• stem cell transplantation;
  • hepatitis viruses;
  • abnormal liver function tests;
  • liver biopsy;
  • liver failure.

Haematological diseases are frequently accompanied by liver dysfunction. Mechanisms include direct liver damage by the haematological disorder, indirect liver damage as a result of therapy for the haematological disease and concomitant liver disease; all of these may co-exist. This review summarizes a clinical approach to liver-related abnormalities in stem cell transplantation recipients.

Several factors need evaluation in the clinical assessment: (i) the underlying haematological condition, as this may make some liver problems more probable than others, (ii) the presence of previous liver disease, (iii) liver function and clotting tests, (iv) a viral marker profile, (v) a drug history, (vi) results of imaging procedures, and, finally, (vii) liver biopsy appearance.

Liver biopsy remains an important diagnostic tool. If coagulation is seriously impaired, which precludes a percutaneous liver biopsy, it can be performed by the transjugular route, as this is safe, simple and rapid in experienced hands (Papatheodoridis et al, 1999); moreover, multiple passes, hepatic venography, CO2 portography, and wedged hepatic venous and caval pressure measurements increase the diagnostic value and scope of the procedure (Vlachogiannakos et al, 2000).

This review is centred on the major clinical presentations of and reasons for referral for hepatic abnormalities during haematopoietic stem cell transplantation: (i) positive hepatic viral markers, (ii) abnormal liver function tests, and (iii) hepatomegaly and liver failure with its complications. The diagnosis of the primary haematological disease is almost always known to the hepatologist.

Stem cell transplantation

  1. Top of page
  2. Stem cell transplantation
  3. Positive viral markers pretransplant
  4. Abnormal liver function tests
  5. Portal hypertension–ascites–liver failure
  6. References

The principal causes of liver injury during haematopoietic stem cell transplantation (SCT) are: (i) high-dose cytoreductive therapy (chemotherapy and/or irradiation) given prior to transplantation which may result in veno-occlusive disease (VOD) or nodular regenerative hyperplasia (NRH), (ii) liver toxicity owing to other drugs used after transplantation, (iii) viral and bacterial infections, and (iv) acute and chronic graft-vs.-host disease (GVHD) in the case of allogeneic transplantation. The differential diagnosis of these complications is guided by knowledge of the timing of their appearance. Veno-occlusive disease of the liver, jaundice owing to sepsis (cholangitis lenta) and drug-induced hepatotoxicity appear in the first few weeks after SCT, acute GVHD usually appears after donor engraftment (approximately d 14–21), viral infection usually appears after d 40, and chronic GVHD and NRH occur after d 100. (Fig 1).


Figure 1. Time course of liver complications after bone marrow transplantation. GVHD, graft-vs.-host disease; CMV, cytomegalovirus; HSV, herpes simplex virus; HBV, hepatitis B virus; HCV, hepatitis C virus; EBV-PTLD, Epstein-Barr virus post-transplant lymphoproliferative diseases; VZV, varicella zoster virus.

Download figure to PowerPoint

Positive viral markers pretransplant

  1. Top of page
  2. Stem cell transplantation
  3. Positive viral markers pretransplant
  4. Abnormal liver function tests
  5. Portal hypertension–ascites–liver failure
  6. References

Hepatitis B (HB) virus serology is routinely performed in the pretransplant period for both recipient and donor. Apart from hepatitis B surface antigen (HBsAg) and anti-HBs, anti-HBc (antibody to hepatitis B core) should be assessed, as its positivity will confirm either a previous infection or will reveal a window phase following recent infection when HBsAg has disappeared and anti-HBs has not yet appeared. Anti-HBs may not be measurable in some patients with anti-HBc who have recovered from infection. Quantification of IgM anti-HBc gives valuable additional information. Thus, in an HBsAg-positive patient, IgM anti-HBc of > 600 units suggests acute infection. Titres between 30 and 600 U/l suggest either chronic infection, very early phase of acute infection, very late acute phase or an immunodeficient patient. Titres of less than 30 U/l usually signify chronic disease, a healthy carrier state or immune deficiency. HBeAg and anti-HBe markers will help to distinguish asymptomatic HBsAg carriers with high and low viraemia, but hepatitis B virus (HBV) DNA detection using polymerase chain reaction (PCR) in the serum confirms continuous viral replication, which implies a potential for progressive disease and high infectivity. HBV DNA must always be measured, even if HBeAg (HBe antigen) is absent in the serum, as precore genetic HBV mutants may exist that prevent formation of HBeAg (Laras et al, 1998). Liver biopsy should be performed in HBsAg(+) recipients pretransplant in order to determine the existence of cirrhosis and/or fibrosis.

When HBV DNA is positive, appropriate assessment for anti-viral therapy must be made before transplantation. Several agents (interferon-alpha, lamivudine, famciclovir or ganciclovir) are effective in reducing HBV replication (Main et al, 1996; Carreno et al, 1999; Dienstag et al, 1999; Hadziyannis et al, 1999; Janssen et al, 1999). Lamivudine 100 mg/d suppresses HBV replication in as many as 97% of patients within 2 weeks of initiation of therapy (Hagmeyer & Pan, 1999), although therapy needs to be continued in the post-transplant phase. It has fewer side-effects than interferon which has the potential for myelotoxicity. Combination therapy with more than one nucleoside analogue may be evaluated in the future (Lau, G.K., et al, 1999). If recipient HBV DNA is negative before transplantation, systematic monitoring should begin from the second week post-transplant onwards at regular intervals. If seroconversion occurs, assessment for anti-viral therapy should be undertaken.

Although there is a low risk of HBV transmission from HBV-infected donors to HBV-unaffected recipients, it has been proposed that HBV DNA testing in donors should be undertaken routinely (Locasciulli et al, 1995). If the donor is HBV DNA-positive, the diagnostic interpretation will be the same as that of an HBV-infected recipient. An excellent approach to the interpretation of the serum hepatitis markers in both patients and donors before haematopoietic cell transplantation has recently been reported (Strasser & McDonald, 1999).

For hepatitis C infection, antibodies against HCV (hepatitis C virus) (anti-HCV) and molecular assessment of HCV RNA, using branch DNA assay and PCR techniques in cases of seronegativity, are used to diagnose chronic HCV infection. If the recipient is anti-HCV-positive and HCV RNA-negative by PCR, it is always worthwhile repeating the PCR before categorizing the patient as a rare example of recovery from acute hepatitis C infection. If HCV RNA is positive, a liver biopsy should be considered to stage and grade the hepatitis before SCT.

If there is an anti-HCV-positive donor and HCV RNA is negative after confirmation, SCT can be safely performed. If HCV RNA is positive, a search should commence for an alternative donor. If this is not possible, it is recommended that the donor is treated, as HCV transmission can potentially occur via infected stem cells (Shuhart et al, 1994). Pretreatment of the hepatitis C viraemic donor with interferon-alpha may prevent HCV transmission to an HCV-seronegative recipient, and current therapy of combination interferon and ribavirin is more effective (Vance et al, 1996; European Association for the Study of the Liver (EASL) International Consensus Conference on Hepatitis C, 1999). Interferon should be discontinued at least 1 week before harvest (Vance et al, 1996).

We are not aware of any literature on the relationship between hepatitis D virus and bone marrow transplantation patients. Hepatitis D infection (HDV) only occurs together with HBV infection, either as a co-infection or as a superinfection, and can be treated in the same way as HBV infection. Although there is currently no satisfactory therapy, recently it has been reported that prolonged high doses of interferon-alpha led to resolution of chronic delta hepatitis and HBV viral markers disappearance, and lamivudine should prove effective (Lau, D.T., et al, 1999).

Abnormal liver function tests

  1. Top of page
  2. Stem cell transplantation
  3. Positive viral markers pretransplant
  4. Abnormal liver function tests
  5. Portal hypertension–ascites–liver failure
  6. References

Sudden, progressive elevations of serum aminotransferases and cholestatic enzymes are a major problem in SCT recipients and can be as a result of reactivation of de novo viral illnesses or owing to non-viral illnesses.

