Alcoholic disease: Liver and beyond

The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world’s third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the “necrosis-fibrosis” sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract.

Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review

AIM: To investigate the efficacy(survival) and safety of treatments for recurrent hepatocellular carcinoma(HCC) in liver transplantation(LT) patients.METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a fulltext evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies.RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo(range 2-132 mo). The majority of patients(67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates(42 and 18 mo, res-pectively). However, Sorafenib, especially when combined with m TOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment.

Cancer stem cell hypothesis and gastric carcinogenesis: Experimental evidence and unsolved questions

Traditionally, the clonal evolution model has been used to explain gastric cancer (GC) growth dynamics. According to this model, GC cells result from multiple mutations over time resulting in a population of continually diversifying cells. This heterogeneity enables the survival of different clones under particular conditions allowing growth at metastatic locations or resistance to chemotherapeutics. Cancer stem cell (CSC) theory completely overturns this traditional understanding of cancer suggesting that only CSCs can self-renew and promote tumor growth. CSCs are relatively refractory to conventional therapies, thus explaining why anti-cancer therapies are far from curative and why relapses of cancer are frequent. The identification of the CSC component of a tumor might, thus, open new therapeutic perspective based on the selective targeting of this small population of cells. In this review we examine the current scientific evidence supporting the existence of CSC in gastric tumors and analyze the main unsolved questions of this difficult field of cancer research.

Wilson's disease: Prospective developments towards new therapies

Wilson's disease(WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7 B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7 B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.

Large Brunner's gland adenoma:Case report and literature review

Brunner＇s gland adenoma （BGA） is a very rare benign tumour of the duodenum, which is usually asymptomatic and discovered incidentally at endoscopy. Occasionally, this lesion may be large, causing upper gastrointestinal haemorrhage or intestinal obstruction. The case had a large Brunner＇s gland adenoma, presenting melena that was managed by endoscopic excision.

Screening for and surveillance of gastric cancer

Although the prevalence of gastric cancer(GC) progressively decreased during the last decades,due to improved dietary habit,introduction of food refrigeration and recovered socio-economic level,it still accounts for 10% of the total cancer-related deaths. The best strategy to reduce the mortality for GC is to schedule appropriate screening and surveillance programs,that rises many relevant concerns taking into account its worldwide variability,natural history,diagnostic tools,therapeutic strategies,and cost-effectiveness. Intestinal-type,the most frequent GC histotype,develops through a multistep process triggered by Helicobacter pylori(H. pylori) and progressing from gastritis to atrophy,intestinal metaplasia(IM),and dysplasia. However,the majority of patients infected with H. pylori and carrying premalignant lesions do not develop GC. Therefore,it remains unclear who should be screened,when the screening should be started and how the screening should be performed. It seems reasonable that screening programs should target the general population in eastern countries,at high prevalence of GC and the high-risk subjects in western countries,at low prevalence of GC.As far as concern surveillance,currently,we are lacking of standardized international recommendations and many features have to be defined regarding the optimal diagnostic approach,the patients at higher risk,the best timing and the cost-effectiveness.Anyway,patients with corpus atrophic gastritis,extensive incomplete IM and dysplasia should enter a surveillance program.At present,screening and surveillance programs need further studies to draw worldwide reliable recommendations and evaluate the impact on mortality for GC.

Computed tomography findings of pneumatosis and portomesenteric venous gas in acute bowel ischemia

AIM:To use more representative sample size to evaluate whether computed tomography(CT)scan evidence of the concomitant presence of pneumatosis and portomesenteric venous gas is a predictor of transmural bowel necrosis.METHODS:Data from 208 patients who were referred for a diagnosis of bowel ischemia were retrospectively reviewed.Only patients who underwent a surgical intervention following a diagnosis of bowel ischemia who also had a post-operative histological confirmation of such a diagnosis were included.Patients were split into two groups according to the presence of histological evidence of transmural bowel ischemia(case group)or partial bowel ischemia(control group).CT images were reviewed for findings of ischemia,including mural thickening,pneumatosis,bowel distension,portomesenteric venous gas and arterial or venous thrombi.RESULTS:A total of 248 subjects who underwent surgery for bowel ischemia were identified.Among the208 subjects enrolled in our study,transmural bowel necrosis was identified in 121 subjects(case group),and partial bowel necrosis was identified in 87 subjects(control group).Based on CT findings,including mural thickening,bowel distension,pneumatosis,pneumatosis plus portomesenteric venous gas and presence of thrombi or emboli,there were no significant differences between the case and control groups.The concomitant presence of pneumatosis and porto-mesenteric venous gas showed an odds ratio of 1.95(95%CI:0.491-7.775,P=0.342)for the presence of transmural necrosis.The presence of pneumatosis plus porto-mesenteric venous gas exhibited good specificity(83%)but low sensitivity(17%)in the identification of transmural bowel infarction.Accordingly,the positive and negative predictive values were 60% and 17%,respectively.CONCLUSION:Although pneumatosis plus porto-mesenteric venous gas is associated with bowel ischemia,we have demonstrated that their co-occurrence cannot be used as diagnostic signs of transmural necrosis.

