Review article: management of hepatic disease following haematopoietic cell transplant

Authors

  • G. B. McDONALD

    1. Gastroenterology/Hepatology Section, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA
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Dr G. B. McDonald, Gastroenterology/Hepatology Section (D2-190), Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA.

Summary

Hepatic diseases are common complications of haematopoietic cell transplant. The causes are multiple: myeloablative conditioning regimens may cause sinusoidal injury; acute and chronic graft-versus-host disease lead to damaged hepatocytes and small bile ducts; microcrystalline deposits in the gall bladder can cause biliary symptoms; drug-induced liver injury is common; and the liver may be infected by viruses and fungi during the period of severe immune suppression that follows transplant.

Pre-transplant evaluation and prevention of liver injury are often more useful than treatment of deeply jaundiced patients in improving transplant outcomes.

This review covers pre-transplant evaluation, common hepatobiliary problems in the six months following transplant, and hepatic problems in long-term survivors.

Background

Hepatobiliary complications of haematopoietic cell transplant (HCT) present unique challenges to physicians who care for these patients. The first challenge is to arrive at an accurate diagnosis of the liver pathology – not an easy proposition when multiple liver problems are in the differential diagnosis and when several pathologic processes may be present simultaneously. The liver may be damaged by drugs used during the transplant process, particularly drugs in high-dose myeloablative regimens that prepare patients for infusion of haematopoietic stem cells. After infusion of stem cells, patients remain profoundly immunosuppressed until engraftment; full recovery of immune function is often delayed for a year or longer, exposing patients to infection with viruses, fungi and bacteria. Recipients of allogeneic stem cells are also at risk for graft-vs.-host disease (GVHD) involving the liver. Thus, a patient undergoing transplant is at risk for drug-liver toxicity, infections and immunologic liver injury (Table 1). The second challenge is treating the underlying causes of liver dysfunction after transplant. Jaundice after transplant is an adverse prognostic sign, with total serum bilirubin in the 68–120 μmol/L (4–7 mg/dL) range conferring 50% mortality and bilirubin values >170 μmol/L (10 mg/dL) conferring >70% mortality at day-200 post-transplant.1 Because treatment of severe liver dysfunction is often futile after transplant, this review will emphasize recognition of risk factors for hepatobiliary problems before the transplant process starts, implementation of measures to prevent liver damage and early recognition of post-transplant liver disorders that have specific treatments. Over the last decade, this approach has resulted in a marked reduction in the incidence of serious liver injury following the transplant.2–4

Table 1.   Hepatobiliary diseases after haematopoietic cell transplant
DiseaseIncidenceTimingDiagnostic featuresTreatmentPrevention
  1. * Formerly known as veno-occlusive disease of the liver.

  2. GVHD, graft-vs-host disease; HSV, herpes simplex virus; VZV, varicella zoster virus; HBV, hepatitis B virus; HCV, hepatitis C virus.