Viral illnesses Mild to severe flares of hepatitis can be observed in pre-existing HBV-infected recipients owing to HBV reactivation in the post-transplant period, especially at the time of immunosuppression tapering and immune reconstitution, even in long-term HBsAg-positive survivors (Martin et al, 1995). Moreover, studies have shown that HBV carriers who receive a marrow graft from an HBsAg(+) donor have a significantly increased risk of severe liver impairment, which may lead to fulminant hepatitis (Chen et al, 1999). SCT patients (particularly allogeneic) are more susceptible to HBV reactivation because of impairment of both T- and B-cell function (caused by poor immune reconstitution or drugs) that modulate HBV hepatitis. Moreover, corticosteroid treatment stimulates HBV replication directly (Tur-Kaspa et al, 1988). Acute HBV infection usually occurs 60 d post transplant. Liver biopsy must always be considered when elevations of liver enzymes appear in an HBV-infected recipient in order to differentiate and exclude a viral reactivation, GVHD, a drug-induced hepatotoxicity or other cause. In cases of increasing titres of HBV DNA post transplant (de novo viral infection or reactivation during cytotoxic chemotherapy), the use of lamivudine or famciclovir may reduce transaminase levels and suppress HBV replication (Lau, G.K., et al, 1998; Picardi et al, 1998). This is particularly necessary in cases of HBV reactivation in order to prevent severe hepatic decompensation (Yeo et al, 1999). Although no guidelines exist as to the duration of treatment or the particular drug regimen (monotherapy or combination) and dosage that should be used, experience in liver transplantation suggests that long-term therapy should be applied. Adefovir may be a useful additional drug if there is no response or in patients who are ‘treatment naive’ (Pessoa & Wright, 1999).

Mild to moderate elevations of serum aminotransferases are commonly seen in HCV-infected SCT recipients, but typically do not exceed 300 U/l (Zuckerman et al, 1998). These flares frequently appear when immunosuppression is tapered (Ljungman et al, 1995). Acute HCV infection usually occurs after d 60 post transplant. Measurement of anti-HCV is not sufficient for diagnosis, as antibody formation is affected by immunosuppression. Consequently, HCV RNA estimation is required (Fujii et al, 1994; Strasser et al, 1999a). There is no correlation between HCV genotype and severity of post-transplant liver disease (Locasciulli et al, 1997). Interferon therapy can be used and, although there is potential for dose-dependent myelotoxicity, it does not adversely affect marrow engraftment (Giardini et al, 1997). Nevertheless, it has been suggested that the use of interferon is associated with a significant risk of GVHD in SCT recipients (Samson et al, 1996). The role of chelation treatment or phlebotomy prior to interferon therapy when iron overload co-exists is not clear and current guidelines do not recommend its use (Bonkovsky et al, 1997). Ribavirin therapy can be given safely to HCV-infected patients undergoing bone marrow transplantation (BMT) and long-term treatment may result in normal liver function and clearance of HCV RNA (Ljungman et al, 1996).

Although previous studies suggested a minor risk of liver failure and cirrhosis secondary to HCV, recent data show that this is an important risk in long-term SCT survivors (Ljungman et al, 1996; Strasser et al, 1999b).

No role for hepatitis G virus (HGV)/GB virus C (GBV-C) infection has been established in relation to liver dysfunction as the virus is not pathogenic in normal individuals. However, there is a high prevalence of HGV infection (20–60%) in BMT recipients (Skidmore et al, 1997; Yamada-Osaki et al, 1999). Identification of HGV RNA in serum using PCR can confirm the presence of the virus, but current knowledge suggests that it has no pathological role even in SCT recipients.

Cytomegalovirus (CMV) infection is a common complication in SCT recipients. It usually occurs between d 40–100 in non-T cell-depleted allografts but has a much wider range in T cell-depleted allografts. Since primary prophylaxis or early pre-emptive therapy with nucleoside analogues was introduced, disseminated CMV infection has decreased markedly. Jaundice with elevation of serum transaminases and alkaline phosphatase levels are the main clinical and laboratory signs of hepatic infection which, in the SCT setting, is usually accompanied by disseminated disease (Rees et al, 1990). Severe liver impairment is rare with CMV infection. Diffuse intra- and extrahepatic duct strictures, as well as ampulla of Vater obstruction, can also occur but these are rarely seen now (Murakami et al, 1997). When CMV infection needs to be excluded or confirmed, in situ PCR techniques show the highest sensitivity for CMV detection in liver specimens with a high negative predictive value (Einsele et al, 1994). Immunohistochemical methods are also very sensitive. An increased expression of human leucocyte antigen (HLA) class II and intercellular adhesion molecule-1 (ICAM-1) have been demonstrated on hepatocytes with local viral presence, and this may be the mechanism whereby CMV viraemia significantly increases the risk of acute (grade III–IV) and chronic GVHD (Matthes-Martin et al, 1998). In protocols of pre-emptive therapy, patients are screened serially using PCR for CMV reactivation in blood. Ganciclovir is most effective in the prevention of CMV infection following reactivation after SCT (Noble & Faulds, 1998).

Adenovirus infection has been reported to occur in approximately 6% of paediatric SCT patients, similar to the percentage reported in the adult population (Shields et al, 1985; Hale et al, 1999). It usually occurs after d 30 in paediatric recipients and after d 90 in adult recipients. Hepatic manifestations of this infection are hepatomegaly, coagulopathy, severe hepatitis and, rarely fulminant hepatic failure (Somervaille et al, 1999). PCR techniques are useful to detect adenovirus DNA in blood, sputum, urine, broncoalveolar lavage samples and liver tissue, either pre- or post mortem (Echavarria et al, 1999). If performed, liver biopsy shows widespread necrosis with intranuclear, irregular, dark, viral inclusions in the surviving hepatocytes. On electron microscopy, paracrystalline arrays of adenovirus virions may be seen. No established form of treatment exists to date, although cidovidir and ribavarin have been used with some success.

Herpes simplex virus (HSV) infection usually occurs after d 45, affecting multiple organs including the liver. Hepatitis is a rare but severe infection in patients with impaired immunity, presenting with markedly raised aminotransferases (often in the many 1000s U/l), progressive jaundice and coagulopathy (Hayashi et al, 1991). Nevertheless, the early prophylactic use of acyclovir post transplant has virtually eliminated HSV hepatic damage of this kind (Hayashi et al, 1991). Histological findings are hepatocytes containing intranuclear basophilic inclusion bodies and focal necrosis. The virus can be demonstrated immunohistochemically using specific anti-HSV type 1 or type 2 antibodies or using in situ hybridization methods (Nikkels et al, 1996). Fulminant hepatic failure owing to HSV type 2 has been reported during acyclovir prophylactic treatment in the early phase of SCT (Gruson et al, 1998). Foscarnet treatment may be a valuable alternative in the presence of acyclovir-resistant HSV-infected SCT patients (Reusser, 1996).

The varicella zoster virus (VZV) infection rate is 30% by 1 year post transplant (Locksley et al, 1985). The mean time interval from BMT to symptomatic VZV infection ranges from 60 d to 280 d (David et al, 1998). Hepatic complications include serum transaminase elevation or, rarely, fatal fulminant hepatic failure (Rogers et al, 1995). Focal necrosis, similar to that seen in HSV infection and similar intranuclear inclusions can be seen at the periphery of the lesions. Immunohistochemistry, using specific monoclonal or polyclonal antibodies, and in situ hybridization, using anti-VZV probes, can provide an accurate, type-specific diagnosis on formalin-fixed paraffin wax-embedded tissue, even in the absence of classical histological or cytological features (Nikkels et al, 1996). PCR, both from blood and liver, can detect the virus and rapidly diagnose the infection. Acyclovir prophylaxis has virtually eliminated this infection, but acyclovir-resistant VZV has been isolated from SCT recipients (Straus et al, 1988; Reusser et al, 1996). It has been suggested that foscarnet should be initiated early (within 7–10 d) in patients with suspicion of acyclovir-resistant VZV infection. This treatment can be continued for at least 10 d or until lesions are completely healed (Balfour et al, 1994).

Human herpesvirus 6 (HHV-6) infection following SCT is usually associated with fever, skin rash, graft failure, GVHD, encephalitis and pneumonia, but HHV-6-induced hepatitis is a rare complication (Tajiri et al, 1997; Lau, Y.L., et al, 1998). Diagnosis can be based on either HHV-6 DNA detection using PCR in peripheral blood mononuclear cells, or from multiple site biopsies (e.g. liver, skin, rectum, etc.), antigen detection or increases in HHV-6-specific antibodies using enzyme-linked immunosorbent assay (ELISA) or immunofluorescence (Kadakia, 1998; Moschettini et al, 2000). Ganciclovir, foscarnet and granulocyte macrophage colony-stimulating factor (GM-CSF) have been used for this viral infection with good response.

