Liver abnormalities are frequent and persistent in patients with Fanconi anemia

Abstract

Liver disease has not been well described in patients with Fanconi anemia (FA). Improvements in outcomes of transplant mean that more individuals with FA are reaching adulthood and new features of the FA phenotype are being discovered. We performed a retrospective review of liver function in a cohort of 97 patients with FA followed-up for at least 10 years at a single center. We identified a high frequency of transaminitis (n = 31, 32%) without elevation of bilirubin and with no evidence of structural hepatic abnormality in patients with FA. Transaminitis was persistent in many cases, sometimes lasting more than a decade without clinical manifestation, although 2 patients with prolonged transaminitis are deceased from liver failure, indicating important long-term clinical consequences. Transaminitis was found in patients who had and had not received transplant but was more frequent in recipients of transplant. Exposure to total body irradiation increased risk (odds ratio, 15.5 [95% confidence interval, 2.44-304.54]; P = .01), whereas treatment with androgens did not. Review of limited numbers of liver biopsies and autopsy material showed a cholestatic pattern of liver injury, with progressive fibrosis, in the majority of patients. Occurrence in cases without transplant as well as cases with transplant argues against a potential diagnosis of atypical liver graft-versus-host disease. Limited data regarding therapy suggest no benefit from treatment with steroids or other immune suppressive medications or ursodeoxycholic acid. Our data show that liver disease is common in patients with FA, and because most children with FA now reach adulthood, end-stage liver disease in young adulthood means systematic testing of potential therapies is urgently needed.

Graphical abstract

Figure 1.

Patients with FA with PLI.

Figure 2.

Individual changes in liver enzymes in patients with FA. The average of 3 values for ALT (U/mL) and AST (U/mL) graphed against the patient’s age in years using a fourth-order smoothing polynomial. Actual values of GGT (U/L) were plotted against the patient’s age in years (green). Shown are representative examples of changes in ALT (U/mL), AST (U/mL), and GGT (U/L) in (A) a patient who received HSCT at age 10.3 years; and (B) a patient who received HSCT at age 5.1 years. (C) A patient who never received HSCT and had liver enzyme elevations starting at birth. (D) A patient who had received androgen therapy and liver enzyme abnormalities were first observed at age 14.3 years.

Figure 3.

Patterns of ALT variation in patients with FA with PLI. Changes in ALT in patients with FA with PLI are graphed and shown. Four patients are shown per graph for ease of comparison. The average of 3 values for ALT (U/mL) were used to graph these values against the patient’s age in years using a fourth-order smoothing polynomial. (A-E) ALT changes in each patient with FA who underwent HSCT and met criteria for PLI. The area under the curve is shaded for each patient and the time of stem cell infusion in recipients of HSCT are noted. (F) ALT changes in patients with PLI who did not receive HSCT.

Figure 4.

Liver biopsy and postmortem findings in a recipient of HSCT with FA and with PLI. Shown are representative images from serial liver biopsy samples and postmortem analysis of liver sample in a recipient of HSCT with FA and with PLI. The patient had a liver biopsy at 15 years after HSCT to investigate transaminitis. (A-B) H&E staining shows inflammation of the portal tracts with associated cholangitis and pericholangitis and reactive changes in the bile ducts. Bridging fibrosis and focal nodule formation are seen. The patient had a repeat liver biopsy at 16-years post-HSCT. (C-D) Hematoxylin and eosin staining demonstrates acute cholangitis and pericholangitis with lobular cholestasis. Extensive fibrosis of the portal tracts is again seen. Postmortem examination of the liver, 1 year later (E-F) shows marked nodular hyperplasia, fibrosis, and ischemia. The portal tracts show reactive expansion secondary to mononuclear infiltrates and associated cholangitis and pericholangitis. (G-H) Trichrome staining shows portal to portal bridging fibrosis with a prominent perisinusoidal component. (I-J) CK7 immunostaining shows ductular proliferation with ectopic staining of hepatocytes.