Raphael B. Merriman

Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease

In the absence of surrogate markers, the evaluation of suspected nonalcoholic fatty liver disease (NAFLD) is highly dependent on histological examination. The extent of sampling variability affecting the reliability of a single liver biopsy in patients with suspected NAFLD is poorly characterized. This prospective study aimed to correlate precise histological findings in paired biopsies—right and left lobe—in the diagnosis of NAFLD in morbidly obese subjects undergoing bariatric surgery employing both Brunt and Matteoni classifications and the NAFLD Activity Score (NAS). We also aimed to determine whether the composite histopathological findings of the two biopsies would improve diagnostic accuracy. Consecutive subjects had an intraoperative biopsy from both right and left lobes, evaluated and scored in a blinded manner. Intraobserver agreement was also assessed. Kappa coefficients of agreement were calculated. Forty‐one subjects had acceptable biopsies. Agreement for steatosis was excellent and moderate for fibrosis. Concordance was only fair for most features of necroinflammation. Intraobserver agreement was only moderate for lobular inflammation. Excellent agreement was seen for the diagnosis of NASH using Brunt criteria and good agreement when using Matteoni and NAS scoring systems. Composite biopsy data particularly improved identification of hepatocyte ballooning. The diagnostic accuracy also improved substantially when composite features were compared with single‐sided biopsy features, especially for the Matteoni and NAS scoring systems. In conclusion, significant sampling variability occurs in NAFLD, particularly for features of necroinflammation. This should be factored into the design of clinical trials and studies of the natural history of the disease. (HEPATOLOGY 2006;44:874–880.)

A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation

In patients with hepatocellular carcinoma (HCC) exceeding conventional (T2) criteria for orthotopic liver transplantation (OLT), the feasibility and outcome following loco‐regional therapy intended for tumor downstaging to meet T2 criteria for OLT are unknown. In this first prospective study on downstaging of HCC prior to OLT, the eligibility criteria for enrollment into a downstaging protocol included 1 lesion >5 cm and ≤8 cm, 2 or 3 lesions at least 1 >3 cm but ≤5 cm with total tumor diameter of ≤8 cm, or 4 or 5 nodules all ≤3 cm with total tumor diameter ≤8 cm. Patients were eligible for living‐donor liver transplantation (LDLT) if tumors were downstaged to within proposed University of California, San Francisco (UCSF) criteria. 13 A minimum follow‐up period of 3 months after downstaging was required before cadaveric OLT or LDLT, with imaging studies meeting criteria for successful downstaging. Among the 30 patients enrolled, 21 (70%) met criteria for successful downstaging, including 16 (53%) who had subsequently received OLT (2 with LDLT), and 9 patients (30%) were classified as treatment failures. In the explant of 16 patients who underwent OLT, 7 had complete tumor necrosis, 7 met T2 criteria, but 2 exceeded T2 criteria. No HCC recurrence was observed after a median follow‐up of 16 months after OLT. The Kaplan‐Meier intention‐to‐treat survival was 89.3 and 81.8% at 1 and 2 yr, respectively. In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow‐up is needed to further access the risk of HCC recurrence after OLT. (Liver Transpl 2005;11:1505–1514.)

A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.

Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m2 (interquartile range, 43‐55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1‐5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1‐6.3), sleep apnea (OR, 4.0; 95% CI, 1.3‐12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2‐7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4‐8.0), and non‐Black race (OR, 8.4; 95% CI, 1.9‐37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). Conclusion: The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high‐risk group in whom liver biopsy would be very likely to detect NASH, as well as a low‐risk group in whom biopsy can be safely delayed or avoided. (HEPATOLOGY 2008.)

