Update on cardiovascular risk in nonalcoholic fatty liver disease.

PURPOSE OF REVIEW: To summarize recent evidence demonstrating increased cardiovascular disease (CVD) risk, and how CVD risk may be reduced, in patients with nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: NAFLD is a multisystem disease, defined by a spectrum of liver fat-associated conditions extending from simple steatosis, to inflammation, fibrosis and cirrhosis. NAFLD not only increases the risk of liver morbidity and mortality but also increases the risk of CVD morbidity and mortality and is associated with recognized CVD risk factors such as hypertension, atherogenic dyslipidaemia, type 2 diabetes mellitus and chronic kidney disease. Evidence suggests that the liver fibrosis stage may be a strong CVD risk factor. Lifestyle measures (e.g. weight loss and increased physical activity) are effective in improving CVD risk factors. Hypoglycaemic agents, such as the peroxisome proliferator-activated receptor gamma agonist pioglitazone and the glucagon-like peptide-1 receptor agonist liraglutide, reduce cardiovascular risk and may improve liver histology. Statin and antihypertensive treatments are well tolerated and currently it is unclear whether novel antifibrotic drugs will reduce CVD risk. SUMMARY: Assessment and treatment of increased cardiovascular risk is important in patients with NAFLD. If not contra-indicated, pioglitazone or a glucagon-like peptide 1 agonist should be considered and may benefit both CVD risk and early liver disease.

Non-invasive liver fibrosis scores are strongly associated with liver cancer mortality in general population without liver disease.

BACKGROUND & AIMS: In a general population without known liver disease, we tested whether: (a) increased liver fibrosis scores (FIB-4 and APRI) are associated with liver cancer mortality and (b) the probability that a person with a higher score died of liver cancer. METHODS: In a retrospective occupational cohort who underwent annual/biennial health examinations (between 2002 and 2015), subjects were excluded with known chronic liver disease. Based on their baseline FIB-4 and APRI scores, subjects were categorised in low-/intermediate-/high-risk groups for advanced liver fibrosis. Using Cox proportional hazards regression analyses adjusted hazard ratios (aHR) were estimated for liver cancer mortality, with the low-risk FIB-4/APRI group as the reference. Harrell's C statistics were also calculated. RESULTS: In 200 479 participants, mean (SD) age was 36.4 (7.7) years. Median follow-up was 4.1 years (IQR 2.10-8.03) with 80 liver cancer deaths. High baseline FIB-4 or APRI scores occurred in 0.25% and 0.09% of subjects respectively. A high FIB-4 or APRI score was associated with a markedly increased risk of liver cancer mortality (aHRs 629.10 [95% CI 228.74-1730.20] and 80.42 [95% CI 34.37-188.18]) respectively. C statistics were FIB-4 = 0.841 (95% CI 0.735-0.946) and APRI = 0.933 (95% CI 0.864-0.999). CONCLUSIONS: In a general population without known liver disease, high FIB-4 or high APRI (in keeping with a high probability of advanced fibrosis) occurred in 0.25% (FIB-4) and 0.09% (APRI) of subjects. Both scores were associated with a markedly increased risk of liver cancer mortality and FIB-4 and APRI models both strongly predicted liver cancer mortality.

Causes of Mortality in Non-Alcoholic Fatty Liver Disease (NAFLD) and Alcohol Related Fatty Liver Disease (AFLD).

Non-alcoholic fatty liver disease (NAFLD) and alcohol related fatty liver disease (AFLD) both represent a spectrum of liver disease severity from hepatic steatosis to fibrosis and cirrhosis. Both NAFLD and AFLD are common diseases in the general population. NAFLD affects ~25% of the adult global population whilst AFLD has become the commonest indication for liver transplantation in the United States. It is often not possible to distinguish between NAFLD and AFLD on examination of liver histology, consequently, differentiation between NAFLD and AFLD is heavily reliant on a history of alcohol consumption. Age, smoking, alcohol consumption and sex appear to influence the risk of mortality in NAFLD or AFLD. In NAFLD and AFLD, the key causes of increased liver-related mortality are advanced liver fibrosis and cirrhosis leading to complications such as hepatocellular carcinoma and decompensated cirrhosis. NAFLD and AFLD are also associated with an increased risk of all-cause mortality including an increased risk of extra-hepatic malignancy. Non-invasive biomarkers of liver disease severity in NAFLD and AFLD perform poorly to predict mortality. However, alanine aminotransferase, gamma-glutamyl transpeptidase, FIB-4 and the NAFLD Fibrosis Score are independently associated with increased mortality in NAFLD. Both NAFLD and AFLD are associated with extra-hepatic risk factors and complications such as metabolic syndrome encompassing obesity, hypertension, type 2 diabetes mellitus, and chronic kidney disease. AFLD is associated with hypertension and cardiovascular disease as well as other organ damage. This narrative review discusses the associations, risk factors and diagnostic biomarkers linking NAFLD and AFLD with increased mortality.

Multi-drug approaches to NASH: what's in the development pipeline?

Introduction: The pandemic of obesity over the last two decades has triggered a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is associated with liver-related and cardiovascular complications. Despite this, the first licensed drug for NAFLD is yet to be approved. Given the scale of the problem and unmet needs, there is a myriad of agents in the development pipeline.Areas covered: We discuss promising agents in early phase clinical trials and categorize these agents based on their action on steatosis, steatohepatitis, and fibrosis. Furthermore, given the multisystemic nature of NAFLD, we consider the effects of these agents on the liver, their cardiometabolic effects, and the potential future strategies of combination therapies.Expert opinion: The paradigm for the ideal drug is the targeting of both steatohepatitis and fibrosis and the amelioration of cardiometabolic risk factors. New drugs that confer benefit in nonalcoholic steatohepatitis (NASH) must also be tested for their effects on type 2 diabetes mellitus and cardiovascular disease. The treatment of NASH will become analogous to the treatment of hypertension; it is very likely that multiple classes of drugs targeting different mechanistic pathways will be necessary because no single agent is likely to control all aspects of this complex liver disease.

Fatal Pneumocystis jirovecii pneumonia in a non-immunocompromised patient with alcohol-related liver cirrhosis.

This report presents the fatal case of a 63-year-old man with a new presentation of liver cirrhosis, presumed concurrent acute alcoholic hepatitis and development of Pneumocystis jirovecii pneumonia. The patient had none of the traditional immunosuppressing risk factors associated with Pneumocystis jirovecii pneumonia such as corticosteroid use, haematological malignancy or HIV infection. In the literature, there are two case reports and a case series of two patients which describe the development of Pneumocystis jirovecii pneumonia in acute alcoholic hepatitis. However, all of these previously described cases include identifiable risk factors - namely corticosteroid use and HIV infection. This case suggests that special consideration should be given to Pneumocystis jirovecii pneumonia as a cause of opportunistic infection in acute alcoholic hepatitis.

Immunotherapy for hepatocellular carcinoma: Current and future.

Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.