Epstein-Barr virus (EBV) infection usually presents as mild hepatitis, but it is also associated with lymphoproliferative disease especially after transplantation (Zutter et al, 1988). Liver involvement usually appears with elevated liver function tests or jaundice. Early diagnosis of EBV-associated post-transplant lymphoproliferative diseases (PTLDs) is of great importance as a reduction in immunosuppression and donor T-cell infusions (Papadopoulos et al, 1994) may result in the regression of PTLDs (Cherqui et al, 1993). Detection of cell-free EBV-DNA in serum with a rising titre, using either a nested or a non-nested PCR method, appears to be a highly sensitive and specific marker for the early detection of PTLDs after SCT (Beck et al, 1999; Limaye et al, 1999). Apart from PCR, in situ hybridization and Southern blot analysis can be used to identify specific RNA or DNA sequences (Markin, 1994). Histologically, portal infiltration with small round lymphocytes (that are immunoblastic B cells) is seen.

Human parvovirus (B19 virus) infection has been identified in 15% of SCT recipients and it may cause hepatitis with abnormal liver tests (Schleuning et al, 1999). It may occur after 2–3 weeks, but it is known that the virus can persist in immunocompromised patients for up to 10 years (Kurtzman et al, 1989). Diagnosis can be made using serological tests and sensitive PCR techniques to identify B19 DNA (Soderlund et al, 1997). Liver biopsy shows hepatocytes with eosinophilic nuclear inclusions and swollen hydropic nuclei. Treatment with high-dose intravenous immunoglobulin has been suggested, but, if there is coincident liver GVHD, corticosteroid treatment may be useful (Schleuning et al, 1999). However, there is no established therapeutic treatment for parvovirus infection.

Transfusion-transmitted virus (TTV) infection has been reported to occur at a high prevalence in SCT recipients (Kanda et al, 1999). Although not always pathogenic, TTV-induced hepatitis with elevated alanine transaminase levels has been reported. TTV DNA detection is either from the serum or from the faeces using PCR (Okamoto et al, 1998). TTV is not sensitive to interferon-alpha treatment.

Figure 2 shows a proposed clinical algorithm for use when a viral infection is suspected.


Figure 2. A proposed path when viral infection is suspected. HBV, hepatitis B virus; HCV, hepatitis C virus; HGV, hepatitis G virus; CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus; HHV-6, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; anti-HBe, antibody to hepatitis B antigen; anti-HBc, antibody to hepatitis B core antigen.

Download figure to PowerPoint

Post-transfusion hepatitis Transmission of viral hepatitis has been a frequent and severe side-effect of blood product transfusion. Post-transfusion hepatitis may be owing to packed or frozen red cells, whole blood, platelet or plasma-component transfusions (transfusion-transmitted hepatitis), or may be incidental to the reason for the transfusion (transfusion-associated hepatitis). Screening of blood donors for hepatitis B and C viruses has reduced the frequency and, consequently, the risk of post-transfusion infection. The risk of transfusion-transmitted HBV infection at this time is in the order of 1:63000 units of blood, whereas for HCV infection it is in the order of 1:125000 units (Holland, 1998). These risks are so small that it can be said that transfusion-transmitted hepatitis has been virtually eliminated. Accordingly, when patients develop hepatitis following blood transfusion, other means of transmission should be sought. Other viruses that have been detected in non-A–E post-transfusion hepatitis, such as HGV/GBV-C and TTV, seem to be coincidental. These latter viruses seem not to be pathogenic. Diagnostic methods and possible treatment in case of viral infection have been discussed previously.

Non-viral illnesses

Veno-occlusive disease (VOD) The diagnosis of VOD of the liver is usually based on clinical grounds alone: a triad of painful hepatomegaly, weight gain more than 2% above baseline and jaundice. It is an early complication usually occurring in the first 2 weeks after SCT. Early phases of VOD may give rise to abnormal liver function tests reflecting hepatocyte necrosis. High aspartate transaminase (AST) concentrations (> 750 U/l) are associated with a poor prognosis (Shulman et al, 1980). Hyperbilirubinaemia usually appears before d 15 (McDonald et al, 1993). Hepatic histological changes include widespread damage to structures in zone 3 of the liver acinus, including venular damage, dilation and enlargement of sinusoids, and necrosis of hepatocytes. The diagnosis of VOD in most series has relied on necropsy histological data, so that Shulman et al, (1994) suggest that there is no single diagnostic histological gold standard, although the severity of clinical VOD appears to be proportional to the number of such histological changes in zone 3 of the liver acinus (Jones et al, 1987; Shulman et al, 1994). A particularly difficult issue is the diagnosis of VOD when it co-exists with hyperacute GVHD or fungal infiltration. Transvenous measurement of hepatic vein pressure using the transjugular route (which also enables transjugular liver biopsy to be performed) is helpful (Shulman et al, 1995). The hepatic venous pressure gradient (HVPG) is significantly higher in VOD than in liver GVHD: in one study, 82% of patients with VOD had a gradient pressure higher than 9 mmHg, but no patient with GVHD had a gradient above this value (Carreras et al, 1993). In another study, a HVPG of more than 10 mmHg was significantly correlated with a histological diagnosis of VOD with a 91% specificity and 86% positive predictive value (Shulman et al, 1995). Doppler sonography may suggest the diagnosis based on decreased or reversed portal venous flow (Brown et al, 1990). Moreover, significant elevation of the hepatic artery resistive index in duplex sonography may be a sensitive index of liver damage related to VOD (Herbetko et al, 1992). However, any cause of liver damage may dampen hepatic venous outflow and reverse portal flow and, in addition, other studies have not demonstrated any strong association between VOD and some sonographic findings (Hommeyer et al, 1992). Other markers have been suggested for diagnosis: serum values greater than 8·0 of the aminopropeptide of type III procollagen, corrected for age by conversion to standard deviation scores, very high interleukin 8 (IL-8) peaking 1–4 d after the diagnosis of the liver disease, or elevated plasminogen activator inhibitor-1 (Eltumi et al, 1993; Remberger & Ringden, 1997; Salat et al, 1997). However, these have not been validated sufficiently and are not universally available.

If VOD of the liver is diagnosed or strongly suspected then treatment should initially be supportive. Regimens proposed as therapy for established VOD include heparin, tissue plasminogen activator and prostaglandin E1 (PGE1), but one third of patients die owing to the complications of progressive liver failure (Gluckman et al, 1990; Bearman et al, 1992, 1997). Preliminary results support the role of defibrotide in the treatment of post-SCT VOD of the liver (Abecasis et al, 1999). A randomized, double-blind, placebo-controlled trial suggests that ursodeoxycholic acid prophylaxis seems to decrease the incidence of hepatic VOD after allogeneic SCT in patients who received a preparative regimen with busulphan plus cyclophosphamide (Essell et al, 1998). The prophylactic effect of ursodeoxycholic acid on VOD after SCT was confirmed recently in a prospective, multicentre open randomized study (Ohashi et al, 2000). Transjugular intrahepatic portosystemic shunts (TIPS) have been used for treatment of VOD following SCT. Fried et al (1996) showed that portal hypertension was improved significantly in all their study patients (mean portal pressure gradient decreased to 6·7 ± 1·9 mmHg post TIPS compared with 20·2 ± 4·6 mmHg before TIPS, P < 0·004). Although there is limited experience, TIPS is an effective procedure for portal decompression and is associated with clinical improvement (resolution of ascites, jaundice and coagulopathy) in a minority of patients (Smith et al, 1996). However, the impact on survival as well as further data on efficacy and safety needs to be evaluated further.

Acute GVHD In acute GVHD, transaminases are usually elevated up to 10 times normal levels, whereas in chronic GVHD these enzymes are usually only slightly elevated, approximately three times the upper normal limit. However, a high elevation of the aminotransferases may occur because chronic GVHD may present as acute hepatitis in patients under tapering immunosuppression or receiving no immunosuppression (Strasser et al, 1997). Cholestasis in acute GVHD of the liver ranges from solely a biochemical form to apparent jaundice. Moderate to marked elevations in alkaline phosphatase are usual and precede hyperbilirubinaemia (McDonald et al, 1987). Liver biopsy is not necessary for the diagnostic confirmation of acute GVHD when the characteristic liver abnormalities are associated with typical skin and gastrointestinal involvement of the syndrome. Nevertheless, it may be needed when the clinical picture could be explained by several liver diseases existing simultaneously (such as early VOD, viral hepatitis, total parenteral nutrition (TPN)- or drug-associated cholestasis) or for confirmation of a diagnosis of isolated hepatic GVHD. The time course of presentation may help in the differential diagnosis. However, it should be noted that characteristic histological findings may appear only after 2 weeks of involvement of acute GVHD. These comprise mild mononuclear and eosinophilic infiltration into the portal triads at the start of the disease. Once the disease progresses, lymphocytic infiltration in both the parenchyma and the portal tracts is seen. Further progression leads to complete obliteration of the small bile ducts. The histological hallmark of acute GVHD is the destructive damage to interlobular bile ducts with epithelial atypia. Early degeneration, acidophilic hepatocellular necrosis and endothelialitis of hepatic and portal venules are other associated features (Snover et al, 1984). Endothelialitis, that is the lymphocytic attachment or transmural migration through the walls of central and portal veins, is a relatively specific feature of GVHD.

