A 43-year-old man with acute lymphoblastic leukemia was treated with three cycles of hyper-CVAD (hyper fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by allogeneic hematopoietic stem cell transplantation (HCT) from a sibling. Six months later, the patient presented with jaundice for the previous 10 days. Ultrasonography did not reveal any ductal dilatation, and the Doppler study noted patency of the hepatic vessels. Serum chemistry tests were remarkable for total bilirubin of 8.4 mg/dL, direct bilirubin of 5.4 mg/dL, aspartate aminotransferase of 109 U/L, alanine aminotransferase of 128 U/L, alkaline phosphatase of 600 U/L, and international normalized ratio of 1.1. Acute viral hepatitis A, hepatitis B, and cytomegalovirus were excluded, and no new drug exposure was documented. Of note, the patient was weaned off tacrolimus 2 weeks prior to the development of symptoms. Prednisone administered at 80 mg/day was empirically started and a transjugular liver biopsy was performed.

On low-power magnification, histologic sections of the liver demonstrated a portal tract infiltrate composed of small lymphocytes, along with obscured bile duct contours due to infiltration of the biliary epithelium by these lymphocytes (Fig. 1A, arrow). The biliary epithelium displayed evidence of injury, including cellular elongation, cytoplasmic vacuolization, apoptotic bodies, nuclear pleomorphism, and hyperchromasia (Fig. 1B, arrow). Canalicular cholestasis and cholate stasis (cholestatic hepatocellular injury) were evident in the lobules (Fig. 1C, arrows). Endothelialitis was also evident (Fig. 1A,B, thin arrows). Bile ducts were present in all of the portal tracts. This constellation of histologic findings was consistent with a pathologic diagnosis of acute graft-versus-host disease (GVHD). (hematoxylin & eosin stain; Fig. 1A–C, multiplication ×40).

Jaundice after HCT is ominous and a total bilirubin of >10 mg/dL confers a >70% mortality by 200 days after transplant.1 GVHD is the most common cause of severe cholestatic injury after allogenic HCT. Acute GHVD (aGVHD) usually develops within 3 months of transplant, while chronic GHVD (cGVHD) usually evolves ≥ 100 days after transplantation.2 However, aGVHD is defined better by clinical manifestations than timing, as not uncommonly it is diagnosed beyond 100 days after HCT.3 GVHD may be mediated by donor T lymphocytes that recognize host antigens, resulting in tissue damage by direct infiltration of the biliary epithelium and by dysregulation of various cytokines. Hepatic aGVHD usually follows intestinal and/or cutaneous GVHD and is characterized by hyperbilirubinemia, and an increase in alkaline phosphatase and, to a lesser degree, an increase in aminotransferase levels. The greatest risk factor for the development of cGVHD is prior aGVHD. Unlike aGVHD in which the gut, skin, and liver symptoms predominate, cGVHD may affect a wider range of organ systems. Cholestatic laboratory findings are nonspecific, and therefore, identifying the cause can be challenging. Other etiologies of liver injury that must also be considered include infections with bacteria, viruses, and fungi; infiltrating tumors; sinusoidal obstructive syndrome; drug injury; and extrahepatic biliary tract disease.

By the time jaundice develops, liver biopsy shows similar findings to those seen in acute liver allograft cellular rejection. Characteristic histologic changes of GVHD are a lymphocyte-enriched portal infiltrate with associated damage to interlobular bile ducts. Persistent bile duct damage may lead to significant bile duct loss (ductopenia), which ultimately can result in a vanishing bile duct syndrome or even cirrhosis. Immunosuppressive therapy with corticosteroids and calcineurin inhibitors are the most effective first-line therapies for GVHD. Biochemical improvement can also be seen after the addition of ursodeoxycholic acid.4 Liver transplantation is an effective treatment in those patients with chronic hepatic GVHD recalcitrant to medical management.5


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  2. References
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    Gooley TA, Rajvanshi P, Schoch HG, McDonald GB. Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation. HEPATOLOGY 2005; 41: 345352.
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    McDonald GB. Review article: management of hepatic disease following haematopoietic cell transplant. Aliment Pharmacol Ther 2006; 24: 441452.
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    Couriel D, Caldera H, Champlin R, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004; 101: 19361946.
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    Fried RH, Murakami CS, Fisher LD, Willson RA, Sullivan KM, McDonald GB. Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver. Ann Intern Med 1992; 116: 624629.
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    Barshes NR, Myers GD, Lee D, Karpen SJ, Lee TC, Patel AJ, et al. Liver transplantation for severe hepatic graft-versus-host disease: an analysis of aggregate survival data. Liver Transpl 2005; 11: 525531.