Characterisation of proguanylin expressing cells in the intestine - evidence for constitutive luminal secretion.

Guanylin, a peptide implicated in regulation of intestinal fluid secretion, is expressed in the mucosa, but the exact cellular origin remains controversial. In a new transgenic mouse model fluorescent reporter protein expression driven by the proguanylin promoter was observed throughout the small intestine and colon in goblet and Paneth(-like) cells and, except in duodenum, in mature enterocytes. In Ussing chamber experiments employing both human and mouse intestinal tissue, proguanylin was released predominantly in the luminal direction. Measurements of proguanylin expression and secretion in cell lines and organoids indicated that secretion is largely constitutive and requires ER to Golgi transport but was not acutely regulated by salt or other stimuli. Using a newly-developed proguanylin assay, we found plasma levels to be raised in humans after total gastrectomy or intestinal transplantation, but largely unresponsive to nutrient ingestion. By LC-MS/MS we identified processed forms in tissue and luminal extracts, but in plasma we only detected full-length proguanylin. Our transgenic approach provides information about the cellular origins of proguanylin, complementing previous immunohistochemical and in-situ hybridisation results. The identification of processed forms of proguanylin in the intestinal lumen but not in plasma supports the notion that the primary site of action is the gut itself.

Fatal breakthrough mucormycosis in a multivisceral transplant patient receiving micafungin: Case report and literature review.

Introduction: Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales. Presentation of case: A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem. Discussion: Non-Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover. Conclusion: A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor.

Graft versus host disease after multivisceral transplantation: A UK center experience and update on management.

Graft versus host disease (GVHD) following transplantation of an intestine-containing graft occurs more frequently than with other solid organ transplants and is known to have a poor outcome. The presentation differs from other solid organ transplants, as the gastrointestinal tract is not involved following intestinal transplant. Diagnosis is based on clinical symptoms arising due to native tissue damage and the detection of donor T lymphocytes in circulating blood (T-cell chimerism). The ideal treatment strategy has not been defined, with advocates for both increased and decreased immunosuppression. We reviewed all cases of GVHD in an adult intestinal transplant center in the United Kingdom and report on management strategies of five cases and methods of detecting T-cell chimerism. The practice in our center has evolved with experience. The first two patients received an increase in immunosuppression, which was only successful in one case. Subsequently, reducing immunosuppression has been more effective. However, patients with bone marrow involvement have a poorer prognosis. We demonstrate successful treatment of GVHD after multivisceral transplant with a reduction in immunosuppression. This should be followed by vigilant graft surveillance and serial monitoring of the level of T-cell chimerism, with reintroduction of immunosuppression at the earliest sign of graft dysfunction.

Urgent Multivisceral Transplantation for Widespread Splanchnic Ischemia.

BACKGROUND: Multivisceral transplantation (transplantation of the stomach, intestine, liver, and pancreas) is usually undertaken as a semi-elective procedure after thorough assessment in patients who have intestinal failure with cirrhosis, cirrhosis with portomesenteric venous thrombosis, or tumors such as desmoids involving the liver and mesentery. STUDY DESIGN: Data were collected prospectively from the time of referral and held in a central database. We used it to report the first cases of urgent multivisceral transplantation (MVT) in patients with widespread splanchnic ischemia (occlusion of the celiac axis and superior mesenteric artery) resulting in small bowel infarction and hepatic failure. RESULTS: Three women (ages 33, 48, and 50 years) were referred to our center with superior mesenteric artery and celiac axis occlusion. All other modes of treatment had been considered and/or attempted. After transfer to our institution, all patients were assessed, urgently listed, and underwent transplantation in 10, 7, and 5 days. Two patients are still alive after 2 years and 1 died at 8 months from multiorgan failure due to infections and graft vs host disease. CONCLUSIONS: Treatment options for patients presenting with widespread splanchnic ischemia with hepatic and intestinal failure/infarction were previously limited to salvage surgery and attempted revascularization. In situations in which these failed, the only previous option would have been palliation. In selected cases, we propose that urgent multivisceral transplantation should be considered as a life-saving treatment. This represents a previously unreported indication for MVT.

