplinary IBD services. RESULTS: A total of 71 hospitals completed the organisational survey. Only one hospital had a complete multidisciplinary IBD service and 17 had a partial IBD service (IBD nurse, helpline and clinical lead). A total of 1440 inpatient records was reviewed from 52 hospitals (mean age 37 years; 51% female, 53% Crohn disease), approximately 26% of IBD inpatient episodes over a 12-month period in Australia. These patients were chronically unwell with high rates of anaemia (30%) and frequent readmissions (40% within 2 years). In general, care was inconsistent, and documentation was poor. Hospitals with a partial IBD service performed better in many processes and outcome measures: for example, 22% reduction in admissions through emergency departments and greater adherence to standards for safety monitoring of biological (89% vs 59%) and immunosuppressive drugs (79% vs 55%) in those hospitals than those without. CONCLUSION: Patients admitted to hospital suffering from IBD are young, chronically unwell and are subject to substantial variations in clinical documentation and quality of care. Only one hospital met accepted standards for multidisciplinary care; hospitals with even a minimal IBD service provided improved care.

Within-host evolution versus immigration as a determinant of Escherichia coli diversity in the human gastrointestinal tract.

When a human host harbors two or more strains of Escherichia coli, the second strain is more likely to be a member of the same phylogroup rather than a different phylogroup. This outcome may be the consequence of a within host evolution event or an independent immigration/establishment event. To determine the relative importance of these two events in determining E. coli diversity in a host, a collection of multiple E. coli isolates recovered from each of 67 patients undergoing colonoscopies was used. Whole genome sequence data were available for one example of every REP-fingerprint type identified in a patient. Sequence type (ST) and single-nucleotide polymorphism (SNP) analyses revealed that 83% of strains observed in the host population were a consequence of immigration/establishment events. Restricting the analysis to hosts harboring two or more strains belonging to the same phylogroup revealed that in about half of these cases, the presence of a second strain belonging to the same phylogroup was the consequence of an independent immigration/establishment event. Thus, the results of this study show that despite hosts being exposed to a diversity of E. coli via their food, factors related to the host also determine what E. coli strains succeed in establishing.

The microbiome of translocated bacterial populations in patients with and without inflammatory bowel disease.

BACKGROUND: Using culture-based methods, bacterial translocation from the gut to draining mesenteric lymph nodes is seen in 5% of normal controls and up to 33% of patients with inflammatory bowel diseases (IBD). Many bacteria cannot be cultured, so these methods are unable to capture the full spectrum of bacteria present. AIMS: To detect viable bacteria in lymph nodes of patients with IBD and non-IBD controls using bacterial RNA as a surrogate for viability and to compare them with the same patient's gut microbiome. METHODS: Bacterial RNA was extracted from lymph nodes and mucosa of 20 patients who had undergone intestinal resection (10 IBD, 10 non-IBD). A previous study had detected bacterial DNA in these patients' lymph nodes; 16S rRNA gene high-throughput sequencing was performed. RESULTS: Bacterial RNA was detected in the lymph nodes of five patients with IBD and three controls (volvulus, diverticulitis and bowel obstruction). Lymph nodes had higher alpha (within sample) diversity compared to mucosal samples (Shannon diversity index 2.41 vs 1.81, one-way ANOVA P = 0.035). Beta diversity (inter-sample variation: lymph node vs intestine) was similar within individuals and did not differ between groups. Common gene polymorphisms linked with IBD (NOD2, ATG16L1, IRGM and IL23R) were not associated with bacterial translocation. CONCLUSIONS: Metabolically active bacteria mirroring the individual's gut microbiome were commonly found in the lymph nodes of patients with IBD undergoing resection. An increase in lymph node alpha diversity is likely due to the larger drainage area. The presence of viable bacteria in non-IBD controls is also not unexpected given the underlying pathology in these patients.

Inflammatory bowel disease-related fatigue is correlated with depression and gender.

