NAFLD risk factors

Certain people are at greater risk than others of developing NAFLD and progressing to advanced fibrosis due to NASH. Understanding the factors that increase the risk of NAFLD and NASH allows for the identification of individuals who might benefit from further clinical investigations. Risk factors include:

Obesity: Defined using either body mass index (BMI; >30 kg/m2) or waist circumference measurements (≥94 cm in men and ≥80 cm in women), and is independently associated with a 3.5-fold greater risk of developing NAFLD compared with weight within the normal range1

Type 2 diabetes mellitus (T2DM): Prevalence of NAFLD in people with T2DM has been estimated to be between 65–75%,2 and the risk of developing NAFLD increases in people with higher fasting glucose levels3

Metabolic syndrome (MetS): Defined by the presence of at least three of the following components: obesity, T2DM, hypertension, hypertriglyceridaemia and low high‑density lipoprotein-cholesterol.4 The presence of any of these factors should prompt investigation for NAFLD5

Genetics: Familial aggregation and twin studies have identified a hereditary component to NAFLD, suggesting that family history may be a risk factor6,7

Racial differences: Racial and ethnic groups have different propensities for progression to advanced disease. Hispanic people have a higher risk of steatosis than Caucasian people, who in turn, have a higher risk than Black people.8 The increased risk in Hispanic people can be explained by higher prevalence of obesity and insulin resistance.8 The difference in prevalence between the Black and Caucasian populations may be due to differences in lipid metabolism9

Role of primary care providers

As the first point of contact for people with potential NAFLD, the role of the primary care provider (PCP) can involve:5

  • Evaluating those at high risk
  • Performing diagnostic liver serum tests/noninvasive fibrosis assessment if NAFLD and/or NASH is suspected
  • Ruling out other causes of liver disease such as excessive alcohol consumption and viral hepatitis
  • Referring people at high risk of advanced fibrosis due to NASH to specialist liver centres
  • Providing lifestyle management advice and monitoring to people with NAFLD to prevent development of advanced fibrosis due to NASH

Primary tests

At present, a diagnosis of advanced fibrosis due to NASH is usually confirmed by liver specialists. However, as a first step, PCPs can assess people with suspected NAFLD for abnormal liver enzyme levels and fibrosis serum biomarkers.5

Liver fibrosis can lead to measureable changes in many serum biomarkers, including the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).5,10 Therefore, assessment of these enzymes should be performed in high risk groups where NAFLD and/or NASH is suspected. A key benefit of serum biomarkers is that they reflect fibrosis in the whole liver, rather than reflecting only a small region provided by alternative investigations, such as liver biopsy.11

It is important to note that liver enzymes can be normal even in people with advanced fibrosis; as many as 37.5% of patients with normal ALT levels may have advanced fibrosis due to NASH.12 To investigate whether there is fibrosis, ALT and AST can be applied to readily available calculations, the simplest of these being the Fibrosis-4 (FIB-4) index.

 

Fibrosis-4 index

The FIB-4 index is a simple algorithm shown to have high diagnostic accuracy for predicting advanced fibrosis (F3/F4). The index uses only four readily available measurements, patient age, AST and ALT levels and platelet counts, to assess fibrosis/cirrhosis.13 The accuracy of FIB‑4 in identifying advanced fibrosis is high.14

FIB-4 score15

Fibrosis severity

<1.3

Low risk (F0-F2)

1.3–2.67

Inconclusive

>2.67

High risk (F3/F4)

A FIB-4 value of >1.3 cannot rule out advanced fibrosis due NASH and it is important to consider further investigation.

Fibrosis-4 (FIB-4) Calculator

This FIB-4 calculator helps to assess liver fibrosis/cirrhosis.
Entering the values into the boxes will produce a final FIB-4 score.

If <1.3:

OFFER LIFESTYLE ADVICE

A result of less than 1.3 indicates a low risk of advanced fibrosis therefore patients do not require referral if their scores stay low.13 To help prevent fibrosis progression, patients may benefit from diet and lifestyle modifications. For further information on diet, exercise and lifestyle advice click here.

If >1.3:

REFER TO A LIVER SPECIALIST

Results above 2.67 indicate an intermediate to high risk of advanced fibrosis and warrant urgent referral to a liver specialist.13 Results above 1.3 indicate inconclusive results therefore patients should still be referred to a specialist for further investigation and confirmation of diagnosis.

For more information on referral and diagnosis, click here.

Disclaimer
No data or values are stored in this calculator.

