LITMUS: SomaSignal panel most accurate for at-risk MASH and advanced fibrosis

The study

LITMUS is a prospective, multicentre diagnostic accuracy study published in The Lancet. Adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were recruited across 13 countries in Europe and the USA. The authors tested 12 single markers and 18 multimarker panels.

The reference standard was centrally scored liver histology using the NASH Clinical Research Network Scoring System. The target conditions were MASH, at-risk MASH (MASH plus fibrosis stage F2 or higher), advanced fibrosis (F3 or higher) and cirrhosis (F4). Performance was measured by area under the receiver operating characteristic curve (AUC). The authors set a minimum acceptable criterion (MAC) of AUC higher than 0.80 to indicate that a test could potentially replace biopsy. Funding was from the Innovative Medicines Initiative 2 Joint Undertaking.

What they found

Data from 1590 participants with centrally scored biopsies and at least one biomarker measurement were analysed (recruitment between Jan 1, 2018 and June 30, 2023). On biopsy, 609 (38%) had at-risk MASH, 678 (43%) had MASH, 585 (37%) had advanced fibrosis and 164 (10%) had cirrhosis.

At-risk MASH: SomaSignal had the highest AUC, 0.83 (95% CI 0.80 to 0.85), significantly above the MAC. According to the abstract, no other test reached the MAC for MASH alone.

Advanced fibrosis: SomaSignal again ranked first (AUC 0.92, 0.90 to 0.94). It was followed by FibroMeter-VCTE (AUC 0.87), Agile 3+ and TSP2 (both AUC 0.84) and NIS4 (AUC 0.82).

Cirrhosis: FibroMeter-VCTE ranked first (AUC 0.94), then SomaSignal (0.92), Agile 3+ (0.88), Agile 4 (0.87) and ADAPT (0.85). ELF, LSM-VCTE and TSP2 each had an AUC of 0.84.

Sequential two-step approaches with gamma-glutamyl transferase as the first-line test met the MAC for both advanced fibrosis and at-risk MASH.

The authors concluded that single markers gave variable and limited performance for at-risk MASH, while multimarker panels showed great potential, with the proteomic panel showing strong performance.

How much weight to give it

The design is a strength. It was prospective and multicentre, and used centrally scored histology as the reference standard in a large sample.

Several limits apply. AUC summarises overall discrimination. The abstract does not report cut-offs, sensitivity, specificity or predictive values, which matter more in daily practice. All participants had biopsy-confirmed MASLD, and the abstract does not report how they were referred or how many were from each country. It also does not report whether the results hold in primary care, in lower-prevalence settings or in Indian patients. The abstract does not say whether the two-step approaches were tested in a separate dataset. The abstract also does not say how widely SomaSignal can be used in routine care. The abstract does not give the number of participants tested for each marker, so the tests may not have been compared in the same participants.

The MAC of 0.80 is a threshold chosen by the authors. Meeting it suggests potential, not proven replacement of biopsy.

For your clinic

These results suggest that some multimarker panels may eventually help identify at-risk MASH and advanced fibrosis without biopsy. They do not yet change how individual patients should be tested. Before changing any pathway, read the full paper for cut-offs, predictive values and the patient groups studied. Check current guidelines as well.

The finding that a simple first test, gamma-glutamyl transferase, can be part of a two-step approach is of practical interest. The abstract does not report cost or availability of the newer tests.