The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

Identification of Maltase Glucoamylase as a Biomarker of Acute Kidney Injury in Patients with Cirrhosis.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of decompensated cirrhosis with increased mortality. Traditional biomarkers such as serum creatinine are not sensitive for detecting injury without functional change. We hypothesize that urinary exosomes potentially carry markers that differentiate the type of kidney injury in cirrhotic patients. METHODS: This is a prospective, single-center, and observational study of adult patients with cirrhosis. The patient groups included healthy normal controls, compensated cirrhosis with normal kidney function, decompensated cirrhosis with normal kidney function, and decompensated cirrhosis with AKI. Data were extracted from the electronic health record including etiology of liver disease, MELD score, history of decompensation, Child-Turcotte-Pugh score, history of AKI, and medication exposures. Urine samples were collected at the time of consent. Urine exosome protein content was analyzed, and proteomic data were validated by immunoblotting. Statistical analysis included partial least squares-discriminant analysis coupled with variable importance in projection identification. RESULTS: Eighteen cirrhotic subjects were enrolled, and six healthy control subjects were extracted from our biorepository. Urine exosomes were isolated, and 1572 proteins were identified. Maltase-glucoamylase was the top discriminating protein confirmed by western blotting. CONCLUSIONS: Patients with cirrhosis and AKI have upregulation of renal brush border disaccharidase, MGAM, in urinary exosomes which may differentiate the type of kidney injury in cirrhosis; however, the clinical significance of this requires further validation.

AGA Clinical Practice Update: Coagulation in Cirrhosis.

DESCRIPTION: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis. METHODS: This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. BEST PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced coagulation abnormalities. BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease.

High risk of delisting or death in liver transplant candidates following infections: Results from the North American Consortium for the Study of End-Stage Liver Disease.

Because Model for End-Stage Liver Disease (MELD) scores at the time of liver transplantation (LT) increase nationwide, patients are at an increased risk for delisting by becoming too sick or dying while awaiting transplantation. We quantified the risk and defined the predictors of delisting or death in patients with cirrhosis hospitalized with an infection. North American Consortium for the Study of End-Stage Liver Disease (NACSELD) is a 15-center consortium of tertiary-care hepatology centers that prospectively enroll and collect data on infected patients with cirrhosis. Of the 413 patients evaluated, 136 were listed for LT. The listed patients' median age was 55.18 years, 58% were male, and 47% were hepatitis C virus infected, with a mean MELD score of 2303. At 6-month follow-up, 42% (57/136) of patients were delisted/died, 35% (47/136) underwent transplantation, and 24% (32/136) remained listed for transplant. The frequency and types of infection were similar among all 3 groups. MELD scores were highest in those who were delisted/died and were lowest in those remaining listed (25.07, 24.26, 17.59, respectively; P < 0.001). Those who were delisted or died, rather than those who underwent transplantation or were awaiting transplantation, had the highest proportion of 3 or 4 organ failures at hospitalization versus those transplanted or those continuing to await LT (38%, 11%, and 3%, respectively; P = 0.004). For those who were delisted or died, underwent transplantation, or were awaiting transplantation, organ failures were dominated by respiratory (41%, 17%, and 3%, respectively; P < 0.001) and circulatory failures (42%, 16%, and 3%, respectively; P < 0.001). LT-listed patients with end-stage liver disease and infection have a 42% risk of delisting/death within a 6-month period following an admission. The number of organ failures was highly predictive of the risk for delisting/death. Strategies focusing on prevention of infections and extrahepatic organ failure in listed patients with cirrhosis are required.

Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis.