Use of the alpha glucosidase inhibitor acarbose in patients with 'Middleton syndrome': normal gastric anatomy but with accelerated gastric emptying causing postprandial reactive hypoglycemia and diarrhea.

Postprandial reactive hypoglycemia, early satiety and diarrhea are well-recognized side effects following full or partial gastrectomy or gastric bypass. It has only recently been realized, however, that patients with normal gastric anatomy may experience similar symptoms and signs due to primary accelerated gastric emptying (Middleton syndrome). In previous case studies, patients responded well to the use of dietary modification (frequent small-volume meals) alone. The authors describe two patients with this syndrome who continued to experience symptoms of reactive postprandial hypoglycemia despite dietary intervention but became asymptomatic following the addition of the alpha-glucosidase inhibitor acarbose.

Preoperative comorbidity correlates inversely with survival after intestinal and multivisceral transplantation in adults.

We investigated the relationship between preoperative comorbidity and postoperative survival after intestinal transplantation. Each patient received a score for preoperative comorbidity. Each comorbidity was given a score based on the degree it impaired function (score range 0-3). A total score was derived from the summation of individual comorbidity scores. Patients (72 adults (M : F, 33 : 39)) received an isolated intestinal graft (27) or a cluster graft (45). Mean (standard deviation) survival was 1501 (1444) days. The Kaplan-Meier analysis revealed a significant inverse association between survival and comorbidity score (logrank test for trend, P < 0.0001). Patients grouped into comorbidity scores of 0 and 1, 2 and 3, 4 and 5, 6, and above had hazard ratios (95% confidence intervals) for death (compared to group 0 + 1), which increased with comorbidity scores: 1.945 (0.7622-5.816), 5.075 (3.314-36.17), and 13.77 (463.3-120100), respectively, (P < 0.0001). Receiver-operator curves at 1, 3, 5, and 10 years postoperative had "C" statistics of 0.88, 0.85, 0.88, and 0.92, respectively. When evaluating patients for transplantation, the degree of comorbidity should be considered as a major factor influencing postoperative survival.

Idiopathic accelerated gastric emptying presenting in adults with post-prandial diarrhea and reactive hypoglycemia: a case series.

INTRODUCTION: We have previously reported the association of gastrointestinal and hypoglycemic symptoms, with idiopathic accelerated gastric emptying. We now report the first series of six similar cases. CASE PRESENTATIONS: Patient 1: A 24-year-old Caucasian man presented to our facility with a six-month history of post-prandial nausea, flatulence, bloating, abdominal discomfort and associated diarrhea. He had associated episodes of fatigue, sweating, anxiety, confusion and craving for sweet foods. Patient 2: A 52-year-old Caucasian woman presented to our facility with a 15-year history of post-prandial bloating, abdominal pain and diarrhea, often associated with nausea, severe sweating, and fatigue. Patient 3: An 18-year-old Caucasian woman presented to our facility with a nine-year history of post-prandial diarrhea, abdominal bloating and pain. There was associated nausea, tremor, lethargy, and craving for sweet foods. Patient 4: A 77-year-old Caucasian woman presented to our facility with a four-month history of epigastric distension, pain after eating and a change in bowel habit. She experienced intermittent severe diarrhea and marked fatigue, nausea and sweating. Patient 5: A 23-year-old Caucasian woman presented to our facility with a two-year history of early satiety, and diarrhea after eating. She also complained of feeling faint and weak between meals, when she became cold and clammy, and on several occasions lost consciousness during these episodes. Patient 6: A 64-year-old Caucasian woman presented to our facility with a 10-year history of nausea, early satiety and profound bloating followed by diarrhea. All symptoms predominantly occurred in the first three hours after eating, when she felt faint, lethargic, and had a craving for sweet foods. In all cases, symptoms were alleviated or resolved by taking sweet food or drink and response to treatment was 90% or greater in all cases. CONCLUSIONS: This series extends our description of this new clinical syndrome. All patients responded well to treatment for accelerated gastric emptying. Clinicians in the disciplines of endocrinology, gastroenterology, neurology and general practice are likely to find this information useful as they will consult patients with some or all of these symptoms and in a proportion of these patients idiopathic accelerated gastric emptying may be present and provide a useful avenue for therapeutic intervention.

