Rocio Lopez

The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a well‐recognized cause of cirrhosis and has been increasingly associated with the development of hepatocellular carcinoma (HCC). The aims of this study were to (1) estimate the incidence of HCC in patients with NASH‐related cirrhosis, (2) compare incidence in NASH‐related cirrhosis with hepatitis C virus (HCV)‐related cirrhosis, and (3) identify risk factors of HCC in patients with NASH‐related cirrhosis compared with HCV‐related cirrhosis. Adult patients with cirrhosis secondary to chronic HCV (n = 315) or NASH (n = 195) were evaluated at our hepatobiliary clinic between 2003 and 2007. To assess for HCC development, all patients were monitored using serial abdominal computed tomography and serum alpha‐fetoprotein every 6 months. Kaplan‐Meier analysis was performed to estimate the cumulative incidence of HCC. Descriptive statistics were computed for all factors. Univariate and multivariate Cox regression analysis were used to assess associations between HCC and factors of interest. The median follow‐up was 3.2 years (25th percentile [P25], 75th percentile [P75]: 1.7, 5.7) during which 25/195 (12.8%) of NASH‐cirrhotic and 64/315 (20.3 %) of HCV‐cirrhotic patients developed HCC (P = 0.03). Yearly cumulative incidence of HCC was found to be 2.6% in patients with NASH‐cirrhosis, compared with 4.0% in patients with HCV cirrhosis (P = 0.09). Multivariate regression analysis revealed that older age (P = 0.006) and alcohol consumption (P = 0.002) were independent variables associated with development of HCC in patients with NASH‐cirrhosis. Compared with nondrinkers, patients who reported any regular alcohol consumption were at greater risk for HCC development (hazard ratio: 3.6; P25, P75: 1.5, 8.3). Conclusion: Patients with NASH cirrhosis have a greatly increased risk of liver cancer. Alcohol consumption, a modifiable risk factor, appears to be the most significant factor associated with risk of HCC development in our study population. (Hepatology 2010;)

Increased Hepatic and Circulating Interleukin-6 Levels in Human Nonalcoholic Steatohepatitis

BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are growing public health problems, and are strongly associated. The link between the two conditions remains poorly understood. Hepatic interleukin-6 (IL-6), a major proinflammatory cytokine, expression is increased in animal models of NAFLD, while in mice, selective sustained upregulation of IL-6 in the liver results in systemic insulin resistance. The extent and clinical significance of hepatic IL-6 expression in human NAFLD, as well as potential mechanisms by which steatosis may increase IL-6 production in the liver, have not been examined.AIMS:To ascertain the occurrence and significance of IL-6 expression in the liver in human NAFLD.PATIENTS AND METHODS: Plasma was obtained at time of liver biopsy from 50 consecutive patients with suspected NAFLD. Histology was assessed blindly. Hepatic IL-6 expression was assessed by immunohistochemistry, while plasma IL-6 levels were determined by an enzyme-linked immunosorbent assay.RESULTS:IL-6 expression was markedly increased in the livers of patients with nonalcoholic steatohepatitis (NASH) as compared to patients with simple steatosis (P < 0.005) or normal biopsies (P < 0.010), confirming the presence of hepatic IL-6 expression in human NASH. A positive correlation was observed between hepatocyte IL-6 expression and degree of inflammation and stage of fibrosis. Furthermore, liver IL-6 expression positively correlated with plasma IL-6 levels and degree of systemic insulin resistance. Culture of liver cells with saturated, but not mono- or polyunsaturated, FFA resulted in a significant increase in IL-6 messenger RNA (mRNA) and protein expression.CONCLUSION:Collectively, these data suggest that increased hepatic IL-6 production may play an important role in NASH development, as well as in systemic insulin resistance and diabetes.

Validity of real time ultrasound in the diagnosis of hepatic steatosis: A prospective study

BACKGROUND/AIMS Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis. METHODS Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings. RESULTS Of 73 consecutive patients studied, macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was > or =20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis. CONCLUSION Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is<20% fat.

Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial

The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention‐to‐treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (HEPATOLOGY 2011)

Propofol Versus Traditional Sedative Agents for Gastrointestinal Endoscopy: A Meta-analysis

BACKGROUND & AIMS Even though propofol has better recovery profile than traditional agents, its use is limited because of the perception of increased complication rates. Because an adequately powered trial comparing risk of propofol with traditional agents is lacking, we performed a meta-analysis of the current literature. METHODS We searched Medline (1966-October 2004), EMBASE (1980-October 2004), and Cochrane controlled trials registry. The following 4 cardiopulmonary complications were assessed: hypoxia, hypotension, arrhythmias, and apnea. Procedures were divided into 3 groups: esophagogastroduodenoscopy group, colonoscopy group, and endoscopic retrograde cholangiopancreatography/endoscopic ultrasonography group. Pooled odds ratios for complications were calculated for all the procedures combined and then separately for the 3 groups. Random effects models were used for 2-proportion comparisons. RESULTS Of the 90 citations identified, 12 original studies qualified for this meta-analysis and included 1161 patients. Of these, 634 received propofol, and 527 received midazolam, meperidine, and/or fentanyl. Most of the included studies were randomized trials of moderate quality and nonsignificant heterogeneity (Cochran Q = 4.81, P = .90). Compared with traditional sedative agents, the pooled odds ratio with the use of propofol for developing hypoxia or hypotension for all the procedures combined was 0.74 (95% confidence interval [CI], 0.44-1.24); for EGD, 0.85 (95% CI, 0.33-2.17); for colonoscopy, 0.4 (95% CI, 0.2-0.79); and for ERCP/EUS, 1.07 (95% CI, 0.38-3.01). CONCLUSIONS Propofol sedation during colonoscopy appears to have lower odds of cardiopulmonary complications compared with traditional agents, but for other procedures, the risk of complications is similar.

Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study

Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well‐characterized, biopsy‐proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin‐eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7‐point scale. The median age was 12 years (range, 4‐18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease. (HEPATOLOGY 2009.)

Deep sedation occurs frequently during elective endoscopy with meperidine and midazolam.

BACKGROUND AND AIMS:Although moderate (conscious) sedation is intended during elective gastrointestinal endoscopy, unintended levels of deep sedation occur. The aims of this study were to prospectively evaluate the incidence and risk factors of deep sedation during elective endoscopy with meperidine and midazolam intended to maintain a level of moderate sedation.METHODS:Eighty American Society of Anesthesiology class 1-2, outpatients presenting for elective esophagogastroduodenoscopy (EGD), colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) were offered enrollment. Intravenous meperidine and midazolam were administered according to a standardized protocol. Hemodynamic parameters and levels of sedation were assessed and recorded by a single observer at 3-min intervals. The Modified Observers Assessment of Alertness/Sedation (MOAA/S) scale (ranging 1–5) is a subjective sedation assessment scale used to assess sedation levels. Occurrence of deep sedation, defined by MOAA/S 1–2, was recorded. Univariable and multivariable analyses were used to assess predictors of deep sedation.RESULTS:Deep sedation occurred in 54/80 (68%) patients for a total of 204/785 (26%) of total sedation assessments. The percentage of deep sedation episodes of all sedation-level observations by procedure was 26% for EGD, 11% for colonoscopy, 35% for ERCP, and 29% for EUS. Deep sedation occurred at least once in 60% of EGD, 45% of colonoscopy, 85% of ERCP, and 80% of EUS. Multivariable analysis showed that only ERCP and EUS were independent risk factors of deep sedation.CONCLUSIONS:Deep sedation occurs frequently during elective endoscopy with meperidine and midazolam used with the intent of moderate sedation. ERCP and EUS are risk factors for the occurrence of deep sedation, independent of sedation dose or length of procedure.

Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to define the circulating profile of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels reflect histological changes in the liver. The levels of multiple structurally specific oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9- and 13-HODEs and 9- and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were significantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (inflammation, fibrosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold (P < 0.0001) more likely to have NASH than those with low levels (bottom tertile). Collectively, these findings support a key role for free radical-mediated linoleic acid oxidation in human NASH and define a risk score, oxNASH, for noninvasive detection of the presence of NASH.

Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD.

Background and Aims: The diagnostic accuracy of hepatic ultrasonography (US) for detection and grading of hepatic steatosis in children with suspected nonalcoholic fatty liver disease (NAFLD) remains poorly characterized. The aim of this study was to prospectively evaluate the clinical utility of ultrasonographic quantification of hepatic steatosis. Patients and Methods: Our cohort consisted of 208 consecutive pediatric patients with biopsy-proven NAFLD. Hepatic US was performed within 1 month of the liver biopsy procedure. Steatosis identified by US was scored using a 0 to 3 scale based on echogenicity and visualization of vasculature, parenchyma, and diaphragm, and compared to histological features based on Brunts classification. Results: The median age at time of first visit was 10.8 years and 64% were boys. Sixty-nine percent had moderate to severe steatosis on histology. Ultrasonographic steatosis score (USS) had an excellent correlation with histological grade of steatosis (with a Spearmans coefficient of 0.80). The area under the receiver operating characteristic curve for ultrasonographic detection of moderate-to-severe steatosis was 0.87. The USS did not correlate significantly with inflammatory activity or fibrosis stage; however, there was significant correlation with the NAFLD activity score (NAS), albeit this was in large part the result of the strong correlation with the steatosis component of NAS. Serum alanine transaminase and aspartate transaminase were not associated with histological grade of steatosis and showed no correlation with USS. Conclusions: Our results, which represent the largest prospective pediatric study evaluating the role of hepatic US in children with biopsy-proven NAFLD, demonstrate the utility of this technique for noninvasive diagnosis and estimation of hepatic steatosis in children.

An open-label, prospective trial of cryospray ablation for Barrett's esophagus high-grade dysplasia and early esophageal cancer in high-risk patients

BACKGROUND Endoscopic ablation of Barretts esophagus (BE) is a treatment option for patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMCA). OBJECTIVE To assess the safety and efficacy of a unique noncontact method of liquid nitrogen cryoablation as measured by histologic response rate and cancer-free survival. DESIGN Single-center, nonrandomized cohort study. SETTING Referral center, conducted between September 2005 and September 2008. PATIENTS Patients with BE and HGD or IMCA who were deemed inoperable or who refused esophagectomy. Age, length of BE, and previous ablation were not exclusion criteria. INTERVENTION Cryoablation every 6 weeks until endoscopic resolution. EMR was used for pathologic staging of nodular areas before cryoablation and focal residual areas during the follow-up period. MAIN OUTCOME MEASUREMENTS Histologic response was defined by the worst pathology obtained at any level of the esophagus or gastric cardia in 1 of 3 categories: (1) incremental = absence of HGD and IMCA in all biopsy specimens, (2) partial = residual IMCA with absence of any dysplasia, and (3) complete = absence of any intestinal metaplasia or dysplasia. RESULTS Thirty patients underwent ablation; 9 had undergone previous ablation or mucosectomy. Twenty-seven of 30 patients (90%) had downgrading of pathology stage after treatment. Elimination of cancer or downgrading of HGD at last follow-up was 68% for HGD and 80.0% for IMCA, with a median follow-up period of 12 months (25th percentile, 6; 75th percentile, 24). Minor adverse events included mild pain (n = 7), a low incidence of mild strictures (n = 3), and lip ulcer (n = 1). One major adverse event (perforation) in a patient with Marfan syndrome occurred with the prototype system. During follow-up, 3 of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. LIMITATIONS A nonrandomized, single-center study with a heterogeneous cohort of patients. CONCLUSIONS Patients with BE and HGD or IMCA have a positive response to endoscopic cryotherapy at 1-year follow-up.