Susanne Bonekamp

Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis†‡

Ultrasonography is a widely accessible imaging technique for the detection of fatty liver, but the reported accuracy and reliability have been inconsistent across studies. We aimed to perform a systematic review and meta‐analysis of the diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver. We used MEDLINE and Embase from October 1967 to March 2010. Studies that provided cross‐tabulations of ultrasonography versus histology or standard imaging techniques, or that provided reliability data for ultrasonography, were included. Study variables were independently abstracted by three reviewers and double checked by one reviewer. Forty‐nine (4720 participants) studies were included for the meta‐analysis of diagnostic accuracy. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasound for the detection of moderate‐severe fatty liver, compared to histology (gold standard), were 84.8% (95% confidence interval: 79.5‐88.9), 93.6% (87.2‐97.0), 13.3 (6.4‐27.6), and 0.16 (0.12‐0.22), respectively. The area under the summary receiving operating characteristics curve was 0.93 (0.91‐0.95). Reliability of ultrasound for the detection of fatty liver showed kappa statistics ranging from 0.54 to 0.92 for intrarater reliability and from 0.44 to 1.00 for interrater reliability. Sensitivity and specificity of ultrasound was similar to that of other imaging techniques (i.e., computed tomography or magnetic resonance imaging). Statistical heterogeneity was present even after stratification for multiple clinically relevant characteristics. Conclusion: Ultrasonography allows for reliable and accurate detection of moderate‐severe fatty liver, compared to histology. Because of its low cost, safety, and accessibility, ultrasound is likely the imaging technique of choice for screening for fatty liver in clinical and population settings. (HEPATOLOGY 2011; 54:1082–1090)

Prevalence of Nonalcoholic Fatty Liver Disease in the United States: The Third National Health and Nutrition Examination Survey, 1988–1994

Previous estimates of the prevalence of nonalcoholic fatty liver disease (NAFLD) in the US population relied on measures of liver enzymes, potentially underestimating the burden of this disease. We used ultrasonography data from 12,454 adults who participated in the Third National Health and Nutrition Examination Survey, conducted in the United States from 1988 to 1994. We defined NAFLD as the presence of hepatic steatosis on ultrasonography in the absence of elevated alcohol consumption. In the US population, the rates of prevalence of hepatic steatosis and NAFLD were 21.4% and 19.0%, respectively, corresponding to estimates of 32.5 (95% confidence interval: 29.9, 35.0) million adults with hepatic steatosis and 28.8 (95% confidence interval: 26.6, 31.2) million adults with NAFLD nationwide. After adjustment for age, income, education, body mass index (weight (kg)/height (m)²), and diabetes status, NAFLD was more common in Mexican Americans (24.1%) compared with non-Hispanic whites (17.8%) and non-Hispanic blacks (13.5%) (P = 0.001) and in men (20.2%) compared with women (15.8%) (P < 0.001). Hepatic steatosis and NAFLD were also independently associated with diabetes, with insulin resistance among people without diabetes, with dyslipidemia, and with obesity. Our results extend previous national estimates of the prevalence of NAFLD in the US population and highlight the burden of this disease. Men, Mexican Americans, and people with diabetes and obesity are the most affected groups.

Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study.

Objective To evaluate the association between non-alcoholic fatty liver disease and all cause and cause specific mortality in a representative sample of the US general population. Design Prospective cohort study. Setting US Third National Health and Nutrition Examination Survey (NHANES III: 1988-94) with follow-up of mortality to 2006. Participants 11 371 adults aged 20-74 participating in the Third National Health and Nutrition Examination Survey, with assessment of hepatic steatosis. Main outcome measure Mortality from all causes, cardiovascular disease, cancer, and liver disease (up to 18 years of follow-up). Results The prevalence of non-alcoholic fatty liver disease with and without increased levels of liver enzymes in the population was 3.1% and 16.4%, respectively. Compared with participants without steatosis, those with non-alcoholic fatty liver disease but normal liver enzyme levels had multivariate adjusted hazard ratios for deaths from all causes of 0.92 (95% confidence interval 0.78 to 1.09), from cardiovascular disease of 0.86 (0.67 to 1.12), from cancer of 0.92 (0.67 to 1.27), and from liver disease of 0.64 (0.12 to 3.59). Compared with participants without steatosis, those with non-alcoholic fatty liver disease and increased liver enzyme levels had adjusted hazard ratios for deaths from all causes of 0.80 (0.52 to 1.22), from cardiovascular disease of 0.59 (0.29 to 1.20), from cancer of 0.53 (0.26 to 1.10), and from liver disease of 1.17 (0.15 to 8.93). Conclusions Non-alcoholic fatty liver disease was not associated with an increased risk of death from all causes, cardiovascular disease, cancer, or liver disease.