Sinusoidal obstruction syndrome (SOS)*0–35% (regimen-dependent)Onset before day +20Hepatomegaly, weight gain, jaundice, ascites
Imaging studies
Wedged hepatic venous pressure gradient, histology
Note atypical presentations (acute hepatitis, anasarca)
None proven
Defibrotide successful in ∼45% of patients with severe SOS
Assess patient risk before conditioning therapy
Choose non-liver toxic agents for conditioning therapy or use a non-myeloablative conditioning regimen
Cholestasis of sepsis (cholangitis lenta)Common in neutropenic patientsFollowing sepsis or neutropenic fever (usually before day +30)Exclude other causes of cholestasis
Diagnosis is inferential
Treat underlying infectionUrsodiol
Infection prophylaxis or expectant treatment
Acute GVHD of the liver∼20% of allograft recipients
Rare after autograft
Day +15–50, later after non-myeloablative transplantsConfirm GVHD in skin, gut
Exclude other causes of cholestasis
Histology
Corticosteroids (2 mg/kg/day)
Ursodiol
Optimal donor selection
Complete GVHD prophylaxis
T-cell depletion protocols
Ursodiol
Acute viral hepatitisUncommon when prophylaxis is used against herpesviruses, hepatitis BHSV, day +20–50
Adenovirus, day +30–80
VZV, day +80–250
HBV and HCV, during immune reconstitution
Pretransplant serology and PCR results
Isolation of virus from other sites (stool and urine for adenovirus)
PCR of serum for specific viruses
Liver histology/ PCR/immuno-stains
HSV, VZV: acyclovir
Adenovirus: cidofovir
HBV: lamivudine, adefovir or entecavir
HSV and VZV infection: acyclovir prophylaxis for all patients
If patient is at risk for HBV infection: lamivudine, choose HBV immune donor
Fungal abscessRare when prophylaxis is usedDay 10–60Hepatic pain, fever
Liver imaging
Serum fungal antigen
Antifungal drugs (vary with organism)Pretransplant screening
Fluconazole prophylaxis for all patients
Drug-liver injuryCommonDay 0–100Clinical evidenceDiscontinue drugNone
Ischaemic liver diseaseConfined to patients with septic or haemorrhagic shockDay 0–30Clinical evidenceRestore cardiac outputEarly treatment of sepsis, bleeding
Biliary obstructionTransient biliary sludge, common
Stones, chloromas rare
Day 15–60History, examination
Biliary ultrasound
Ursodiol to increase bile-salt dependent bile flow
Papillotomy ± stent if obstruction persists
None
Idiopathic hyperammonaemiaRareDay 10–50Venous blood ammoniaNone provenUnknown
Chronic hepatitis CFormerly commonAfter day 80HCV RNA in serum
Elevations in serum AST, ALT after immune reconstitution
Interferon-alpha plus ribavirin after immune reconstitutionScreen haematopoietic cell donors
Iron overloadVery commonPretransplant
Long-term follow-up after transplant
Transferrin saturation
Marrow iron quantitation
Liver iron quantitation
May not be necessary
Phlebotomy, chelation if iron burden is very high (see text)
Iron mobilization before transplant
Avoid medicinal iron supplements
Chronic GVHDCommon after allograftsAfter day 80Prior acute GVHD history
Chronic GVHD in other organs
Consistent ALT, alkaline phosphatase
Histology
Immunosuppressive drug therapy
Ursodiol
Screening for chronic GVHD at day 80
Monitor serum ALT, alkaline phosphatase during tapering of immunosuppressive drugs

The methods used in preparing this review involved recalling the literature of the last 35 years; reading journals devoted to hepatology, pharmacology, oncology and haematopoietic cell transplant; attending meetings and talking to investigators; updating references by directed topic and author searches via PubMed and Ovid and integrating this information with my clinical experience.

Liver problems before haematopoietic cell transplant

Viral hepatitis in stem cell donors

Donors who are viremic with hepatitis viruses may passage these viruses to the recipients of their stem cells.3 When equally Human leukocyte-antigen (HLA)-matched donors are available, the donor who is not infected should be chosen. In some circumstances, it is possible to treat HBsAg+ or hepatitis C virus (HCV) RNA+ donors with anti-viral therapy to reduce the risk of transmission, but hepatitis B virus (HBV) may persist in donor peripheral blood stem cells despite clearance from serum.5, 6 Thus, the goal of anti-viral therapy of infected donors should be to clear serum and buffy coat cells of virus, as determined by polymerase chain reaction (PCR) before stem cell harvest. Anti-HBc-positive but HBV DNA-negative donors can be used. A donor who is naturally anti-HBs-positive is preferred for an HBV-infected recipient, as adoptive transfer of immunity can lead to clearance of virus from the recipient after transplant.7

