Severe hepatocellular injury after hematopoietic cell transplant: incidence, etiology and outcome

Abstract

Hepatic complications of transplant are a common cause of mortality. Although mild elevations of serum aminotransferase enzymes (aspartate and alanine (AST, ALT)) do not carry an adverse prognosis, this is not the case with severe hepatocellular injury. We reviewed 6225 consecutive recipients to determine the incidence and outcomes of severe hepatocellular injury (AST >1500 U/l) before day 100, which occurred in 88 patients. Causes were sinusoidal obstruction syndrome (SOS) (n = 46), hypoxic hepatitis (n = 33), varicella zoster virus (VZV) hepatitis (n = 4), drug-liver injury (n = 2) and unknown (n = 3). The incidence declined from 1.9% in the 1990s to 1.1% recently (owing to a fivefold decline in SOS and disappearance of VZV hepatitis). In hypoxic hepatitis, peak serum AST was 3545 U/l (range, 1380-25 246) within days of shock or prolonged hypoxemia; case fatality rate was 88%. In SOS, AST increases occurred 2-6 weeks after diagnosis; peak AST was 2252 U/l (range, 1437-8281); case fatality rate was 76%, with only serum bilirubin able to distinguish survivors (2.7 vs 11.3 mg/100 ml, P=0.0009). We conclude that circulatory insults (sinusoidal injury, hypotension and hypoxemia), and not infection, are the most common cause of severe hepatocellular injury, the frequency of which has declined because of a falling incidence of SOS and VZV hepatitis.

Figure 1

Photomicrographs of liver tissue illustrating causes of severe hepatitis following hematopoietic cell transplant. A. Sinusoidal Obstruction Syndrome. A liver acinus is shown here, with a central vein on the left; diffuse hepatocyte necrosis in zone 3, surrounding the vein (the area within the arc); and deposition of collagens within sinusoids in zone 2 of the acinus (outside the arc). Masson trichrome. B. Hypoxic hepatitis following respiratory failure and hypotension. Zones 2 and 3 of a liver acinus, with the central vein in the lower right. Numerous hepatocytes that have lost nuclei as a result of ischemia are seen in zone 3; arrows point to some of these dying cells. Hematoxylin and eosin. C. Varicella zoster virus infection. The left panel illustrates a punched-out area of confluent hepatocyte necrosis without distinguishing features (hematoxylin and eosin); the right panel shows reaction product from staining with a monoclonal antibody to VZV (immunohistochemistry). D. Unknown. There is a large circular area of confluent hepatocyte necrosis surrounded by normal hepatocytes. There were no areas of viral cytopathic effect, and immunohistochemical stains were negative for viruses. Masson trichrome.