Cholangitis lenta Cholangitis lenta is a form of chronic sepsis associated with biliary tract inflammation without obvious extrinsic obstruction (Lefkowitch, 1982). It typically occurs in the early neutropenic phase post SCT. Systemic illness with jaundice may appear. Endotoxins and cytokines directly mediate the cholestatic effect of the infection (Roelofsen et al, 1994; Whiting et al, 1995; Green et al, 1996). Serum bilirubin and alkaline phosphatase elevation are the most usual manifestations that occur in the context of fever/sepsis. VOD or acute hepatic GVHD are important differential diagnoses (Gimson, 1987). The diagnosis of cholangitis lenta is usually one of exclusion and resolution following antibiotics.

Drugs/parenteral nutrition Mild elevations in alkaline phosphatase, bilirubin, 5-nucleotidase and transaminases are commonly seen in post-transplant patients treated with TPN. Marked hyperbilirubinaemia and appearance of jaundice owing to TPN therapy may present in patients with sepsis or multiple transfusions and haemolysis. Although acalculous cholecystitis is an uncommon disorder of the biliary tract, sludge formation and cholelithiasis have been associated with TPN administration (Fisher, 1989; Jardines et al, 1993). Liver biopsy can show steatosis, steatohepatitis, periportal inflammation, intrahepatic cholestasis, non-specific triaditis and, in cases of long-term nutritional support, fibrosis and cirrhosis, abnormalities which are non-specific for the diagnosis of TPN-related hepatotoxicity (Kowdley & Keeffe, 1995) The diagnosis is made by exclusion of other causes of liver damage in this clinical context. In cases of TPN-induced hepatotoxicity, reduction or cessation of treatment, initiation of small enteral feeds, ursodeoxycholic acid institution and modification of administration timing or solution composition,may all have a role (Lindor & Burnes, 1991; Briones & Iber, 1995).

Drug-induced liver dysfunction is common after BMT. Cyclosporin may induce hepatotoxicity, which is most frequently seen as alkaline phosphatase and bilirubin elevation. The cholestatic effect is probably as a result of a decrease of bile flow and bile salt secretion (Chan & Shaffer, 1997). Blood levels should be monitored in order to avoid hepatotoxicity, as damage is dose dependent.

Azathioprine is used in the treatment of chronic GVHD and can cause asymptomatic elevation of liver tests, cholestasis, hepatic sinusoidal congestion and dilatation, centrilobular dilatation or necrosis, peliosis hepatis, hepatic VOD and NRH. Some of these changes can also be observed in chronic GVHD (Duvoux et al, 1991). Exclusion of other possible aetiological factors, evidence of a combined cholestatic-hepatocellular injury and, most important, clinical improvement after drug withdrawal can be helpful tools in order to diagnose azathioprine hepatotoxicity.

Antibiotics (e.g. high-dose cotrimoxazole) and anti-fungal drugs (e.g. itraconazole) can also cause hepatotoxicity with a predominant transaminitis.

Fungal infection Fungal infection (most often Candida species) usually occurs in the first weeks post transplant or later in patients treated for GVHD with corticosteroids or those who have graft failure. A raised serum alkaline phosphatase is non-specific, while liver imaging studies [ultrasonography, computerized tomography (CT)] show low sensitivity for the detection of liver lesions (Rossetti et al, 1995). Magnetic resonance imaging seems to be superior to other techniques in detecting fungal hepatic lesions (Anttila et al, 1996). Liver biopsy, culture of biopsy specimens, guided fine-needle aspiration or laparoscopy may be useful for the diagnosis (Phillips et al, 1992). Amphotericin B, fluconazole and recombinant human GM-CSF (for restoration of granulocyte and macrophage function) may be successful therapeutic regimens for fungal liver infection. Fluconazole prophylaxis results in a significant reduction in Candida species infection (van Burik et al, 1998). Invasive aspergillosis is an important infection in BMT patients. Liver infection is unusual but has been described in the literature (de Medeiros et al, 1999); this requires systemic amphotericin therapy.

Mycobacterial infection Even though tuberculosis (TB) is rarely seen in stem cell transplant recipients, in countries where TB is prevalent, its frequency after allografting seems to be far greater than that in the general population (Budak-Alpdogan et al, 2000). Granulomas in the liver may be observed in patients with either pulmonary or extrapulmonary infection. Liver imaging techniques (ultrasonography, computerized tomography, magnetic resonance imaging), liver biopsy, cultures and PCR analysis of biopsy specimens can be useful for the diagnosis. Anti-mycobacterial therapy, either in the pre- or post-transplant period, will achieve complete resolution of the infection (Navari et al, 1983). Prophylaxis should be considered in recipients with a history of inadequately treated TB, known family contacts, recent skin conversion or patients from areas of high endemicity.

Chronic GVHD Although chronic GVHD usually occurs after d 100, the differential diagnosis still includes chronic viral hepatitis. In chronic GVHD, hyperbilirubinaemia and elevations of alkaline phosphatase are 5–30 times the normal upper limit. The main histological manifestation is a lymphocytic and eosinophilic infiltratration in and around the bile duct (Nonomura et al, 1996). Other features are severe disruption/loss of bile duct epithelium, marked cholestasis, portal fibrosis and piecemeal necrosis. Shulman et al (1988) found that the histological diagnosis of GVHD had a positive predictive value of 86%, a sensitivity of 66% and a specificity of 91%, thus making liver biopsy an important diagnostic tool for GVHD diagnosis. Extracorporeal photochemotherapy (ECP) is a novel adjunct therapy for the treatment of both acute and chronic GVHD that are resistant to conventional therapy including cyclosporin A, corticosteroids or azathioprine. Greinix et al (1998) found that 7 out of 10 patients (70%) with liver involvement had complete responses after ECP. However, these results need to be verified. Other immunosuppressive approaches may be considered, e.g. tacrolimus, thalidomide or mycophenalate mofetil. Liver transplantation can be considered for GVHD-induced end-stage liver disease (Rhodes et al, 1990).

Post-transfusion iron overload Iron overload is one of the late complications of intensive transfusion therapy seen in survivors of SCT. Marrow transplant recipients have a high liver iron content at 50–100 d post transplant with the hepatic iron index in the hereditary haemochromatosis range (Strasser et al, 1998). Liver biopsy with quantitative iron determination and histochemistry is still the reference method for the assessment of body iron status for patients with iron overload (Angelucci et al, 2000). This should be performed in all patients (e.g. thalassaemics) prior to SCT. Important predictors of outcome of allogenic SCT for treatment of thalassaemia include hepatomegaly, hepatic fibrosis and a poor history of chelation with substantial iron overload (Angelucci et al, 2000). Computerized morphometric analysis of marrow iron content is a readily available means of estimating hepatic iron stores in stem cell transplant recipients (Strasser et al, 1998). Non-invasive measurements such as computerized tomography and magnetic resonance imaging are widely used nowadays in order to demonstrate body iron deposition, but are still investigational procedures (Hollan, 1997; Kornreich et al, 1997). It is important for these patients to receive iron chelation as soon as possible. Venesection is a standard, safe, efficient and widely applicable form of therapeutic practice (Angelucci et al, 1997). Pharmacological iron chelation is a safe and effective alternative therapy in the reduction of iron deposits (Giardini et al, 1995). Intravenous desferrioxamine therapy during SCT does not seem to affect the engraftment parameters, the incidence of infections or GVHD (Gaziev et al, 1995). This therapy should be followed by post-SCT iron removal either by venesection or by desferrioxamine, in order to accelerate the clearance of iron deposits (Li et al, 2000). Repeated determinations of the hepatic iron concentration can provide a quantitative means of measuring the long-term iron balance (Angelucci et al, 2000). Moreover, it is advisable to screen for the hereditary haemochromatosis gene before starting any kind of transfusion therapy, in order to avoid gross iron-overload development.

A diagnostic algorithm for abnormal liver function tests is proposed in Fig 3.


Figure 3. Diagnostic algorithm in cases of abnormal liver function tests after bone marrow transplantation. *interleukin 8, plasminogen activator inhibitor-1, aminopropeptide of type III procollagen. SCT, stem cell transplantation; VOD, veno-occlusive disease; GVHD, graft-vs.-host disease; HVP, hepatic venous pressure; AST, aspartate transaminase; ALT, alanine transaminase.

