Agostino Di Ciaula

Coordinate regulation of gallbladder motor function in the gut‐liver axis

Gallstones are one of the most common digestive diseases with an estimated prevalence of 10%‐15% in adults living in the western world, where cholesterol‐enriched gallstones represent 75%‐80% of all gallstones. In cholesterol gallstone disease, the gallbladder becomes the target organ of a complex metabolic disease. Indeed, a fine coordinated hepatobiliary and gastrointestinal function, including gallbladder motility in the fasting and postprandial state, is of crucial importance to prevent crystallization and precipitation of excess cholesterol in gallbladder bile. Also, gallbladder itself plays a physiopathological role in biliary lipid absorption. Here, we present a comprehensive view on the regulation of gallbladder motor function by focusing on recent discoveries in animal and human studies, and we discuss the role of the gallbladder in the pathogenesis of gallstone formation. (HEPATOLOGY 2008;47:2112–2126.)

Gallbladder motor function in gallstone patients: sonographic and in vitro studies on the role of gallstones, smooth muscle function and gallbladder wall inflammation

Gallbladder motility was studied by ultrasound in 100 healthy adult volunteers and 150 gallstone patients, in a subgroup of whom gallstone burden, type and number, gallbladder histology and tensiometric responses of gallbladder strips to cholecystokinin octapeptide were evaluated. Patients were divided into contractors (n = 108) and hypocontractors (n = 42), according to their gallbladder motility pattern in vivo. Contractors showed slower gallbladder emptying and increased fasting and postprandial residual volumes, although the ejected amount of bile was greater than that of controls (20.2 +/- SEM 1.1 vs 16.0 +/- 0.7 ml; p < 0.001). In contrast, hypocontractors exhibited slower and less complete gallbladder emptying than controls with a reduction in the absolute amount of ejected bile. Although gallbladder wall inflammation was mild and comparable in specimens from both groups of patients, the thickness of the muscular layer was greater in hypocontractors than in contractors (1073 +/- 76 vs 745 +/- 75 microns, p < 0.01) and related inversely to postprandial ejected volume (r = -0.42; p < 0.03; n = 32) but positively to gallstone volume (r = 0.40; p < 0.03; n = 32). Compared to contractors, gall-bladder muscle strips of hypocontractors exhibited a decrease in frequency and amplitude of spontaneous contraction and in maximal stress and receptor sensitivity to cholecystokinin octapeptide (0.1 nM-1 microM). Postprandial gallbladder evaculation was unaffected by stone number, and by the presence or absence of stone calcification. Gallstone volume was larger in hypocontractors (19.4 +/- 3.0 ml vs 9.6 +/- 0.9 ml, p < 0.001) than contractors. The comparison of in vitro contractility patterns between cholesterol, mixed and pigment stone patients showed a more severe defect in patients with cholesterol and mixed stones than in those with pigment calculi. In conclusion, in gallstone patients: (i) gallbladder motor dysfunction manifests mainly with increased fasting and postprandial residual volumes in contractors and with markedly increased postprandial residual volumes and decreased gallbladder emptying in hypocontractors; (ii) gallbladder kinetics seem to be influenced by stone volume and cholesterol content of calculi but not stone number, calcification or mild chronic cholecystitis; (iii) a form of hypertrophic leiomyopathy is observed in gallstone patients with the most impaired gallbladder motor function.