Diet,H pylori infection and gastric cancer:Evidence and controversies

Despite decreasing incidence and mortality rates, gastric cancer (GC) still remains the fourth most common cancer and the second most common cause of cancer-related deaths worldwide. Due to the limited treatment options, at present, prevention is likely to be the only effective means of controlling this disease. The success of a prevention strategy depends upon the understanding of etiological and pathogenic mechanisms underlying gastric carcinogenesis. The etiology of GC is multi-factorial, however, in the recent years, mounting evidence suggests that environmental factors play a key role. The most important environmental factors implicated in the pathogenesis of GC are diet and H pylori infection. Thus, modifications in lifestyle and dietary habit associated with eradication of H pylori infection could hypothetically represent the most promising potential targets for GC prevention. In this review we will address the evidence and the controversies on the role of these agents in noncardia GC by focusing on retrospective and prospective observational studies and interventional trials.

Long lasting response to second-line everolimus in kidney cancer

In the case presented here, everolimus was administered after first line therapy with sunitinib in a patient with metastatic renal cell carcinoma. The safety profile was excellent. The prolonged progression-free survival(PFS) obtained with everolimus in this case is of peculiar interest, as it is a multiple of the median PFS obtained in with everolimus in the regulatory trial. Such finding suggests that a subset of patients with renal cell carcinma may particularly benefit from everolimus.

Assessment of proximal gastric accommodation in patients with functional dyspepsia

Impaired gastric accommodation is one of the most important etiologic factors in the pathophysiology of functional dyspepsia.Ultrasound is a potential alternative method to study changes in gastric volume as a reflection of gastric accommodation.Ultrasound is suitable for patients because it is a non-invasive,easily repeated and non-radioactive procedure,and a previous study has demonstrated the feasibility of 3-dimensional ultrasound in examining functional dyspepsia.The brief article by Fan et al demonstrated that both the proximal gastric area and volume,measured by 2-and 3-dimensional ultrasound respectively,were significantly smaller in patients with functional dyspepsia than in healthy controls.These results are very interesting,but we raise the relevant point that it should have been mandatory to study both changes in gastric volume and their relationship with upper gastrointestinal symptoms in functional dyspepsia.In fact,the relationship between cardinal symptoms and several pathophysiologic mechanisms in functional dyspepsia remains a matter of debate.Moreover,further evaluation of distal gastric volume that has been previously implicated in the origin of functional dyspeptic symptoms is advisable.Therefore,impaired gastric accommodation does not serve as a clear marker of the cardinal symptoms experienced by patients with functional dyspepsia in daily life.

Growth hormone regulates intestinal ion transport through a modulation of the constitutive nitric oxide synthase-nitric oxide-cAMP pathway

AIM： Growth hormone （GH） directly interacts with the enterocyte stimulating ion absorption and reducing ion secretion induced by agonists of cAMR Since nitric oxide （NO） is involved in the regulation of transepithelial ion transport and acts as a second messenger for GH hemodynamic effects, we tested the hypothesis that NO may be involved in the resulting effects of GH on intestinal ion transport. METHODS： Electrical parameters reflecting transepithelial ion transport were measured in Caco-2 cell monolayers mounted in Ussing chambers and exposed to GH and cholera toxin （CT） alone or in combination, in the presence or absence of the NO synthase （NOS） inhibitor, Nω-nitro-L-arginine methyl ester （L-NAME）. Similar experiments were conducted to determine cAMP and nitrite/nitrate concentrations. NOS expression was assayed by Western blot analysis. RESULTS： L-NAME causes total abrogation of absorptive and antisecretory effects by GH on intestinal ion transport, In addition, L-NAME was able to inhibit the GH-effects on intracellular cAMP concentration under basal conditions and in response to CT, GH induced a Ca^2＋ -dependent increase of nitrites/nitrates production, indicating the involvement of the constitutive rather than the inducible NOS isoform, which was directly confirmed by Western blot analysis. CONCLUSION： These results suggest that the GH effects on intestinal ion transport, either under basal conditions or in the presence of cAMP-stimulated ion secretion, are mediated at an intracellular level by the activity of cNOS.