Download figure to PowerPoint

Portal hypertension–ascites–liver failure

  1. Top of page
  2. Stem cell transplantation
  3. Positive viral markers pretransplant
  4. Abnormal liver function tests
  5. Portal hypertension–ascites–liver failure
  6. References

In VOD of the liver, ascites develops in 20% and peripheral oedema in 60% of patients (McDonald et al, 1993). Nodular regenerative hyperplasia (NRH) of the liver is a rare disorder characterized by diffuse micronodular transformation of the hepatic parenchyma with areas of regenerative activity alternating with areas of atrophy, without fibrous septa between the nodules. It can present with similar signs as VOD, although it is associated with non-cirrhotic portal hypertension and ascites developing after d 100 post BMT (Wanless, 1990). Clinical criteria for the diagnosis of NRH do not exist and histological examination is useful, although wedge liver biopsy or laparoscopically guided multiple-needle biopsies may be necessary (Snover et al, 1989; Trauner et al, 1992). Sonographic, CT and magnetic resonance imaging (MRI) features may be useful to diagnose the syndrome, but these are not specific (Clouet et al, 1999). Although no specific treatment exists, reduction or substitution of potentially hepatotoxic drugs is often performed.


  1. Top of page
  2. Stem cell transplantation
  3. Positive viral markers pretransplant
  4. Abnormal liver function tests
  5. Portal hypertension–ascites–liver failure
  6. References
  • Abecasis, M.M., Conceicao Silva, J.P., Ferreira, I., Guimaraes, A., Machado, A. (1999) Defibrotide as salvage therapy for refractory veno-occlusive disease of the liver complicating allogeneic bone marrow transplantation. Bone Marrow Transplantation, 23, 843846.
  • Angelucci, E., Muretto, P., Lucarelli, G., Ripalti, M., Baronciani, D., Erer, B., Galimberti, M., Giardini, C., Gaziev, D., Polchi, P. (1997) Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Blood, 90, 994998.
  • Angelucci, E., Brittenham, G.M., McLaren, C.E., Ripalti, M., Baronciani, D., Giardini, C., Galimberti, M., Polchi, P., Lucarelli, G. (2000) Hepatic iron concentration and total body iron stores in thalassemia major. New England Journal of Medicine, 343, 327331.
  • Anttila, V.J., Lamminen, A.E., Bondestam, S., Korhola, O., Farkkila, M., Sivonen, A., Ruutu, T., Ruutu, P. (1996) Magnetic resonance imaging is superior to computed tomography and ultrasonography in imaging infectious liver foci in acute leukaemia. European Journal of Haematology, 56, 8287.
  • Balfour, Jr, H.H., Benson, C., Braun, J., Cassens, B., Erice, A., Friedman-Kien, A., Klein, T., Polsky, B., Safrin, S. (1994) Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections. Journal of Acquired Immune Deficiency Syndromes, 7, 254260.
  • Bearman, S.I., Shuhart, M.C., Hinds, M.S., McDonald, G.B. (1992) Recombinant human tissue plasminogen activator for the treatment of established severe venocclusive disease of the liver after bone marrow transplantation. Blood, 80, 24582462.
  • Bearman, S.I., Lee, J.L., Baron, A.E., McDonald, G.B. (1997) Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood, 89, 15011506.
  • Beck, R., Westdorp, I., Jahn, G., Schafer, H., Kanz, L., Einsele, H. (1999) Detection of Epstein-Barr virus DNA in plasma from patients with lymphoproliferative disease after allogeneic bone marrow or peripheral blood stem cell transplantation. Journal of Clinical Microbiology, 37, 34303431.
  • Bonkovsky, H.L., Banner, B.F., Rothman, A.L. (1997) Iron and chronic viral hepatitis. Hepatology, 25, 759768.
  • Briones, E.R. & Iber, F.L. (1995) Liver and biliary tract changes and injury associated with total parenteral nutrition: pathogenesis and prevention. Journal of American College of Nutrition, 14, 219228.
  • Brown, B.P., Abu-Yousef, M., Farner, R., LaBrecque, D., Gingrich, R. (1990) Doppler sonography: a noninvasive method for evaluation of hepatic venocclusive disease. American Journal of Roentgenology, 154, 721724.
  • Budak-Alpdogan, T., Tangun, Y., Kalayoglu-Besisik, S., Ratip, S., Akan, H., Baslar, Z., Soysal, T., Bayik, L.A., Koc, H. (2000) The frequency of tuberculosis in adult allogeneic stem cell transplant recipients in Turkey. Biology of Blood and Marrow Transplantation, 6, 370374.
  • Carreno, V., Marcellin, P., Hadziyannis, S., Salmeron, J., Diago, M., Kitis, G.E., Vafiadis, I., Schalm, S.W., Zahm, F., Manzarbeitia, F., Jimenez, F.J., Quiroga, J.A. (1999) Retreatment of chronic hepatitis B e antigen-positive patients with recombinant interferon alfa-2a. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology, 30, 277282.
  • Carreras, E., Granena, A., Navasa, M., Bruguera, M., Marco, V., Sierra, J., Tassies, M.D., Garcia-Pagan, J.C., Marti, J.M., Bosch, J., Rodes, J., Rozman, C. (1993) Transjugular liver biopsy in bone marrow transplantation. Bone Marrow Transplantation, 11, 2126.
  • Chan, F.K. & Shaffer, E.A. (1997) Cholestatic effects of cyclosporine in the rat. Transplantation, 63, 15741578.
  • Chen, P.M., Chiou, T.J., Fan, F.S., Liu, J.M., Hsieh, R.K., Yen, C.C., Wang, W.S., Liu, J.H. (1999) Fulminant hepatitis is significantly increased in hepatitis B carriers after allogeneic bone marrow transplantation. Transplantation, 67, 14251433.
  • Cherqui, D., Duvoux, C., Plassa, F., Gaulard, P., Julien, M., Fagniez, P.L., Dhumeaux, D., Goossens, M., Farcet, J.P. (1993) Lymphoproliferative disorder of donor origin in a liver transplant recipient: complete remission after drastic reduction of immunosuppression without graft loss. Transplantation, 56, 10231026.
  • Clouet, M., Boulay, I., Boudiaf, M., Soyer, P., Nemeth, J., Kiselman, R., Rymer, R. (1999) Imaging features of nodular regenerative hyperplasia of the liver mimicking hepatic metastases. Abdominal Imaging, 24, 258261.
  • David, D.S., Tegtmeier, B.R., O'Donnell, M.R., Paz, I.B., McCarty, T.M. (1998) Visceral varicella-zoster after bone marrow transplantation: report of a case series and review of the literature. American Journal of Gastroenterology, 93, 810813.
    Direct Link:
  • De Medeiros, C.R., Dantas da Cunha, Jr, A., Pasquini, R., Arns da Cunha, C. (1999) Primary renal aspergillosis: extremely uncommon presentation in patients treated with bone marrow transplantation. Bone Marrow Transplantation, 24, 113114.
  • Dienstag, J.L., Schiff, E.R., Wright, T.L., Perrillo, R.P., Hann, H.W., Goodman, Z., Crowther, L., Condreay, L.D., Woessner, M., Rubin, M., Brown, N.A. (1999) Lamivudine as initial treatment for chronic hepatitis B in the United States. New England Journal of Medicine, 341, 12561263.
  • Duvoux, C., Kracht, M., Lang, P., Vernant, J.P., Zafrani, E.S., Dhumeaux, D. (1991) Nodular regenerative hyperplasia of the liver associated with azathioprine therapy. Gastroenterologie Clinique et Biologique, 15, 968973.
  • EASL International Consensus Conference on Hepatitis C (1999) Paris, 26–28 February, 1999, Consensus Statement. European Association for the Study of the Liver. Journal of Hepatology, 30, 956961.
  • Echavarria, M.S., Ray, S.C., Ambinder, R., Dumler, J.S., Charache, P. (1999) PCR detection of adenovirus in a bone marrow transplant recipient: hemorrhagic cystitis as a presenting manifestation of disseminated disease. Journal of Clinical Microbiology, 37, 686689.
  • Einsele, H., Waller, H.D., Weber, P., Frickhofen, N., Dette, S., Horny, H.P., Roos, A., Roos, H., Hebart, H., Schmidt, H. (1994) Cytomegalovirus in liver biopsies of marrow transplant recipients: detection methods, clinical, histological and immunohistological features. Medical Microbiology and Immunology (Berlin), 183, 205216.
