Francesco Azzaroli

Adverse effects of proton pump inhibitors.

Proton pump inhibitors (PPI) are very effective drugs used largely in acid related disorders. During the last years concern have been raised regarding their overutilisation in benign condition, such as gastroesophageal reflux disease. The debate focussed also on the risk of adverse events related to long term use of PPI. Apart of the case of Helicobacter Pylori (H. Pylori) positive patients, in whose long term acid suppression lead to the development of corpus predominant atrophic gastritis, precursor of cancer; the other assumed adverse events, have never been demonstrated in prospective studies. The attention should move towards the appropriate prescription of PPI, rather than the fear adverse effects of PPI. In fact, in clinical practise, PPI are often prescribed in patients without a specific acid related disease and continued long term based on their safety profile. This review focus on the main adverse events related to long term PPI use.

Pneumatosis cystoides intestinalis

Pneumatosis cystoides intestinalis (PCI) is a rare condition that may be associated with a variety of diseases. The presenting clinical picture may be very heterogeneous and represent a challenge for the clinician. In the present paper we describe both a common and an uncommon clinical presentation of PCI and review the pertaining literature. Our cases confirm that, apart from asymptomatic cases, the clinical presentation of PCI may be widely different and suggest that a new onset of stipsis might be the presenting symptom. Diagnosis might be suggested by a simple X-ray of the digestive tract showing a change in the characteristics of the intestinal wall in two-thirds of these patients. However, one third of the patients do not have a suggestive X-ray and require a computed tomography (CT) scan/nuclear magnetic resonance that may reveal a thickened bowel wall containing gas to confirm the diagnosis and distinguish PCI from intraluminal air or submucosal fat. CT also allows the detection of additional findings that may suggest an underlying, potentially worrisome cause of PCI such as bowel wall thickening, altered contrast mucosal enhancement, dilated bowel, soft tissue stranding, ascites and the presence of portal air. Our results also point out that clinicians and endoscopists should be aware of the possible presentations of PCI in order to correctly manage the patients affected with this disease and avoid unnecessary surgeries. The increasing number of colonoscopies performed for colon cancer screening makes PCI more frequently casually encountered and/or provoked, therefore the possible endoscopic appearances of this disease should be well known by endoscopists.

The Pharmacological Management of Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy is the most common liver disease occurring in the second half of pregnancy, characterized by pruritus and elevated serum bile acids often coupled to abnormal liver tests. Maternal prognosis is favourable with a complete symptom resolution after delivery, while preterm deliveries, fetal respiratory distress and stillbirths may occur. The goal of the pharmacological treatment of the disease is to improve maternal symptoms and biochemical alterations and, most importantly, to reduce fetal adverse events.The present manuscript will review the current knowledge on the pharmacological treatment of intrahepatic cholestasis of pregnancy.

High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy.

Background Ursodeoxycholic acid (UDCA) administration in intrahepatic cholestasis of pregnancy (ICP) induces bile acids (BA) efflux from the foetal compartment, but the molecular basis of this transplacental transport is only partially defined. Aim To determine if placental breast cancer resistance protein (BCRP), able to transport BA, is regulated by UDCA in ICP. Methods 32 pregnant women with ICP (14 untreated, 34.9±5.17 years; 18 treated with UDCA - 25 mg/Kg/day, 32.7±4.62 years,) and 12 healthy controls (33.4±3.32 years) agreed to participate in the study. Placentas were obtained at delivery and processed for membrane extraction. BCRP protein expression was evaluated by immunoblotting techniques and chemiluminescence quantified with a luminograph measuring emitted photons; mRNA expression with real time PCR. Statistical differences between groups were evaluated by ANOVA with Dunn’s Multiple Comparison test. Results BCRP was expressed only on the apical membrane of the syncytiotrophoblast. A significant difference was observed among the three groups both for mRNA (ANOVA, pu200a=u200a0.0074) and protein (ANOVA, p<0.0001) expression. BCRP expression was similar in controls and in the untreated ICP group. UDCA induced a significant increase in placental BCRP mRNA and protein expression compared to controls (350.7±106.3 vs 100±18.68% of controls, p<0.05 and 397.8±56.02 vs 100±11.44% of controls, p<0.001, respectively) and untreated ICP (90.29±17.59% of controls, p<0.05 and 155.0±13.87%, p<0.01). Conclusion Our results confirm that BCRP is expressed only on the apical membrane of the syncytiotrophoblast and show that ICP treatment with high dose UDCA significantly upregulates placental BCRP expression favouring BA efflux from the foetal compartment.