Slow-transit constipation: Solitary symptom of a systemic gastrointestinal disease

INTRODUCTION: Autonomic neuropathy is thought to play a role in the pathogenesis of slow-transit constipation, but other gastrointestinal organs may also be involved, even if they are symptom-free. We investigated whether motility in gastrointestinal organs other than the colon was impaired in patients with slow-transit constipation and whether the autonomic nervous system was involved. METHODS: Twenty-one consecutive patients (18 females; median age, 46 years) with severe chronic constipation (≤2 defecations/week and delayed colonic transit time) were studied. Autonomic neuropathy function was tested with esophageal manometry, gastric and gallbladder emptying (fasting and postprandial motility) by ultrasonography, orocecal transit time (H2-breath test), colonic transit time (radiopaque markers), and anorectal volumetric manometry. The integrity of the autonomic nervous system was assessed by a quantitative sweat-spot test for preganglionic and postganglionic fibers, tilt-table test, and Valsalva electrocardiogram R-R ratio. RESULTS: Esophageal manometry showed gastroesophageal reflux or absence of peristalsis in five of the seven patients examined. Gallbladder dysmotility (i.e., increased fasting, postprandial residual volume, or both) was observed in 6 of 14 (43 percent) patients. Gastric emptying was decreased in 13 of 17 (76 percent) patients. Orocecal transit time was delayed in 18 of 20 (90 percent) patients; median transit time was 160 (range, 90–200) minutes. Median colonic transit time was 97 (range, 64–140) hours. Anorectal function showed abnormal rectoanal inhibitory reflex and decreased rectal sensitivity in 11 of 19 (58 percent) patients. Signs of autonomic neuropathy of the sympathetic cholinergic system were found in 14 of 18 (78 percent) patients. Only one of nine patients had vagal abnormalities detected with the Valsalva test and four of five patients with a history of orthostatic hypotension had a positive tilt-table test. CONCLUSIONS: Slow-transit constipation may be associated with impaired function of other gastrointestinal organs. More than 70 percent of patients with slow-transit constipation present some degree of autonomic neuropathy. Severe constipation may be the main complaint in patients with a systemic disease involving several organs and possibly involving the autonomic nervous system. This should be considered in the management of such cases.

Gastrointestinal symptoms and motility disorders in patients with systemic scleroderma

BackgroundStudies on gastrointestinal symptoms, dysfunctions, and neurological disorders in systemic scleroderma are lacking so far.MethodsThirty-eight scleroderma patients (34 limited, 4 diffuse), 60 healthy controls and 68 dyspeptic controls were scored for upper and lower gastrointestinal symptoms (dyspepsia, bowel habits), gastric and gallbladder emptying to liquid meal (functional ultrasonography) and small bowel transit (H2-breath test). Autonomic nerve function was assessed by cardiovascular tests.ResultsThe score for dyspepsia (mainly gastric fullness) was greater in scleroderma patients than healthy controls, but lower than dyspeptic controls who had multiple symptoms, instead. Scleroderma patients with dyspepsia had a longer disease duration. Fasting antral area and postprandial antral dilatation were smaller in scleroderma patients than dyspeptic and healthy controls. Gastric emptying was delayed in both scleroderma patients (particularly in those with abnormal dyspeptic score) and dyspeptic controls, who also showed a larger residual area. Despite gallbladder fasting and postprandial volumes were comparable across the three groups, gallbladder refilling appeared delayed in dyspeptic controls and mainly dependent on delayed gastric emptying in scleroderma. Small intestinal transit was also delayed in 74% of scleroderma and 66% of dyspeptic controls. Bowel habits were similar among the three groups. Autonomic neuropathy was not associated with dyspepsia, gastric and gallbladder motility and small intestinal transit.ConclusionIn scleroderma patients dyspepsia (mainly gastric fullness), restricted distension of the gastric antrum and diffuse gastrointestinal dysmotility are frequent features. These defects are independent from the occurrence of autonomic neuropathy.

Targets for Current Pharmacologic Therapy in Cholesterol Gallstone Disease

Gallstone disease is a frequent condition throughout the world and, cholesterol stones are the most frequent form in Western countries. The standard treatment of symptomatic gallstone subjects is laparoscopic cholecystectomy. The selection of patients amenable for nonsurgical, medical therapy is of key importance; a careful analysis should consider the natural history of the disease and the overall costs of therapy. Only patients with mild symptoms and small, uncalcified cholesterol gallstones in a functioning gallbladder with a patent cystic duct are considered for oral litholysis by hydrophilic ursodeoxycholic acid, in the hope of achieving cholesterol desaturation of bile and progressive stone dissolution. Recent studies have raised the possibility that cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, may offer, alone or in combination, additional medical therapeutic tools for treating cholesterol gallstones. Recent perspectives on medical treatment of cholesterol gallstone disease are discussed in this article.