  • Eltumi, M., Trivedi, P., Hobbs, J.R., Portmann, B., Cheeseman, P., Downie, C., Risteli, J., Risteli, L., Mowat, A.P. (1993) Monitoring of veno-occlusive disease after bone marrow transplantation by serum aminopropeptide of type III procollagen. Lancet, 342, 518521.
  • Essell, J.H., Schroeder, M.T., Harman, G.S., Halvorson, R., Lew, V., Callander, N., Snyder, M., Lewis, S.K., Allerton, J.P., Thompson, J.M. (1998) Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine, 128, 975981.
  • Fisher, R.L. (1989) Hepatobiliary abnormalities associated with total parenteral nutrition. Gastroenterology Clinics of North America, 18, 645666.
  • Fried, M.W., Connaghan, D.G., Sharma, S., Martin, L.G., Devine, S., Holland, K., Zuckerman, A., Kaufman, S., Wingard, J., Boyer, T.D. (1996) Transjugular intrahepatic portosystemic shunt for the management of severe venoocclusive disease following bone marrow transplantation. Hepatology, 24, 588591.
  • Fujii, Y., Kaku, K., Tanaka, M., Kaneko, T., Matumoto, N., Shinohara, K. (1994) Hepatitis C virus infection and liver disease after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 13, 523526.
  • Gaziev, D., Giardini, C., Angelucci, E., Polchi, P., Galimberti, M., Baronciani, D., Erer, B., Maiello, A., Lucarelli, G. (1995) Intravenous chelation therapy during transplantation for thalassemia. Haematologica, 80, 300304.
  • Giardini, C., Galimberti, M., Lucarelli, G., Polchi, P., Angelucci, E., Baronciani, D., Gaziev, D., Erer, B., La Nasa, G., Barbanti, I. (1995) Desferrioxamine therapy accelerates clearance of iron deposits after bone marrow transplantation for thalassaemia. British Journal of Haematology, 89, 868873.
  • Giardini, C., Galimberti, M., Lucarelli, G., Polchi, P., Angelucci, E., Baronciani, D., Erer, B., Gaziev, D., Piga, A., Di Gregorio, F., Romeo, M.A., Mangiagli, A., Petrelli, E., Muretto, P. (1997) Alpha-interferon treatment of chronic hepatitis C after bone marrow transplantation for homozygous beta-thalassemia. Bone Marrow Transplantation, 20, 767772.
  • Gimson, A.E. (1987) Hepatic dysfunction during bacterial sepsis. Intensive Care Medicine, 13, 162166.
  • Gluckman, E., Jolivet, I., Scrobohaci, M.L., Devergie, A., Traineau, R., Bourdeau-Esperou, H., Lehn, P., Faure, P., Drouet, L. (1990) Use of prostaglandin E1 for prevention of liver veno-occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation. British Journal of Haematology, 74, 277281.
  • Green, R.M., Beier, D., Gollan, J.L. (1996) Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology, 111, 193198.
  • Greinix, H.T., Volc-Platzer, B., Rabitsch, W., Gmeinhart, B., Guevara-Pineda, C., Kalhs, P., Krutmann, J., Honigsmann, H., Ciovica, M., Knobler, R.M. (1998) Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood, 92, 30983104.
  • Gruson, D., Hilbert, G., Le Bail, B., Portel, L., Boiron, J.M., Reiffers, J., Gbikpi-Benissan, G. (1998) Fulminant hepatitis due to herpes simplex virus-type 2 in early phase of bone marrow transplantation. Hematology and Cell Therapy, 40, 4144.
  • Hadziyannis, S.J., Manesis, E.K., Papakonstantinou, A. (1999) Oral ganciclovir treatment in chronic hepatitis B virus infection: a pilot study. Journal of Hepatology, 31, 210214.
  • Hagmeyer, K.O. & Pan, Y.Y. (1999) Role of lamivudine in the treatment of chronic hepatitis B virus infection. Annals of Pharmacotherapy, 33, 11041112.
  • Hale, G.A., Heslop, H.E., Krance, R.A., Brenner, M.A., Jayawardene, D., Srivastava, D.K., Patrick, C.C. (1999) Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplantation, 23, 277282.
  • Hayashi, M., Takeyama, K., Takayama, J., Ohira, M., Tobinai, K., Shimoyama, M. (1991) Severe herpes simplex virus hepatitis following autologous bone marrow transplantation: successful treatment with high dose intravenous acyclovir. Japanese Journal of Clinical Oncology, 21, 372376.
  • Herbetko, J., Grigg, A.P., Buckley, A.R., Phillips, G.L. (1992) Venoocclusive liver disease after bone marrow transplantation: findings at duplex sonography. American Journal of Roentgenology, 158, 10011005.
  • Hollan, S.R. (1997) Transfusion-associated iron overload. Current Opinion in Hematology, 4, 436441.
  • Holland, P.V. (1998) Post-transfusion hepatitis: current risks and causes. Vox Sanguinis, 74, 135141.
  • Hommeyer, S.C., Teefey, S.A., Jacobson, A.F., Higano, C.S., Bianco, J.A., Colacurcio, C.J., McDonald, G.B. (1992) Venocclusive disease of the liver: prospective study of US evaluation. Radiology, 184, 683686.
  • Janssen, H.L., Gerken, G., Carreno, V., Marcellin, P., Naoumov, N.V., Craxi, A., Ring-Larsen, H., Kitis, G., Van Hattum, J., De Vries, R.A., Michielsen, P.P., Ten Kate, F.J., Hop, W.C., Heijtink, R.A., Honkoop, P., Schalm, S.W. (1999) Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology, 30, 238243.
  • Jardines, L.A., O'Donnell, M.R., Johnson, D.L., Terz, J.J., Forman, S.J. (1993) Acalculous cholecystitis in bone marrow transplant patients. Cancer, 71, 354358.
  • Jones, R.J., Lee, K.S.K., Berchorner, W.E., Vogel, V.G., Grochow, L.B., Braine, H.G., Vogelsang, G.B., Sensenbrenner, L.L., Santos, G.W., Saral, R. (1987) Venoocclusive disease of the liver following bone marrow transplantation. Transplantation, 44, 778783.
  • Kadakia, M.P. (1998) Human herpesvirus 6 infection and associated pathogenesis following bone marrow transplantation. Leukemia and Lymphoma, 31, 251266.
  • Kanda, Y., Tanaka, Y., Kami, M., Saito, T., Asai, T., Izutsu, K., Yuji, K., Ogawa, S., Honda, H., Mitani, K., Chiba, S., Yazaki, Y., Hirai, H. (1999) TT virus in bone marrow transplant recipients. Blood, 93, 24852490.
  • Kornreich, L., Horev, G., Yaniv, I., Stein, J., Grunebaum, M., Zaizov, R. (1997) Iron overload following bone marrow transplantation in children: MR findings. Pediatric Radiology, 27, 869872.
  • Kowdley, K.V. & Keeffe, E.B. (1995) Hepatotoxicity of transplant immunosuppressive agents. Gastroenterology Clinics of North America, 24, 9911001.
  • Kurtzman, G., Frickhofen, N., Kimball, J., Jenkins, D.W., Nienhuis, A.W., Young, N.S. (1989) Pure red-cell aplasia of 10 years' duration due to persistent parvovirus B19 infection and its cure with immunoglobulin therapy. New England Journal of Medicine, 321, 519523.
  • Laras, A., Koskinas, J., Avgidis, K., Hadziyannis, S.J. (1998) Incidence and clinical significance of hepatitis B virus precore gene translation initiation mutations in e antigen-negative patients. Journal of Viral Hepatitis, 5, 241248.
  • Lau, D.T., Kleiner, D.E., Park, Y., Di Bisceglie, A.M., Hoofnagle, J.H. (1999) Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology, 117, 12291233.
  • Lau, G.K., Liang, R., Wu, P.C., Lee, C.K., Lim, W.L., Au, W.Y. (1998) Use of famciclovir to prevent HBV reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation. Journal of Hepatology, 28, 359368.
  • Lau, G.K., Carman, W.F., Locarnini, S.A., Okuda, K., Lu, Z.M., Williams, R., Lam, S.K. (1999) Treatment of chronic hepatitis B virus infection: an Asia-Pacific perspective. Journal of Gastroenterology and Hepatology, 14, 312.
  • Lau, Y.L., Peiris, M., Chan, G.C., Chan, G.C., Chiu, D., Ha, S.Y. (1998) Primary human herpesvirus 6 infection transmitted from donor to recipient through bone marrow infusion. Bone Marrow Transplantation, 21, 10631066.