OBJECTIVES: Fatigue is a common and disabling problem in inflammatory bowel disease. We sought to explore the possible determinants of inflammatory bowel disease-associated fatigue including demographic, psychological and disease variables. METHODS: Surveys were distributed to 100 patients undergoing infliximab infusion for inflammatory bowel disease in an infusion lounge, assessing attachment style (Experiences in Close Relationships Revised scale), fatigue (Functional Assessment of Chronic Illness Therapy Fatigue - Fatigue Subscore), and depression and anxiety (Hospital Anxiety and Depression Scale). Disease severity was assessed via file review through an independent gastroenterologist rating (Harvey-Bradshaw Index). RESULTS: There were 67 responses. Depression, as measured by the Hospital Anxiety and Depression Scale, was found to be highly correlated with fatigue (Functional Assessment of Chronic Illness Therapy Fatigue - Fatigue Subscore). Anxiety, insecure attachment, disease severity and female gender were moderately correlated with fatigue. In a hierarchical regression model, depression and female gender emerged as significant predictors of variance in fatigue scores. CONCLUSIONS: Depression was the strongest predictor of variance in fatigue scores. Gender as a cause of fatigue in inflammatory bowel disease requires further exploration. Attachment style, however, may still help clinicians to conceptualise help-seeking behaviour and clinician-patient relationships in medically unexplained symptoms.

Comparative genomics of Crohn's disease-associated adherent-invasive Escherichia coli.

OBJECTIVE: Adherent-invasive Escherichia coli (AIEC) are a leading candidate bacterial trigger for Crohn's disease (CD). The AIEC pathovar is defined by in vitro cell-line assays examining specific bacteria/cell interactions. No molecular marker exists for their identification. Our aim was to identify a molecular property common to the AIEC phenotype. DESIGN: 41 B2 phylogroup E. coli strains were isolated from 36 Australian subjects: 19 patients with IBD and 17 without. Adherence/invasion assays were conducted using the I-407 epithelial cell line and survival/replication assays using the THP-1 macrophage cell line. Cytokine secretion tumour necrosis factor ((TNF)-α, interleukin (IL) 6, IL-8 and IL-10) was measured using ELISA. The genomes were assembled and annotated, and cluster analysis performed using CD-HIT. The resulting matrices were analysed to identify genes unique/more frequent in AIEC strains compared with non-AIEC strains. Base composition differences and clustered regularly interspaced palindromic repeat (CRISPR) analyses were conducted. RESULTS: Of all B2 phylogroup strains assessed, 79% could survive and replicate in macrophages. Among them, 11/41 strains (5 CD, 2 UCs, 5 non-IBD) also adhere to and invade epithelial cells, a phenotype assigning them to the AIEC pathovar. The AIEC strains were phylogenetically heterogeneous. We did not identify a gene (or nucleic acid base composition differences) common to all, or the majority of, AIEC. Cytokine secretion and CRISPRs were not associated with the AIEC phenotype. CONCLUSIONS: Comparative genomic analysis of AIEC and non-AIEC strains did not identify a molecular property exclusive to the AIEC phenotype. We recommend a broader approach to the identification of the bacteria-host interactions that are important in the pathogenesis of Crohn's disease.

Paradoxical psoriasiform reactions of anti-tumour necrosis factor therapy in inflammatory bowel disease patients.

Anti-tumour necrosis factor (TNF) agents have demonstrated efficacy in inflammatory bowel disease (IBD). Cutaneous reactions such as new onset psoriasis or psoriasiform-like reactions are among the most common adverse reactions. We retrospectively identified cases of anti-TNF-induced psoriasis or psoriasiform manifestations in IBD patients at a tertiary centre in Australia. A total of 10 (six females) of 270 (3.7%) IBD patients treated with anti-TNF therapy developed drug-induced psoriatic or psoriasiform-like reactions: five patients were treated with infliximab and five with adalimumab; nine had Crohn disease. The time from initiation of anti-TNF agent to onset of rash was 7.5 months on average. The most frequent distributions were the scalp (7/10) and extremities (6/10). Three patients discontinued anti-TNF treatment with resolution of the rash. Topical treatment of the lesions allowed continued use of biological agent in the majority. Paradoxical psoriatic lesions are recognised adverse events associated with anti-TNF therapy, but discontinuation of therapy due to dermatological complications is required only rarely, even in patients with psoriasiform lesions.

Gut feelings 2. Mind, mood and gut in inflammatory bowel disease: approaches to psychiatric care.

