Digestive and Liver Disease

Editorial Board

2010-08-01

A review of mast cells and liver disease: What have we learned?

Heather Francis, Cynthia J. Meininger — 2010-04-05

Abstract: Background: Mast cells are recognized as diverse and highly complicated cells. Aside from their notorious role in allergic inflammatory reactions, mast cells are being implicated in numerous disease processes from heart disease to cancer. Mast cells have been implicated in liver pathogenesis including hepatitis and host allograft rejection after liver transplantation.Aims: The aim of this review is to discuss the traditional function of mast cells, their location and anatomy with regards to hepatic vasculature and the role of mast cells in hepatic diseases including liver regeneration and rejection. Finally, we will touch on the role of mast cells in liver cancer. In conclusion, we hope that the reader comes away with a better understanding of the diverse and potential role(s) that mast cells may play in liver pathologies.

The search for a new endpoint for antiviral prophylaxis in hepatitis B virus transplanted patients

Daniel Shouval — 2010-08-01

Significant progress has been achieved in the prevention of hepatitis B virus (HBV) re-infection in at risk liver transplant patients since the landmark report by Samuel et al in 1993 . At present, the majority of transplant centers recommend long-term prophylaxis with a combination of hepatitis B immune globulin (HBIG) and a nucleos(t)ide analogue, while in a minority of centers monoprophylaxis with lamivudine is still practiced.The long-term protection rates of monotherapy for the newer nucleos(t)ide analogs are still unknown. In recent years, regimens containing HBIG in combination protocols have undergone major changes . There is currently only partial consensus regarding the dosing, the threshold of anti-HBs levels which requires re-administration, the interval between injections and route of administration of HBIG (i.e. i.v., i.m. or s.c.) and the optimal duration of treatment . Yet, regardless of some controversies on the preferred treatment protocols, the long-term risk of HBV re-infection post liver transplantation with combination strategies has now been reduced to <10% as compared to ∼80% before introduction of peri-and post transplant prophylaxis. At present, post transplantation treatment is usually prescribed indefinitely although some centers will restrict HBIG prophylaxis to a 6–12 months period post transplantation and than continue with a nucleos(t)ide analog monotherapy. Regardless of the combination protocol used, such treatment is costly and unavailable to the majority of patients residing in countries where HBV is most endemic. The absence of stopping rules for prophylaxis against graft HBV re-infection is derived from several observations which suggest that total eradication of persistent HBV infection is an elusive goal. HBV may persist for decades after clearance from the circulation and may “hide”in hepatocyte nuclei, in the molecular form of covalently closed circular DNA (cccDNA), even after anti-HBs seroconversion . Nuclear cccDNA with cellular histones and nuclear proteins form minichromosomes. and provides a template for HBV transcription‘of pregenomic RNA. . In general, cccDNA levels have been higher in HBeAg positive patients with a high viral load and lower but variable in HBeAg negative patients with a low viral load . Clearance of cccDNA is believed to be a pre-requisite for total resolution of persistent HBV infection. However, at present, cccDNA has been shown to be relatively resistant to treatment and short-term suppression and elimination of cccDNA even by the newer nucleos(t)ide analogs seem inefficient. A number of observations in animal models and in humans suggest that short-term treatment (i.e. 48 weeks) with peginterferon alpha and Lamivudine or Adefovir dipivoxil (and most probably also Entecavir and Tenofovir) may reduce the amount of intra-hepatic cccDNA but will not completely clear cccDNA . Werle et al, have predicted based on a mathematical model that clearance of cccDNA in persistent HBV infection will require at least 10 years of continuous anti-viral treatment . In view of this complex situation, it is important to identify cohorts of post transplant HBV patients who are more likely to clear cccDNA and consequently may cautiously discontinue anti-viral therapy.

Wireless capsule endoscopy: A proven role in obscure gastrointestinal bleeding

John Richard Cangemi — 2010-06-21

As new technologies become increasingly available, it is important to subject them to critical review before we can accurately establish their clinical role. Wireless capsule endoscopy (WCE), for example, has been in use for 10 years, yet its position in the diagnostic algorithm has yet to be fully defined. In the evaluation of obscure gastrointestinal (OGI) bleeding, WCE has proven to have a higher diagnostic yield when compared with a small bowel series in the detection of small bowel lesions (67% vs 8%) and clinically significant lesions (42% vs 6%) . Compared with push enteroscopy in patients with OGI bleeding, WCE proved clinically superior finding bleeding sites in 50% vs 24%. Yet these results cannot be applied to all patients with gastrointestinal bleeding and more importantly it remains to be established what clinical impact WCE has on patient outcomes.

