Gladys Smok

Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients.

Oxidative stress is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In the present study, hepatic and plasma oxidative stress-related parameters were measured and correlated with clinical and histological findings in 31 NAFLD patients showing increased body mass index. Liver protein carbonyl content was enhanced by 403% in patients with steatosis (n=15) compared with control values (n=12), whereas glutathione content, superoxide dismutase (SOD) activity and the ferric reducing ability of plasma (FRAP) were decreased by 57%, 48% and 21% (P<0.05) respectively. No changes in microsomal p-nitrophenol hydroxylation and the total content of cytochrome P450 (CYP) or CYP2E1 were observed. Patients with steatohepatitis (n=16) exhibited protein carbonyl content comparable with that of controls, whereas glutathione content, SOD and catalase activities were decreased by 27%, 64% and 48% (P<0.05). In addition, FRAP values in patients with steatohepatitis were reduced by 33% and 15% (P<0.05) when compared with controls and patients with steatosis respectively, whereas p-nitrophenol hydroxylation (52%) and CYP2E1 content (142%) were significantly increased (P<0.05) compared with controls. It is concluded that oxidative stress is developed in the liver of NAFLD patients with steatosis and is exacerbated further in patients with steatohepatitis, which is associated with CYP2E1 induction. Substantial protein oxidation is followed by proteolysis of the modified proteins, which may explain the co-existence of a diminished antioxidant capacity and protein oxidation in the liver of patients with steatohepatitis.

Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: Correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion

Sterol receptor element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mRNA expression was assessed in liver as signaling mechanisms associated with steatosis in obese patients. Liver SREBP-1c and PPAR-alpha mRNA (RT-PCR), fatty acid synthase (FAS) and carnitine palmitoyltransferase-1a (CPT-1a) mRNA (real-time RT-PCR), and n-3 long-chain polyunsaturated fatty acid (LCPUFA)(GLC) contents, plasma adiponectin levels (RIA), and insulin resistance (IR) evolution (HOMA) were evaluated in 11 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 8 non-obese subjects who underwent laparoscopic cholecystectomy (controls). Liver SREBP-1c and FAS mRNA levels were 33% and 70% higher than control values (P<0.05), respectively, whereas those of PPAR-alpha and CPT-1a were 16% and 65% lower (P<0.05), respectively, with a significant 62% enhancement in the SREBP-1c/PPAR-alpha ratio. Liver n-3 LCPUFA levels were 53% lower in obese patients who also showed IR and hipoadiponectinemia over controls (P<0.05). IR negatively correlated with both the hepatic content of n-3 LCPUFA (r=-0.55; P<0.01) and the plasma levels of adiponectin (r=-0.62; P<0.005). Liver SREBP-1c/PPAR-alpha ratio and n-3 LCPUFA showed a negative correlation (r=-0.48; P<0.02) and positive associations with either HOMA (r=0.75; P<0.0001) or serum insulin levels (r=0.69; P<0.001). In conclusion, liver up-regulation of SREBP-1c and down-regulation of PPAR-alpha occur in obese patients, with enhancement in the SREBP-1c/PPAR-alpha ratio associated with n-3 LCPUFA depletion and IR, a condition that may favor lipogenesis over FA oxidation thereby leading to steatosis.

Late follow-up of polypoid lesions of the gallbladder smaller than 10 mm.

ObjectiveTo determine the variation in number, size, and symptoms in patients with polypoid lesions of the gallbladder. Summary Background DataA polypoid lesion is any elevated lesion of the gallbladder mucosa. Several studies have been reported in patients undergoing cholecystectomy, but little information exits regarding the natural history of these lesions in nonoperated patients. MethodsA total of 111 patients with ultrasound diagnosis of polypoid lesions smaller than 10 mm were followed up by clinical evaluation and ultrasonography. Twenty-seven patients underwent cholecystectomy. ResultsThere was no difference in terms of gender. Nearly 80% of the lesions were smaller than 5 mm; they were single in 74%. In nonoperated patients, 50% remained of similar size at the late follow-up, 26.5% increased in number and size, and 23.5% shrank or disappeared. Among the operated patients, 70% corresponded to cholesterol polyps. None of the patients developed symptoms of biliary disease or gallstones or adenocarcinoma. ConclusionsUltrasound is useful in the follow-up of patients with polypoid lesions of the gallbladder. Lesions smaller than 10 mm do not progress to malignancy or to development of stones, and none produced symptoms or complications of biliary disease.