Therapy of gallstone disease: What it was, what it is, what it will be

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors, increasing age, female gender, and metabolic factors. Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones, new perspectives regarding medical therapy of cholelithiasis are currently under discussion, also taking into account the pathogenesis of gallstones, the natural history of the disease and the analysis of the overall costs of therapy. A careful selection of patients may lead to successful non-surgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones. The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations, suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, might be proposed as additional approaches for treating cholesterol gallstones. In this review we discuss old, recent and future perspectives on medical treatment of cholesterol cholelithiasis.

Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

Medicinal Treatments of Cholesterol Gallstones: Old, Current and New Perspectives

Cholesterol cholelithiasis is one of the most common and costly digestive diseases. Although gallstones are usually asymptomatic and no treatment is generally required, it is imperative to treat symptomatic gallstones with or without complicated conditions. Laparoscopic cholecystectomy is first-line therapy for symptomatic gallstones. By contrast, a cautious study on the natural history of the disease and costs of therapy, indicates that non-surgical treatment of gallstones is currently restricted to a subgroup of patients with mild symptoms or with small radiolucent cholesterol gallstones in a functioning gallbladder. Appropriate selection of patients suitable for medical therapy is therefore of key importance. Oral litholysis with the hydrophilic bile acid ursodeoxycholic acid induces cholesterol desaturation of bile and may lead to gallstone dissolution in patients with small, radiolucent, cholesterol-enriched stones in a functioning gallbladder with a patent cystic duct. Recent studies from experimental animal models and preliminary findings in humans also suggest that blocking intestinal absorption of cholesterol with the powerful, specific, and effective NPC1L1 inhibitor ezetimibe, may offer a novel and exciting strategy for the treatment of cholesterol gallstones. A similar possibility might arise from manipulation of specific nuclear receptors involved in cholesterol and bile acid homeostasis. Current views and perspectives on medicinal treatment of cholesterol gallstone disease are discussed here.

Gallbladder and gastric motility in obese newborns, pre‐adolescents and adults

Background and Aim:  Impaired gallbladder and gastric motility have been associated with obesity in adults. The timing of appearance of this dysfunction, however, is unclear.

Emergency visits and hospital admissions in aged people living close to a gas-fired power plant

BACKGROUND Combustion of natural gas for energy generation produces less pollutants than coke/oil. However, little is known about the short-term effect of pollution generated by gas-fired power plants on the health of elderly people. METHODS During three months, daily emergency visits/hospital admissions of subjects living within 3 km from a gas-fueled power plant were counted and related to ambient concentrations of nitrogen dioxide (NO(2)) and particulate matter of median aerometric diameter <10 μm (PM10). A generalized additive model served to correlate visits/hospital admissions to pollutants, controlling for meteorological confounders. RESULTS Mean air concentrations of PM10 and NO(2) were higher after-than before the start of operation of the plant, with the highest concentrations recorded within 1 km. Although pollutants were below the limits set by the European legislation, in elderly people there was a positive correlation between the number of emergency visits and daily air concentrations of PM10 and NO(2), as measured at 1 and 3 km from the plant. In subjects aged 70 years or more, the number of hospital admissions was positively correlated with PM10 levels measured within 3 km from the power plant, whereas in older subjects (≥80 year) it was also significantly linked with the lowest air concentration of PM10 (measured at 6 km from the plant). DISCUSSION Combustion of natural gas for energy generation produces a rise in air concentration of PM10 and NO(2) close to the plant, with a concentration-dependent increment of daily emergency visits and hospital admissions in elderly people, and with an age-dependent susceptibility.