Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts

Alexander, Mathew; Loomis, A. Katrina; Lei, Johan van der; Duarte‐Salles, Talita; Prieto‐Alhambra, Daniel; Ansell, David; Pasqua, Alessandro; Lapi, Francesco; Rijnbeek, Peter R.; Mosseveld, Mees; Waterworth, Dawn; Kendrick, Stuart; Sattar, Naveed; Alazawi, William

doi:10.1186/s12916-019-1321-x

Cited by 236 publications

(212 citation statements)

References 28 publications

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“…Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States, potentially leading to fibrosis, cirrhosis, and hepatocellular carcinoma progress [1][2][3][4]. NAFLD is manifested with a wide spectrum of clinical symptoms while disease pathogenesis is described through a "multiple-hit model."…”

Section: Introductionmentioning

confidence: 99%

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers

Shah

Pearce

et al. 2020

JCM

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Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p < 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted.

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Section: Introductionmentioning

confidence: 99%

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers

Shah

Pearce

et al. 2020

JCM

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“…Diabetes mellitus, especially when poorly controlled, is a wellknown risk factor for the development of HCC, even in patients without underlying cirrhosis. In 4 large European cohorts, diabetes has been identified as an independent risk factor to develop either HCC or cirrhosis in NAFLD or NASH, respectively [6]. In this patient, HbA 1c has been continuously above 9 %.…”

Section: Discussionmentioning

confidence: 80%

“…For many years viral-and alcoholic-related causes were recognized as the main risk factors for developing liver-related pathologies. More recently, NAFLD and NASH have become the predominant causes to develop cirrhosis and HCC in western countries [5], with a much higher risk in patients suffering from NASH [6]. In fact, NASH-cirrhosis is thought to be the fastest growing indication for liver transplantation in the United States [7].…”

Section: Introductionmentioning

confidence: 99%

A young patient with type 2 diabetes associated non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma

et al. 2020

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The rising prevalence of the metabolic syndrome has led to an increase of non-alcoholic fatty liver disease (NAFLD), and its progressive-inflammatory form called non-alcoholic steatohepatitis (NASH). In recent years, NAFLD and NASH have become major risk factors for developing liver cirrhosis and hepatocellular carcinoma (HCC). In this case, we report a 46-year-old patient with type 2 diabetes mellitus and metabolic comorbidities including obesity and arterial hypertension, who was referred because of rising liver enzymes. After clinical and diagnostic evaluation, the patient was diagnosed with NASH-associated liver cirrhosis, Child-Pugh stage B. A normal blood sugar level was difficult to achieve, and the patient presented with consistently elevated HbA1c-levels irresponsive to insulin therapy. Due to the underlying liver cirrhosis, the patient was enrolled in the HCC-surveillance program. Sonography during follow up showed a focal lesion. On magnetic resonance imaging (MRI), the diagnosis of HCC (BCLC stage A) was confirmed based on typical contrast enhancement and portal-venous wash-out. The patient was evaluated for liver transplantation with a labMELD of 17, and an intermittent therapy with TACE was initiated. Only 2 months after liver transplantation, the patient developed severe and lethal complications. Overall, this case highlights the different medical issues of patients with metabolic syndrome developing a chronic liver disease. In this patient, a rapid progression from NASH-associated liver cirrhosis to HCC was seen, and therefore highlights the importance of close surveillance to identify and treat potential risk factors early in the course of the disease.

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“…Such findings highlight the need for systematic identification of asymptomatic but high‐risk NAFLD patients who would benefit from an earlier clinical intervention as well as monitoring for disease progression. Factors associated with mortality and disease progression in this and previous analyses, such as older age, higher body mass index, biomarkers for liver function and insulin resistance, and components of the metabolic syndrome 5,8,26,31,32 should be included in multivariable risk assessment algorithms. Such non‐invasive diagnostic approaches can make the screening process accurate and cost‐effective 33 …”

Section: Discussionmentioning

confidence: 94%

Patterns and predictors of mortality and disease progression among patients with non‐alcoholic fatty liver disease

Canbay

Kachru

Haas³

et al. 2020

Aliment Pharmacol Ther

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SummaryBackgroundFactors associated with mortality and disease progression in non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are poorly understood.AimsTo assess the impact of liver disease severity, demographics and comorbidities on all‐cause mortality and liver disease progression in a large, real‐world cohort of NAFLD patients.MethodsClaims data from the German Institut für angewandte Gesundheitsforschung database between 2011 and 2016 were analyzed retrospectively. Adult patients diagnosed with NAFLD and/or NASH were categorised as NAFLD, NAFLD non‐progressors, compensated cirrhosis, decompensated cirrhosis, liver transplant or hepatocellular carcinoma (HCC). The longitudinal probability of mortality and incidence of progression were calculated for disease severity cohorts and multivariable analyses performed for adjusted mortality.ResultsAmong 4 580 434 patients in the database, prevalence of NAFLD was 4.7% (n = 215 655). Of those, 36.8% were non‐progressors, 0.2% compensated cirrhosis, 9.6% decompensated cirrhosis, 0.0005% liver transplant and 0.2% HCC. Comorbidity rates were significantly higher in compensated cirrhosis, decompensated cirrhosis and HCC compared with non‐progressors. The longitudinal probability of mortality for non‐progressors, compensated cirrhosis, decompensated cirrhosis and HCC was 3.6%, 18.7%, 28.8% and 68%, respectively. Independent predictors of mortality included cardiovascular disease, type 2 diabetes mellitus, hypertension, obesity and renal impairment. The cumulative incidence of progression in NAFLD and compensated cirrhosis patients was 10.7% and 16.7%, respectively, over 5 years of follow‐up.ConclusionNAFLD patients were severely under‐diagnosed and had a high probability of mortality that increased with disease progression. Early identification and effective management to halt or reverse fibrosis are essential to prevent progression.

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Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts

Cited by 236 publications

References 28 publications

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

A young patient with type 2 diabetes associated non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma

Patterns and predictors of mortality and disease progression among patients with non‐alcoholic fatty liver disease

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