Efficacy of H. pylori eradication with a sequential regimen followed by rescue therapy in clinical practice

Stefano Pontone, Monica Standoli, Rita Angelini, Paolo Pontone — 2010-01-11

Abstract: Background: Current Italian guidelines suggest sequential therapy as first-line therapy and a levofloxacin-based rescue therapy for Helicobacter pylori eradication. We evaluated the efficacy of these therapies in clinical practice.Methods: 84 consecutive patients with dyspeptic symptoms and proven H. pylori infection by either UBT or upper endoscopy with biopsies were enrolled. Patients received a 10-day sequential therapy with lansoprazole 30mg plus amoxycillin 1g (all twice daily) for the first 5 days, followed by lansoprazole 30mg, clarithromycin 500mg, and metronidazole 500mg (all twice daily) for the remaining 5 days. Eradication failure patients received triple therapy with lansoprazole 30mg, levofloxacin 250mg, and amoxycillin 1g (all twice daily) for 10 days.Results: Following the sequential therapy H. pylori eradication was achieved in 70/84 (83.3%; 95% CI=75.4–91.3) patients, and in 70/77 (90.9%; 95% CI=84.5–97.3) patients at ITT and PP analyses, respectively. The infection was cured in all 7 eradication failure patients by using second-line therapy.Conclusions: A sequential regimen as first-line therapy and a 10-day levofloxacin-based triple regimen in those patients who failed to clear the infection, appear to be a valid therapeutic strategy for management of H. pylori infection in clinical practice.

Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease

2010-01-11

Abstract: Aims: To determine mRNA expression of telomeric binding proteins in inflammatory bowel disease (IBD), and to note any effects of pharmacotherapy on telomere binding protein expression.Methods: Peripheral blood mononuclear cells (PBMC) obtained from 31 IBD patients and 13 controls were activated with phytohaemagglutinin and purified to yield activated (CD25+) T lymphocytes. TPP1, POT1, RAP1, TRF1 and TRF2 mRNA expression in PBMC and activated T lymphocytes was measured with RT-PCR.Results: In activated (CD25+) T lymphocytes, mean TRF2 mRNA levels were lower in both UC (6.6 vs 10, p=0.004) and CD subjects (6.9 vs 10; p=0.004). Similarly. in activated (CD25+) T lymphocytes mean RAP1 mRNA expression was significantly lower in UC subjects (4.5 vs 9.8, p=0.029) but not in CD subjects. In resting PBMC, mean TRF1 mRNA levels were lower in both UC (2.6 vs 3.5; p=0.008) and CD subjects (1.0 vs 3.5; p=0.04). No difference in PBMC and activated (CD25+) T lymphocytes mRNA levels of TPP1 and POT1 were noted in either UC or CD subjects. An association with 5-aminosalicylate therapy (R2=0.4) was only detected with RAP1 mRNA expression. TRF2 mRNA expression was inversely associated with disease duration only in UC subjects (p=0.05; R2=−0.6).Conclusions: The downregulation of TRF2 and RAP1 mRNA expression in CD25+ T-lymphocytes in IBD suggests that these telomere binding proteins play a role in telomere regulation and may contribute to the telomeric fusions and chromosomal abnormalities observed in UC. These findings may also indicate a systemic process of telomere uncapping which could represent a biomarker for IBD associated cancer risk.

13C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer®): Toward standardization for testing gastric emptying of solids

2010-01-29

Abstract: Background: Standardization of the 13C-octanoic acid breath test is still lacking.Aim: To evaluate the accuracy of the 13C-octanoic acid breath test using a new standardized ready-to-eat, gluten-, glucose-, and lactose-free muffin.Methods: Healthy subjects were recruited and sorted by sex and age. Patients with diabetic gastroparesis and untreated celiac disease with known gastric motility disorders were also tested with the new labelled muffin. Expired breath 13CO2 was analysed and t1/2 was calculated.Results: Overall, 131 healthy subjects were enrolled. The reference range of t1/2 was 88±29min with the value of 146min as the upper limit of normal range. No significant difference in t1/2 was found among subjects sorted by sex or age. The within-subject variability of t1/2 was 17%. Mean (±standard deviation) t1/2 values were 179±50min in patients with diabetic gastroparesis (n=8) and 151±20min in those with untreated celiac disease (n=11) (p≤0.001 vs controls).Conclusions: A new standardized test meal simplifies the execution of the 13C-octanoic acid breath test, is not influenced by sex or age, has low intra-individual variability, is palatable, does not cause side effects, and is able to evaluate gastric emptying in both patients and healthy controls. Moreover, it can be used in subjects with lactose intolerance, diabetes, and celiac disease.

Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition

2010-06-10

Abstract: Background: Small intestine essentially regulates cholesterol homeostasis.Aims: To evaluate cholesterol metabolism in short bowel syndrome (SBS).Methods: Cholesterol precursors (e.g., cholestenol, desmosterol and lathosterol) and plant sterols (campesterol and sitosterol), respective markers of cholesterol synthesis and absorption, were determined in SBS patients (n=12) an average of 31 months after weaning off parenteral nutrition and in age-matched controls (n=80).Results: Among patients, serum cholesterol precursor sterol to cholesterol ratios were 2–10 times higher (P<0.0001 for each). Those without any remaining ileum had 1.2–2.8 times higher precursor sterol to cholesterol ratios than those with an ileal remnant (P<0.05 for each). Serum cholesterol concentration, campesterol/cholesterol and campesterol/sitosterol were 34–39% lower (P<0.05 for each) in relation to controls. Bile acid absorption was markedly impaired (2.4 (0.2–3.2)%). Plant sterol ratios reflected the absolute length of remaining jejunum (r=0.625–0.663), and precursor sterol ratios inversely that of ileum (r=−0.589 to 0.750, P<0.05 for all).Conclusion: After weaning off parenteral nutrition, patients with pediatric onset SBS continue to have marked intestinal malabsorption of bile acids and moderate cholesterol malabsorption resulting in decreased serum cholesterol despite a marked compensatory increase in cholesterol synthesis.

Unexplained iron deficiency anaemia: Is it worthwhile to perform capsule endoscopy?

2010-03-15

Abstract: Background: In around 30% of iron deficiency anaemia (IDA) cases a definite diagnosis cannot be made.Aim: To investigate the role of capsule endoscopy (CE) in detecting lesions in patients with unexplained IDA after a negative endoscopic, serologic and haematologic diagnostic work up and its possible role in influencing clinical outcome.Methods: 138 patients suffering from IDA were identified among 650 consecutive patients undergoing CE at our unit.Results: CE revealed the following positive findings in 91/138 patients: angiodysplasias in 51 patients; jejunal and/or ileal micro-ulcerations in 12; tumours/polyps in 9; erosive gastritis in 4; Crohn's disease in 5; jejunal villous atrophy in 5; a solitary ileal ulcer in 1 and active bleeding in the last 4 patients. Follow up data were available for 80/91 patients (87.9%). In 15 out of 46 patients with angiodysplasias IDA spontaneously resolved without any treatment; 9 patients required iron supplementation; 10 patients healed after lanreotide administration; APC was performed in 9 out of 46 patients and 3 patients underwent regular blood transfusion without any success on IDA. 10 out of the 12 patients with small bowel micro-ulcers spontaneously recovered from IDA whilst 2 patients after iron supplementation. All 9 patients affected by tumours/polyps were surgically addressed. In all erosive gastritis cases, patients recovered from IDA after PPI and Helicobacter pylori eradication. Four patients with Crohn's disease diagnosis restored to health with medical therapy. One out of the 4 patients with jejunal villous atrophy and the sole patient with a solitary ileal ulcer spontaneously healed. In 1 out of 3 patients with active bleeding IDA resolved without further treatment after blood transfusion whilst 2 patients were referred for surgical treatment. At follow up, complete resolution of IDA was achieved in 96.25%.Conclusions: Small bowel investigation is a matter of great importance in IDA patients after negative upper and lower gastrointestinal endoscopy.

ERCP-induced and non-ERCP-induced acute pancreatitis: Two distinct clinical entities with different outcomes in mild and severe form?