Effect of a 12-Month Intensive Lifestyle Intervention on Hepatic Steatosis in Adults With Type 2 Diabetes

OBJECTIVE Weight loss through lifestyle changes is recommended for nonalcoholic fatty liver disease (NAFLD). However, its efficacy in patients with type 2 diabetes is unproven. RESEARCH DESIGN AND METHODS Look AHEAD (Action for Health in Diabetes) is a 16-center clinical trial with 5,145 overweight or obese adults with type 2 diabetes, who were randomly assigned to an intensive lifestyle intervention (ILI) to induce a minimum weight loss of 7% or a control group who received diabetes support and education (DSE). In the Fatty Liver Ancillary Study, 96 participants completed proton magnetic resonance spectroscopy to quantify hepatic steatosis and tests to exclude other causes of liver disease at baseline and 12 months. We defined steatosis >5.5% as NAFLD. RESULTS Participants were 49% women and 68% white. The mean age was 61 years, mean BMI was 35 kg/m2, mean steatosis was 8.0%, and mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 20.5 and 24.2 units/l, respectively. After 12 months, participants assigned to ILI (n = 46) lost more weight (−8.5 vs. −0.05%; P < 0.01) than those assigned to DSE and had a greater decline in steatosis (−50.8 vs. −22.8%; P = 0.04) and in A1C (−0.7 vs. −0.2%; P = 0.04). There were no significant 12-month changes in AST or ALT levels. At 12 months, 26% of DSE participants and 3% (1 of 31) of ILI participants without NAFLD at baseline developed NAFLD (P < 0.05). CONCLUSIONS A 12-month intensive lifestyle intervention in patients with type 2 diabetes reduces steatosis and incident NAFLD.

Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately

The accurate diagnosis and staging of hepatic fibrosis is crucial for prognosis and treatment of liver disease. The current gold standard, liver biopsy, cannot be used for population-based screening, and has well known drawbacks if used for monitoring of disease progression or treatment success. Our objective was to assess performance and promise of radiologic modalities and techniques as alternative, noninvasive assessment of hepatic fibrosis. A systematic review was conducted. Six hundred twenty-eight studies were identified via electronic search. One hundred fifty-three papers were reviewed. Most described techniques that could differentiate between cirrhosis or severe fibrosis and normal liver. Accurate staging of fibrosis or diagnosis of mild fibrosis was often not achievable. Ultrasonography is the most common modality used in the diagnosis and staging of hepatic fibrosis. Elastographic measurements, either ultrasonography-based or magnetic resonance-based, and magnetic resonance diffusion weighted imaging, show the most promise for accurate staging of hepatic fibrosis. Most currently available imaging techniques can detect cirrhosis or significant fibrosis reasonably accurately. However, to date only magnetic resonance elastography has been able to stage fibrosis or diagnose mild disease. Utrasonographic elastography and magnetic resonance diffusion weighted appear next most promising.

Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low‐ versus high‐fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130‐item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low‐ (<15 g/day) versus high‐fructose (≥15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α‐ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ‐ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). Conclusions: High‐fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD. (HEPATOLOGY 2012;56:952–960)

Oncologic applications of diffusion-weighted MRI in the body

Diffusion‐weighted MRI (DWI) allows the detection of malignancies in the abdomen and pelvis. Lesion detection and characterization using DWI largely depends on the increased cellularity of solid or cystic lesions compared with the surrounding tissue. This increased cellularity leads results in restricted diffusion as indicated by reduction in the apparent diffusion coefficient (ADC). Low pretreatment ADC values of several malignancies have been shown to be predictive of better outcome. DWI can assess response to systemic or regional treatment of cancer at a cellular level and will therefore detect successful treatment earlier than anatomical measures. In this review, we provide a brief technical overview of DWI, discuss quantitative image analysis approaches, and review studies which have used DWI for the purpose of detection and characterization of malignancies as well as the early prediction of treatment response. J. Magn. Reson. Imaging 2012;257–279.