Post-prandial reactive hypoglycaemia and diarrhea caused by idiopathic accelerated gastric emptying: a case report.

INTRODUCTION: The majority of cases of post-prandial reactive hypoglycemia are considered idiopathic. Abnormalities of B-cell function and glucose regulation by insulin and glucagon have been postulated as causes but associated gastrointestinal dysfunction has not been reported. We report the first case of accelerated gastric emptying associated with post-prandial reactive hypoglycemia, abdominal bloating and diarrhea. We consider that gastric dysmotility is an important cause of this condition as treatment of the underlying abnormal gastric emptying allows effective control of symptoms. CASE PRESENTATION: A 20-year-old Caucasian woman presented with post-prandial fatigue, sweating, nausea, faintness and intermittent confusion, which had led to pre-syncope and syncope on occasions. She also experienced marked abdominal bloating and diarrhea over the same period. These episodes responded to oral administration of sweet drinks. Her symptoms were ameliorated by modification of her diet. CONCLUSION: This is an original case report of the association of idiopathic accelerated gastric emptying with post-prandial reactive hypoglycemia and diarrhea. Family physicians, endocrinologists and gastroenterologists often consult patients with a constellation of post-prandial symptoms, which are considered to be idiopathic in most cases. This case indicates that gastric dysmotility might be the primary cause of these symptoms in some patients and, if found, offers a therapeutic target which in our case was successful.

Is intestinal transplantation now an alternative to home parenteral nutrition?

Patients with irreversible intestinal failure and complications of parenteral nutrition should now be routinely considered for small intestine transplantation. Despite attempts for >40 years immunological graft intolerance presented an impenetrable barrier to successful engraftment until the development in the late 1970s of the powerful calcineurin-inhibitor immunosuppressive agents. Their use over the last 17 years has led to small intestinal transplantation being generally considered as a routine option for patients with irreversible intestinal failure and failing parenteral nutrition. The 1-year patient survival rates (%) are now excellent for renal (95), liver (78), heart (82) and lung (75) transplantation. In contrast, survival rates for small intestinal transplantation have been slow to improve, although they are now approaching those for lung and liver transplantation (intestine 78%, intestine and liver 60%, multivisceral 66%), and well-performing centres report recent 1-year graft survival rates as high as 92%. Patient 5-year survival (%) has also improved (intestine alone 50, intestine and liver 50 and multivisceral 62) and compares increasingly favourably with renal (85), liver (67), heart (67) and lung (46). Currently, small intestinal transplantation is reserved for patients with irreversible small intestinal failure who have a poor prognosis on parenteral nutrition. However, as 5-year patient survival following intestinal transplantation approaches that for parenteral nutrition there will be increasing pressure to offer this modality of treatment as an alternative to parenteral nutrition, especially for those patients who have a poor quality of life as a result of parenteral nutrition.

Quantification of disease activity in patients undergoing leucocyte scintigraphy for suspected inflammatory bowel disease.