NAFLD fibrosis score (NFS)

The NFS uses the same four variables as the FIB-4 index, along with hyperglycaemia, albumin and BMI to predict the presence or absence of advanced fibrosis due to NASH.16

NAFLD score16

Fibrosis severity

<−1.455

F0–F2

−1.455–0.676

Inconclusive

>0.676

F3/F4

This test is widely used due to its convenience and accessibility of the clinical data required.17 The accuracy of the NFS in identifying advanced fibrosis is also high and test results can help decide if referral to a liver specialist is needed.18

ELF™ score

The enhanced liver fibrosis (ELF™) score measures three blood parameters (hyaluronic acid, procollagen III amino terminal peptide and tissue inhibitor of metalloproteinase 1) to determine the severity of fibrosis. High levels of these biomarkers results in a high ELF™ score indicating a greater risk or more severe grade of fibrosis.11

Studies indicate that the accuracy of ELF™ is also high.11 National Institute for Health and Care Excellence (NICE) guidelines advocate the use of the ELF™ algorithm for detecting and monitoring advanced fibrosis due to NASH, however, ELF™ biomarkers are not routinely investigated in clinical tests and so its use is limited.19

Figure 1.0: Summary of noninvasive serum fibrosis testing15,16,20,21,22

 

*From a meta-analysis of various databases from 1998-2012

BMI: Body mass index; HA: hyaluronic acid; PIIINP: pro-peptide amino-terminal of pro-collagen type III;

TIMP-1: tissue inhibitor metalloproteinase 1

Specialist referral and primary care management

Currently, it is not possible to accurately diagnose advanced fibrosis due to NASH in primary care settings. The assessments outlined here can, however, be used to identify people who require referral for further investigations to confirm or rule out a diagnosis of advanced fibrosis due to NASH.

If the assessments do not rule out the possibility of advanced fibrosis due to NASH, referral to a liver specialist for more advanced assessments is recommended.

If results of primary care assessments reveal little to no risk of fibrosis, lifestyle management advice (diet and exercise) should be provided and follow‑up assessments performed as recommended in the EASL guidelines.

NAFLD and NASH

An introduction to the NASH and NAFLD section and related pages.

The Burden of NAFLD and NASH

This page covers definitions of NAFLD and NASH, epidemiology, societal impact and more.

Referral and diagnosis of NASH

Covering diagnostic tests including liver biopsy, Fibroscan® and noninvasive tests

Management of NAFLD and NASH

Referencing current guidelines and management goals for people with NAFLD and NASH.

Obesity and NASH

Information on the links between obesity and NAFLD and obesity and advanced fibrosis due to NASH.

Diabetes and NASH

Information on the links between type 2 diabetes mellitus, NAFLD and advanced fibrosis due to NASH.

NASH and NAFLD toolkit

Collated resources and links related to NAFLD and NASH, covering management, lifestyle advice and screening tools and more.

References

  1. Li L, et al. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev 2016;17:510–9.
  2. Targher G, et al. Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients. Diabetes Care 2007;30:1212–8.
  3. Sung KC, et al. Predicting incident fatty liver using simple cardio-metabolic risk factors at baseline. BMC Gastroenterol 2012;12:84.
  4. McCracken E, et al. Pathophysiology of the metabolic syndrome. Clin Dermatol 2018;36:14–20.
  5. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Obes Facts 2016;9:65–90.
  6. Schwimmer JB, et al. Heritability of Nonalcoholic Fatty Liver Disease. Gastroenterology 2009;136:1585–92.
  7. Loomba R, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015;149:1784–93.
  8. Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–95.
  9. Foster T, et al. The prevalence and clinical correlates of nonalcoholic fatty liver disease (NAFLD) in African Americans: the multiethnic study of atherosclerosis (MESA). Dig Dis Sci 2013;58:2392–8.
  10. Afdhal N. Fibroscan (Transient Elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol 2012;8:605–7.
  11. Xie Q, et al. The performance of Enhanced Liver Fibrosis (ELF) test for the staging of liver fibrosis: A meta-analysis. PLoS ONE 2014;9:e92772.
  12. Verma S, et al. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int 2013;33:
    1398–405.
  13. Sterling R, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–25.
  14. McPherson S, et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic liver disease. Gut 2010;59:1265–9.
  15. Shah A, et al. Use of the FIB4 index for non-invasive evaluation of fibrosis in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104–12.
  16. Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846–54.
  17. Arulanandan A and Loomba R. Non-invasive testing for NASH and NASH with advanced fibrosis: Are we there yet? Curr Hepatol Rep 2015;14:109–18.
  18. Dowman JK, et al. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2011;33:525-540.
  19. Cheah MCC, et al. Current modalities of fibrosis assessment in non-alcoholic fatty liver disease. J Clin Transl Hepatol 2017;5:261–71.
  20. Castera L, et al. Non-Invasive Assessment of Liver Disease in Patients with NAFLD. Gastroenterology 2019. [Epub ahead of print]
  21. Lichtinghagen R, et al. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol 2013;59:236–42.
  22. Crossan C,et al. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess 2015;19:1–409.

LID/IHQ/18-12//1048d(1) Date of preparation August 2019