Unexplained gastrointestinal symptoms: think mitochondrial disease.

Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic. The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected.

Obesity: a window of opportunity to intervene? Characteristics and management of morbidly obese adult inpatients in three trusts in Southern England.

Obesity affects 22% of men and 24% of women over the age of 16 years in the general population of the UK and is associated with multiple comorbidities. Little is known about the magnitude of the obesity problem among hospitalised adults and, although significant focus has been given to the identification and treatment of the malnourished inpatient, it is not known to what extent obese inpatients are equally -targeted. National guidelines for consideration of bariatric surgery exist, but it is not known to what extent potentially eligible individuals are referred. This multi-centre study -demonstrates a significant burden of obesity (defined as body mass index [BMI] ≥30 kg/m(2)) among those in hospital, affecting 22% of patients. This was more marked among orthopaedic patients and all-comers to intensive care units than on medical or surgical wards. Of those with BMI ≥35 kg/m(2), only 21% had been reviewed by dietetics and only 10% of patients who were potentially eligible for bariatric surgery had been referred to bariatric services. This study shows that there is an opportunity to recognise obesity and intervene in its management during hospital admission.

Etiopathogenesis of primary biliary cirrhosis: an overview of recent developments.

Substantial advancements in the field of primary biliary cirrhosis (PBC) research have broadened our understanding of this enigmatic disease. Genome-wide studies have identified several new candidate genes involved in the immunoregulatory process, particularly those responsible for antigen presentation and lymphocyte signaling. Examples include the HLA class-II region and genes implicated in IL12-JAK/STAT signaling, and the NF-κB and TNF signaling pathways. Environmental triggers appear to disrupt the pre-existing, unstable immune tolerance in genetically susceptible individuals, and molecular mimics of the PBC-specific autoantigen (PDC) may be derived from microbes or xenobiotic compounds, which modify native proteins, making them immunogenic. Although the vast majority of patients with PBC are AMA-positive, a variety of disease-specific antinuclear antibodies have been recognized in conferring a worse clinical outcome. There has also been a revived interest in the role of antibody-secreting B cells in murine models suggesting that depletion of these cells paradoxically exacerbates cholangiopathy. Biliary specificity in PBC is most likely driven by the uniqueness of cholangiocyte apoptosis in which the PDC-E2 autoantigen undergoes differential glutathiolation. Cholangiocytes also possess the ability to phagocytose neighboring apoptotic cells, present intact immunoreactive antigen, and undergo attack from autoantibodies, the innate immune system, and autoreactive lymphocytes. Cellular senescence and a lack of functioning T-regulatory cells are proposed mechanisms by which this multi-lineage process is thought to be enhanced. This review summarizes these key advances as the true complexities of the disease process begin to be unraveled.

Gastrostomy tube feeding in adults: the risks, benefits and alternatives.

Enteral feeding (or 'tube feeding') is a very common inpatient intervention to maintain nutritional status where the oral route is inadequate, unsafe or inaccessible. A proportion of patients will need to continue tube feeding in the community after their admission and will require a gastrostomy tube. Although gastrostomy insertion is relatively straightforward, it is not without complications in an often frail and vulnerable group of patients and a multidisciplinary approach is necessary to ensure that the procedure is appropriate. Some patients are better managed with careful assisted hand feeding or nasogastric tubes. Particular care needs to be taken in deciding whether patients with dementia should have a gastrostomy in view of data suggesting that this group of patients have a particularly poor prognosis after the procedure. Decisions regarding the provision of enteral nutrition at the end of life or where patients are not competent to make an informed judgement are particularly challenging and need to be made on a case-by-case basis.

Renewing the spirit of nursing: Embracing evidence-based practice in a rural state.

A group of nursing leaders from several organizations in the central and northern regions of the state established the Maine Nursing Practice Consortium (MNPC). The MNPC has created educational opportunities through workshops that assist nurses with the development and implementation of evidence-based practice (EBP) in rural Maine. Through collaboration and consultation with EBP leaders, members have ignited a spirit of inquiry and gained the support of nurses from varied backgrounds to engage actively in EBP initiatives. This article briefly summarizes the process of establishing these collaborative partnerships, describes some of the outcomes from the workshops, and describes the organizational and individual commitment that was essential to the work.

Etiopathogenesis of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.

Immunopathogenesis of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.

Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1.

Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a fibrosing disease of the intra- and extra-hepatic bile ducts, and is closely associated with inflammatory bowel disease. It is immune mediated, rather than being a classical autoimmune disease. A range of immune abnormalities have been demonstrated in PSC, in particular the findings of a range of autoantibodies, a portal tract infiltrate of functional T cells, a restricted T-cell receptor repertoire, and aberrant expression of HLA molecules on biliary epithelial cells. The immunogenetics of PSC is currently under study and to date 4 key HLA haplotypes associated with PSC have been developed. The trigger factor for the initiation of the immune response may be the ingress of bacteria or other toxic metabolites into the portal circulation through a diseased and permeable bowel wall.

The molecular classification of the clinical manifestations of Crohn's disease.

BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.