Mary E. Rinella

Nonalcoholic Fatty Liver Disease: A Systematic Review

IMPORTANCE Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. OBJECTIVES To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. EVIDENCE REVIEW PubMed was queried for published articles through February 28, 2015, using the search terms NAFLD and cirrhosis, mortality, biomarkers, and treatment. A total of 88 references were selected, including 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses. FINDINGS Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The incidence of nonalcoholic fatty liver disease-related hepatocellular carcinoma is increasing and up to 50% of cases may occur in the absence of cirrhosis. CONCLUSIONS AND RELEVANCE Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis.

Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events

Nonalcoholic steatohepatitis (NASH) is an independent predictor of coronary artery disease (CAD). Our aim was to compare the incidence of cardiovascular (CV) events between patients transplanted for NASH and alcohol (ETOH)‐induced cirrhosis. This is a retrospective cohort study (August 1993 to March 2010) of 242 patients (115 NASH and 127 ETOH) with ≥12 months follow‐up after liver transplantation (LT). Those with hepatocellular carcinoma or coexisting liver diseases were excluded. Kaplan‐Meiers and Coxs proportional hazard analyses were conducted to compare survival. Logistic regression was used to calculate the likelihood of CV events, defined as death from any cardiac cause, myocardial infarction, acute heart failure, cardiac arrest, arrhythmia, complete heart block, and/or stroke requiring hospitalization <1 year after LT. Patients in the NASH group were older (58.4 versus 53.3 years) and were more likely to be female (45% versus 18%; P < 0.001). They were more likely to be morbidly obese (32% versus 9%), have dyslipidemia (25% versus 6%), or have hypertension (53% versus 38%; P < 0.01). On multivariate analysis, NASH patients were more likely to have a CV event <1 year after LT, compared to ETOH patients, even after controlling for recipient age, sex, smoking status, pretransplant diabetes, CV disease, and the presence of metabolic syndrome (26% versus 8%; odds ratio = 4.12; 95% confidence interval = 1.91‐8.90). The majority (70%) of events occurred in the perioperative period, and the occurrence of a CV event was associated with a 50% overall mortality. However, there were no differences in patient, graft, or CV mortality between groups. Conclusions: CV complications are common after LT, and NASH patients are at increased risk independent of traditional cardiac risk factors, though this did not affect overall mortality. (HEPATOLOGY 2012;56:1741–1750)

Nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10–40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.

The role of diet and nutrient composition in nonalcoholic Fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed world. NAFLD is tightly linked to insulin resistance and considered to be the hepatic manifestation of the metabolic syndrome. The cornerstone of any treatment regimen for patients with NAFLD is lifestyle modification focused on weight loss, exercise, and improving insulin sensitivity. Here we review the literature and discuss the role of diet and nutrient composition in the management of NAFLD. Because there are currently no specific dietary guidelines for NAFLD, this review proposes a dietary framework for patients with NAFLD based on the available evidence and extrapolates from dietary guidelines aimed at reducing insulin resistance and cardiovascular risk.

Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study

Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity‐related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown. We performed a cross‐sectional analysis of 2,713 participants from the multicenter, community‐based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year‐25 examination (age, 43‐55 years; 58.8% female and 48.0% black). NAFLD was defined as liver attenuation ≤40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers. Prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e’) velocity (10.8 ± 2.6 vs. 11.9 ± 2.8 cm/s), higher LV filling pressure (E/e’ ratio: 7.7 ± 2.6 vs. 7.0 ± 2.3), and worse absolute GLS (14.2 ± 2.4% vs. 15.2 ± 2.4%) than non‐NAFLD (P < 0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (P < 0.01). The association of NAFLD with e’ velocity (β = −0.36 [standard error = 0.15] cm/s; P = 0.02), E/e’ ratio (β = 0.35 [0.16]; P = 0.03), and GLS (β = −0.42 [0.18]%; P = 0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed. Conclusions: NAFLD is independently associated with subclinical myocardial remodeling and dysfunction and provides further insight into a possible link between NAFLD and HF. (Hepatology 2015;62:773–783)