BACKGROUND & AIMS: Bacterial infections, particularly repeated infections, are significant causes of morbidity and mortality among patients with cirrhosis. We investigated and characterized risk factors for repeat infections in these patients. METHODS: In a prospective study, we collected data from 188 patients hospitalized with cirrhosis and infections and enrolled in the North American Consortium for the Study of End-Stage Liver Disease (12 centers). Patients were followed up for 6 months after hospital discharge and data were analyzed on type of infections and factors associated with subsequent infections. RESULTS: Six months after hospital discharge, 14% of subjects had received liver transplants, 27% died, and 59% were alive without liver transplantation. After discharge, 45% had subsequent infections, but only 26% of the subsequent infections occurred at the same site. Compared with patients not re-infected, patients with repeat infections were older and a higher proportion used proton pump inhibitors (PPIs) (P = .006), rifaximin (P < .001), or prophylactic therapy for spontaneous bacterial peritonitis (SBP) (P < .001). Logistic regression showed that SBP prophylaxis (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.56-7.63), PPI use (OR, 2.94; 95% CI, 1.39-6.20), SBP at hospital admission (OR, 0.37; 95% CI, 0.15-0.91), and age (OR, 1.06; 95% CI, 1.02-1.11) were independent predictors of subsequent infections. CONCLUSIONS: Patients hospitalized with cirrhosis and infections are at high risk for subsequent infections, mostly at different sites, within 6 months of index infection resolution. Those at highest risk include previously infected older patients receiving PPIs and/or SBP prophylaxis, although these associations do not prove that these factors cause the infections. New strategies are needed to prevent infections in patients with cirrhosis.

Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T.

PURPOSE: To compare the accuracy of several magnetic resonance (MR) imaging-based methods for hepatic proton-density fat fraction (FF) estimation at 3.0 T, with spectroscopy as the reference technique. MATERIALS AND METHODS: This prospective study was institutional review board approved and HIPAA compliant. Informed consent was obtained. One hundred sixty-three subjects (39 with known hepatic steatosis, 110 with steatosis risk factors, 14 without risk factors) underwent proton MR spectroscopy and non-T1-weighted gradient-echo MR imaging of the liver. At spectroscopy, the reference FF was determined from frequency-selective measurements of fat and water proton densities. At imaging, FF was calculated by using two-, three-, or six-echo methods, with single-frequency and multifrequency fat signal modeling. The three- and six-echo methods corrected for T2*; the two-echo methods did not. For each imaging method, the fat estimation accuracy was assessed by using linear regression between the imaging FF and spectroscopic FF. Binary classification accuracy of imaging was assessed at four reference spectroscopic thresholds (0.04, 0.06, 0.08, and 0.10 FF). RESULTS: Regression intercept of two-, three-, and six-echo methods were -0.0211, 0.0087, and -0.0062 (P <.001 for all three) without multifrequency modeling and -0.0237 (P <.001), 0.0022, and -0.0007 with multifrequency modeling, respectively. Regression slope of two-, three-, and six-echo methods were 0.8522, 0.8528, and 0.7544 (P <.001 for all three) without multifrequency modeling and 0.9994, 0.9775, and 0.9821 with multifrequency modeling, respectively. Significant deviation of intercept and slope from 0 and 1, respectively, indicated systematic error. Classification accuracy was 82.2%-90.1%, 93.9%-96.3%, and 83.4%-89.6% for two-, three-, and six-echo methods without multifrequency modeling and 88.3%-92.0%, 95.1%-96.3%, and 94.5%-96.3% with multifrequency modeling, respectively, depending on the FF threshold. T2*-corrected (three- and six-echo) multifrequency imaging methods had the overall highest FF estimation and classification accuracy. Among methods without multifrequency modeling, the T2-corrected three-echo method had the highest accuracy. CONCLUSION: Non-T1-weighted MR imaging with T2 correction and multifrequency modeling helps accurately estimate hepatic proton-density FF at 3.0 T.

Association between metabolic syndrome and liver histology among children with nonalcoholic Fatty liver disease.