A case of multiple intra-abdominal splenosis with computed tomography and magnetic resonance imaging correlative findings

Hepatic splenosis refers to heterotopic auto- transplantation and implantation of splenic tissue resulting from the spillage of cells from the spleen after splenic trauma or splenectomy. The true incidence of splenosis is unknown, because this entity is usually an incidental finding at surgery. Splenic implants are usually multiple, and can be localized anywhere in the peritoneal cavity. Splenic implants in the peritoneal cavity may be confused with renal tumors, abdominal lymphomas and endometriosis. We describe computed tomography (CT) and magnetic resonance imaging (MRI) findings in a rare case of multiple intra-abdominal splenosis located along the hepatic surface and adjacent to the upper pole of the right kidney, mimicking a renal neoplasm.

Fecal calprotectin in coeliac disease

We would like to share with the readers the results of our experience in 50 celiac disease (CD) patients, enrolled between September 2012 and April 2013, who were referred to our third-level CD Unit. The fecal calprotectin (FC) concentration of 50 adults with newly diagnosed CD was compared to that of a control group of 50 healthy subjects. FC level was determined by enzyme linked immunosorbent assay with diagnostic cut-off of 75 μg/g. In addition, we tried to correlate the FC level with symptoms, histological severity of CD (Marsh grade) and level of tissue transglutaminase antibodies (aTg) in CD patients. Finally, FC level was increased in five CD patients and in four controls (10% vs 8%, P = NS); mean FC concentration of patients and controls were 57.7 (SD ± 29.1) and 45.1 (SD ± 38.4) respectively. Furthermore, no significant correlation was seen between FC levels and symptoms/Marsh grade/aTg. The five CD patients did not show inflammatory lesions (e.g., ulcers, erosions) at upper endoscopy. The four healthy controls with positive FC were followed-up for further six months; in this observational period they did not show clinical signs of any underlying disease. On these bases, we think that FC is not able to investigate the subclinical inflammatory changes of active CD and FC should be considered a useless tool in the diagnostic work-up of uncomplicated CD but it should be accompanied by aTg when ruling out organic disease in patients with irritable bowel syndrome.

Human leukocyte antigen DQ2/8 prevalence in non-celiac patients with gastrointestinal diseases

AIM: To investigate the prevalence of human leukocyte antigen (HLA) DQ2/8 alleles in Southern Italians with liver and gastrointestinal (GI) diseases outside of celiac disease. METHODS: HLA DQ2/8 status was assessed in 443 patients from three ambulatory gastroenterology clinics in Southern Italy (University of Federico Ⅱ, Naples, Loreto Crispi Hospital, Ruggi D'Aragona Hospital, Salerno). Patients were grouped based on disease status [pre-post transplant liver disease, esophageal/gastric organic and functional diseases, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)] and DQ2/8 alleles, which correspond to a celiac disease genetic risk gradient. Subject allele frequencies were compared to healthy Italian controls. RESULTS: One hundred and ninety-six out of four hundred and forty-three (44.2%) subjects, median age 56 years and 42.6% female, were DQ2/8 positive. When stratifying by disease we found that 86/188 (45.7%) patients with liver disease were HLA DQ2/8 positive, 39/73 (53.4%) with functional upper GI diseases and 19/41 (46.3%) with organic upper GI diseases were positive. Furthermore, 38/105 (36.2%) patients with IBS and 14/36 (38.9%) with IBD were HLA DQ2/8 positive (P = 0.21). Compared to healthy controls those with functional upper GI diseases disorders had a 1.8 times higher odds of DQ2/8 positivity. Those with liver disease had 1.3 times the odds, albeit not statistically significant, ofDQ2/8 positivity. Both those with IBS and IBD had a lower odds of DQ2/8 positivity compared to healthy controls. CONCLUSION: The proportion of individuals HLA DQ2/8 positive is higher in those with liver/upper functional GI disease and lower in IBS/IBD as compared to general population estimates.

Staple-line leak after sleve gastrectomy in obese patients: A hot topic in bariatric surgery

Laparoscopic sleeve gastrectomy is a surgical procedure that is being increasingly performed on obese patients. Among its complications, leaks are the most serious and life threatening. The placement of esophageal, covered, self-expandable metal stents in these cases has been performed by many authors but reports on the outcome of this procedure are limited and the technical aspects are not well defined. Stent migration is the main complication of the procedure and poses a challenge to the surgeon, with a limited number of options. Here we evaluate the technical and clinical outcome of a new, dedicated, self-expanding metal stent, comparing the advantages of this stent to those traditionally used to treat staple-line leak after sleeve gastrectomy. While published data are limited, they seem support the use of this kind of new stent as the best option for the stenting treatment of a staple-line leak after sleeve gastrectomy, over other kinds of stents. Further studies based on larger series are needed to better evaluate patient outcome.

Is liver biopsy mandatory in children with chronic hepatitis C?