Chronic liver disease in transplant candidates

The risk of fatal hepatic sinusoidal injury [sinusoidal obstruction syndrome, or SOS, formerly known as veno-occlusive disease (VOD) of the liver] after some myeloablative regimens is significantly greater among patients with inflammatory liver diseases such as chronic hepatitis C, steatohepatitis, sinusoidal fibrosis related to extramedullary haematopoiesis, and amyloidosis than among patients who come to transplant with normal livers.8 Cirrhosis is a contraindication to most myeloablative regimens and increases the risk of death from liver decompensation after non-myeloablative regimens.9 In transplant candidates who have risk factors for fatal SOS, modification of the conditioning regimen to exclude the more liver-toxic agents may increase the chance of survival (see below, SOS). There is a 35% risk of post-HCT reactivation of HBV in patients with isolated anti-HBc antibodies; viremia is usually seen following treatment for acute GVHD with corticosteroids.3 Severe hepatitis B after transplant has been seen in anti-HBc+/anti-HBs+ patients and in a patient with occult hepatitis B.10 In the absence of anti-viral prophylaxis, fatal fulminant hepatitis develops in approximately 15% of hepatitis B-infected HCT recipients, sometimes after reactivation of occult HBV.3, 10 Lamivudine prophylaxis has virtually eliminated HBV-related liver failure after transplant among patients at risk.11

Gall-bladder and bile duct stones

Patients with asymptomatic gallstones do not require operative intervention, but cholecystectomy should be considered before transplant if symptomatic cholelithiasis or choledocholithiasis is found. The risk of cholangitis and uncontrolled sepsis is high and the therapeutic options limited if gallstones cause cystic duct or biliary obstruction during a time post-transplant when a patient lacks neutrophils and platelets.

Iron overload

Hepatic iron levels may be very high in diseases such as thalassaemia, aplastic anaemia and chronic leukaemia or lymphoma. The accumulation of iron in these disorders cannot be explained solely by transfusional iron, as an alternative explanation lies in intestinal hyperabsorption of dietary iron in patients who have ineffective erythropoiesis. In patients with extreme iron overload, effective pre-HCT chelation therapy improves post-HCT survival.12 In most patients, quantitation of tissue iron stores and its mobilization can be deferred until after transplant (see below, Liver problems in long-term transplant survivors).

Fungal liver infections

Hepatic fungal infection is best identified by liver pain, positive serum tests for fungal antigens or DNA, magnetic resonance imaging, and, if necessary, histology.13 It may be difficult to determine whether defects seen with liver imaging represent active infection or focal areas of fibrosis and granulation tissue. If there is a suspicion of active infection in the liver, liposomal amphotericin, voriconazole or caspifungin should be given until engraftment is established.14 Prophylaxis with antifungal drugs will prevent almost all candidal infections after transplant, but azole drugs inhibit hepatic cytochrome P450 enzymes, affecting metabolism of many drugs, including cyclophosphamide (CY).15

Liver problems in the first 200 days after transplant

Hepatic drug toxicity

Except for the typical clinical syndrome of sinusoidal liver toxicity caused by high-dose myeloablative therapy, the diagnosis of drug-liver injury in the transplant setting is difficult. The majority of patients receive drugs for infection prophylaxis (usually acyclovir, fluconazole and trimethoprim-sulfamethoxazole), GVHD prophylaxis (usually tacrolimus or ciclosporin plus methotrexate or mycophenolate mofetil), antiemetics, antihypertensives and ursodiol. Specific infections and GVHD are treated with many other drugs (Table 1).

Sinusoidal obstruction syndrome (SOS)

Myeloablative conditioning regimens may damage hepatic sinusoids, leading to hepatomegaly, fluid retention, weight gain and elevated serum bilirubin in the first 20–30 days after transplant. This form of injury is termed SOS.16 The term ‘VOD’ is a misnomer; as the disease process begins in the sinusoids and affects venules only late in the course of the disease. In fact, hepatic venules are patent in up to 25% of fatal cases of SOS.17 Individual variability in CY metabolism (Figure 1), total body irradiation (TBI) dose, use of gemtuzumab ozogamicin and pre-existing liver inflammation and fibrosis are risk factors.8, 18, 19 The frequency of SOS varies in proportion to these factors; the case fatality rate, however, is relatively constant from centre to centre at 15–20%. At our centre, the overall incidence of SOS among patients with haematological malignancy conditioned with CY 120 mg/kg plus TBI 12–13 Gy is 38% (16% moderate to severe) and among patients with myelodysplastic syndrome conditioned with targeted busulfan (BU) plus CY 120 mg/kg, 23% (9% moderate to severe).

