Noninvasive monitoring of liver fibrosis in sickle cell disease: Longitudinal observation of a cohort of adult patients
Authors: Valeria Maria Pinto, Barbara Gianesin, Manuela Balocco, Lorenzo Bacigalupo, Gian Luca Forni
Journal: American Journal of Hematology (2017)

Acute vaso-occlusive events (VOCs) and liver iron overload (LIO), or viral hepatitis due to multiple blood transfusions, are the main factors in Sickle Cell Disease (SCD) associated with hepatic damage resulting in fibrosis/cirrhosis. There is a high frequency of cirrhosis (around 11%-14%) as a result of these complications based on autopsy findings at the time of death in patients with SCD.1 Acute VOCs with hepatic damage can result with catastrophic consequences, including acute hepatic failure, and they may contribute to early mortality.2, 3 Unfortunately, due to the paucity of sizeable or controlled studies on sickle hepatopathy, as well as incomplete information regarding additional causes of liver disease, it is very difficult to evaluate the contribution of single factors in liver damage. Hepatic function in 37 adult patients with SCD (68% HbSβ°, mean age 40 ± 14 years, 46% male, 13% non-Caucasian) who attended our center was retrospectively evaluated using a combination of biochemical markers (every six months), vibration-controlled transient elastography (VCTE; every two years), liver imaging (ultrasound, Magnetic Resonance Imaging [MRI]), and noninvasive iron measurement (MRI-T2*). Data were collected from 01 January 2002 to 31 December 2016. The chart review was approved by the local Ethics Committee. All participants gave written informed consent and the research was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008. VCTE was performed using a FibroScan® device (Echosens, Paris, France) by appropriately trained physicians. Liver stiffness was measured in kiloPascals (kPa) and VCTE values were converted to the corresponding METAVIR score, a widely used histopathological staging system for liver fibrosis.4 At the time of VCTE, patients were fasting and at least one month away from an acute VOC. Descriptive statistics were reported as percentages, means with standard deviations, and ranges. Comparisons were performed using the Mann-Whitney-Wilcoxon Test or the t-test, and correlations were performed using the Pearson (Rp) correlation coefficient. All P-values were two sided with the level of significance set at .05. The characteristics of patients with SCD are reported online in Table 1. The mean value of liver stiffness was 9 (±6) kPa and the mean number of evaluations for each patient was 3.5 (±1.6; range 2–9). We documented significant fibrosis (stiffness values ≥8.7 kPa) in 30% of patients (11% F2, 19% F3–F4). No significant differences in mean liver stiffness were identified in terms of gender or disease type. Both age and body mass index showed a weak positive correlation with liver stiffness, although neither reached significance. In total, 8% of patients (3/37) were positive for HCV-RNA; no significant differences were identified between patients with versus without HCV-RNA in terms of stiffness values. There were no significant differences in terms of mean liver stiffness for the main complications of SCD, including acute chest syndrome, VOCs, splenic sequestration, osteonecrosis, and central nervous system events. Of the 37 patients with SCD, 14 were treated with hydroxycarbamide (HU, 20 mg/Kg day, mean duration 12 ± 3 yrs), 11 were on exchange blood transfusion (EBT, interval ranging from 45 to 90 days, mean duration 16 ± 5 yrs.), 6 were on transfusion programs (10–15 mL packed red blood cell/Kg body weight at 3- to 4-week intervals), and 6 patients did not need therapy. Eleven patients were treated with chelation therapy and all had a history of transfusions. The remaining 26 patients were never chelated. LIO was detected by MRI-T2* in 5 patients, all on transfusion programs. For patients with SCD on EBT, the mean liver stiffness value was significantly lower compared with patients who were transfused (P = .007). Retrospective, long-term, follow-up data for 7 patients with SCD from the present study who were unresponsive to HU and treated continuously with EBT, has also been described previously.5 No significant correlation was found between mean liver stiffness and liver iron concentration. We also found significantly lower values of stiffness in patients with SCD on HU therapy compared with those transfused (P = .04). Looking at laboratory markers, we documented significant correlations between liver stiffness and γ-glutamyl transferase (GGT) (Rp = 0.68, P < .001), alkaline phosphatase (ALP) (Rp = 0.61, P = .012), serum ferritin (Rp = 0.43, P = .037), aspartate transaminase (AST) (Rp = 0.54, P = .006), and conjugated bilirubin (Rp = 0.52, P = .009) at baseline (Figure 1); all correlations except serum ferritin and AST were maintained at the final follow-up assessment (Figure 1). A significant negative correlation was identified between liver stiffness and albumin at follow-up only (Rp = −0.65, P = .0038) (Figure 1). All significant laboratory correlations with liver stiffness described above were also confirmed in a subgroup of 26 patients who were HCV-negative without LIO. Correlation between stiffness and (A and B) γ-glutamyl transferase (GGT), (C and D) alkaline phosphatase (ALP), (E and F) albumin, and (G and H) conjugated bilirubin at baseline and at follow-up for patients with sickle cell disease In our cohort of patients, 19% had severe fibrosis and cirrhosis was unexpectedly detected in 8% of patients (3/37), all HCV-negative without LIO with pauci-symptomatic disease in terms of VOCs. Our longitudinal observations documented a strong link between GGT, albumin, and ALP levels, and fibrosis according to the progression of liver dysfunction and correlation between liver stiffness and conjugated bilirubin. Feld et al. also described bilirubin as a factor independently associated with mortality in SCD.6 This suggests that hepatic dysfunction may impair the ability to tolerate systemic insults. No significant correlation was documented between liver stiffness and alanine transaminase (ALT) at baseline or at follow-up, suggesting that ALT elevation in this subset of patients is an imperfect tool and is not appropriate to use as a sole marker. Therefore, in our experience, we suggest only the combination of data obtained by annual VCTE and with six-month specific serum markers may be valid tools for the early detection of sickle hepatopathy. In addition, our results suggest that both EBT and HU appear to be effective in protecting hepatic function from chronic damage/fibrosis in patients with SCD compared with those transfused. Further prospective trials are needed to confirm these observations. To our knowledge, this report is the first longitudinal follow-up of patients with SCD who have been monitored over time using VCTE and specific serum markers. Limitations in this study include its retrospective nature, the lack of correlation with histological data, and the small patient population. The authors thank Melanie Gatt, an independent medical writer, who provided English editorial assistance on behalf of Springer Healthcare Communications. This assistance was funded by Associazione Ligure Talassemici. The authors declare no conflicts of interest.