Effect of gastric bypass on Barrett's esophagus and intestinal metaplasia of the cardia in patients with morbid obesity.

Gastric bypass in patients with morbid obesity should be an excellent antireflux procedure, because no acid is produced at the small gastric pouch and no duodenal reflux is present, due to the long Roux-en-Y limb. Five hundred fifty-seven patients with morbid obesity submitted to resectional gastric bypass, and routine preoperative upper endoscopy with biopsy samples demonstrated 12 patients with Barrett’s esophagus (2.1%) and three patients with intestinal metaplasia of the cardia (CIM). An endoscopic procedure was repeated twice after surgery, producing seven patients with short-segment Barrett’s esophagus (BE) and five patients with long-segment BE. Body mass index (BMI) decreased significantly, from 43.2 kg/m2 to 29.4 kg/m2 2 years after surgery. Symptoms of reflux esophagitis, which were present in 14 of the 15 patients, disappeared in all patients 1 year after surgery. Preoperative erosive esophagitis and peptic ulcer of the esophagus healed in all patients. There was regression from intestinal metaplasia to cardiac mucosa in four patients (57%) with short-segment BE, and in one patient (20%) with long-segment BE. Two (67%) of three cases with CIM had regression to cardiac mucosa. There was no progression to low- or high-grade dysplasia. Gastric bypass in patients with Barrett’s esophagus and morbid obesity is an excellent antireflux operation, proved by the disappearance of symptoms and the healing of endoscopic esophagitis or peptic ulcer in all patients, which is followed by an important regression to cardiac mucosa that is length-dependent and time-dependent.

Latest results (12-21 years) of a prospective randomized study comparing Billroth II and Roux-en-Y anastomosis after a partial gastrectomy plus vagotomy in patients with duodenal ulcers.

Introduction:After a partial resection of the stomach, the continuity of the gastrointestinal tract can be restored either by a Billroth II gastrojejunal anastomosis or a Roux-en-Y gastrojejunostomy. Each procedure has its advantages and disadvantages. Objective:To determine through a prospective and random clinical trial, the clinical outcome and the endoscopic and histologic alterations of the distal esophagus and the gastric remnant in patients who received a partial distal gastrectomy due to duodenal ulcers and a Billroth II or Roux-en-Y reconstruction. Material and Methods:In this prospective random trial, a total of 75 patients with duodenal ulcers were included. A bilateral selective vagotomy and partial distal gastrectomy were performed in all patients. A Billroth II or Roux-en-Y 60-cm-long loop was randomly used for reconstruction of the gastrointestinal tract. During the latest follow-up clinical evaluation, upper endoscopy and biopsy samples from the distal esophagus and gastric remnant were obtained. Results:There was 1 operative mortality and 6 patients had some morbidity. The average follow-up period was 15.5 years (range, 11–21). Patients with Roux-en-Y gastrojejunostomy were significantly more asymptomatic and had greater Visick I grading than patients with Billroth II reconstruction (P < 0.001). In the distal esophagus, endoscopic findings were normal in 90% of the Roux-en-Y group, but only in 51% of the Billroth II group (P < 0.0009). Nearly 25% of the latter group had the appearance of a short-segment Barrett esophagus compared with 3% of the Roux-en-Y group (P < 0.0001). The gastric remnant endoscopic findings were normal in 100% of the Roux-en-Y group and in 18% of the Billroth II group (P < 0.02). Histologic analyses showed similar proportions of normal fundic mucosa and chronic active fundic gastritis. However, chronic atrophic fundic gastritis and intestinal metaplasia were significantly more frequent after Billroth II reconstruction (P < 0.008). Helicobacter pylorus was present in a similar proportion of patients. Conclusions:This prospective and random study showed that Roux-en-Y gastrojejunostomy is significantly better than a Billroth II reconstruction in patients with duodenal ulcers, through subjective and objective endoscopic and histologic evaluations during the latest follow-up evaluation.