Health‐related fitness and physical activity in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has been referred to as the hepatic manifestation of the metabolic syndrome. There is a lower prevalence of metabolic syndrome in individuals with higher health‐related fitness (HRF) and physical activity (PA) participation. The relationship between NAFLD severity and HRF or PA is unknown. Our aim was to compare measures of HRF and PA in patients with a histological spectrum of NAFLD severity. Thirty‐seven patients with liver biopsy–confirmed NAFLD (18 women/19 men; age = 45.9 ± 12.7 years) completed assessment of cardiorespiratory fitness (CRF, VO2peak), muscle strength (quadriceps peak torque), body composition (%fat), and PA (current and historical questionnaire). Liver histology was used to classify severity by steatosis (mild, moderate, severe), fibrosis stage (stage 1 versus stage 2/3), necroinflammatory activity (NAFLD Activity Score; ≤4 NAS1 versus ≥5 NAS2) and diagnosis of NASH by Brunt criteria (NASH versus NotNASH). Analysis of variance and independent t tests were used to determine the differences among groups. Fewer than 20% of patients met recommended guidelines for PA, and 97.3% were classified at increased risk of morbidity and mortality by %fat. No differences were detected in VO2peak (x = 26.8 ± 7.4 mL/g/min) or %fat (x = 38.6 ± 8.2%) among the steatosis or fibrosis groups. Peak VO2 was significantly higher in NAS1 versus NAS2 (30.4 ± 8.2 versus 24.4 ± 5.7 mL/kg/min, P = 0.013) and NotNASH versus NASH (34.0 ± 9.5 versus 25.1 ± 5.7 mL/kg/min, P = 0.048). Conclusion: Patients with NAFLD of differing histological severity have suboptimal HRF. Lifestyle interventions to improve HRF and PA may be beneficial in reducing the associated risk factors and preventing progression of NAFLD. (HEPATOLOGY 2008.)

Long‐term follow‐up of portopulmonary hypertension: Effect of treatment with epoprostenol

Moderate to severe portopulmonary hypertension (PPHTN) increases the risks of orthotopic liver transplantation (OLT). Epoprostenol is an effective treatment of PPHTN, but long‐term effects on pulmonary hemodynamics or liver function in PPHTN are poorly defined. We sought to describe the long‐term effects of treatment with or without epoprostenol on pulmonary hemodynamics, liver biochemistries, and survival in patients with moderate to severe PPHTN at a single center. A large retrospective cohort was identified with moderate to severe PPHTN diagnosed before OLT. Baseline and follow‐up pulmonary hemodynamics and liver biochemistries were compared and outcomes assessed. Nineteen patients were treated with epoprostenol and 17 were not treated with epoprostenol. There were significant improvements in mean pulmonary artery pressure (MPAP, 48.4‐36.1 mm Hg; P < 0.0001), pulmonary vascular resistance (PVR, 632‐282 dynes · s · cm−5; P < 0.0001), and cardiac output (5.7 to 7.7 L/min; P = 0.0009) with epoprostenol after a median of 15.4 months. Liver biochemistries did not change significantly, and survival did not seem to differ between the 2 groups (hazard ratio, 0.85; P = 0.77). In the epoprostenol group, patients who survived had greater absolute changes in MPAP, transpulmonary gradient, and PVR than those who died. Two patients in the epoprostenol group successfully underwent OLT. Long‐term epoprostenol therapy greatly improves pulmonary hemodynamics in patients with PPHTN. Liver biochemistries are not greatly changed. Survival seemed not to differ between treatment groups. A minority of patients treated with epoprostenol will improve sufficiently to undergo OLT. Liver Transpl 13:875–885, 2007.

Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross‐sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18‐64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory‐Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high‐density lipoprotein (OR = 8.35, P = 0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. (HEPATOLOGY 2013;58:1644–1654)

Growth rate of hepatocellular carcinoma : Evaluation with serial computed tomography or magnetic resonance imaging

Objective: To evaluate the growth rate of untreated hepatocellular carcinoma (HCC) by calculating tumor volume doubling time (TVDT) on serial computed tomography (CT) or magnetic resonance imaging (MRI) and to predict TVDT based on initial tumor size. Methods: Sixteen untreated HCCs in 11 patients with cirrhosis who underwent serial CT or MRI at our institution were retrospectively identified. Two independent readers recorded bidimensional measurements for all tumors, which were used to determine tumor volume (TV). Growth rate was expressed as TVDT. A mathematic model was used to predict TVDT based on baseline tumor size. Results: Mean baseline and follow-up TVs were 10.5 cm3 (range: 0.7-243.6 cm3) and 22.0 cm3 (range: 2.5-870.8 cm3), respectively. Mean duration of follow-up was 176 days (range: 76-472 days). Mean TVDT was 127 days (95% confidence interval: 80, 203; range: 17.5-541.4 days). Expected TVDT could be expressed as TVDT = 114 × (baseline volume) 0.14 (P < 0.002). Conclusion: The results of this study suggest a preferred interval follow-up of approximately 4.5 months (127 days) for HCC screening. Small HCCs show a tendency toward faster growth and may require shorter follow-up to demonstrate progression.