2009-12-17

Abstract: Background: Acute pancreatitis is a complication of endoscopic retrograde cholangio-pancreatography. Aim of the study was to compare endoscopic retrograde cholangio-pancreatography-related acute pancreatitis with attacks caused by other factors.Methods: A series of consecutive patients with non-endoscopic retrograde cholangio-pancreatography-related acute pancreatitis referred to our hospital in 2007–2008 were examined retrospectively, and compared with the same number of patients with post-endoscopic retrograde cholangio-pancreatography acute pancreatitis done in the same institution. Both groups comprised 116 patients and were comparable for mean age, sex, and body mass index. Duration of abdominal pain, pancreatic enzyme elevation, hospital stay, and type of analgesia administered were retrieved.Results: There were no differences between the groups as regards the severity of pancreatitis, mortality rate and hospitalisation, although mortality was double in severe post-endoscopic retrograde cholangio-pancreatography acute pancreatitis. In the mild acute pancreatitis cases, serum amylase fell 50% from the peak in a mean of 46.4h (range 24–72) in group 1 and 38.9h (range 24–72) in group 2 (p<0.001). The peak amylase serum level halved within 48h in 73.6% of cases with non-endoscopic retrograde cholangio-pancreatography-related acute pancreatitis, and in 92% of patients with endoscopic retrograde cholangio-pancreatography-related acute pancreatitis (p<0.001).Conclusions: Non-endoscopic retrograde cholangio-pancreatography- and endoscopic retrograde cholangio-pancreatography-induced pancreatitis did not differ as regards severity, hospital stay or mortality; in mild pancreatitis, serum amylase halved significantly sooner in post-endoscopic retrograde cholangio-pancreatography cases.

Garlic extract prevents CCl4-induced liver fibrosis in rats: The role of tissue transglutaminase

2009-12-09

Abstract: Background and aim: Tissue transglutaminase contributes to liver damage in the development of hepatic fibrosis. In a model of neurodegeneration, the therapeutic benefit of cystamine has been partly attributed to its inhibition of transglutaminase activity. Garlic extract contains many compounds structurally related to cystamine. We investigated the anti-fibrotic effect of garlic extract and cystamine as specific tissue transglutaminase inhibitors.Methods: Rat liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4) for 7 weeks. Cystamine or garlic extract was administrated by daily intraperitoneal injection, starting from the day after the first administration of CCl4. Hepatic function, histology, tissue transglutaminase immunostaining and image analysis to quantify Red Sirius stained collagen deposition were examined. Reverse transcription-polymerase chain reaction to detect alpha-SMA, IL-1β and tissue transglutaminase expression and Western blot for tissue transglutaminase protein amount were performed. Transglutaminase activity was assayed on liver homogenates by a radio-enzymatic method.Results: Transglutaminase activity was increased in CCl4 group and reduced by cystamine and garlic extract (p<0.05). Treatment with cystamine and garlic extract reduced the liver fibrosis and collagen deposition, particularly in the garlic extract group (p<0.01). Moreover, the liver damage improved and serum alanine aminotransferase was decreased (p<0.05). Tissue transglutaminase immunolocalised with collagen fibres and is mainly found in the ECM of damaged liver. Alpha-SMA, IL-1β, tissue transglutaminase mRNA and tissue transglutaminase protein were down-regulated in the cystamine and garlic extract groups compared to controls.Conclusion: These findings concurrently suggest that transglutaminase may play a pivotal role in the pathogenesis of liver fibrosis and may identify garlic cystamine-like molecules as a potential therapeutic strategy in the treatment of liver injury.

Total and covalently closed circular DNA detection in liver tissue of long-term survivors transplanted for HBV-related cirrhosis

2010-01-25

Abstract: Background: Life-long prophylaxis against HBV recurrence is recommended in patients transplanted for HBV-related disease. The risk of HBV reactivation is due to persistence of covalently closed circular (ccc) DNA in hepatocytes. Whether cccDNA persists in livers of long-term transplant survivors who received conventional prophylaxis is unknown.Aim: To investigate the presence of intrahepatic total and cccDNA in transplanted patients with no evidence of biochemical markers of HBV recurrence.Methods: Intrahepatic total and cccDNA were assessed using sensitive nested and real-time PCR from 44 HBsAg-positive patients (75% male; mean age 55.2±8.9 years) who had undetectable serum HBV-DNA at transplant. The mean follow-up after transplant was 88.3 months (range, 18–159).Results: One patient underwent HBV recurrence after transplant and was the only who tested positive for both intrahepatic total HBV-DNA and cccDNA. Of the 43 patients negative for all serological markers of HBV infection, only 2 tested positive for intrahepatic total HBV-DNA, but none for cccDNA.Conclusions: Most patients with undetectable HBV-DNA at transplant, who received conventional HBV prophylaxis, have no evidence of intrahepatic total HBV-DNA and cccDNA. cccDNA should be considered a new additional diagnostic tool, also to identify patients at low risk of HBV recurrence after liver transplantation.

