Graft-versus-host-disease (GVHD) is a major complication after allogeneic hematopoietic SCT (alloHSCT). Although GVHD of the liver is not known as a fibrogenic process, we recently observed two cases of cirrhosis attributed to the evolution of hepatic GVHD.
Both patients received an alloHSCT after reduced-intensity conditioning regimen, for an advanced hematological malignancy (Table 1). The source of stem cells was peripheral blood and GVHD prophylaxis was CsA and mycophenolate mofetil. Before the alloHSCT, none of the patients had any history of hepatic failure; liver function tests (LFTs) were within the normal range and viral hepatitis serologies were negative for both donors and recipients.
The first patient presented abnormal LFTs 2 months after transplantation, together with acute grade II skin GVHD. No liver biopsy examination was performed, but LFTs normalized under immuno-suppressive treatment with high-dose steroids. The patient then developed chronic extensive cutaneo-mucous GVHD and several episodes of abnormal LFTs. She remained under immuno-suppressive treatment for more than 5 years, with complete skin and oral mucosa response. LFTs normalized slowly, but recurred several times after treatment withdrawal (Figure 1a). The patient did not present any other signs of chronic GVHD (cGVHD). Two years after steroid withdrawal, she abruptly presented with an oedemato-ascitic failure of a cirrhosis. Etiological explorations excluded viral hepatitis, hemochromatosis or autoimmune chronic hepatitis. Liver histology showed an architectural disorganization with lymphocytic infiltration and fibrosis, compatible with the diagnosis of cirrhosis. The absence of bile ducts on the biopsy was considered as a consequence of cGVHD. The immunosuppressive treatment remained unchanged. One year later, the patient presented another episode of hepatic failure and died from end-stage liver disease in intensive care unit.
The second patient presented 2 months after transplantation a steroid-responsive acute stage III skin GVHD. In the subsequent months, he presented several acute GVHD flares with gut and skin grade III localizations, and was treated with steroids and tacrolimus. Tacrolimus was stopped after 1 year, because of acute renal failure. A first episode of LFTs abnormalities occurred 18 months after transplantation. No liver biopsy was performed, but LFTs normalized under steroids and no other cause was identified. During the seven following years, he presented several episodes of steroid-dependent LFTs abnormalities (Figure 1b). Almost 9 years after transplantation, he abruptly presented inner hemorrhage from bleeding esophageal varices. Hemodynamic measurements showed a high hepatic venous gradient. Liver biopsy examination did not allow pathologists to draw any formal conclusion, as no bile ducts could be seen at all. However, the biopsy showed interface and lobular hepatitis and, in the absence of extensive portal fibrosis or injury suggesting regenerative nodular hyperplasia, the diagnosis of macronodular cirrhosis was retained. Etiological explorations remained negative and cirrhosis was considered as the evolution of the hepatic GVHD.
Cirrhosis is a rare complication after alloHSCT and is usually related to HBV and HCV infections.1, 2 Hepatic GVHD typically presents as cholestasis, although it can sometimes occur as an acute cytolitic hepatitis, but it has rarely been associated with cirrhosis. According to the NIH criteria for liver cGVHD, liver biopsy is required to confirm the diagnosis of hepatic GVHD and to exclude other diagnoses.3 However, in daily practice, hepatic biopsy is rarely performed. Liver GVHD is usually diagnosed clinically and liver biopsy is only performed to exclude other causes of hepatic injuries, in the absence of clinical evidence of extra-hepatic GVHD or in cases of nonresponse to increased immuno-suppression.4 Reported histological findings of hepatic cGVHD include lobular hepatitis, marked loss of bile ducts, portal inflammation and fibrosis.5, 6 Quaglia et al.4 analyzed 48 liver biopsies to describe the histopathological features of liver GVHD: the most characteristic features were destructive bile duct damage (bile duct epithelial changes with or without lymphocytosis) and cholestasis. Fibrosis was identified in 48%, mostly of mild degree. No cirrhosis was identified and the authors concluded that liver GVHD is not a fibrogenic process. The low prevalence of cirrhosis complicating hepatic cGVHD has been confirmed by the longi-tudinal study by Strasser et al.;1 indeed, if only 31 cases of cirrhosis were diagnosed during the long follow-up of more than 3700 patients, 25 were HCV-related. Only four of the remaining cases had liver histology examination showing cGVHD injury associated with extensive fibrosis or cirrhosis. Of note, all cases were diagnosed by portal hypertension-related complications and rapidly progressed towards end-stage liver disease. In this context, the intervention of specific autoimmune pathological processes cannot be ruled out, as suggested by frequent positivity for various autoantibodies.7
The first patient presented cutaneo-mucous cGVHD together with abnormal LFTs. She had a slowly progressive jaundice, preceded by cytolysis and cholestasis. Although the abnormal LFTs seemed to be steroid sensitive and steroid dependent, they never normalized under immuno-suppressive therapy. The histological findings on the liver biopsy were compatible with hepatic GVHD. Biochemical and immunological explorations excluded other causes of liver cirrhosis. Although no portal fibrosis was described on the biopsies (with limitations due to small length specimens), the patient clearly presented with clinical features of cirrhosis.
Although our second patient had presented several flares of skin and digestive GVHD, he did not have any acute hepatic GVHD. However, he abruptly presented more than 18 months after HSCT with severe isolated LFTs abnormalities. Like our first patient, hepatic GVHD was steroid-sensitive and steroid-dependent, and the discovery of cirrhosis was unexpected, revealed by portal hypertension-related complications in the absence of intra-hepatic causes (such as regenerative nodular hyperplasia).
Chronic LFTs abnormalities should not be underestimated in the context of clinical manifestations of GVHD, as they may be a sign of ongoing hepatic GVHD. In cases of prolonged or treatment-resistant hepatic GVHD, morphological liver explorations including transjugular liver biopsy should be performed. Early treatment of hepatic GVHD may prevent extensive bile duct damage and possibly the development of extensive fibrosis. Physicians should be aware of this rare complication that seems to often lead to end-stage liver disease, as liver transplantation can be successively achieved in this context.8
Quaranta S, Shulman H, Ahmed A, Shoenfeld Y, Peter J, McDonald GB et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood 1999; 93: 3259–3266.
Peffault de Latour R, Lévy V, Asselah T, Marcellin P, Scieux C, Adès L et al. Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 2004; 103: 1618–1624.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.
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Greinix HT, Loddenkemper C, Pavletic SZ, Holler E, Socié G, Lawitschka A et al. Diagnosis and staging of chronic graft-versus-host disease in the clinical practice. Biol Blood Marrow Transplant 2011; 17: 167–175.
Quaranta S, Shulman H, Ahmed A, Shoenfeld Y, Peter J, McDonald GB et al. Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation. Clin Immunol 1999; 91: 106–116.
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The authors declare no conflict of interest.
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Xhaard, A., Nahon, P., Robin, M. et al. Hepatic GVHD leading to cirrhosis after allogeneic hematopoietic SCT. Bone Marrow Transplant 47, 1484–1485 (2012) doi:10.1038/bmt.2012.53
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