Figure 1.

 Metabolism and disposition of cyclophosphamide (CY) and its major metabolites. Chloroacetaldehyde, acrolein and phosphoramide mustard (PM) are cytotoxins, but acrolein and PM are the major toxins because of the abundance of their formation. 4-hydroxycyclophosphamide is formed primarily in the liver but circulates in blood, entering cells as its tautomer aldocyclophosphamide (AldoCY). Acrolein and PM are formed from AldoCY when it decomposes via β-elimination. Other metabolites include O-carboxyethyl-phosphoramide mustard (CEPM), deschloroethyl-cyclophosphamide, hydroxypropyl-phosphoramide mustard and glutathionyl-cyclophosphamide.

The realization that CY is the primary cause of sinusoidal liver injury caused by myeloablative conditioning regimens came as a result of several observations: (i) CY is a component of the most hepatotoxic myeloablative regimens;20, 21 (ii) in vitro, hepatic sinusoidal endothelial cells are injured by metabolites of CY that are generated within hepatocytes;22 (iii) damage to the microcirculation of the liver is central to the development of hepatic dysfunction post-transplant; and16, 17, 23 (iv) there is patient-to-patient variability in CY metabolism (Figure 1) and a relation of aberrant metabolism to toxicity in other organs.24, 25

In a prospective study of 147 patients who received myeloablative conditioning therapy with CY and TBI, 23 (16%) developed moderate or severe SOS. Metabolism of CY was highly variable, particularly for the metabolite O-carboxyethyl-phosphoramide mustard (CEPM), whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to SOS, bilirubin elevation, non-relapse mortality (Figure 2) and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of CEPM exposure had a sixfold higher risk of non-relapse mortality, compared with patients in the lowest quartile. Engraftment and tumour relapse were not statistically and significantly related to CY metabolite exposure.

Figure 2.

 Cumulative incidence estimates of the probability of non-relapse mortality after a myeloablative conditioning regimen of CY and total body irradiation. The estimates are displayed as a function of exposure to the CY metabolite, CEPM, expressed as the lowest (first) quartile through highest (fourth) quartile of AUCCEPM. (Reprinted with permission from McDonald et al.18).

A clinical diagnosis of SOS may suffice if typical signs develop before day +20 post-transplant, but Doppler ultrasound, measurement of the wedged hepatic venous pressure gradient and liver histology may be needed in difficult cases.26 Initial histologic changes of SOS are dilatation of sinusoids, extravasation of red cells through the space of Disse, necrosis of perivenular hepatocytes and widening of the subendothelial zone in central veins.16 The later stages are characterized by extensive collagenization of sinusoids and, to a lesser extent, venules, and venule walls. In the 30-day period following transplant, the most common cause of serum alanine aminotransferase (ALT) elevation over 500 U/L is hepatic necrosis caused by SOS, with peak values at day 23 ± 9 post-transplant, a result of ischaemia in zone 3 of the liver acinus, related to poor perfusion. Extreme elevations of ALT portend a poor prognosis. Septic shock with prolonged hypotension and fulminant hepatic failure caused by viruses may also present with rapidly rising serum ALT values.

The severity of SOS has been classified as mild (clinically obvious, requires no treatment, and resolves completely), moderate (signs and symptoms require treatment such as diuretics or pain medications, but resolve completely) or severe (requires treatment but does not resolve before death or day 100). A range of clinical and laboratory findings correspond to these operational definitions of disease severity.2 A statistical model has been developed that predicts the outcome of SOS after CY-based regimens, derived from rates of increase of both bilirubin and weight in the weeks following the transplant.2 A poor prognosis correlates with the rate of bilirubin elevation and weight gain, higher serum ALT values, higher portal pressure, development of portal vein thrombosis and multiorgan failure. Treatment of severe SOS is unsatisfactory; the best current results (45% response) are with i.v. defibrotide (25 mg/kg/day), a porcine oligonucleotide that has effects on microvascular endothelial cells.27 Whenever possible, patients with severe SOS should be enrolled in clinical trials.