OBJECTIVES: The authors aim to provide a clinically-focused summary of psychiatric complications of inflammatory bowel disease (IBD), and give treatment recommendations.A narrative review of literature drawn from PubMed and Medline. CONCLUSIONS: IBD is a chronic, debilitating and potentially body integrity altering condition with significant morbidity and a slight increase in mortality. Co-morbidity with anxiety and depression is common. Onset in the younger years can disturb development. Psychotherapy may be most useful for addressing fatigue, pain and assisting with coping. There is a lack of evidence to guide treatment of depression in this population.

Gut feelings 1. Mind, mood and gut in irritable bowel syndrome: approaches to psychiatric care.

OBJECTIVE: Psychiatrists are likely to encounter patients with irritable bowel syndrome (IBS). We aim to provide a clinically-focused summary of psychiatric comorbidities and management. CONCLUSIONS: IBS affects up to 15% of the population. Antidepressants and brief psychotherapy can reduce symptom severity and improve coping. These treatments are effective for patients without comorbid mental illness, as well as those with increased somatisation, health-care seeking and sexual abuse histories.

Detection of bacterial DNA in lymph nodes of Crohn's disease patients using high throughput sequencing.

OBJECTIVE: Our aim was to determine whether or not specific microorganisms were transported selectively to lymph nodes in Crohn's disease (CD) by comparing node and mucosal microbial communities in patients and controls. We also sought evidence of dysbiosis and bacterial translocation. DESIGN: Lymph nodes, and involved and uninvolved mucosal samples were obtained from resections of 58 patients (29 CD, eight 'other inflammatory bowel disease' (IBD) and 21 non-IBD). Universal primers targeting V1-V3 regions of bacterial 16S rRNA genes were used to amplify bacterial DNA and amplicons sequenced using high throughput sequencing. 20 patients (eight CD (28%), two other IBD (25%) and 10 non-IBD (48%)) had PCR positive nodes. RESULTS: All samples from an individual were similar: there was no evidence of selective concentration of any microorganism in nodes. No specific microorganism was present in the nodes of all CD samples. Escherichia/Shigella were common in all patient groups but patients with ileal CD had a greater proportion of Escherichia coli reads in their nodes than other CD patients (p=0.0475). Campylobacter, Helicobacter and Yersinia were uncommon; Mycobacterium and Listeria were not detected. Dysbiosis was present in all groups but shifts were specific and no common pattern emerged. CONCLUSIONS: It is unlikely that a single bacterium perpetuates inflammation in late stage CD; dysbiosis was common and we found no evidence of increased bacterial translocation. We believe that future studies should focus on early disease and viable bacteria in nodes, aphthous ulcers and granulomas, as they may be more relevant in the initiation of inflammation in CD.

Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: a review.

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four- to sixfold and the absolute risk varies between 1 in 4000-5000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti- tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post-transplant-like LD in those with latent epstein-barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.

Comparative genomics and phenotypic studies to determine site-specificity of Escherichia coli in the lower gastrointestinal tract of humans.

Escherichia coli (E. coli) is an important commensal in the human gut; however, it is unknown whether strains show site-specificity in the lower gut. To investigate this, we assessed genotypic and phenotypic differences in 37 clone pairs (two strains with very similar multiple locus variable-number-tandem-repeat analysis [MLVA] profiles) of E. coli isolated from mucosal biopsies of two different gut locations (terminal ileum and rectum). The clone pairs varied at the genomic level; single nucleotide polymorphisms (SNPs) were common, multiple nucleotide polymorphisms (MNPs) were observed but less common, and few indels (insertions and deletions) were detected. The variation was higher in clone pairs that are associated with non-human-associated sequence types (ST) compared to human-associated STs, such as ST95, ST131, and ST73. No gene(s) with non-synonymous mutations were found to be commonly associated with either the terminal ileum or the rectal strains. At the phenotypic level, we identified the metabolic signatures for some STs. Rectum strains of some STs showed consistently higher metabolic activity with particular carbon sources. Clone pairs belonging to specific STs showed distinct growth patterns under different pH conditions. Overall, this study showed that E. coli may exhibit genomic and phenotypic variability at different locations in the gut. Although genomics did not reveal significant information suggesting the site-specificity of strains, some phenotypic studies have suggested that strains may display site-specificity in the lower gut. These results provide insights into the nature and adaptation of E. coli in the lower gut of humans. To the best of our knowledge, no study has investigated or demonstrated the site-specificity of commensal E. coli in the human gut.

