Invited Editorial: 'Measuring inflammatory and fibrotic components of portal hypertension: a non-invasive HVPG?'.

Victoria K. Snowdon1 and Jonathan A.Fallowfield2*

1 UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

2 MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh, UK

*Correspondence to:Dr Jonathan A. Fallowfield, MRC/University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. E-mail: Jonathan.Fallowfield@.ed.ac.uk. Tel: (+44)1312426655.

The gold standard measurement for PHT is the hepatic venous pressure gradient (HVPG). The prognostic value of HVPG in chronic liver disease (CLD)is well-documented. An HVPG >10mmHg (‘clinically significant PHT’ (CSPH)) is predictive of variceal development and reduction of HVPG with therapy to <12mmHg or >20% from baseline has been shown to reduce variceal re-bleeding rates 1, 2. However, HVPG is an invasive andhighly specialized technique. A‘non-invasive HVPG’ would be extremely valuable to assess prognosis, disease progression and response to drug therapy in CLD. Baveno VIConsensusrecommendations included the use of non-invasive methods for screening and surveillance of varicesand PHT in CLD. Liver stiffness measurement (LSM) by transient elastography(TE) and platelet countwere proposed toidentify patients withcompensated CLD in whom screening endoscopy could be safely avoided3. However, TE has known limitations 4and LSM does not correlate well with HVPG above 12mmHg5.

It is therefore with interest that Sandahlet al6report a novel serum biomarker test - sCD163combined with Enhanced Liver Fibrosis (ELF) score - to predict CSPH. This approach comprises a macrophage activation markerreflecting the influence of inflammation on HVPG7, 8 and another marker validated formeasuring fibrosis9, such that together they might capture both dynamic and structural components of raised intrahepatic vascular resistance (IHVR). This two-centre study usingindependent estimation (EC, n=80) and validation (VC, n=80) cohorts of cirrhotic patients undergoing HVPG measurement and a small control group (n=21) showed that sCD163and ELFcomponents(hyaluronic acid, amino-terminal propeptide of type-III procollagen and tissue inhibitor of matrix metalloproteinase-1)were all significantly associated with risk of CSPH.Moreover, the combined sCD163-fibrosis PHT score had an AUROC of 0.91 (EC) and 0.9 (VC) for predicting CSPH. A high cut-off of 3.6 to rule-in CSPH identified 68% of patients with CSPH (PPV 0.99, NPV 0.27inEC;PPV 0.93, NPV 0.73 in VC) and a low cut-off of 1.4 to rule-out CSPH (NPV 1.0, PPV 0.93 in EC; NPV 0.94, PPV 0.89 in VC). Furthermore, in the VC a score higher than 3.6 was associated with increased 4-year mortality.

The authors should be commended on developing a methodology to assess CSPH based on the underlying pathobiology of PHT. The diagnostic accuracyof the sCD163-fibrosis score for CSPH is good and, notably, the low cut-off value has a very high NPV which in a real-world clinical setting may be useful foridentifying patients who could avoid endoscopy with a low risk of decompensation. However, it is not yet clear whether this test is predictive of clinical outcomes or whether it is sensitive enough to detect dynamic changes in HVPG over time or in response to therapy (sCD163 values did not change after TIPS insertion7). In the ongoing search for the most responsive and reliable biomarker test for PHT it would be informative to explore other markers/combinations, including factors associated with endothelial dysfunction (e.g. vWF10),also implicated in PHT. Prospective studies are required to define the clinical utility and cost-effectiveness of this test.

REFERENCES:

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