Prevention of sinusoidal injury is likely to be more effective than treatment, a process that begins with assessment of the risk of a fatal outcome from a myeloablative conditioning regimen (see above, Chronic liver disease in transplant candidates). Figure 3 illustrates a hierarchy of conditioning regimens according to the risk of sinusoidal liver toxicity.

Figure 3.

 Schematic of conditioning regimens for haematopoietic cell transplant, arranged from the lowest risk of sinusoidal liver toxicity to the highest risk. Abbreviations: SOS, sinusoidal obstruction syndrome; CY, cyclophosphamide; TBI, total body irradiation; Gy, grey (a unit of radiation exposure); BU, busulfan; FLU, fludarabine; i.v., intravenous.

If a CY/TBI regimen must be used for a patient at high risk for fatal SOS, modifications should be considered for both CY and TBI dosing, with the understanding that clinical trials to prove efficacy and safety have not been performed. The total dose of CY should be in the 75–100 mg/kg range, and TBI doses should not exceed 12 Gy.28 If a BU/CY regimen must be used for a patient at high risk for fatal SOS, liver toxicity appears to be less frequent if CY is given before targeted BU (this requires i.v. BU, as oral BU is poorly tolerated after CY infusions);29 or if dosing of CY is delayed for 1–2 days after completion of BU.30 Busulfan (and the use of phenytoin to prevent seizures) has marked effects on CY metabolism when CY is given second in order, that is, increased exposure to 4-hydroxycyclophosphamide (HCY), phosphoramide mustard and acrolein. It is not clear whether i.v. BU offers any advantage over oral BU with regard to liver toxicity from a BU/CY regimen when both are dosed to the same steady state concentration. A myeloablative regimen of fludarabine and targeted BU does not appear to cause similar sinusoidal damage.31, 32 Thus, substituting fludarabine for CY may reduce liver toxicity.31, 32 There is no sinusoidal liver toxicity from a non-myeloablative regimen of fludarabine plus low-dose TBI.9 There may be value in prophylaxis of SOS with repletion of intracellular reduced glutathione (GSH) or inhibition of matrix metalloproteinase enzymes or infusion of defibrotide. Large-scale clinical trials of these modalities with proper stratification for risk of fatal outcomes have not been reported. Prospective studies have shown no benefit from use of heparin, ursodiol or antithrombin III for prevention of fatal SOS (reviewed in Deleve et al.16).

Calcineurin inhibitors

Ciclosporin and tacrolimus inhibit canalicular bile transport and contribute to mild jaundice, particularly when blood levels are above the therapeutic range;33 the effect is solely on bilirubin levels, as ALT and alkaline phosphatase levels remain normal.34 Disposition of calcineurin inhibitors may be abnormal in patients with cholestasis.

Antimicrobial drugs

Of drugs used in the transplant setting, trimethoprim-sulfamethoxazole, itraconazole, voriconazole and fluconazole are the most commonly associated with elevations of serum ALT and alkaline phosphatase.

Gemtuzumab ozogamicin

When gemtuzumab ozogamicin (a conjugate of toxin and anti-CD33) is given for relapsed acute myeloid leukaemia following transplant, liver damage may result, probably because of CD33+ cells resident in sinusoids (Kupffer cells, possibly stellate cells). Clinical manifestations are hepatomegaly, ascites and jaundice, similar to SOS following high-dose myeloablative therapy.35 Liver histology reveals activated stellate cells and intense deposition of collagen in sinusoids.

