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  1. Robin Spiller, Editor

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ACID REFLUX IN PATIENTS WITH EPIGASTRIC PAIN

Although the management of heartburn is usually straightforward, patients presenting with dyspepsia without reflux symptoms are more difficult because in most cases routine investigations, including endoscopy, are normal. The underlying pathophysiology in such “functional dyspeptics” includes visceral hypersensitivity, impaired accommodation, and delayed gastric emptying. The current study examined these mechanisms in 247 such patients who also underwent 24 hour pH monitoring. While the majority (75%) had normal (<5%) oesophageal acid exposure, 58 (25%) showed significant reflux. However, 34 out of the 58 denied any reflux symptoms. There were no differences in sensitivity, accommodation, or emptying between those with or without pathological acid reflux. Considering all 247 patients the best symptom discriminator proved to be “moderate or severe epigastric pain” found in 40/58 with acid reflux versus 91/189 in those without. The conclusion is that a trial of therapy for reflux is rational for epigastric pain, even if the patient denies typical reflux symptoms.
See p 1370

FUNCTIONAL GI SYMPTOMS AND OBESITY

While epidemiological data clearly link obesity with symptoms of heartburn, the mechanisms are unclear. This study examined gastrointestinal symptoms in a random sample (1001) of the Swedish population who were all endoscoped. As expected, obesity was a risk for reflux symptoms but this appeared to depend on the presence of reflux oesphagitis because when those with oesphagitis were excluded the excess of reflux symptoms disappeared. In keeping with previous reports obesity is also associated with nearly double the rate of diarrhoea (33% v 19.9% in normal weight individuals). Whether it is the type or amount of food that obese people eat that are responsible remains to be seen.
See p 1377

HEPCIDIN: MEDIATOR OF INCREASED IRON ABSORPTION IN HYPOXIA?

Hypoxia is associated with polycythaemia and increased iron absorption but the mechanisms are unclear. The current study examined the role of hepcidin, a protein synthesised in the liver, recently shown to regulate intestinal iron absorption. Iron uptake into isolated duodenal segments tripled in rats exposed to hypoxia (10% oxygen) for 4 weeks. Blood levels of the labelled iron rose threefold in intact animals while duodenal content fell, implying a stimulation of transfer from intestine to blood. Hypoxia also reduced liver mRNA for hepcidin to <40% of control. This is likely to be a direct effect of hypoxia on hepatocytes because the authors also showed that when isolated hepatic cell lines were exposed to 1% oxygen, hepcidin mRNA selectively decreased within 24 hours. This work confirms the key role of hepcidin and suggests that modulating its actions could be used in the treatment of disordered iron absorption.
See p 1391

ASICS: TARGETS FOR INTESTINAL SPECIFIC ANALGESICS?

There is much current interest in designing drugs to treat visceral pain associated with the functional gastrointestinal diseases. A prerequisite is understanding how the gut signals pain. Unlike the skin, burning or cutting the mucosa rarely causes discomfort, while distension or powerful contractions often do. Transforming pressure or distortion into changes in neural firing rate is done via two families of ion channels, the acid sensitive ion channel (ASIC) and the transient receptor potential (TRP) family. Page and colleagues examined the gut response to mucosal stroking, stretch, and probing in animals with specific deletions of the ASIC 1a, 2, and 3 genes. While loss of ASIC 3 uniformly reduced sensitivity, loss of ASIC1a had the opposite effect. By contrast ASIC 2 disruption had a variable effect, increasing sensitivity to touch but decreasing it to stretch. This complex pattern is due to the fact that the different channels combine to form heteromultimers, whose properties depend on the precise mix. The most important feature is that these channels have quite different roles in the gut compared with the skin so that ASIC3 blockers might well provide gut specific analgesia.
See p 1408

UNRAVELLING THE GENETIC BASIS OF IDIOPATHIC CHRONIC PANCREATITIS

A copious flow of fluid through the pancreatic duct is an important part of the defence of the pancreas against the ever present risk of self-digestion. Fluid secretion depends on the activation of the chloride channel encoded by the cystic fibrosis transmembrane conductance regulator gene (CFTR). There are >1000 different mutations in this gene with a wide range of severity of the associated defect. CFTR function needs to fall to <5% of normal before the classic cystic fibrosis features appear but homozygotes with milder mutations or heterozygotes with combinations of mutations may result in subtler defects, which may include idiopathic chronic pancreatitis (ICP). After excluding individuals with any known risk factor for pancreatitis and those with classical cystic fibrosis or mutations of cationic trypsinogen (PRSS1), Weis and colleagues undertook the laborious task of sequencing the entire CFTR coding region in 67 ICP patients. They were rewarded by detecting three times the number that would have been detected using commercially available panels alone. Mutated CFTR alleles were more frequent in ICP with 25/134 versus 11/120 in geographically and ethnically matched controls. Eight had SPINK1 mutation but in only 1 case was this combined with a CFTR mutation. Thus, in total 45% of ICP patients were shown to have a defined genetic abnormality. The next challenge is to define how these genetic defects interact with environmental triggers to cause disease so that these findings can be translated into clinical practice.
See p 1456

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