Marked Elevation of Serum Hyaluronic Acid in Patients Exhibiting Late-Phase Ascites after Allogeneic Hematopoietic Stem Cell Transplantation

Refractory ascites may develop after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the early phase within 100 days after allo-HSCT, sinusoidal obstruction syndrome (SOS) is well known as an etiology of refractory ascites. We previously reported 3 patients who exhibited refractory ascites, which developed in the late phase more than 3 months after allo-HSCT [1]. The 3 patients had liver fibrosis as revealed on autopsy [1]; therefore, we hypothesized that liver fibrosis causes refractory ascites in late-phase allo-HSCT more frequently than previously thought. It has been reported that serum hyaluronic acid (HA) is a useful noninvasive biomarker for evaluating fibrotic change in the liver [2]. Considering the possible involvement of liver fibrosis, we measured the serum HA of patients with refractory ascites in the late phase following allo-HSCT.

We searched for patients exhibiting refractory ascites in the late phase after allo-HSCT among 109 patients who received allo-HSCT at our hospital between 2011 and 2016. The search criteria included: (1) ascites that developed more than 3 months after allo-HSCT, (2) lack of other defined causes of ascites, (3) ascites-dominant fluid retention at onset, and (4) lack of chronic graft versus host disease (GVHD) features involving other organs. The day when ascites was verified by CT or echogram was defined as the onset day of ascites. We defined control patients as patients without ascites during the 3- to 12-month period after allo-HSCT.

We found 9 patients who met the criteria. Among these, serum HA levels were measured in 6 patients. Liver biopsy was not performed for any patient because of the considerable risks of procedure-related death. The clinical characteristics of the 9 patients are summarized in Table 1. They did not develop ascites due to SOS in the early phase or acute hepatic GVHD during transplantation. Abdominal CT or echogram demonstrated liver atrophy and ascites, but no evidence of liver cirrhosis or liver fibrosis was found. We did not evaluate the patients by elastometry. The content of ascites obtained from 4 out of 6 patients was exudative, and malignant cells were not observed. Three patients (No. 1, 2, and 4) were found to have liver fibrosis on autopsy. The serum HA levels in the 6 patients (No. 2 and 5–9) were markedly elevated compared with those in control patients (Fig. 1a). Although liver fibrosis was not histologically confirmed in 5 patients, excluding patient 2, these 5 patients exhibited high levels of serum HA. These results suggested that fibrotic changes in the liver occurred in the 5 patients. Moreover, the values increased as ascites worsened (Fig. 1b), suggesting that serum HA levels are associated with disease progression.

Previous studies reported patients with liver fibrosis or cirrhosis due to SOS [3], viral hepatitis [4], chronic GVHD [5], or iron overload [6] after allo-HSCT. We found bile obstruction, one of the histological characteristics of chronic hepatic GVHD, in patient No. 2 on autopsy [1]; therefore, we suspected that chronic GVHD may have been involved in the pathogenesis of liver fibrosis. We did not completely rule out ascites due to GVHD-induced peritonitis. On the other hand, extensive immunosuppressive therapies did not improve the ascites, suggesting that mechanisms other than chronic GVHD caused the ascites and liver fibrosis. Recently, it has been reported that late-onset SOS may result in refractory ascites and liver damage [7]. We therefore speculated that the late-onset SOS may have functioned in the pathogenesis of the ascites and liver fibrosis seen in our patients. We are currently examining the mechanisms of liver fibrosis.

In conclusion, our observation suggests that refractory ascites in the late phase after allo-HSCT can occur due to liver fibrosis following allo-HSCT. Although liver biopsy is necessary to diagnose liver fibrosis, serum HA should be measured as a surrogated marker of liver fibrosis when refractory ascites develops in the late phase after allo-HSCT. Other biomarkers of liver fibrosis or elastometry may be useful for the diagnosis of fibrotic change in patients exhibiting such refractory ascites.