Effects of bacterial products on enterocyte-macrophage interactions in vitro.

We describe a coculture model of a human intestinal epithelial cell line and human peripheral blood monocytes in which monocytes differentiate into cells with features of resident intestinal macrophages. Caco-2 cells are grown on the lower surface of a semipermeable filter with pore size of 3 µm (Transwells) until they differentiate into enterocytes. Peripheral-blood monocytes are added and the co-culture incubated for two days. Monocytes migrate through the pores of the membrane, come into direct contact with the basolateral surfaces of the epithelial cell monolayer, and develop characteristics of resident intestinal macrophages including downregulation of CD14 expression and reduced pro-inflammatory cytokine responses (IL-8, TNF and IL-1ß) to bacterial products. The apical application of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) resulted in an increased number of integrated monocytes, but abrogated the downregulation of CD14 expression and the diminished cytokine responses. MDP also reduced tight-junctional integrity, whilst LPS had no effect. These data indicate that LPS and MDP have significant pathophysiological effects on enterocyte-monocyte interactions, and confirm other studies that demonstrate that enterocytes and their products influence monocyte differentiation. This model may be useful in providing insights into the interaction between monocytes, epithelial cells and intestinal bacteria in health and disease.

Australia IBD Microbiome (AIM) Study: protocol for a multicentre longitudinal prospective cohort study.

INTRODUCTION: Crohn's disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia's first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. METHODS: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619000911190.

Psychological distress is highly prevalent in inflammatory bowel disease: A survey of psychological needs and attitudes.

BACKGROUND AND AIM: Data on patient needs and access to psychological services in inflammatory bowel disease (IBD) are scarce. This study aimed to describe the levels of distress and the needs, attitudes, and access to psychological services for people within Australia against established Australian IBD Standards. METHODS: An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics, and the Royal Flying Doctor Service. K10 was used to measure psychological distress. The Chi-square test was used to compare those with and without distress on key variables. RESULTS: Overall, 731 respondents provided complete data (71.5% female, mean age 46.5 years). Overall, 50% of respondents reported distress; only 15.2% were currently seeing a mental health practitioner; only 16.1% were asked about their mental health by their IBD specialist or IBD nurse; and only 12.2% reported access to a mental health practitioner as part of their IBD service. Those with psychological distress were significantly less satisfied with their IBD care; more commonly hospitalized; had an active disease, fistula or perianal disease, pain, or fatigue; and were receiving steroids, opioids, or antidepressants (all P < 0.05). As many as 68.2% of those with severe distress were not seeing a mental health practitioner. CONCLUSIONS: The integrated biopsychosocial model of health care, with regular mental health screening and good access to mental health professionals, is requested by people living with IBD to improve their outcomes.

Vedolizumab in combined immune checkpoint therapy-induced infliximab-refractory colitis in a patient with metastatic melanoma: A case report.

BACKGROUND: Dual checkpoint inhibition improves response rates in treatment naïve patients with metastatic melanoma compared to monotherapy. However, it confers a higher rate of toxicity, including immune-related colitis. Steroids may not resolve symptoms in all cases. The use of vedolizumab, a humanized monoclonal antibody against α4ß7 integrin has proven effective in cases refractory to standard treatment. CASE SUMMARY: We report the case of a 27-year-old female with Stage IVd metastatic melanoma treated with ipilimumab and nivolumab. She developed severe colitis refractory to methylprednisolone, infliximab and mycophenolate mofetil but responded to vedolizumab. CONCLUSION: This case report supports vedolizumab use in severe immune related colitis refractory to standard immunosuppression.

Rational investigation of upper abdominal pain.

BACKGROUND: Upper abdominal pain is a common problem with an extraordinary diversity of possible causes. Many patients have no structural disease, and making the correct diagnosis can be a challenge. The roles of endoscopy, testing for Helicobacter pylori, and imaging techniques have been debated widely and continue to be a matter for discussion. OBJECTIVE: This article details the value of various investigations in the setting of specific presentations of upper abdominal pain. DISCUSSION: Functional dyspepsia is a common cause of upper abdominal pain but the diagnosis should only be made after consideration of more serious pathology. The various organic causes of upper abdominal pain and the appropriate investigations are discussed. Early endoscopy is advisable in the presence of alarm symptoms and in patients over 55 years of age.