Transjugular intrahepatic portosystemic shunt placement for refractory ascites: a single-centre experience

Abstract Background. The presence of refractory ascites is a common indication for transjugular intrahepatic portosystemic shunt (TIPS). Different models have been proposed for the prediction of survival after TIPS. The aim of this study was to evaluate the predictive factors associated with patients survival after TIPS placement for refractory ascites. Methods. Data from all consecutive patients undergoing TIPS placement in our center for refractory ascites between February 2003 and January 2008 were prospectively recorded. Results. Seventy-three patients (52M/21F; 57 ± 10 years) met the inclusion criteria; mean follow-up was 17 ± 2 months. Mean MELD value, before TIPS placement, was 15.7 ± 5.3. TIPS placement led to an effective resolution of refractory ascites in 54% of patients (n = 40) with no significant increase in severe portosystemic encephalopathy. The 1-year survival rate observed was 65.7%, while the overall mortality was 23.3% (n = 17) with a mean survival of 17 ± 14 months. MELD score (B = 0.161, p = 0.042), basal AST (B = 0.020, p = 0.090), and pre-TIPS HVPG (B = 0.016, p = 0.093) were independent predictors of overall mortality, while MELD (B = 0.419, p = 0.018) and HVPG (B = 0.223, p = 0.060) independently predicted 1-year survival. ROC curves identified MELD ≥ 19 and HVPG ≥ 25 mmHg as the best cut-off points for the prediction of 1-year mortality. Conclusions. TIPS is an effective treatment for refractory ascites in cirrhotic patients, leading to an effective ascites control in more than half patients. Improvement in patients selection criteria could lead to better outcome and survival after this procedure. Liver function (MELD), presence of active necroinflammation (AST), and portal hypertension (HVPG) are independent predictors of patients outcome after TIPS.

Generation of a Novel Antibody Probe to the Apical Sodium-Dependent Bile Acid Transporter That Inhibits Ileal Bile Acid Absorption

Intestinal bile acid absorption is mediated by a sodium-dependent transporter located in the brush border apical membrane of ileocytes. The transmembrane topology and the role of individual amino acid residues in the bile acid transport process have been investigated by means of various experimental approaches, leading to multiple hypotheses. We raised a monoclonal antibody against a segment of the transporter comprising vicinal cysteine residues, in order to evaluate its functional role. A 14 amino acid peptide, corresponding to amino acids 104-117 of the transporter, was synthesized, and a monoclonal anti-peptide antibody was raised. In vitro uptake-inhibition studies in the presence of the monoclonal anti-peptide antibody were performed using ileal brush border membrane vesicles. Rabbit ileum was perfused in vivo with 5 mM taurocholic acid in the presence of the monoclonal antibody, and bile acid absorption inhibition was evaluated. The anti-peptide monoclonal antibody significantly reduced the in vitro uptake and in vivo absorption of taurocholic acid. The present data demonstrate the functional relevance of the 104-117 peptide segment and report the generation of a novel antibody against the apical sodium-dependent bile acid transporter (ASBT) that may be used as a therapeutic agent in hypercholesterolemia and in cholestatic pruritus.

A new model for portal protein profile analysis in course of ileal intraluminal bile acid infusion using an in situ perfused rat intestine.

Due to the importance of intestinal transport in pharmacological studies and the emerging role of intestinal signaling activity in the gut-liver axis, we have developed a new method to investigate intestinal transport and liver signaling using cell and serum free mesenteric perfusion system in the rat. The method regarding bile acid active absorption was validated, then, the portal venous content was examined for fibroblast growth factor 15(FGF15), a putative signaling protein produced by the ileal enterocytes following bile acid absorption. After isolation and cannulation of the relevant vessels (abdominal aorta and portal vein), the abdominal aorta and the terminal ileum were infused with respectively Krebs-Ringer solution and tauroursodeoxycholate (TUDCA) and the absorption was assessed by its recovery in the portal vein. After immunoblot, liquid chromatography and mass spectrometry analysis were performed both on gel bands digestion products and on portal outflow samples in order to evaluate if negligible amounts of FGF15 were present in the portal circulation. TUDCA absorption was efficient, intestinal morphology and oxygen consumption were normal. Despite accurate analysis, we could not find FGF15. Our method proved to be reliable for studying the active bile acid absorption. It is also suitable to identify molecules produced by enterocytes and transferred to the portal circulation in response to absorption of different substances such as nutrients or drugs. Since FGF15 was not recovered we suggest the possibilities that this protein is produced in very little amounts, poorly transferred outside the cell, or that it is extremely unstable and rapidly degraded.

Correlation between Indocyanine green retention test and esophageal varices among patients with hepatocellular carcinoma.