Graft-vs.-host disease

Acute GVHD is the most common cause of severe cholestatic injury after allogeneic HCT. In patients with GVHD, alloreactive T cells recognize foreign major and minor histocompatibility antigens as well as adhesion molecules expressed on biliary epithelial cells. Hepatic GVHD usually follows cutaneous and/or intestinal GVHD, and is heralded by a gradual rise in serum bilirubin, alkaline phosphatase and aminotransferase enzymes.2 In allograft recipients on minimal immunosuppression or after donor lymphocyte infusion, GVHD may present as an acute hepatitis. 36, 37 A cholestatic condition identical to GVHD occurs rarely in autologous HCT recipients.38 Characteristic liver biopsy findings in GVHD include lymphocytic infiltration of small bile ducts, nuclear pleomorphism and epithelial cell dropout.39–41 The peribiliary glands in the hilar connective tissue are also affected by GVHD.42 Patients with severe concomitant gut GVHD may develop a picture that resembles cholangitis lenta with extensive ductular reaction, a proliferation of ductules at the margin of portal spaces, along with periportal bile thrombi and increased inflammation. Because these patients are frequently pancytopenic, inflammatory infiltrates may be minimal. In advanced hepatic GVHD, it may be difficult to identify small bile ducts because they have been destroyed. Only 30% of patients with liver GVHD have resolution of liver abnormalities after initial immunosuppressive treatment. Over 50% of patients with acute liver GVHD develop chronic GVHD.

Although GVHD usually presents with jaundice and a cholestatic picture, histologically there is often a component of hepatocyte necrosis, and under some circumstances the presentation is that of an acute hepatitis with serum ALT levels in the 400–2000 U/L range.36, 37 The most common circumstances for a hepatitic presentation of GVHD are following donor lymphocyte infusions in the absence of immunosuppressive drugs (usually performed because of relapse of leukaemia, to achieve a graft-vs.-leukaemia effect) and following a taper or discontinuation of immunosuppressive drugs, usually after day 100. Liver biopsy is necessary to make a diagnosis, and treatment is with prednisone and tacrolimus. If untreated, hepatitic GVHD may rapidly progress to ductopenia and deep jaundice.36

Other cholestatic liver disorders

Cholestasis is the most common mechanism for jaundice following HCT, but dissecting out the exact cause is difficult, as there may be overlapping causes. Prophylaxis with ursodiol, started several weeks before transplant and continued to day 80 post-HCT, has been shown to reduce the frequency of jaundice and ALT elevations and to reduce mortality, compared with placebo.4

Cholangitis lenta

Sepsis-associated cholestasis is an important contributor to hyperbilirubinaemia after HCT, mediated by endotoxins, interleukin-6 and TNFα.43 In the past, what was assumed to be GVHD mediated by donor T cells involving the liver in patients with a rapidly progressing skin rash and protein-losing enteropathy was probably a consequence of translocation of endotoxin and bacteria into the portal circulation, causing IL-6 release and cholestasis, as histology of the liver in these patients often fails to show typical bile duct injury.39

Extrahepatic obstruction and cholecystitis

Gall-bladder sludge composed of calcium bilirubinate is found at autopsy in 100% of HCT patients.44 Biliary passage of sludge may cause epigastric pain, nausea and abnormal serum liver enzymes. Endoscopic papillotomy is rarely indicated. Biliary sludge may be a cause of acute ‘acalculous’ cholecystitis, acute pancreatitis and bacterial cholangitis.45, 46 Diagnosis of cholecystitis is difficult because of the high frequency of gall-bladder wall thickening and sludge on ultrasound following HCT, but pericholecystic fluid, gall-bladder wall necrosis or localized tenderness suggest cholecystitis. A radionuclide bile excretion study, with morphine infusion to enhance gall-bladder filling, can be useful; non-visualization of the gall-bladder suggests cholecystitis.47 Persistent biliary obstruction is a rare event, caused by a variety of disorders [e.g. lymphoblastic infiltration of the common bile duct and gall-bladder in Epstein–Barr virus (EBV) lymphoproliferative disease; CMV-related biliary disease; dissecting duodenal haematoma complicating endoscopic biopsy; inspissated biliary sludge; and leukaemic relapse (chloroma) in the head of pancreas].48

Liver infections

Viral infections

Acute hepatitis caused by herpes simplex virus (HSV), varicella zoster virus (VZV), adenovirus and hepatitis B virus are now very uncommon, but can be fatal after HCT.3, 49, 50 Hepatic infections caused by CMV and Hepatitis C virus are seldom severe.8 The mechanisms of hepatocyte necrosis varies with the virus: HSV, VZV and adenovirus often develop during severe immune suppression, whereas hepatitis viruses B and C replicate during immune suppression but seldom cause hepatitis until there has been recovery of immunity.3 With prophylactic acyclovir, acute hepatitis because of HSV and VZV is now rare, but after acyclovir has been discontinued, VZV hepatitis can present with abdominal bloating, pain and elevations of serum ALT.51 HHV-6 and -8 reactivation have been associated with the development of fever, rash and hepatitis in HCT recipients.