Hepatocellular Carcinoma: Response to TACE Assessed with Semiautomated Volumetric and Functional Analysis of Diffusion-weighted and Contrast-enhanced MR Imaging Data

PURPOSE To determine the association of early changes in posttreatment apparent diffusion coefficient (ADC) and venous enhancement (VE) with tumor size change after transarterial chemoembolization (TACE) by using an investigational semiautomated software. MATERIALS AND METHODS This retrospective HIPAA-compliant study was approved by the institutional review board, with waiver of informed consent. Patients underwent magnetic resonance (MR) imaging at 1.5 T before TACE, as well as 1 and 6 months after TACE. Volumetric analysis of change in ADC and VE 1 month after TACE compared with pretreatment values was performed in 48 patients with 71 hepatocellular carcinoma (HCC) lesions. Diagnostic accuracy was evaluated with receiver operating characteristic (ROC) analysis, using tumor response at 6 months according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST as end points. RESULTS According to RECIST criteria, 6 months after TACE, 30 HCC lesions showed partial response (PR), 35 showed stable disease (SD), and six showed progressive disease (PD). Increase in ADC and decrease in VE 1 month after TACE were significantly different between PR, SD, and PD. At area under the ROC curve (AUC) analysis of the ADC increase, there was an AUC of 0.78 for distinguishing PR from SD and PD and an AUC of 0.89 for distinguishing PR and SD from PD. The AUC for decrease in VE was 0.73 for discrimination of PR from SD and PD and 0.90 for discrimination of PR and SD from PD. CONCLUSION Volumetric analysis of increase in ADC and decrease in VE 1 month after TACE can provide an early assessment of response to treatment. Volumetric analysis of multiparametric MR imaging data may have potential as a prognostic biomarker for patients undergoing local-regional treatment of liver cancer.

Quantitative comparison and evaluation of software packages for assessment of abdominal adipose tissue distribution by magnetic resonance imaging

Objective:To examine five available software packages for the assessment of abdominal adipose tissue with magnetic resonance imaging, compare their features and assess the reliability of measurement results.Design:Feature evaluation and test–retest reliability of softwares (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision) used in manual, semi-automated or automated segmentation of abdominal adipose tissue.Subjects:A random sample of 15 obese adults with type 2 diabetes.Measurements:Axial T1-weighted spin echo images centered at vertebral bodies of L2–L3 were acquired at 1.5 T. Five software packages were evaluated (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision), comparing manual, semi-automated and automated segmentation approaches. Images were segmented into cross-sectional area (CSA), and the areas of visceral (VAT) and subcutaneous adipose tissue (SAT). Ease of learning and use and the design of the graphical user interface (GUI) were rated. Intra-observer accuracy and agreement between the software packages were calculated using intra-class correlation. Intra-class correlation coefficient was used to obtain test–retest reliability.Results:Three of the five evaluated programs offered a semi-automated technique to segment the images based on histogram values or a user-defined threshold. One software package allowed manual delineation only. One fully automated program demonstrated the drawbacks of uncritical automated processing. The semi-automated approaches reduced variability and measurement error, and improved reproducibility. There was no significant difference in the intra-observer agreement in SAT and CSA. The VAT measurements showed significantly lower test–retest reliability. There were some differences between the software packages in qualitative aspects, such as user friendliness.Conclusion:Four out of five packages provided essentially the same results with respect to the inter- and intra-rater reproducibility. Our results using SliceOmatic, Analyze or NIHImage were comparable and could be used interchangeably. Newly developed fully automated approaches should be compared to one of the examined software packages.

Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-Defined Steatosis Based on Data From the Third National Health and Nutrition Examination Survey

BACKGROUND & AIMS A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. METHODS We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. RESULTS The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. CONCLUSIONS We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.