Transplantation Reviews 29 (2015) 8–15

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Liver disease after hematopoietic cell transplantation in adults J.P. Norvell ⁎ Department of Medicine, Division of Digestive Diseases, Emory Transplant Center, Emory University, Atlanta, GA, USA

a b s t r a c t Liver-related complications constitute a large component of the overall morbidity and mortality associated with hematopoietic cell transplantation. Affecting up to 80% of allogeneic HCT recipients, prompt recognition and treatment are essential. The differential diagnosis is broad and is best categorized by time of onset after transplantation. Early complications include drug-induced liver injury, sinusoidal obstruction syndrome, and graftversus-host disease. Late complications include infectious sequelae, cirrhosis, and hepatic malignancies. Patients being considered for hematopoietic cell transplantation should be screened and evaluated for liver-related complications to help improve outcomes. © 2014 Elsevier Inc. All rights reserved.

1. Introduction The indications and use of both autologous and allogeneic hematopoietic cell transplantation (HCT) have rapidly grown and have now become a standard procedure for many patients with hematologic disorders and malignancies. Although the overall outcomes after allogeneic HCT have significantly improved over the past two decades [1], liver-related complications are often encountered after HCT and are a large component of the associated overall morbidity and mortality. Hepatic complications affect nearly 80% of allogeneic HCT recipients and account for up to 15% of transplantation-related mortality (TRM) [2,3]. The differential diagnosis is broad and includes drug toxicity, infectious complications, graft versus host disease (GVHD), sinusoidal obstruction syndrome (SOS), metabolic conditions, and development of neoplastic conditions. The outcome of the transplant is often determined by prompt recognition and management of these complications, and thus it is imperative for the treating clinician to be familiar with the potential complications. For the purposes of this review, these complications are grouped together into categories based on timing of presentation (Fig. 3). Careful assessment and screening of the hepatic function of both donors and recipients of HCT are important to reduce liver-related complications. 2. Early complications 2.1. Jaundice and hepatotoxicity The development of jaundice after HCT is always an ominous sign and is associated with increased non-relapse mortality. An increase in total bilirubin of 4–7 mg/dL from any cause within 100 days of HCT is

⁎ Department of Medicine, Division of Digestive Diseases, Emory Transplant Center, 1365 Clifton Road, NE, Clinic B, Suite 1200, Atlanta, GA 30322, USA. Fax: +1 404 778 2350. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.trre.2014.08.001 0955-470X/© 2014 Elsevier Inc. All rights reserved.

associated with mortality hazard ratio of 6.4 and a 50% non-relapse mortality rate. Patients with bilirubin levels above 10 mg/dL have a dismal 79% non-relapse mortality rate by day +200 [4]. The reason jaundice portends such a poor prognosis is not always obvious, although jaundice is a likely marker for several ominous conditions such as SOS, GVHD, cholestasis of sepsis, and renal failure. Studies have shown a relatively constant correlation between levels of bilirubin and mortality across time despite different underlying diagnoses causing the jaundice, suggesting that the cause of jaundice is not as important in prognosis as its severity [4]. Prophylactic use of ursodiol at 10–15 mg/kg/d has been shown to reduce the frequency of hepatotoxicity, presumably by reducing prolonged cholestasis and the rate of GVHD [5,6]. One of the most common causes of biochemical liver tests after HCT is drug-induced liver injury (DILI). DILI can be caused by both dosedependent and idiosyncratic hepatotoxic mechanisms. The pattern of liver injury is variable and can include hepatocellular injury, autoimmune-like hepatitis, cholestasis, and venous outflow obstruction. Given the number of medications used and their often unpredictable liver injury, attribution to a single drug is often guesswork. When jaundice or increased serum ALT occurs following a round of multi-course treatment, it can be difficult to accurately predict the safety for another round. The most common culprit medications are myeloablative therapy with cyclophosphamide, anti-GVHD medications such as cyclosporine and methotrexate, antifungal agents such as amphotericin and azole antifungals, and antibiotics. Hepatotoxicity is a common complication after conditioning regimens containing cyclophosphamide and total body irradiation (TBI). Metabolism of cyclophosphamide is highly variable and exposure to its toxic metabolites is thought related to the later development SOS, elevation in bilirubin, nonrelapse mortality, and survival [7]. Reduced dosing of cyclophosphamide, limiting the total dose of TBI, and use of alternative conditioning drugs such as fludarabine may reduce hepatotoxicity [8–10]. Drug kinetics may be altered in patients with chronic liver disease, further