Management of NAFLD: a stage-based approach

NAFLD is the most prevalent form of liver disease in the USA, affecting an estimated 30% of the population. The condition is associated with increased mortality related to cardiovascular disease, malignancy and liver disease. Identification of patients who might be at increased risk of adverse outcomes is critical as it is not feasible to screen all patients with suspected NAFLD. Patients with NASH, the progressive subtype of NAFLD, should be targeted for treatment, especially if they have concomitant fibrosis because such patients are more likely than those without fibrosis to have adverse outcomes. Treatment goals in patients with NAFLD vary depending on the disease stage owing to differential risk of progression and the particularities of an individuals comorbid disease. Lifestyle intervention is important for all patients irrespective of disease stage, but other therapies should be targeted to those most likely to benefit. In this Review, we highlight risk factors for disease progression and offer a stage-based treatment approach for patients with NAFLD.

Non-Alcoholic Fatty Liver Disease: Is Bariatric Surgery the Answer?

As the worldwide obesity epidemic continues to increase, the prevalence of non-alcoholic fatty liver disease (NAFLD) and specifically non-alcoholic steatohepatitis (NASH) will become increasingly prominent. NASH will surpass chronic hepatitis C infection as the primary indication for orthotopic liver transplantation in the near future. With the evolution of surgical techniques, bariatric surgery is currently recognized as the most effective method for achieving sustained weight loss and reversing numerous comorbidities in severely obese individuals. This review focuses on the potential risks and benefits of bariatric surgery in subjects with NAFLD and explores its role in the management of NASH in the obese patient.

The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.

Nonalcoholic Fatty Liver Disease, Diabetes, Obesity, and Hepatocellular Carcinoma

Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies.

Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis†

In humans with nonalcoholic fatty liver, diabetes is associated with more advanced disease. We have previously shown that diabetic db/db mice are highly susceptible to methionine choline‐deficient diet (MCD)‐induced hepatic injury. Because activation of the unfolded protein response (UPR) is an important adaptive cellular mechanism in diabetes, obesity, and fatty liver, we hypothesized that dysregulation of the UPR may partially explain how diabetes could promote liver injury. Db/db and db/m mice were fed the MCD or control diet for 4 weeks to characterize differences in UPR activation and downstream injury. Wildtype mice (C57BLKS/J) fed the MCD or control diet were treated with SP600125; a c‐Jun N‐terminal kinase (JNK) inhibitor and its effect on liver injury and UPR activation was measured. The MCD diet resulted in global up‐regulation of the UPR in both diabetic db/db and nondiabetic db/m mice. db/db mice had an inadequate activation of recovery pathways (GADD34, XBP‐1(s)) and accentuated activation of injury pathways related to persistent eif2‐α phosphorylation (activating transcription factor 4 [ATF‐4], C/EBP homologous transcription factor [CHOP], oxireductase endoplasmic reticulum oxidoreductin‐1 [ERO‐1α], JNK, nuclear factor kappaB [NF‐κB]) compared to db/m mice. This led to increased expression of inflammatory mediators such as tumor necrosis factor alpha (TNF‐α), ICAM‐1, and MCP‐1 compared to db/m mice. Interestingly, whereas pharmacologic JNK inhibition did not prevent the development of MCD diet‐induced steatohepatitis, it did attenuate UPR and downstream inflammatory signaling. Conclusion: MCD‐fed db/db mice develop a more proinflammatory milieu than db/m mice associated with an impaired ability to dephosphorylate eif2‐α through GADD34, impairing cellular recovery. These data may enhance our understanding of why diabetics with nonalcoholic steatohepatitis are prone to develop more severe liver injury than nondiabetic patients. (HEPATOLOGY 2011;)