2 The diagnostic tests

Clinical need and practice

The condition

2.1 Non-alcoholic fatty liver disease (NAFLD) is the term for a range of conditions caused by a build‑up of fat in the liver. NAFLD develops in 4 stages:

  • simple fatty liver (steatosis): a largely harmless build‑up of fat in the liver cells

  • non-alcoholic steatohepatitis (NASH): build‑up of fat leads to inflammation

  • fibrosis: persistent inflammation causes scar tissue to develop in the liver and nearby blood vessels, but the liver still functions normally

  • cirrhosis: severe scarring from chronic inflammation, causing permanent damage, which can lead to liver failure and liver cancer.

Diagnosis

2.2 NAFLD is usually diagnosed using ultrasound. There are several non-invasive tests available to assess the level of fibrosis in NAFLD, including blood-based tests and imaging, such as transient elastography or acoustic radiation force impulse (ARFI) elastography. Specific tests and pathways used vary across the country.

2.3 NICE's guideline on NAFLD recommends considering using the enhanced liver fibrosis (ELF) test to look for advanced liver fibrosis in people with NAFLD. If the result of the ELF test is 10.51 or above, the NICE guideline for cirrhosis in over 16s recommends testing for cirrhosis using transient or ARFI elastography. Routine liver blood tests are not recommended to rule out NAFLD or test for advanced fibrosis.

2.4 The British Society of Gastroenterology (BSG) guideline on NAFLD recommends testing for fibrosis in people with NAFLD using the NAFLD fibrosis score or FIB‑4. If these scores indicate an intermediate risk, then transient elastography or the ELF test can be used to further clarify the diagnosis. If the non-invasive tests are not able to exclude advanced fibrosis, BSG recommends that liver biopsy is considered to stage the level of inflammation and fibrosis, and to rule out other concomitant liver disease. Biopsy results are used to decide referral and treatment strategies for people with NAFLD. The NICE guideline for cirrhosis in over 16s recommends that liver biopsy is considered to diagnose cirrhosis when transient elastography is not suitable. NASH is diagnosed using biopsy. However, liver biopsy is an invasive procedure that is associated with well-recognised complications including bleeding and death. NICE's guideline on NAFLD includes a research recommendation to identify which non-invasive tests most accurately identify NASH in people with NAFLD.

2.5 The British Society of Paediatric Gastroenterology Hepatology and Nutrition guideline on fatty liver recommends that, if available, non-invasive markers of fibrosis should be used to assess NAFLD in children. In certain situations, referral for review at a national paediatric liver unit may be appropriate. Liver biopsy may be done in these units to confirm histological diagnosis or assess for NASH, fibrosis or cirrhosis.

Management

2.6 Treatment for NAFLD with no or minimal fibrosis is education on risk factors for advanced fibrosis and advice on weight management. According to NICE's guideline on NAFLD, people with advanced fibrosis may be offered pioglitazone or vitamin E. There are currently no medicines available specifically for NAFLD or NASH, but people with NASH or advanced fibrosis may enter clinical trials for new therapies.

2.7 The NICE guideline on cirrhosis in over 16s recommends that people with cirrhosis have monitoring for end-stage liver disease and liver cancer every 6 months, have testing for varices, are offered treatment for complications of cirrhosis (for example, variceal band ligation), and potentially are offered prophylactic treatment depending on comorbidities.

The interventions

LiverMultiScan

2.8 LiverMultiScan is a standalone software application produced by Perspectum that provides quantitative multiparametric analysis of non-contrast MRI. LiverMultiScan is intended to help clinicians diagnose and stage liver disease by non-invasively imaging the liver.

2.9 LiverMultiScan uses iron-corrected T1 (cT1), proton density fat fraction (PDFF) and T2* MRI protocols for its analyses. cT1 outputs are measured in milliseconds (ms), and correlate with liver fibro-inflammation. MRI PDFF is an MRI estimate of fat content and is expressed as a percentage. T2* is a measure correlated with the iron content of the liver and is used to produce the cT1 scan. The diagnosis indicated by the cT1 output and the clinical recommendations proposed by the company are as follows:

  • less than 800 ms: fatty liver

    • no inflammation present

    • reassess with MRI in 3 years

  • 800 ms to 875 ms: NASH

    • recommend lifestyle modification

    • manage type 2 diabetes and cardiovascular disease

    • monitor disease status with MRI after 6 months

  • more than 875 ms: high-risk NASH

    • reassess with MRI every 6 months

    • consider liver biopsy if cirrhosis is suspected

    • cancer surveillance

    • consider inclusion in NASH therapeutic trials.

Magnetic resonance elastography

2.10 Magnetic resonance elastography (MRE) combines MRI with low-frequency vibrations to create a 2D or 3D elastogram showing the stiffness of tissue. In addition to the usual MRI, an external mechanical driver passes vibrations through a flexible tube to a passive driver placed on a person's abdomen over the liver. The driver is manufactured by Resoundant. MRE is intended to generate acoustic vibrations in the body during an MRI exam to assess tissue elasticity for diagnostic purposes.

2.11 MRE is used for detecting and evaluating different stages of fibrosis and is usually added to a conventional abdominal MRI protocol. MRE outputs are provided in kilopascals (kPa). The company stated that MRE liver stiffness outputs can be used to stage liver fibrosis as follows:

  • more than 2.9 kPa: any fibrosis

  • more than 3.3 kPa: significant fibrosis

  • more than 3.9 kPa: advanced fibrosis

  • more than 4.8 kPa: cirrhosis.

    Before the second committee meeting, the company stated that these thresholds were suggestions and that other thresholds could be used depending on intended use.

The comparator

No further testing before a decision to do a biopsy or any other care decision

2.12 After testing as described in sections 2.2 to 2.5, in the absence of MRI-based testing, no other tests would be done before a decision to do a biopsy or any other care decision.

  • National Institute for Health and Care Excellence (NICE)