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complicating the dosing of chemotherapy with narrow therapeutic ranges [11]; hopefully the future will bring individualized drug dosing based on pharmacogenomics. 2.2. Sinusoidal obstruction syndrome 2.2.1. Definition and clinical presentation Sinusoidal obstruction syndrome is a constellation of clinical and pathologic findings consisting of tender hepatomegaly, renal sodium retention resulting in fluid retention and weight gain, and elevated serum bilirubin that classically develops within 1 month of high-dose myeloablative conditioning therapy and HCT. One of the most feared complications of HCT, it accounts for a significant burden of HCTrelated mortality and severe cases are often fatal. Sinusoidal obstruction syndrome has previously been referred to as “veno-occlusive disease”, although some prominent experts feel the term is inaccurate as the liver injury is initiated by damage to hepatic sinusoids, and the occlusion of the hepatic venules is not essential in its pathogenesis of disease signs and symptoms [12]. The most commonly used diagnostic criteria from the Seattle group are displayed in Table 1 [13]. Hyperbilirubinemia is a sensitive but not specific finding for SOS with a median total bilirubin level of 11.9 mg/dL [12,14]. Additionally, refractory thrombocytopenia as well as respiratory and renal dysfunction may also be observed. Hepatic imaging with ultrasound is useful to identify features supportive of the diagnosis and to rule out other conditions but is rarely diagnostic. Common findings include hepatomegaly, ascites, periportal edema, gallbladder wall thickening, decreased hepatic venous flow, and a hepatic artery resistance index greater than 0.75 [15]. Late radiographic findings may include evidence of portal hypertension, such as an enlarged portal vein diameter, hepatofugal flow, and rarely portal vein thrombosis [14]. Although seldom needed to make the diagnosis, a transjugular liver biopsy with pressure measurements is the most accurate diagnostic test; a hepatic venous pressure gradient above 10 mmHg is highly specific for SOS with a specificity of 91% and positive predictive value of 86% and correlates with a worse prognosis [16]. 2.2.2. Incidence, pathophysiology, and risk factors Sinusoidal obstructive syndrome is caused by toxins in certain conditioning regimens. Thus the incidence is quite variable depending on the composition and intensity of the conditioning regimen with a reported range from zero to over 50% after cyclophosphamide and TBI [17,18]. In the early era of transplantation, all conditioning regimens were myeloablative, with most consisting of cyclophosphamide and TBI with associated high rates of SOS. However the overall incidence of SOS in recent years has dramatically decreased with less toxic and reduced-intensity conditioning regimens, use of peripheral blood stem cells, and improved patient selection. One large recent review found that in the past decade the incidence had declined to 6.5% and the mortality of the once-fatal condition had decreased to 9–14%, depending on the diagnostic criteria [19]. Sinusoidal obstruction syndrome occurs with injury to the hepatic sinusoidal and venular endothelium and is thought to induce a hypercoaguable state by activation of the coagulation cascade. Fibrinogen and factor VIII are deposited within the venular walls and liver sinusoids which are reduced to an edematous concentric subendothelial zone containing fragments of red blood cells and fibrillar material; this causes subsequent fibrotic obliteration of the venular lamina [13,20].