Liver NF‐κB and AP‐1 DNA Binding in Obese Patients

Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in the progression from steatosis to nonalcoholic steatohepatitis (NASH). Our aim was to assess nuclear factor‐κB (NF‐κB) and activating protein‐1 (AP‐1) activation and Toll‐like receptor 4 (TLR4) expression as signaling mechanisms related to liver injury in obese NAFLD patients, and examined potential correlations among them, oxidative stress, and IR. Liver NF‐κB and AP‐1 (electromobility shift assay (EMSA)), TLR4 expression (western blot), ferric reducing ability of plasma (FRAP), and IR evolution (HOMA) were evaluated in 17 obese patients who underwent subtotal gastrectomy with gastro‐jejunal anastomosis in Roux‐en‐Y and 10 nonobese subjects who underwent laparoscopic cholecystectomy (controls). Liver NF‐κB and AP‐1 DNA binding were markedly increased in NASH patients (n = 9; P < 0.05) compared to controls, without significant changes in NAFLD patients with steatosis (n = 8), whereas TLR4 expression was comparable between groups. Hepatic NF‐κB activation was positively correlated with that of AP‐1 (r = 0.79; P < 0.0001); both liver NF‐κB and AP‐1 DNA binding were inversely associated with FRAP (r = −0.43 and r = −0.40, respectively; P < 0.05) and directly correlated with HOMA (r = 0.66 and r = 0.62, respectively, P < 0.001). Data presented show enhanced liver activation of the proinflammatory transcription factors NF‐κB and AP‐1 in obese patients with NASH, parameters that are significantly associated to oxidative stress and IR.

Histological Findings in the Liver Before and After Gastric Bypass

Background: Bariatric surgery results in massive loss of excess weight, changes in co-morbidities and improvement in quality of life. In these patients, liver histology taken before or during surgery reveals several histological abnormalities. In a prospective study of patients previously submitted to gastric bypass, we determined the changes in liver histology late after the surgery. Methods: In 16 out of a total of 557 patients who were submitted to open gastric bypass, a second liver biopsy was taken during the repair of an incisional hernia, performed at a mean of 17 months after the gastric bypass. Results: All patients had lost weight, now having a mean BMI of 28.6 kg/m2 (which had been 44.3 kg/m2 before gastric bypass). One patient with normal pre-operative liver histology remained normal at the second study. 11 out of 15 who had had liver abnormalities returned to a normal condition or had only minimal change (73.3%). 2 patients (13.3%) showed improvement, while 1 patient presented a slight worsening of liver condition. One patient who had had liver cirrhosis showed no change. Conclusion: Gastric bypass for morbid obesity is followed by a dramatic improvement or normalization of liver histological abnormalities in the great majority of the patients. Liver cirrhosis in the one patient remained unchanged.

Clinical, endoscopic, and functional studies in 408 patients with Barrett's esophagus, compared to 174 cases of intestinal metaplasia of the cardia

OBJECTIVE:The pathophysiology of gastroesophageal reflux disease (GERD) has been studied extensively in patients with long-segment Barretts esophagus (LSBE), but few reports have explored GERD pathophysiology in patients who have short-segment Barretts esophagus (SSBE) or intestinal metaplasia at the cardia (IMC). We aimed to compare clinical, endoscopic, histological, and functional features in patients with LSBE, SSBE, and IMC.METHODS:We identified 582 patients who had intestinal metaplasia at the squamocolumnar junction in the distal esophagus and divided them into three groups based on the extent of columnar-lined esophagus observed endoscopically: 1) patients with IMC who had no columnar-lined esophagus (i.e., the squamocolumnar and gastroesophageal junctions coincided), 2) patients with LSBE who had >3 cm of columnar-lined esophagus, and 3) patients with SSBE who had <3 cm of columnar-lined esophagus. All patients had esophageal manometric evaluation, and 24-h esophageal pH monitoring was performed to determine the extent of acid and bile (bilirubin) reflux.RESULTS:There were 174 patients with IMC, 155 with LSBE, and 25 with SSBE. Compared to patients with LSBE and SSBE, patients with IMC had significantly lower frequencies of GERD symptoms, hiatal hernia, and erosive esophagitis; significantly higher lower esophageal sphincter pressures; and significantly shorter durations of acid and bile reflux. Between patients with SSBE and LSBE, significant differences were found in the frequency of hiatal hernia and duration of acid reflux (both greater in the patients with LSBE). Also, dysplasia was significantly more frequent in patients with LSBE than in those with SSBE or IMC.CONCLUSION:GERD symptoms, signs, and physiological abnormalities are found more often in patients with Barretts esophagus than in those with IMC, and the duration of acid reflux in patients with LSBE is greater than that in patients with SSBE. These findings suggest that the extent of intestinal metaplasia in the esophagus is related directly to the severity of underlying GERD.