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of metabolic syndrome (MetS) among adults. Emerging data suggest that MetS may be associated with nonalcoholic fatty liver disease (NAFLD) in children as well. We sought to determine whether MetS or its component features are associated with specific histological features or severity of NAFLD. METHODS: Children and adolescents aged 6-17 years enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with clinical data obtained within 6 months of liver biopsy were included. MetS was defined as the presence of three or more of the following features as determined by application of age-adjusted normative values: central obesity, dyslipidemia, impaired fasting glucose, and elevated blood pressure. Liver biopsies were evaluated by the Pathology Committee of the NASH CRN. RESULTS: Two hundred fifty four children were included in the analysis, of whom 65 (26%) met specified criteria for MetS. Among children with MetS, there is a higher proportion of females who were on average older in age and pubertal. The risk of MetS was greatest among those with severe steatosis (odds ratio (OR)=2.58 for grade 3 vs. grade 1 steatosis, P=0.001). The presence of hepatocellular ballooning was also significantly associated with MetS (OR=2.10, P=0.03). Those with advanced fibrosis (stage 3/4) had an OR for MetS of 3.21 (P=0.04) vs. those without fibrosis (stage 0). Borderline zone 1 or definite NASH patterns compared with "not NASH" were strongly associated with MetS (OR=4.44, P=0.005 and OR=4.07, P=0.002, respectively). The mean NAFLD Activity Score (NAS) was greater among children with MetS vs. those without (4.8 +/- 1.4 vs. 4.3 +/- 1.4, P=0.01). Central obesity was significantly associated with steatosis, fibrosis, hepatocellular ballooning, and NAFLD pattern. Insulin resistance was significantly associated with steatosis, fibrosis, hepatocellular ballooning, NAS, and NAFLD pattern. CONCLUSIONS: MetS is common among children with NAFLD and is associated with severity of steatosis, hepatocellular ballooning, NAS, NAFLD pattern, and the presence of advanced fibrosis. Individual MetS features, particularly central obesity and insulin resistance, were also associated with severity of NAFLD. MetS features should be considered in children with NAFLD as individually and collectively they help identify children with more advanced disease.

Effect of PRESS and STEAM sequences on magnetic resonance spectroscopic liver fat quantification.

PURPOSE: To compare PRESS and STEAM MR spectroscopy for assessment of liver fat in human subjects. MATERIALS AND METHODS: Single-voxel (20 x 20 x 20 mm) PRESS and STEAM spectra were obtained at 1.5T in 49 human subjects with known or suspected fatty liver disease. PRESS and STEAM sequences were obtained with fixed TR (1500 msec) and different TE (five PRESS spectra between TE 30-70 msec, five STEAM spectra between TE 20-60 msec). Spectra were quantified and T2 and T2-corrected peak area were calculated by different techniques. The values were compared for PRESS and STEAM. RESULTS: Water T2 values from PRESS and STEAM were not significantly different (P = 0.33). Fat peak T2s were 25%-50% shorter on PRESS than on STEAM (P < 0.02 for all comparisons) and there was no correlation between T2s of individual peaks. PRESS systematically overestimated the relative fat peak areas (by 7%-263%) compared to STEAM (P < 0.005 for all comparisons). The peak area given by PRESS was more dependent on the T2-correction technique than STEAM. CONCLUSION: Measured liver fat depends on the MRS sequence used. Compared to STEAM, PRESS underestimates T2 values of fat, overestimates fat fraction, and provides a less consistent fat fraction estimate, probably due to J coupling effects.

Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T.

PURPOSE: To assess the accuracy of four fat quantification methods at low-flip-angle multiecho gradient-recalled-echo (GRE) magnetic resonance (MR) imaging in nonalcoholic fatty liver disease (NAFLD) by using MR spectroscopy as the reference standard. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA-compliant prospective study, 110 subjects (29 with biopsy-confirmed NAFLD, 50 overweight and at risk for NAFLD, and 31 healthy volunteers) (mean age, 32.6 years +/- 15.6 [standard deviation]; range, 8-66 years) gave informed consent and underwent MR spectroscopy and GRE MR imaging of the liver. Spectroscopy involved a long repetition time (to suppress T1 effects) and multiple echo times (to estimate T2 effects); the reference fat fraction (FF) was calculated from T2-corrected fat and water spectral peak areas. Imaging involved a low flip angle (to suppress T1 effects) and multiple echo times (to estimate T2* effects); imaging FF was calculated by using four analysis methods of progressive complexity: dual echo, triple echo, multiecho, and multiinterference. All methods except dual echo corrected for T2* effects. The multiinterference method corrected for multiple spectral interference effects of fat. For each method, the accuracy for diagnosis of fatty liver, as defined with a spectroscopic threshold, was assessed by estimating sensitivity and specificity; fat-grading accuracy was assessed by comparing imaging and spectroscopic FF values by using linear regression. RESULTS: Dual-echo, triple-echo, multiecho, and multiinterference methods had a sensitivity of 0.817, 0.967, 0.950, and 0.983 and a specificity of 1.000, 0.880, 1.000, and 0.880, respectively. On the basis of regression slope and intercept, the multiinterference (slope, 0.98; intercept, 0.91%) method had high fat-grading accuracy without statistically significant error (P > .05). Dual-echo (slope, 0.98; intercept, -2.90%), triple-echo (slope, 0.94; intercept, 1.42%), and multiecho (slope, 0.85; intercept, -0.15%) methods had statistically significant error (P < .05). CONCLUSION: Relaxation- and interference-corrected fat quantification at low-flip-angle multiecho GRE MR imaging provides high diagnostic and fat-grading accuracy in NAFLD.

Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in American children. Noninvasive means to discriminate between NAFLD and nonalcoholic steatohepatitis (NASH) might diminish the requirement for liver biopsy or predict those at increased risk for progression. METHODS: Data obtained prospectively from children (age, 6-17 y) enrolled in the NASH Clinical Research Network were analyzed to identify clinical-pathologic correlates of pediatric NAFLD. All participants underwent liver biopsy within 6 months of clinical data that were reviewed by a central pathology committee. RESULTS: A total of 176 children (mean age, 12.4 y; 77% male) were eligible for inclusion. By using ordinal logistic regression analysis, increasing aspartate aminotransferase (AST) level (odds ratio [OR], 1.017 per U/L; 95% confidence interval [CI], 1.004-1.031) and gamma-glutamyltransferase level (OR, 1.016 per U/L; 95% CI, 1.000-1.033) were associated independently with increasing severity of NASH. Increasing AST level (OR, 1.015 per U/L; 95% CI, 1.006-1.024), increasing white blood cell count (OR, 1.22 per 1000/mm(3); 95% CI, 1.07-1.38), and decreasing hematocrit (OR, 0.87 per %; 95% CI, 0.79-0.96) were associated independently with increasing severity of fibrosis. Area under the receiver operator characteristic curve for a model with AST and alanine aminotransferase was 0.75 (95% CI, 0.66-0.84) and 0.74 (95% CI, 0.63-0.85) for distinguishing steatosis from more advanced forms of NASH and bridging fibrosis from lesser degrees of fibrosis, respectively. CONCLUSIONS: Certain components of routine laboratory tests are predictive of NAFLD pattern and fibrosis severity, but do not have adequate discriminate power to replace liver biopsy in evaluating pediatric NAFLD.

Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research.

Although population prevalence is very difficult to establish, nonalcoholic fatty liver disease (NAFLD) is probably the most common cause of liver disease in the preadolescent and adolescent age groups. There seems to be an increase in the prevalence of NAFLD, likely related to the dramatic rise in the incidence of obesity during the past 3 decades. Despite an increase in public awareness, overweight/obesity and related conditions, such as NAFLD, remain underdiagnosed by health care providers. Accurate diagnosis and staging of nonalcoholic steatohepatitis (NASH) requires liver biopsy. The development of noninvasive surrogate markers and the advancements in imaging technology will aid in the screening of large populations at risk for NAFLD. Two distinct histological patterns of NASH have been identified in the pediatric population, and discrete clinical and demographic features are observed in children with these 2 patterns. The propensity for NASH to develop in obese, insulin-resistant pubertal boys of Hispanic ethnicity or a non-Hispanic white race may provide clues to the pathogenesis of NAFLD in children. The natural history of pediatric NASH has yet to be defined, but most biopsies in this age group demonstrate some degree of fibrosis. In addition, cirrhosis can be observed in children as young as 10 years. While the optimal treatment of pediatric NAFLD has yet to be determined, lifestyle modification through diet and exercise should be attempted in children diagnosed with NAFLD. A large, multicenter trial of vitamin E and metformin is underway as part of the NASH clinical research network.

The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients.

BACKGROUND/AIMS: Questions remain regarding the etiology of steatosis in hepatitis C, and its impact on disease progression and treatment outcomes. METHODS: We evaluated liver biopsies from 574 patients with chronic hepatitis C from a single center. RESULTS: Severity of steatosis was associated with body mass index, HCV genotype 3 infection, age, and duration of infection (P