When there is uncertainty about the cause of rising serum ALT, DNA blood tests for herpesviruses, adenovirus and HBV, transvenous measurement of the wedged hepatic venous pressure gradient and liver biopsy are indicated. On liver histology, infections caused by herpesviruses or adenovirus can be distinguished from SOS as there is a random distribution of necrotic foci with infection, whereas in SOS the necrosis is always in zone 3. The PAS stain is very useful for demonstrating necrotic foci because dead hepatocytes contain no glycogen. If acyclovir is not being given, it should be started empirically, particularly if the patient presents with abdominal bloating and elevated serum ALT typical of VZV infection.51 If the patient has concomitant pulmonary, renal, bladder or intestinal symptoms, adenovirus should be suspected; the most effective treatments are cidofovir and donor leucocyte infusions.50, 52–54 Fulminant hepatitis B may develop during immune reconstitution in patients at risk, including those who activate occult HBV, but can be prevented with prophylactic lamivudine or adefovir.3, 11 HCV infections are seldom severe; asymptomatic elevation of ALT is commonly seen from days +60 to +120, frequently coinciding with the tapering of immunosuppressive drugs.8 Therapy directed at chronic HCV infection should be deferred for at least a year post-transplant (see below). EBV lymphoproliferative disease was commonly seen in allogeneic HCT recipients at day +70–100, with the highest incidence in recipients of HLA-mismatched T-cell depleted grafts and after potent anti-T-cell therapies, manifest in the liver by abnormal serum alkaline phosphatase and massive hepatosplenomegaly.55 EBV–lymphoproliferative disease (LPD) is now infrequent because of EBV–DNA surveillance and pre-emptive treatment. 56

Fungi and moulds

Prophylaxis prevents almost all candidal infections in the liver; fungi in the liver after transplant are likely to be moulds or resistant Candida species.57 The signs are fever, tender hepatomegaly and increased serum alkaline phosphatase levels, but the sensitivity of imaging tests for disseminated military fungal lesions is <30%.58 Assays for fungal elements are useful in diagnosis–serum galactomannan assay for mould infection59, 60 and β-d-glucan assay for Candida infection.61 Identification of fungal elements in liver tissue may be difficult without special stains.

Bacterial infections

Reactivation of latent mycobacterial infection, including Bacillus Calmette-Guerin, within the liver may occur with prolonged immunosuppressive therapy.62 Bacterial liver abscesses are rare after transplant, probably owing to prompt antibiosis for neutropenic fever. Disseminated clostridial infection and gall-bladder infection with gas-producing organisms may lead to air in the liver and biliary system.63

Idiopathic hyperammonaemia

A syndrome of hyperammonaemia and coma occurs rarely after transplant.64 The presentation is with progressive lethargy, confusion, weakness, incoordination, vomiting and hyperventilation. The diagnosis is confirmed when the plasma ammonia exceeds 200 μmol/L and there is no evidence of liver failure. The outcome is usually fatal.