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Progressive occlusion of terminal hepatic venules causes widespread zonal liver disruption and centrilobular hemorrhagic necrosis. Histologic findings typically include dilated sinusoids congested by erythrocytes, and perivenular hepatocyte necrosis (Fig. 1). Late findings include sinusoidal collagen deposits due to activated stellate cells, terminal venule occlusion, and obliteration of sinusoidal blood flow. The risk factors for the development of SOS are due to both pretransplant features as well as factors related to the transplant process such as the conditioning regimen and are displayed in Table 2. No factor alone or in combination explains the observed variability in the odds of developing SOS. While most of the listed factors cannot easily be modified, they can be used to educate both clinicians and patients of the odds and to further avoid other risks and heighten clinical suspicion when appropriate. 2.2.3. Prevention, outcomes, and treatment The prophylaxis and treatment of SOS are aimed at preventing or relieving thrombotic obstruction of hepatic sinusoids and venules, restoring sinusoidal endothelium, and re-establishing balance of the proinflammatory cytokines and procoagulants. Prevention begins with an assessment of the risk of SOS. The clinician can use reducedintensity conditioning therapy, a regimen with lower doses or no cyclophosphamide, and avoid other medications that add risk. Pharmaceutical prophylaxis for SOS has not been effectively studied in clinical trials and its use is variable between transplant centers. Trials have evaluated the use of ursodeoxycholic acid, heparin, glutamine, and fresh frozen plasma. Mild to moderate cases of SOS generally do well and regain liver function without particular treatment other than supportive care. One series found survival at day + 100 for mild and moderate cases to be 91 and 77%, respectively [18]. For the 25–30% of SOS cases that are severe, therapeutic options are limited and outcomes are dismal. Severe cases can be quickly recognized by steep rises in both body weight and total serum bilirubin, ALT values N 750 U/L, hepatic venous pressure gradient N20 mmHg, portal vein thrombosis, and multi-organ failure especially in those requiring hemodialysis and/or mechanical ventilation [14,16,21]. Serum bilirubin and percent of weight gain within 1–2 weeks of HCT have been identified as the most powerful independent predictors of development of severe disease [22]. Treatment of mild to moderate cases focuses on supportive care by maintaining intravascular volume and renal perfusion with sodium restriction and diuretics while transfusing to minimize anemia. Unfortunately there are still no satisfactory therapies for severe cases. Several antithrombotic agents have been studied with mixed results. One agent,

Table 1 Modified Seattle diagnostic criteria for sinusoidal obstruction syndrome [13]. Two or more of the following criteria within 20 days of HCT: • Serum total bilirubin concentration N2 mg/dL • Hepatomegaly or right upper quadrant pain • Acute weight gain due to fluid accumulation of N2% from pre-HCT weight

Fig. 1. Graft-versus-host-disease. In the background of cholestatic hepatocellular degeneration, lymphocytes infiltrate portal tracts where they prominently invade the epithelial layer of bile ducts resulting in ductular epithelial damage and eventual ductular loss (hematoxylin and eosin stain). Figure courtesy of Thomas E. Rogers, MD.

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Table 2 Risk factors for development of sinusoidal obstruction syndrome (SOS). Pre-transplant risk factors: Underlying patient characteristics: older age [91], poor functional status [17] Underlying liver disease: hepatic dysfunction, hepatitis B virus, hepatitis C virus [44], hemachromatosis, jaundice caused by intrahepatic cholestasis [44], cirrhosis [29], extramedullary hematopoiesis with sinusoidal fibrosis [12] Laboratory findings: hypoalbuminemia, hyperbilirubinemia [92], CMV seropositivity [93] Prior history of: pancreatitis, TPN within 30 days of HCT [93], prior SOS from conventional chemotherapy [12], prior myeloablative HCT [12,94], prior abdominal radiation [18] Hematologic disease factors: increased severity of malignancy [92] Transplant-related risk factors: HCT characteristics: allogeneic HCT, unrelated and/or mismatched donor [18] Conditioning regimen: cyclophosphamide 120 mg/kg plus total body irradiation N 14 Gy [18], busulfan with cyclophosphamide, melphalan, gemtuzumab [12] Concomittant drugs during conditioning therapy: itraconazole, sirolimus, norethisterone