  • Lefkowitch, J.H. (1982) Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and ‘cholangitis lenta’. Human Pathology, 13, 1924.
  • Li, C.K., Lai, D.H., Shing, M.M., Chik, K.W., Lee, V., Yuen, P.M. (2000) Early iron reduction programme for thalassaemia patients after bone marrow transplantation. Bone Marrow Transplantation, 25, 653656.
  • Limaye, A.P., Huang, M., Atienza, E.E., Ferrenberg, J.M., Corey, L. (1999) Detection of Epstein Barr Virus DNA in sera from transplant recipients with lymphoproliferative disorders. Journal of Clinical Microbiology, 37, 11131116.
  • Lindor, K.D. & Burnes, J. (1991) Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report. Gastroenterology, 101, 250253.
  • Ljungman, P., Johansson, N., Aschan, J., Glaumann, H., Lonnqvist, B., Ringden, O., Sparrelid, E., Sonnerborg, A., Winiarski, J., Gahrton, G. (1995) Long-term effects of hepatitis C virus infection in allogeneic bone marrow transplant recipients. Blood, 86, 16141618.
  • Ljungman, P., Andersson, J., Aschan, J., Bjorkstrand, B., Hagglund, H., Lonnqvist, B., Ringden, O., Winiarski, J. (1996) Oral ribavirin for prevention of severe liver disease caused by hepatitis C virus during allogeneic bone marrow transplantation. Clinical Infectious Diseases, 23, 167169.
  • Locasciulli, A., Alberti, A., Bandini, G., Polchi, P., Arcese, W., Alessandrino, P., Bosi, A., Testa, M., Bacigalupo, A. (1995) Allogeneic bone marrow transplantation from HBsAg+ donors: a multicenter study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood, 86, 32363240.
  • Locasciulli, A., Testa, M., Pontisso, P., Bacigalupo, A., Ljungman, P., Frickhofen, N., Alberti, A. (1997) Hepatitis C virus genotypes and liver disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplantation, 19, 237240.
  • Locksley, R.M., Flournoy, N., Sullivan, K.M., Meyers, J.D. (1985) Infection with varicella-zoster virus after marrow transplantation. Journal of Infectious Diseases, 152, 11721181.
  • Main, J., Brown, J.L., Howells, C., Galassini, R., Crossey, M., Karayiannis, P., Georgiou, P., Atkinson, G., Thomas, H.C. (1996) A double blind, placebo-controlled study to assess the effect of famciclovir on virus replication in patients with chronic hepatitis B virus infection. Journal of Viral Hepatitis, 3, 211215.
  • Markin, R.S. (1994) Manifestations of Epstein-Barr virus-associated disorders in liver. Liver, 14, 113.
  • Martin, B.A., Rowe, J.M., Kouides, P.A., DiPersio, J.F. (1995) Hepatitis B reactivation following allogeneic bone marrow transplantation: case report and review of the literature. Bone Marrow Transplantation, 15, 145148.
  • Matthes-Martin, S., Aberle, S.W., Peters, C., Holter, W., Popow-Kraupp, T., Potschger, U., Fritsch, G., Ladenstein, R., Rosenmayer, A., Dieckmann, K., Gadner, H. (1998) CMV-viraemia during allogenic bone marrow transplantation in paediatric patients: association with survival and graft-versus-host disease. Bone Marrow Transplantation, 21, S53S56.
  • McDonald, G.B., Shulman, H.M., Wolford, J.L., Spencer, G.D. (1987) Liver disease after human marrow transplantation. Seminars in Liver Disease, 7, 210220.
  • McDonald, G.B., Hinds, M.S., Fisher, L.D., Schoch, H.G., Wolford, J.L., Banaji, M., Hardin, B.J., Shulman, H.M., Clift, R.A. (1993) Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Annals of Internal Medicine, 118, 255267.
  • Moschettini, D., Galieni, P., Valensin, P.E., Laszlo, D., Scalia, G., Tozzi, G., Lauria, F., Donati, D. (2000) Human herpesvirus 6 infection in autologous bone marrow transplant recipients: a prospective study. Journal of Medical Virology, 60, 3942.
  • Murakami, C.S., Chan, G.S., McDonald, G.B. (1997) Incidence and etiology of extrahepatic biliary obstruction in bone marrow transplant patients (Abstract). Gastroenterology, 112, 1340a.
  • Navari, R.M., Sullivan, K.M., Springmeyer, S.C., Siegel, M.S., Meyers, J.D., Buckner, C.D., Sanders, J.E., Stewart, P.S., Clift, R.A., Fefer, A., Storb, R., Thomas, E.D. (1983) Mucobacterial infections in marrow transplant patients. Transplantation, 36, 509513.
  • Nikkels, A.F., Delvenne, P., Sadzot-Delvaux, C., Debrus, S., Piette, J., Rentier, B., Lipcsei, G., Quatresooz, P., Pierard, G.E. (1996) Distribution of varicella zoster virus and herpes simplex virus in disseminated fatal infections. Journal of Clinical Pathology, 49, 243248.
  • Noble, S. & Faulds, D. (1998) Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs, 56, 115146.
  • Nonomura, A., Kono, N., Mizukami, Y., Nakanuma, Y. (1996) Histological changes of the liver in experimental graft-versus-host disease across minor histocompatibility barriers. VIII. Role of eosinophil infiltration. Liver, 16, 4247.
  • Ohashi, K., Tanabe, J., Watanabe, R., Tanaka, T., Sakamaki, H., Maruta, A., Okamoto, S., Aotsuka, N., Salto, K., Nishimura, M., Oh, H., Matsuzaki, M., Takahashi, S., Yonekura, S. (2000) The Japanese multicenter open randomized trial of Ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. American Journal of Hematology, 64, 3238.
  • Okamoto, H., Akahane, Y., Ukita, M., Fukuda, M., Tsuda, F., Miyakawa, Y., Mayumi, M. (1998) Fecal excretion of a nonenveloped DNA virus (TTV) associated with posttransfusion non-A-G hepatitis. Journal of Medical Virology, 56, 128132.
  • Papadopoulos, E.B., Ladanyi, M., Emanuel, D., Mackinnon, S., Boulad, F., Carabasi, M.H. (1994) Infusions of donor leucocytes to treat Epstein-Barr virus associated lymphoproliferative disorder after allogeneic bone marrow transplantation. New England Journal of Medicine, 330, 11851191.
  • Papatheodoridis, G., Patch, D., Watkinson, A., Tibballs, J., Burroughs, A.K. (1999) Transjugular liver biopsy in the 1990s: a 2-year audit. Alimentary Pharmacology and Therapeutics, 13, 603608.
  • Pessoa, M.G. & Wright, T.L. (1999) Update on clinical trials in the treatment of hepatitis B. Journal of Gastroenterology and Hepatology, 14, S6S11.
  • Phillips, E.H., Carroll, B.J., Chandra, M., Sullivan, L.A., Ruane, P.J., Decker, R.W., Rosenfelt, F.P. (1992) Laparoscopic-guided biopsy for diagnosis of hepatic candidiasis. Journal of Laparoendoscopic Surgery, 2, 3338.
  • Picardi, M., Selleri, C., De Rosa, G., Raiola, A., Pezzullo, L., Rotoli, B. (1998) Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 21, 12671269.
  • Rees, G.M., Sarmiento, J.I., Myerson, D., Coen, D., Meyers, J.D., McDonald, G.B. (1990) Cytomegalovirus hepatitis in marrow transplant patients: clinical, histologic and histochemical analysis (Abstract). Gastroenterology, 98, 470a.
  • Remberger, M. & Ringden, O. (1997) Serum levels of cytokines after bone marrow transplantation: increased IL-8 levels during severe veno-occlusive disease of the liver. European Journal of Haematology, 59, 254262.
  • Reusser, P. (1996) Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options. Journal of Hospital Infection, 33, 235248.
  • Reusser, P., Cordonnier, C., Einsele, H., Engelhard, D., Link, D., Locasciulli, A., Ljungman, P. (1996) European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients. Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation, 17, 813817.
  • Rhodes, D.F., Lee, W.M., Wingard, J.R., Pavy, M.D., Santos, G.W., Shaw, B.W., Wood, R.P., Sorrell, M.F., Markin, R.S. (1990) Orthotopic liver transplantation for graft-versus-host disease following bone marrow transplantation. Gastroenterology, 99, 536538.
  • Roelofsen, H., Van Der Veere, C.N., Ottenhoff, R., Schoemaker, B., Jansen, P.L., Oude Elferink, R.P. (1994) Decreased bilirubin transport in the perfused liver of endotoxemic rats. Gastroenterology, 107, 10751084.