Liver problems in long-term transplant survivors

Chronic GVHD

Cholestasis is present in 80% of patients with extensive chronic GVHD, but bile duct damage in a transplant survivor is not considered to be diagnostic of chronic GVHD, but rather a manifestation of protracted acute GVHD.65 The spectrum of liver disease in patients with protracted liver GVHD ranges from elevations of serum ALT and alkaline phosphatase to jaundice. By the time jaundice develops, liver biopsy shows extensive damage to small bile ducts. In patients receiving no, or tapering doses of immunosuppression, liver GVHD may also present with abrupt elevations of aminotransferase levels to over 2000 U/L.36 Infusion of donor lymphocytes in a patient whose immunosuppressive drug therapy has been discontinued may results in a similar acute hepatitis.37 Liver biopsy and PCR of serum are essential to exclude acute viral hepatitis due to a herpesvirus (HSV or VZV) or a hepatitis virus and to make a definitive diagnosis of hepatic GVHD.66 The outcome of acute hepatitis as a manifestation of GVHD in the liver is dependent on prompt recognition and treatment with calcineurin inhibitor and prednisone; delayed treatment may result in death.36 Immunosuppressive drug treatment of chronic GVHD is successful in 50–80% of patients with extensive multiorgan disease. The addition of ursodeoxycholic acid (15 mg/kg/day) may result in biochemical improvement in those with liver involvement.67 In rare patients who are long-term survivors of allogeneic transplant, ductopenia caused by GVHD does not appear to be reversible, resulting in persistent deep jaundice. Liver transplantation may be the only option for treatment.68

Chronic viral hepatitis

Hepatitis C virus infection in HCT survivors almost always results in chronic hepatitis.8, 69 In the first 10 years of HCV infection after HCT, there is little liver-related morbidity. However, cirrhosis of the liver related to chronic HCV infection is rising in frequency among patients who were transplanted more than 20 years ago.69, 70 Patients with chronic HCV should be offered therapy with combination pegylated interferon-alpha plus ribavirin.71 Pegylated interferons, with their longer half-lives, should be administered with caution, as some HCT patients experience rapid falls in platelet and granulocyte counts. Interferon-alpha may also activate chronic GVHD, but the risk of this complication in patients with only a remote history of chronic GVHD is small.

Iron overload

Iron overload is particularly severe in thalassaemic patients who have undergone HCT.72 Iron overload is caused by a combination of multiple red cell transfusions and dyserythropoiesis leading to increased iron transport by the intestine. After HCT, iron accumulation stops and body iron stores fall slowly over time.73 The consequences of extreme iron overload in HCT survivors are primarily those of cardiac, pituitary and pancreatic endocrine dysfunction. Iron overload may also be a cause of persistent hepatic dysfunction after HCT.74 Patients with liver iron content >15 000 mg/g dry weight should be treated aggressively with both phlebotomy and chelation; when liver iron content is 7000–15 000 mg/g dry weight, phlebotomy is indicated; when liver iron content is under 7000 mg/g dry weight, treatment is indicated only if there is evidence of liver disease.75 Mobilization of iron from heavily overloaded patients improves cardiac function, normalizes serum ALT levels, and results in improved liver histology.74–76

Other causes of liver injury

Drug-liver injury may be related to antihypertensive drugs, lipid lowering agents, hypoglycaemic agents, non-steroidal anti-inflammatory drugs, antidepressants, antibiotics and herbal preparations. A particular risk of non-sterile herbal remedies in immunosuppressed individuals is the potential for fungal contamination of herbal preparations leading to translocation of fungal spores into the portal circulation and liver abscesses.77 Compared with the general population, patients who survive over 10 years post-HCT have an eightfold risk of developing a new solid malignancy; the risk of hepatocellular carcinoma is particularly elevated.78 There is a higher-than expected incidence of gallstones and stone-related biliary problems after HCT than in an age-matched population, probably related to formation of biliary sludge (calcium bilirubinate) as nucleating factors immediately after transplant.44 Chronic ciclosporin or tacrolimus dosing may also lead to gallstones, biliary symptoms and pancreatis.79

Cirrhosis

Cirrhosis has emerged as an important late complication of transplantation as a result of a high frequency of hepatitis C in patients transplanted before the mid-1990s. The rate of progression of chronic hepatitis C to cirrhosis appears to be accelerated after transplant, with 25–35% of such patients developing cirrhosis within 25 years.69, 70 Translant survivors whose immune reconstitution is complete and who do not evince chronic GVHD should be strongly considered for anti-viral therapy.71 Liver transplantation should be considered in any HCT survivor with incipient liver decompensation; in some cases, the original allogeneic cell donor can be a partial liver donor.68, 80

Ancillary