Assessment of Liver Damage with Transient Hepatic Elastography (FIBROSCAN) in patients with chronic Graft-Versus-Host Disease

Introduction Chronic GVHD (cGVHD) is the most common non-relapse problem in long-term survivors after allogeneic stem cell transplantation (SCT). Liver is a commonly target-organ, being often refractory to immunosuppressive therapy. Hepatic cGVHD develops generally as an indolent cholestatic disease or as an autoimmune hepatitis. Both primary biliary cirrhosis and cGVHD show some analogies in the damage of bile ducts. Liver biopsy specimens show degeneration of the small bile ducts, portal fibrosis and are helpful to confirm the diagnosis and the prognosis of hepatic cGVHD. However, liver biopsy is not always feasible, because it may generate clinical complications such as bleeding and infections. Transient hepatic elastography (FibroScan) is a new, fast and non-invasive technique to measure liver stiffness. FibroScan has been validated to detect significant positive relationship between liver stiffness values and histological fibrosis in chronic liver diseases such as chronic hepatitis B and C, cirrhosis and, primary biliary cirrhosis. Being fibrosis a hallmark of cGVHD, we prospectively evaluated the usefulness of FibroScan as non-invasive tool to make diagnosis of liver cGVHD.

Patients and methods Liver stiffness measurements were performed on 10 healthy subjects and on 18 patients undergoing allogeneic SCT (15 with related and 3 with unrelated donor) before transplantation, then every 3 months and at the diagnosis of cGVHD. Median age was 42 years (range, 22–62); 61% of patients were male. 72% received a reduced intensity conditioning and stem cells source was mainly peripheral blood (83%). Cyclosporine A and short course of methotrexate were used for GVHD prophylaxis. One patient was HCV RNA-positive. No patients had any sign of liver disease at transplantation. In transient elastography (TE), only procedures with at least ten successful acquisitions and a success rate of at least 60% were considered reliable. The median value of successful measurements was considered representative of the liver stiffness in a given patient, only if the interquartile range (IQR) of all validated measurements was less than 30% of the median value. Results were expressed in kilopascals (kPa). Wilcoxon test was used for statistical analysis of the data.

Results Eight patients (44%) developed cGVHD at a median time of 5 months (range, 4–6). cGVHD was extensive in 6 patients (75%) with a median onset time of 6 months (range, 4–10). Liver was involved in 6 patients (75%). Liver stiffness values did not differ significantly in healthy subjects, patients before allo-SCT and patients after allo-SCT without cGVHD. Patients with hepatic cGVHD had higher stiffness values than healthy subjects (7,7 ± 4,6 vs 4,6 ± 1,5 kPa, p=0,03) and than patients without cGVHD (7,7 ± 4,6 vs 4,6 ± 1,9 kPa, p=0,03). Furthermore, liver stiffness values were higher in all patients with cGVHD than in healthy subjects (7 ± 3,9 vs 4,6 ± 1,5 kPa, p=0,04) and patients without cGVHD (7 ± 3,9 vs 4,6 ± 1,9 kPa, p=0,04). A trend to higher liver stiffness in patients with cGVHD was observed at 3^rd month as well (6,4 ± 2,5 vs 4,6 ± 1,5 kPa, p=0,05).

Discussion Our prospective study suggests that FibroScan could be a reliable non-invasive technique for the early diagnosis of hepatic cGVHD, which could replace liver biopsy in the future. In addition, TE could be an effective procedure to assess disease progression or response to therapy. However, it was not possible to demonstrate significantly different stiffness values in the setting of cGVHD between patients with and without liver involvement. The small number of patients included in the survey or a clinically silent involvement of liver in all cases of cGVHD may account for this observation. Further studies could support these preliminary results and answer to other interesting open questions.