  • Rogers, S.Y., Irving, W., Harris, A., Russell, N.H. (1995) Visceral varicella zoster infection after bone marrow transplantation without skin involvement and the use of PCR for diagnosis. Bone Marrow Transplantation, 15, 805807.
  • Rossetti, F., Brawner, D.L., Bowden, R., Meyer, W.G., Schoch, H.G., Fisher, L., Myerson, D., Hackman, R.C., Shulman, H.M., Sale, G.E., Meyers, J.D., McDonald, G.B. (1995) Fungal liver infection in marrow transplant recipients: prevalence at autopsy, predisposing factors, and clinical features. Clinical Infectious Diseases, 20, 801811.
  • Salat, C., Holler, E., Kolb, H.J., Reinhardt, B., Pihusch, R., Wilmanns, W., Hiller, E. (1997) Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation. Blood, 89, 21842188.
  • Samson, D., Volin, L., Schanz, U., Bosi, A., Gahrtron, G. (1996) Feasibility and toxicity of interferon maintenance therapy after allogeneic BMT for multiple myeloma: a pilot study of the EBMT. Bone Marrow Transplantation, 17, 759762.
  • Schleuning, M., Jager, G., Holler, E., Hill, W., Thomssen, C., Denzlinger, C., Lorenz, T., Ledderose, G., Wilmanns, W., Kolb, H.J. (1999) Human parvovirus B19-associated disease in bone marrow transplantation. Infection, 27, 114117.
  • Shields, A.F., Hackman, R.C., Fife, K.H., Corey, L., Meyers, J.D. (1985) Adenovirus infections in patients undergoing bone-marrow transplantation. New England Journal of Medicine, 312, 529533.
  • Shuhart, M.C., Myerson, D., Childs, B.H., Fingeroth, J.D., Perry, J.J., Snyder, D.S., Spurgeon, C.L., Bevan, C.A., McDonald, G.B. (1994) Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course. Blood, 84, 32293235.
  • Shulman, H.M., McDonald, G.B., Matthews, D., Doney, K.C., Kopecky, K.J., Gauvreau, J.M., Thomas, E.D. (1980) An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology, 79, 11781191.
  • Shulman, H.M., Sharma, P., Amos, D., Fenster, L.F., McDonald, G.B. (1988) A coded histologic study of hepatic graft-versus-host disease after human bone marrow transplantation. Hepatology, 8, 463470.
  • Shulman, H.M., Fisher, L.B., Schoch, H.G., Henne, K.W., McDonald, G.B. (1994) Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology, 19, 11711181.
  • Shulman, H.M., Gooley, T., Dudley, M.D., Kofler, T., Feldman, R., Dwyer, D., McDonald, G.B. (1995) Utility of transvenous liver biopsies and wedged hepatic venous pressure measurements in sixty marrow transplant recipients. Transplantation, 59, 10151022.
  • Skidmore, S.J., Collingham, K.E., Harrison, P., Neilson, J.R., Pillay, D., Milligan, D.W. (1997) High prevalence of hepatitis G virus in bone marrow transplant recipients and patients treated for acute leukemia. Blood, 89, 38533856.
  • Smith, F.O., Johnson, M.S., Scherer, L.R., Faught, P., Breitfeld, P.P., Albright, E., Hillier, S.C., Gowan, D., Smith, P.D., Robertson, K.A., Emanuel, D. (1996) Transjugular intrahepatic portosystemic shunting (TIPS) for treatment of severe hepatic veno-occlusive disease. Bone Marrow Transplantation, 18, 643646.
  • Snover, D.C., Weisdorf, S.A., Ramsay, N.K., McGlave, P., Kersey, J.H. (1984) Hepatic graft versus host disease: a study of the predictive value of liver biopsy in diagnosis. Hepatology, 4, 123130.
  • Snover, D.C., Weisdorf, S.A., Bloomer, J., McGlave, P., Weisdorf, D. (1989) Nodular regenerative hyperplasia of the liver following bone marrow transplantation. Hepatology, 9, 443448.
  • Soderlund, M., Ruutu, P., Ruutu, T., Asikainen, K., Franssila, R., Hedman, K. (1997) Primary and secondary infections by human parvovirus B19 following bone marrow transplantation: characterization by PCR and B-cell molecular immunology. Scandinavian Journal of Infectious Diseases, 29, 129135.
  • Somervaille, T.C., Kirk, S., Dogan, A., Landon, G.V., Mackinnon, S. (1999) Fulminant hepatic failure caused by adenovirus infection following bone marrow transplantation for Hodgkin's disease. Bone Marrow Transplantation, 24, 99101.
  • Strasser, S.I. & McDonald, G.B. (1999) Hepatitis viruses and hematopoietic cell transplantation: a guide to patient and donor management. Blood, 93, 11271136.
  • Strasser, S.I., Shulman, H.M., McDonald, G.B. (1997) Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis (Abstract). Hepatology, 26, 605a.
  • Strasser, S.I., Kowdley, K.V., Sale, G.E., McDonald, G.B. (1998) Iron overload in bone marrow transplant recipients. Bone Marrow Transplantation, 22, 167173.
  • Strasser, S.I., Myerson, D., Spurgeon, C.L., Sullivan, K.M., Storer, B., Schoch, H.G., Kim, S., Flowers, M.E., McDonald, G.B. (1999a) Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology, 29, 18931899.
  • Strasser, S.I., Sullivan, K.M., Myerson, D., Spurgeon, C.L., Storer, B., Schoch, H.G., Murakami, C.S., McDonald, G.B. (1999b) Cirrhosis of the liver in long-term marrow transplant survivors. Blood, 93, 32593266.
  • Straus, S.E., Ostrove, J.M., Inchauspe, G., Felser, J.M., Freifeld, A., Croen, K.D., Sawyer, M.H. (1988) NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention. Annals of Internal Medicine, 108, 221237.
  • Tajiri, H., Tanaka-Taya, K., Ozaki, Y., Okada, S., Mushiake, S., Yamanishi, K. (1997) Chronic hepatitis in an infant, in association with human herpesvirus-6 infection. Journal of Pediatrics, 131, 473475.
  • Trauner, M., Stepan, K.M., Resch, M., Ebner, F., Pristautz, H., Klimpfinger, M. (1992) Diagnostic problems in nodular regenerative hyperplasia (nodular transformation) of the liver. Review of the literature and report of two cases. Zeitschrift Fur Gastroenterologie, 30, 187194.
  • Tur-Kaspa, R., Shaul, Y., Moore, D.D., Burk, R.D., Okret, S., Poellinger, L., Shafritz, D.A. (1988) The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology, 167, 630633.
  • Van Burik, J.H., Leisenring, W., Myerson, D., Hackman, R.C., Shulman, H.M., Sale, G.E., Bowden, R.A., McDonald, G.B. (1998) The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients. Medicine (Baltimore), 77, 246254.
  • Vance, E.A., Soiffer, R.J., McDonald, G.B., Myerson, D., Fingeroth, J., Ritz, J. (1996) Prevention of transmission of hepatitis C virus in bone marrow transplantation by treating the donor with alpha-interferon. Transplantation, 62, 13581360.
  • Vlachogiannakos, J., Patch, D., Watkinson, A., Tibballs, J., Burroughs, A.K. (2000) Carbon dioxide portography. An expanding role? Lancet, 355, 987988.
  • Wanless, I.R. (1990) Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology, 11, 787797.
  • Whiting, J.F., Green, R.M., Rosenbluth, A.B., Gollan, J.L. (1995) Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. Hepatology, 22, 12731278.
  • Yamada-Osaki, M., Sumazaki, R., Tsuchida, M., Koike, K., Fukushima, T., Matsui, A. (1999) Persistence and clinical outcome of hepatitis G virus infection in pediatric bone marrow transplant recipients and children treated for hematological malignancy. Blood, 93, 721727.
  • Yeo, W., Steinberg, J.L., Tam, J.S., Chan, P.K., Leung, N.W., Lam, K.C., Mok, T.S., Johnson, P.J. (1999) Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. Journal of Medical Virology, 59, 263269.
  • Zuckerman, E., Zuckerman, T., Douer, D., Qian, D., Levine, A.M. (1998) Liver dysfunction in patients infected with hepatitis C virus undergoing chemotherapy for hematologic malignancies. Cancer, 83, 12241230.
  • Zutter, M.M., Martin, P.J., Sale, G.E., Shulman, H.M., Fisher, L., Thomas, E.D., Durnam, D.M. (1988) Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood, 72, 520529.