Dysplasia and Adenocarcinoma After Classic Antireflux Surgery in Patients With Barrett’s Esophagus: The Need for Long-Term Subjective and Objective Follow-Up

ObjectiveTo assess the clinical, endoscopic, and functional results in a group of patients with Barrett’s esophagus undergoing classic antireflux surgery in whom dysplasia and adenocarcinoma were found at a late objective follow-up. Summary Background DataThere have been isolated reports of patients with Barrett’s esophagus undergoing antireflux surgery who show dysplasia or even adenocarcinoma on follow-up. MethodsOf 161 patients undergoing surgery, dysplasia developed in 17 (10.5%) at late follow-up and adenocarcinoma developed in 4 (2.5%). These 21 patients represent the group assessed and were compared with 126 surgical patients with long-segment Barrett’s in whom dysplasia did not develop. They were evaluated by clinical questionnaire, multiple endoscopic procedures and biopsy specimens, 24-hour pH studies, and 24-hour bilirubin monitoring. ResultsOf the 17 patients with dysplasia, 3 were asymptomatic at the time that dysplastic changes appeared; all patients with adenocarcinoma had symptoms. Two patients (12%) in the dysplasia group had short-segment Barrett’s; all patients with adenocarcinoma had long-segment Barrett’s. Manometric studies revealed an incompetent lower esophageal sphincter in 70% of the dysplasia group, similar to nondysplasia patients with recurrence, and in 100% of the adenocarcinoma group. The 24-hour pH study showed pathologic acid reflux in 94% of the patients with dysplasia, similar to patients with recurrence without dysplasia, whereas bilirubin monitoring showed duodenal abnormal reflux in 86% of the patients. Among patients with dysplasia, three different histologic patterns were identified. All patients with adenocarcinoma had initially intestinal metaplasia, with appearance of this tumor 6 to 8 years after surgery. ConclusionsPatients with Barrett’s esophagus who undergo antireflux surgery need close and long-term endoscopic and histologic surveillance because dysplasia or even adenocarcinoma can appear at late follow-up. Metaplastic changes from fundic to cardiac mucosa and then to intestinal metaplasia and later to dysplasia or adenocarcinoma can clearly be documented. There were no significant differences in terms of clinical, endoscopic, manometric, 24-hour pH, and bilirubin monitoring studies between patients with recurrence of symptoms without dysplastic changes, and patients with dysplasia. Therefore, the high-risk group for the development of dysplasia is mainly the group with failed antireflux surgery.

The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone

BACKGROUND/AIMS Many therapies have been tried in primary biliary cirrhosis. It has been suggested that a combination of ursodeoxycholic acid and methotrexate may offer advantages. Because the benefit and safety of this combination is uncertain, we conducted this prospective, randomized, double-blind, controlled trial. METHODS Twenty-five patients with well-defined primary biliary cirrhosis were randomly assigned to receive either ursodeoxycholic acid (500 mg/day) plus methotrexate (10 mg/week) or ursodeoxycholic acid plus placebo for a period of 48 weeks. Clinical, biochemical and histologic evolution were assessed. RESULTS In both groups the clinical response was similar and heterogeneous. In patients of ursodeoxycholic acid alone group, biochemical and histologic changes were comparable to those of patients of ursodeoxycholic acid plus methotrexate at 48 weeks. The addition of methotrexate was not associated with substantial adverse affects. CONCLUSIONS The use of methotrexate in combination with ursodeoxycholic acid was not followed by an additive benefit over ursodeoxycholic acid alone, nor was substantial toxicity added. Unless larger and longer controlled trials with clinical, biochemical and histologic controls show it to be a safe and effective therapy for primary biliary cirrhosis, ursodeoxycholic acid+methotrexate should not be used as a proven and accepted treatment.