Clinical and pathologic risk factors for atherosclerosis in cirrhosis: A comparison between NASH-related cirrhosis and cirrhosis due to other aetiologies

BACKGROUND/AIMS The precise prevalence of risk factors for atherosclerosis in NASH-related cirrhosis is unknown. The aims of this study were: (1) to compare the prevalence of major risk factors for atherosclerosis between subjects who underwent liver transplantation for NASH-related cirrhosis and those with cirrhosis of other aetiologies and (2) to compare pathologic changes of atherosclerosis within the explants hepatic hilar arteries between the groups. METHODS Sixty subjects with NASH-related cirrhosis and 60 subjects with cirrhosis of other aetiologies were reviewed retrospectively. Demographic and clinical characteristics related to atherosclerosis were analyzed and compared. The hepatic hilar arteries of the explanted livers were examined for pathologic changes. RESULTS The prevalence of all coronary artery disease (CAD) risk factors and the metabolic syndrome was significantly higher in NASH-related cirrhosis group compared to cirrhosis of other aetiologies. The proportion of patients with a diagnosis of CAD was also significantly higher in the NASH-related cirrhosis group (21.6% vs. 5%, p=0.005). Pathological examination of hilar arteries showed possible atherosclerotic changes in only 4 cases (3 NASH-related cirrhosis; 1 HCV). CONCLUSIONS Major risk factors for atherosclerosis are significantly more prevalent in subjects with NASH-related cirrhosis than in subjects with cirrhosis of other aetiologies and are predictive of an increased prevalence of CAD. This study suggests that NASH-related cirrhosis is not protective against atherosclerosis.

Lack of Support for the Association between GAD2 Polymorphisms and Severe Human Obesity

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (−243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (−243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase—GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the −243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the −243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83–1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the −243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90–1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the −243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.

Liver steatosis: investigation of opposed-phase T1-weighted liver mr signal intensity loss and visceral fat measurement as biomarkers

PURPOSE To investigate if opposed-phase T1-weighted and fat-suppressed T2-weighted liver signal intensity (SI) loss and visceral fat measurement at magnetic resonance (MR) imaging and body mass index (BMI) are correlated with grade of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-related liver disease. MATERIALS AND METHODS Committee on Human Research approval and patient consent were obtained for this HIPAA-compliant study. Fifty-two patients (15 men, 37 women) with NAFLD (n = 29) or HCV and HIV-related liver disease (n = 23) underwent prospective contemporaneous MR imaging and liver biopsy. Liver SI loss was measured on opposed-phase T1-weighted and fat-suppressed T2-weighted MR images. Visceral fat area was measured at three levels on water-suppressed T1-weighted MR images (n = 44). Spearman rank correlation coefficients and recursive partitioning were used to examine correlations. RESULTS Histopathologic liver steatosis correlated well with liver SI loss on opposed-phase T1-weighted MR images (rho = 0.78), fat-suppressed T2-weighted MR images (rho = 0.75), and average visceral fat area (rho = 0.77) (all P < .01) but poorly with BMI (rho = 0.53, P < .01). Liver SI losses on opposed-phase T1-weighted MR imaging of less than 3%, at least 3% but less than 35%, at least 35% but less than 49%, and at least 49% corresponded to histopathologic steatosis grades of 0 (n = 16 of 17), 1 (n = 11 of 16), 2 (n = 7 of 13), and 3 (n = 5 of 6), respectively. A visceral fat area of greater than or equal to 73.8 cm(2) was associated with the presence of histopathologic steatosis in 41 of 44 patients. CONCLUSION Liver SI loss on opposed-phase T1-weighted MR images and visceral fat area may be used as biomarkers for the presence of liver steatosis and appear to be superior to BMI.