Vincenzo Savarino

Liver enzyme alteration: a guide for clinicians

ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

A Comparison of Five Maintenance Therapies for Reflux Esophagitis

BACKGROUND Patients with reflux esophagitis have a high rate of relapse within one year after therapy is discontinued. METHODS We enrolled 175 adults with endoscopy-confirmed reflux esophagitis in a prospective study comparing five maintenance therapies. All the patients were initially treated with omeprazole (40 mg orally once a day) for four to eight weeks, and healing was confirmed by endoscopy. Participants were then stratified according to their initial grade of esophagitis and randomly assigned to 12 months of treatment with one of the following: cisapride (10 mg three times a day), ranitidine (150 mg three times a day), omeprazole (20 mg per day), ranitidine plus cisapride (10 mg three times a day), or omeprazole plus cisapride. Endoscopy was repeated after 6 and 12 months of treatment; the endoscopists were blinded to the treatment assignments. Remission was defined as the absence of esophageal lesions on scheduled or unscheduled follow-up endoscopy. RESULTS In an intention-to-treat analysis, the numbers of patients in continued remission at 12 months were 19 of 35 (54 percent) in the cisapride group, 17 of 35 (49 percent) in the ranitidine group, 28 of 35 (80 percent) in the omeprazole group, 23 of 35 (66 percent) in the ranitidine-plus-cisapride group, and 31 of 35 (89 percent) in the omeprazole-plus-cisapride group. Omeprazole was significantly more effective than cisapride (P = 0.02) or ranitidine (P = 0.003), and combination therapy with omeprazole plus cisapride was significantly more effective than cisapride alone (P = 0.003), ranitidine alone (P < 0.001), or ranitidine plus cisapride (P = 0.03). Ranitidine plus cisapride was significantly better than ranitidine alone (P = 0.05). CONCLUSIONS For maintenance treatment of reflux esophagitis, omeprazole alone or in combination with cisapride is more effective than ranitidine alone or cisapride alone, and the combination of omeprazole and cisapride is more effective than ranitidine plus cisapride.

Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis

Background and aims: Cirrhotic patients frequently undergo screening endoscopy for the presence of oesophageal varices (OV). In the future, this social and medical burden will increase due to the greater number of patients with chronic liver disease and their improved survival. In this study, our aims were (1) to identify clinical, biochemical, and ultrasonographic parameters which might non-invasively predict the presence of OV in patients with liver cirrhosis; (2) to evaluate the reproducibility of the obtained results in a different, although related, further group of patients; and (3) to assess the predictiveness of the identified rules in patients with compensated cirrhosis. Methods: In the first part of the study we retrospectively evaluated the presence of OV in 145 cirrhotic patients, and in the second part we evaluated the reproducibility of the study results in a subsequent group of 121 patients. Finally, we evaluated these parameters in a subgroup of 145 patients with compensated disease. All 266 patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio was calculated for all patients. Results: The prevalence rates of OV were 61% and 58% in the first and second groups of patients, respectively. In the first part of the study, we found that platelet count, spleen diameter, platelet count/spleen diameter ratio, and Child- Pugh class were significantly different among patients with or without OV, although the platelet count/spleen diameter ratio was the only parameter which was independently associated with the presence of OV in a multivariate analysis. A platelet count/spleen diameter ratio cut off value of 909 had 100% negative predictive value for a diagnosis of OV. This result was reproduced in the second group of patients as well as in patients with compensated disease. In a cost-benefit analysis, screening cirrhotic patients according to the “platelet count/spleen diameter ratio strategy” was far more cost effective compared with the “scope all strategy”. Conclusions: The platelet count/spleen diameter ratio is the only parameter which is independently associated with the presence of OV, and its negative predictive value is reproducible. Its use is of value even in the subgroup of patients with compensated disease, and it is also cost effective.

Mongersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn’s Disease

BACKGROUND Crohns disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. METHODS In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohns disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohns Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. RESULTS The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohns disease. CONCLUSIONS We found that study participants with Crohns disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).