Intrahepatic IgG/IgM plasma cells ratio helps in classifying autoimmune liver diseases

2010-01-08

Abstract: Background/Aim: Plasma cells infiltrate in the liver is a prototype lesion of autoimmune liver diseases. The possible role of plasma cells isotyping (IgM and IgG) in the liver in the diagnostic definition of autoimmune liver disease, and particularly in variant syndromes such as autoimmune cholangitis and the primary biliary cirrhosis/autoimmune hepatitis overlap syndrome, is less defined.Methods: We analysed the clinical, serological and histological features of 83 patients with autoimmune liver disease (40 primary biliary cirrhosis, 20 autoimmune hepatitis, 13 primary sclerosing cholangitis, 4 autoimmune cholangitis and 6 overlap syndrome) compared to 34 patients with chronic hepatitis C and evaluated the expression of IgM and IgG plasma cells in their liver by immunostaining.Results: By Spearman's correlation, the mean-counts of IgM plasma cells in portal tracts were significantly correlated with female gender, serum alkaline phosphatase, gamma-glutamyl transferase and IgM values, positivity for anti-mitochondrial antibody-M2 and, on liver biopsy, with bile duct changes, orcein-positive granules and granulomas. Whereas IgG plasma cells resulted more correlated with alanine aminotransferase levels. IgG/IgM ratio lower than 1 was found no only in primary biliary cirrhosis but also in all patients with autoimmune cholangitis. Conversely, all patients with overlap syndrome showed IgG/IgM ratio higher than 1.Conclusion: Immunostaining for IgM and IgG plasma cells on liver tissue can be a valuable parameter for better diagnosis of autoimmune liver disease and also for variant or mixed syndromes.

Congenital Extrahepatic Portosystemic shunts (CEPS) Type Ib: MDCT finding

Settimo Caruso, Silvia Riva, Marco Spada, Angelo Luca, Bruno Gridelli — 2009-04-09

Type I CEPS is a rare anomaly frequently associated with other congenital anomalies, more frequent in females (74%), and characterized by drainage into the systemic vein bypassing the liver. CEPS, usually asymptomatic, can cause minimal abnormalities of liver enzymes. In adulthood, CEPS is often complicated by hepatic encephalopathy, hepatopulmonary syndrome or hepatic tumors .

A new practical alternative for tumoural gastrointestinal bleeding: Ankaferd blood stopper

Ersan Ozaslan, Tugrul Purnak, Ayla Yildiz, Ibrahim C. Haznedaroglu — 2009-12-11

We read with great interest the paper written by Kurt et al. , describing the beneficial haemostatic effect of Ankaferd blood stopper (ABS) in 10 cases of neoplastic gastrointestinal (GI) bleeding. We would like to present our ABS experience in similar cases, and add a few comments about their results.

The combined application of advanced endoscopic imaging techniques may increase the duodenal villous morphology definition in suspected celiac disease

Paolo Fedeli, Giovanni Gasbarrini, Giovanni Cammarota — 2009-12-21

We read with interest the commentary by Cucchiara and Di Nardo on the ability of advanced endoscopic imaging techniques to identify celiac disease (CD) . In this paper, the authors point out the role in the diagnosis of CD of optical coherence tomography, which has been reported by Masci et al. having a sensitivity and specificity of 82% and 100%, respectively . The authors also give a rapid overview of results obtained in identifying CD by other endoscopic tools such as high resolution endoscopy and water-immersion technique, as well as the promising results obtained in case series by confocal endomicroscopy.

Comment to “The efficacy of Helicobacter pylori eradication regimen with and without vitamin C supplementation”

Levent Filik — 2009-12-14

I read with a great interest the recently published article by Zojaji et al. . The article has important outcomes supporting the favourable effects of vitamin C on H. pylori eradication rates. However, there are some issues to be discussed. First one is the study population features. The authors did not define the previous H. pylori treatment history of patients. Are there any patients with a history of previous H. pylori treatment? If yes, the effect on the study results should be discussed. Secondly, vitamin C dietary consumption of patients should be reported and the impact on the study results should be considered. Thirdly, even though the eradication rates of new regimens in controlled studies are generally higher than 90%, the efficacy rates in clinical practice is somehow lower. In the literature, this is attributed to genetic composition and antibiotic resistance of H. pylori, and patients’ geographical localization . Lastly, untoward effects of vitamin C supplementation should also be considered . H. pylori is still a common health problem especially in the developing world and adverse effects (increased iron absorption, kidney stones, etc.) should also be considered before it is suggested to be included as a part of H. pylori treatment regimens.