PURPOSE: Whole-body gamma camera counting is an alternative to faecal 111In collection for quantifying disease activity in inflammatory bowel disease (IBD) but requires administration of imaging activities of 111In. The aim of this study was to explore a dedicated whole-body counter which requires 20-fold less activity than gamma camera counting. METHODS: Thirty patients with known or suspected IBD received 99mTc-granulocytes (approximately 200 MBq) and 111In-granulocytes (approximately 0.5 MBq). The 99mTc-cells were injected 45 min after the 111In-cells and immediately after a baseline 111In whole-body count. The decay-corrected count at 120 h was expressed as a fraction of baseline to give whole-body 111In retention (WBR). One patient was excluded as the injected cells were non-viable. RESULTS: Median 45-min intravascular 111In recovery was 35% in patients compared with 43% in six normal volunteers (p<0.05). WBR in normals ranged from 91% to 93% and in 11 patients with negative 99mTc imaging from 87% to 96%. Only one of 11 patients with negative imaging had WBR <90% while 11/12 patients with WBR <90% had abnormal imaging. Ten of 13 patients with Crohn's disease (CD) had abnormal imaging. The lowest WBR in these ten was 77% and six had values of >90%. There was a significant association between WBR and 99mTc image grade (Rs=0.73, p<0.002) in 16 patients without CD, but not in 13 patients with CD (Rs=0.54, p>0.05). CONCLUSION: Dedicated whole-body counting is able to quantify disease activity in IBD but may give normal values in active CD.

Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A's negligible PC1 activity, some mature ACTH and glucagon-like peptide 17-36(amide) were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

A double-blind, randomized, placebo-controlled trial of essential fatty acid supplementation in the maintenance of remission of ulcerative colitis.

BACKGROUND: Essential fatty acid supplementation has been found to ameliorate certain chronic inflammatory diseases. This effect is thought to be mediated through the modulation of eicosanoid synthesis. Pro-inflammatory eicosanoids have been implicated in ulcerative colitis. AIM: To investigate the possible therapeutic benefit of essential fatty acids in quiescent ulcerative colitis to reduce the frequency of disease relapse. METHODS: A randomized, double-blind, placebo-controlled study was performed with a treatment duration of 12 months. Patients with quiescent disease received either trial medication (gamma-linolenic acid, 1.6 g, eicosapentaenoic acid, 270 mg, and docosahexaenoic acid, 45 mg, per day) or placebo (sunflower oil, 500 mg/day). The primary end-point was disease activity, assessed by a previously validated clinical index, sigmoidoscopic appearance and histology. RESULTS: Sixty-three patients were randomized, 31 to receive essential fatty acid treatment and 32 to receive placebo. Disease relapse rates were similar at 12 months (placebo, 38%; essential fatty acids, 55%), as were changes in sigmoidoscopic grade from baseline. CONCLUSIONS: The supplementation of the diet with this combination of essential fatty acids does not prolong the period of disease remission of ulcerative colitis.

Three-year prospective validation of a pre-endoscopic risk stratification in patients with acute upper-gastrointestinal haemorrhage.

OBJECTIVE: To assess the accuracy of a risk stratification that is used at initial assessment to identify groups with increased risk of mortality and requirement for urgent treatment intervention. DESIGN: Prospective assessment of risk stratification in consecutive patients with acute upper-gastrointestinal haemorrhage. METHODS: Over a 3-year period, 1349 consecutive patients with acute upper-gastrointestinal haemorrhage presenting to a single teaching hospital were prospectively risk stratified before endoscopy and followed up for outcome. MAIN OUTCOME MEASURES: Two-week, all-cause mortality, re-bleeding, and need for urgent treatment intervention. RESULTS: Stratification within the high-risk group predicted a significant increased risk of 2-week, all-cause mortality (P < 0.001) when compared with intermediate- and low-risk patients (11.8%, 3% and 0%, respectively), re-bleeding (P < 0.001) (44.1%, 2.3% and 0%, respectively), and need for urgent treatment intervention (P < 0.001) (71%, 40.6% and 2.6%, respectively). CONCLUSIONS: Over a 3-year period, medical staff at this institution have routinely used this risk stratification, which identifies groups of patients at high and low risk of mortality, re-bleeding and need for urgent treatment intervention following acute upper-gastrointestinal haemorrhage. Use of this risk stratification should allow targeting of more intensive treatment where it might be of most benefit. Those patients at lowest risk from outpatient management are also identified.