Derivation and Validation of a Cardiovascular Risk Score for Prediction of Major Acute Cardiovascular Events in Non-alcoholic Fatty Liver Disease

The Importance of an Elevated Mean Platelet Volume

Robin D. Abeles; Benjamin H. Mullish; Roberta Forlano; Torben Kimhofer; Maciej Adler; Alexandros Tzallas; Nikolaos Giannakeas; Michael Yee; Jamil Mayet; Robert D. Goldin; Mark R. Thursz; Pinelopi Manousou


Aliment Pharmacol Ther. 2019;49(8):1077-1085. 

In This Article

Abstract and Introduction


Background: Atherosclerotic cardiovascular disease is a key cause of morbidity in non-alcoholic fatty liver disease (NAFLD) but appropriate means to predict major acute cardiovascular events (MACE) are lacking.

Aim: To design a bespoke cardiovascular risk score in NAFLD.

Methods: A retrospective derivation (2008–2016, 356 patients) and a prospective validation (2016–2017, 111 patients) NAFLD cohort study was performed. Clinical and biochemical data were recorded at enrolment and mean platelet volume (MPV), Qrisk2 and Framingham scores were recorded one year prior to MACE (Cardiovascular death, acute coronary syndrome, stroke and transient ischaemic attack).

Results: The derivation and validation cohorts were well-matched, with MACE prevalence 12.6% and 12%, respectively. On univariate analysis, age, diabetes, advanced fibrosis, collagen proportionate area >5%, MPV and liver stiffness were associated with MACE. After multivariate analysis, age, diabetes and MPV remained independently predictive of MACE. The "NAFLD CV-risk score" was generated using binary logistic regression:

0.06*(Age) + 0.963*(MPV) + 0.26*(DM1) – 16.44;

1Diabetes mellitus: 1: present; 2: absent.

(AUROC 0.84). A cut-off of −3.98 gave a sensitivity 97%, specificity 27%, PPV 16%, and NPV 99%. An MPV alone of >10.05 gave a sensitivity 97%, specificity 59%, PPV 24% and NPV 97% (AUROC 0.83). Validation cohort AUROCs were comparable at 0.77 (NAFLD CV-risk) and 0.72 (MPV). In the full cohort, the NAFLD CV-risk score and MPV outperformed both Qrisk2 and Framingham scores.

Conclusions: The NAFLD CV risk score and MPV accurately predict 1-year risk of MACE, thereby allowing better identification of patients that require optimisation of their cardiovascular risk profile.


Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 25% of the world's population and represents a spectrum of liver disease that ranges from simple steatosis (SS) to steatohepatitis (NASH), found in 30%-70% on biopsy, with or without fibrosis.[1] Approximately 41% of patients with NASH will experience progression of liver fibrosis over time, with the associated risks of developing cirrhosis, liver failure and hepatocellular carcinoma.[2] NASH is projected to become the leading indication for liver transplant in the USA by 2020.[2] However, the leading causes for morbidity and mortality in patients with NAFLD are due to atherosclerotic cardiovascular complications, with patients who have NASH or advanced fibrosis being at greater risk than those with SS.[3,4]

Various cardiovascular risk scoring systems are widely-used in clinical practice including the Framingham[5] and Qrisk2 Score.[6] These estimate the 10-year risk of atherosclerotic cardiovascular events (including acute coronary syndrome and stroke) and have been validated in large cohorts of the general population. However, patients with NAFLD may be considered of higher risk as NAFLD is associated with various markers of subclinical atherosclerosis[7,8] and high-risk coronary disease.[9] Furthermore, the Framingham risk score does not include key features of the metabolic syndrome (including obesity and insulin resistance), which are evidently important risk factors for atherosclerotic events in those with NAFLD.[10] The standard cardiovascular screening calculations may therefore not perform as well in patients with NAFLD.

Platelet activation is a typical feature in the pathophysiology of a range of diseases, including inflammatory and vascular disorders.[11] Larger platelets are metabolically and enzymatically more active than smaller platelets, with greater aggregability, and contain a greater amount of pro-thrombotic material.[12] As such, there is interest as to whether markers of platelet size and function may be a useful biomarker of activity of such disorders. Mean platelet volume (MPV) is provided with every complete blood count result and has been shown to be elevated in patients with atherothrombotic disease[13] and insulin resistance.[14]

Although there are some conflicting data,[15,16] MPV has also been shown to be elevated in people with NAFLD.[17–22] Higher MPV levels are found in patients with more advanced fibrosis compared to earlier fibrosis, and in those with NASH compared to those without.[20,22]

We aimed to investigate whether elevated MPV is associated with an increased risk of cardiovascular events in patients with NAFLD and whether its incorporation in a cardiovascular risk score for patients with NAFLD would identify patients at higher risk for major acute cardiovascular events (MACE) compared to current standard cardiovascular risk scores.