We recently read with great interest the manuscript entitled ‘‘Prophylactic impact of endoscopic treatment for esophageal varices in liver resection: a prospective study’’ [1] in which Dr. Yamazaki et al. demonstrated the usefulness of endoscopic prophylactic treatment of esophageal varices (EV) and evaluated different risk factors for post-operative progression and bleeding. The authors observed that in patients with hepatocellular carcinoma (HCC), various laboratory variables were significantly different according to the presence or absence of EV; for example, indocyanine green (ICG) retention rate at 15 min (ICG-r15) was 10.9 % (2.1–37.7) in patients without EV and 15.4 % (3.7–46.0) in patients with EV (P 0.001). Finally, they observed that ICG-r15 [ 30 % is independently correlated with the risk of worsening varices. We recently reported our experience [2] aimed to evaluate ICG 15-min retention test as a non-invasive marker of PH and EV in patients with compensated liver cirrhosis in which we demonstrated that among patients with well-preserved liver function, ICG retention tests indirectly correlate with the presence and degree of portal hypertension and its complications (EV). According to the observations of Dr. Yamazaki et al., ICG-r15 correlated with the presence of esophageal varices; we found two different ICG-r15 cut-off points able to accurately rule out and rule in the presence of EV (10 % and C22.9 %, respectively). Liver-mediated uptake of organic anions (drugs or xenobiotics) is mainly mediated by organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs); ICG presents a potent inhibitor effect on OATP isoforms and Na-taurocholate transporting polypeptide (NTCP). OATP1B3 and NTCP are the transporters involved in the hepatic uptake of ICG [3]. The organic anion transporter peptides (OATP) 1B1 and 1B3 are variably and progressively lost during liver carcinogenesis; a previous study performed on patients who underwent OLT because of HCC demonstrated a correlation between the loss of OATP 1B1/ 1B3 and tumor morphological features [4]. These molecular findings could, in our opinion, justify the higher ICG-r15 values observed by Dr. Yamazaki et al. in their population. Indeed, the ICG retention test, among patients with liver cirrhosis, represents both liver parenchymal reserve and hepatic blood flow; in patients with HCC, this interplay is altered by the introduction of a third variable (cancer biology) and could not be argued. This comment refers to the article available at doi:10.1007/s00535013-0841-y.

Severe esophagitis in a patient with gastrointestinal stromal tumor treated with imatinib

kinase and represents the standard treatment for metastatic and unresectable gastrointestinal stromal tumor (GIST) [1, 2]. Imatinib is orally administered and generally well tolerated; cases of severe toxicity have rarely been described [3]. We report the first case of severe esophagitis occurring during imatinib administration. A 56-year-old man with a high-risk GIST underwent gastric resection and liver metastasectomy. He was started on treatment with imatinib 400 mg/day, which was prematurely suspended because of grade 3 dyspepsia. The patient restarted the treatment with imatinib when metastasis recurred in the liver and showed a good response (l Fig. 1). However, during the treatment the patient reported severe dysphagia and retrosternal burning pain that was aggravated by food and water intake, and he experienced a weight loss of 11 kg in 2 months. Proton pump inhibitors, antacids, and prokinetics were ineffective. The only identifiable responsible agent was imatinib. We suggested splitting the drug intake into two administrations and performed esophagogastroduodenoscopy shortly afterwards. This showed erosive–ulcerative lesions of the esophageal mucosa starting at 27 cm from the dental arches and ending at the gastroesophageal anastomosis (l Fig. 2). Some biopsies were taken and a diagnosis was made of grade III esophagitis with granulation tissue and necrotic material at the bottom of the ulcerative lesion (l Fig. 3). Two months after treatment suspension, the patient’s clinical condition is greatly improved. In our patient, severe esophagitis occurred during treatment with imatinib. This case demonstrates that in clinical practice it is necessary to pay attention to every symptom reported by patients before irreversible damage appears: firstly, in orSevere esophagitis in a patient with gastrointestinal stromal tumor treated with imatinib

An unusual cause of weight loss in a young Caucasian man

A 37-year-old Caucasian male presented to our institution for progressive weight loss and recurrent abdominal pain. An enteral CT performed in another centre showed a diffuse thickening of the duodenal walls suggestive of lymphoma or Crohn’s disease.nnEsophagogastroduodenoscopy showed a normal appearance of gastroesophageal mucosa while the duodenal and proximal jejunal mucosa appeared completely covered with pseudo-polypoid lesions with maximum size of 5u2005mm (figure 1A,B). At the ileocolonoscopy, the colorectal mucosa was diffusely micronodular (figure 1D), while the terminal ileum presented same lesions detected in the duodenum (figure 1C).nnnnFigurexa01 nEndoscopic view: (A) duodenum, (B) jejunum, (C) ileum, (D) colon.nnnnEnteroscopy confirmed the presence of pseudopolypoid lesions also in the jejunum …