Liver biopsy is considered the most accurate means to estimate the necroinflammatory activity and the extent of fibrosis. However, histology evaluation is an invasive procedure associated with risk to the patient, risk of sampling error and diagnostic inconsistencies due to inter- and intra-observer error. On the basis of histological studies performed so far, chronic hepatitis C in children appears morphologically benign in the majority of cases. At the Pediatric Liver Unit of our university, a total of 67 children with chronic hepatitis C underwent liver biopsy. Liver biopsy was repeated 5.5 years after the initial histological evaluation in 21 children. On a total number of 88 liver biopsies, micronodular cirrhosis was detected only in one genotype 1b-infected obese child. Since liver histology investigation of a child with chronic hepatitis C has few chances to highlight severe lesions, we question how liver biopsy helps in the management of children with chronic hepatitis C.

Contrast enhanced multi-detector CT and MR findings of a well-differentiated pancreatic vipoma

Pancreatic vipoma is an extremely rare tumor accounting for less than 2% of endocrine pancreatic neoplasms with a reported incidence of 0.1-0.6 per million. While cross-sectional imaging findings are usually not specific, exact localization of the tumor by means of either computed tomography(CT) or magnetic resonance(MR) is pivotal for surgical planning. However, cross-sectional imaging findings are usually not specific and further characterization of the tumor may only be achieved bysomatostatin-receptor scintigraphy(SRS). We report the case of a 70 years old female with a two years history of watery diarrhoea who was found to have a solid, inhomogeneously enhancing lesion at the level of the pancreatic tail at Gadolinium-enhanced MR(Somatom Trio 3T, Siemens, Germany). The tumor had been prospectively overlooked at a contrast-enhanced multi-detector CT(Aquilion 64, Toshiba, Japan) performed after i.v. bolus injection of only 100 cc of iodinated non ionic contrast media because of a chronic renal failure(3.4 mg/mL) but it was subsequently confirmed by SRS. The patient first underwent a successful symptomatic treatment with somatostatin analogues and was then submitted to a distal pancreasectomy with splenectomy to remove a capsulated whitish tumor which turned out to be a well-differentiated vipoma at histological and immuno-histochemical analysis.

Everolimus plus long-acting somatostatin analogs in thymic epithelial malignancies

Although thymic epithelial tumors(TETs) are rare in the general population, they represent the most frequently diagnosed primary malignant tumor of the anterior mediastinum. Unlike localized disease, metastatic disease is invariably fatal. While several chemotherapy agents have proven to be effective in TETs, somatostatin analogs are the only targeted agents with an established role in this disease. Everolimus is an m TOR inhibitor with multiple application in oncology. In this report, we show for the first time that everolimus was effective in two heavily pretreated patients with advanced TETs, with a progression-free survival longer than 1 year and minimal toxicity.

Obese children with fatty liver: Between reality and disease mongering

Following the current epidemic of obesity, the worldwide prevalence of nonalcoholic fatty liver disease(NAFLD)has increased with potential serious health implications. While it is established that in adults NAFLD can progress to end-stage liver disease in many cases, the risk of progression during childhood is less well defined. Since most obese children are not adherent to lifestyle modifications and hypocaloric diets, there is a growing number of studies on pharmacological interventions with the risk of disease mongering, the practice of widening the boundaries of illness in order to expand the markets for treatment. Here, we propose a critical appraisal of the best available evidence about long-term course of pediatric NAFLD and efficacy of treatments other than hypocaloric diet and physical exercise. As a result, the number of NAFLD children with a poor outcome is small in spite of the alarming tones used in some papers; large-scale longitudinal studies with longterm follow-up of pediatric NAFLD patients are lacking; the studies on ancillary pharmacological interventions have been performed in few patients with inconclusive and conflicting results.

Volvulus of the ascending colon in a non-rotated midgut:Plain film and MDCT findings

Colonic volvulus is a relatively uncommon cause of large bowel obstruction usually involving mobile,intraperitoneal,colonic segments.Congenital or acquired anatomic variation may be associated with an increased risk of colonic volvulus which can occasionally involve retro-peritoneal segments.We report a case of 54-year-old female who presented to our Institution to perform a plain abdominal film series for acute onset of cramping abdominal pain.Both the upright and supine films showed signs of acute colonic obstruction which was thought to be due to an internal hernia of the transverse colon into the lesser sac.The patient was therefore submitted to a multi-detector contrast-enhanced computed tomography(CT).CT findings were initially thought to be consistent with the presumed diagnosis of internal hernia but further evaluation and coronal reformatting clearly depicted the presence of a colonic volvulus possibly resulting from a retro-gastric colon.At surgery,a volvulus of the ascending colon was found and a right hemi-colectomy had to be performed.However,a non rotated midgut with a right-sided duodeno-jejunal flexure and a left sided colon was also found at laparotomy and over-looked in the pre-operative CT.Retrospective evaluation of CT images was therefore performed and a number of CT signs of intestinal malrotation could be identified.