Reassessment of the Diagnostic Value of Histology in Patients with GERD, Using Multiple Biopsy Sites and an Appropriate Control Group

BACKGROUND:Histology is generally considered as a tool of limited value in the diagnosis of gastro-esophageal reflux disease (GERD).AIM:To reevaluate the diagnostic role of histological alterations in GERD, using multiple biopsy sites and an appropriate control group.METHODS:We studied 135 patients with typical and atypical symptoms of GERD. They underwent upper GI endoscopy and Los Angeles classification was used for grading cases with mucosal breaks. Biopsies were taken at the Z-line, 2 and 4 cm above it. Microscopic esophagitis was identified by necrosis/erosion, neutrophil/eosinophil intraepithelial infiltration, basal cell hyperplasia, elongation of papillae, dilation of intercellular spaces and a score (range: 0–2) was given for each lesion. Twenty-four-hour esophageal pH monitoring was performed in each patient. Twenty subjects without reflux symptoms, and with normal endoscopy and pH testing were considered as controls.RESULTS:Histological alterations were found in 100 of 119 GERD patients (84%) and in 3 of 20 controls (15%) with a significant difference (p < 0.00001). Histology was abnormal in 96% of patients with erosive esophagitis and in 76% of patients with nonerosive reflux disease (NERD). The sum of scores of microscopic lesions found in all biopsy sites ranged from 0 to 22 and we identified a cut-off value (score 2) that distinguished efficiently controls from GERD patients.CONCLUSIONS:In contrast with previous reports on the marginal role of histology in patients with GERD, our study shows that this technique can be a useful diagnostic tool, particularly in patients with NERD, when biopsies are taken at two sites including Z-line and 2 cm above it.

Functional Heartburn has more in common with Functional Dyspepsia than with Non-Erosive Reflux Disease

Introduction: Functional dyspepsia and non-erosive reflux disease (NERD) are prevalent gastrointestinal conditions with accumulating evidence regarding an overlap between the two. Still, patients with NERD represent a very heterogeneous group and limited data on dyspeptic symptoms in various subgroups of NERD are available. Aim: To evaluate the prevalence of dyspeptic symptoms in patients with NERD subclassified by using 24 h impedance-pH monitoring (MII-pH). Methods: Patients with typical reflux symptoms and normal endoscopy underwent impedance-pH monitoring off proton pump inhibitor treatment. Oesophageal acid exposure time (AET), type of acid and non-acid reflux episodes, and symptom association probability (SAP) were calculated. A validated dyspepsia questionnaire was used to quantify dyspeptic symptoms prior to reflux monitoring. Results: Of 200 patients with NERD (105 female; median age, 48 years), 81 (41%) had an abnormal oesophageal AET (NERD pH-POS), 65 (32%) had normal oesophageal AET and positive SAP for acid and/or non-acid reflux (hypersensitive oesophagus), and 54 (27%) had normal oesophageal AET and negative SAP (functional heartburn). Patients with functional heartburn had more frequent (p<0.01) postprandial fullness, bloating, early satiety and nausea compared to patients with NERD pH-POS and hypersensitive oesophagus. Conclusion: The increased prevalence of dyspeptic symptoms in patients with functional heartburn reinforces the concept that functional gastrointestinal disorders extend beyond the boundaries suggested by the anatomical location of symptoms. This should be regarded as a further argument to test patients with symptoms of gastro-oesophageal reflux disease in order to separate patients with functional heartburn from patients with NERD in whom symptoms are associated with gastro-oesophageal reflux.

Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring.

RATIONALE Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. OBJECTIVES To characterize GER (acid and nonacid) in patients with SSc with and without ILD. METHODS Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). MEASUREMENTS AND MAIN RESULTS Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. CONCLUSIONS Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.

Platelet Count/Spleen Diameter Ratio for the Noninvasive Diagnosis of Esophageal Varices: Results of a Multicenter, Prospective, Validation Study

BACKGROUND AND AIMS:Noninvasive assessment of esophageal varices (EV) may improve the management of patients with cirrhosis and decrease both the medical and financial burden related to screening. In this multicenter, international study, our aim was to prospectively validate the use of the platelet count/spleen diameter ratio for the noninvasive diagnosis of EV.METHODS:A total of 218 cirrhotic patients underwent screening endoscopy for EV. Platelet count/spleen diameter ratio ((N/mm3)/mm) was assessed in all patients and its diagnostic accuracy was calculated. On the basis of previous results, a platelet count/spleen diameter ratio cutoff of 909 was applied to this population. The diagnostic accuracy of the platelet count/spleen diameter ratio was further evaluated for both severity and etiology of disease subgroups.RESULTS:Prevalence of EV was 54.1%. The platelet count/spleen diameter ratio had 86.0% (95% CI, 80.7–90.4%) diagnostic accuracy for EV, which was significantly greater as compared with either accuracy of platelet count alone (83.6%, 95% CI 78.0–88.3%, P = 0.038) or spleen diameter alone (80.2%, 95% CI 74.3–85.3%, P = 0.018). The 909 cutoff had 91.5% sensitivity (95% CI 85.0–95.9%), 67.0% specificity (95% CI 56.9–76.1%), 76.6% positive predictive value, 87.0% negative predictive value, 2.77 positive likelihood ratio, and 0.13 negative likelihood ratio for the diagnosis of EV. Accuracy of the platelet count/spleen diameter ratio was maintained for both severity and etiology of disease subgroups.CONCLUSIONS:The platelet count/spleen diameter ratio may be proposed as a safe and reproducible means to improve the management of cirrhotic patients who should undergo screening endoscopy for EV.

Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy.

OBJECTIVES:We sought to compare reflux and symptom association patterns in patients with nonerosive reflux disease (NERD), erosive esophagitis (EE), and in healthy volunteers (HVs).METHODS:Patients with EE and NERD underwent combined impedance–pH monitoring. Normal values were defined on the basis of previously collected data from 48 HVs. We evaluated distal esophageal acid exposure time (AET), number and type of reflux episodes (acid, nonacid), acid and bolus clearance times, proximal extension of reflux episodes, and symptom association probability (SAP).RESULTS:Distal AET (percentage time, pH<4) was higher (P<0.01) in 58 EE patients (median 7.4%, 25–75th percentile 4.2–9.9%) compared with 168 NERD patients (4.2% (1.2–6.4%)) and 48 HVs (0.7% (0.2–1.4%)). Patients with EE and NERD had a higher (P<0.01) number of acid reflux episodes compared with HVs (51 (37–66) vs. 34 (22–51) vs. 17 (8–31); P<0.05), but a similar number of nonacid reflux episodes (22 (15–39) vs. 23 (15–38) vs. 18 (14–26); P=NS). The percentage of reflux episodes reaching the proximal esophagus was higher (P<0.01) in EE patients (57% (45–73%)) than in NERD patients (45% (36–60%)) and HVs (33% (19–46%)). A positive SAP for heartburn or regurgitation was found in 161 of 168 (96%) NERD and 54 of 58 (93%) EE patients (P=NS).CONCLUSIONS:Acid reflux episodes, volume, and acid clearance are important factors in the pathogenesis of reflux-induced lesions. Nonacid reflux contributes less to esophageal mucosa damage, but is involved in the development of reflux symptoms in both NERD and EE patients.

Partial regression of Barrett's esophagus by long-term therapy with high-dose omeprazole☆☆☆★

BACKGROUND Barretts esophagus is mainly regarded as an acquired condition related to increased gastroesophageal reflux. Thus it is conceivable that abolition of acid reflux would lead to its regression. The aim of this study was to assess whether long-term treatment with high-dose omeprazole (60 mg/day) produces a consistent control of gastric acid production and normalizes the esophageal acid exposure, thus reducing the length of Barretts epithelium. METHODS Fourteen patients (8 men and 6 women, mean age 52 years) with histologic diagnosis of columnar epithelium longer than 3 cm in the distal part of the esophagus were enrolled and began receiving 60 mg of omeprazole in a single daily morning dose. Before therapy and after 6 and 12 months of therapy, all patients had endoscopy with four-quadrant biopsies at 2 cm intervals. A 24-hour esophagogastric pH recording was performed at entry and after 10 days, 6 months, and 12 months of treatment in all patients. RESULTS The initial length of Barretts epithelium (4.5 +/- 1.9 cm) was significantly reduced after 6 months (3.1 +/- 1.1; p < 0.01) and 12 months (2.1 +/- 1.6; p < 0.005) of treatment. Values were significantly lower at 12 than at 6 months (p < 0.03). The 24-hour mean gastric pH after 10 days (5.89 +/- 0.58), 6 months (5.71 +/- 0.55), and 12 months (5.54 +/- 0.76) of therapy was always higher (p < 0.001) than the basal level (1.9 +/- 0.49). No significant difference in gastric pH was seen over the treatment period. The 24-hour mean percent of time in which pH in the esophagus was below 4.0 decreased significantly (p < 0.001) from a basal rate of 29.4% to 3.5%, 3.0%, and 4.9% in the various time intervals of therapy. There was a normalization of esophageal acid exposure in all patients but two. CONCLUSIONS It can be concluded that the antisecretory effect of 60 mg/day of omeprazole is consistent and is kept constant throughout the entire 1-year treatment period. The consequent normalization of esophageal acid exposure in almost all patients in our series led to a partial, but significant, regression in the length of Barretts epithelium.