defibrotide, has antithrombotic effects, has minimal systemic anticoagulant activity which is an advantage over alteplase and heparin which has also been used for SOS. There are encouraging reports of use of defibrotide including a phase II trial of 149 patients with severe SOS with a survival rate over 40% and low adverse events [23]. Its use remains controversial and obtaining the agent in a timely fashion remains challenging. 2.3. Sepsis-associated cholestasis An important contributor to hyperbilirubinemia, sepsis-associated cholestasis is commonly experienced in the first few weeks after HCT in febrile and neutropenic patients with gut mucosal injury from conditioning regimens. Jaundice is often severe and may persist for weeks. Previously referred to as “cholangitis lenta,” it is associated with infection but can occur in patients with fever alone and in the presence of localized infection in the lungs and soft tissues. Canilicular cholestasis, ventral venous ischemic changes, and dilated non-suppurative ductules are the most common findings on a liver biopsy. Hepatocyte retention of conjugated bilirubin is thought to be mediated by endotoxins, interleukin-6, and TNFα due to infection which directly inhibits intrahepatic biliary secretion [12,24,25]. There is no specific therapy other than supportive management, eliminating the infection, and avoiding exacerbating factors of the cholestasis such as drugs or total parenteral nutrition (TPN).

when donor T cells react to genetically defined proteins on host cells such as human leukocyte antigens (HLAs). The frequency of acute GVHD is directly related to the degree of mismatch between donor and recipient HLA proteins; it ranges from 35 to 45% in recipients of full-matched sibling donor grafts to 60–80% in one-antigen HLAmismatched unrelated donor grafts. A cholestatic condition identical to GVHD can rarely occur after autologous HCT which is clinically and histologically indistinguishable from allogeneic GVHD [26]. Acute GVHD, which develops in up to 70% of allogeneic HCT recipients, has liver involvement in 50% of cases. Liver involvement usually presents in patients with the other typical manifestations of acute GVHD such as the classic maculopapular rash and secretory, voluminous diarrhea [27]. Liver involvement typically follows skin and/or gastrointestinal presentation and is characterized by progressive elevation of all liver function tests; the rise in conjugated bilirubin and alkaline phosphatase are the most common and earliest findings. Additionally severe hypercholesterolemia can occur and is due either to high concentrations of lipoprotein X or low-density lipoprotein but may not be atherogenic [28]. Several presentations of hepatic GVHD have been observed. One common presentation is asymptomatic elevation of serum alanine aminotransferase (ALT) and alkaline phosphatase as isolated laboratory abnormalities without jaundice and is often accompanied by manifestations of GVHD in other organ systems. The second variety is characterized by slowly progressive hyperbilirubinemia and cholestasis as a result of damage to small bile ducts. Finally, a hepatitic-variant of acute GVHD has been described with abrupt elevations of serum aminotransferase enzymes elevated above 10 times the upper limits of normal without preceding signs of hepatic decompensation which often occurs during tapering of immunosuppression or after donor lymphocyte infusion [12,29,30]. This can be difficult to distinguish from other causes of liver dysfunction after HCT such as acute viral hepatitis, SOS, DILI, viral infection, and sepsis. Although liver biopsies are often deferred due to thrombocytopenia early after transplantation, it is characterized by endothelialitis, lymphocytic infiltration of the portal areas, pericholangitis, and bile-duct destruction (Fig. 2). There is recent interest in the use of biomarkers for both diagnosis and as a predictor of treatment response such as suppression of tumorigenicity 2 (ST2) [31]. Chronic GVHD develops in approximately 60% of allograft recipients, and approximately half of these patients will have some involvement of the liver [32]. The same presentation and liver findings occur in both acute and chronic GVHD including the abrupt severe acute hepatitis presentation [30]. Cholestasis develops in 80% of patients with extensive chronic GVHD and a biopsy is reflective of damage to the small

2.4. Ischemic hepatitis Ischemic hepatitis occurs due to inadequate sinusoidal perfusion usually caused by clinically obvious hypotension and hypoxia. Typically the transaminases acutely rise and fall followed by a slow rise in bilirubin; jaundice following an episode is a poor prognostic finding. No specific therapy is indicated other than treatment of the underlying cause and avoidance of other hepatotoxic agents. 3. Early or late complications 3.1. Graft-versus-host disease Acute and chronic GVHD are immunological multisystem disorders that are perhaps the most important complication after allogeneicHCT and remain a source of widespread morbidity and mortality. Acute and chronic variants have classically been divided by the time of onset using a cutoff of 100 days after HCT; however recognition that signs of acute and chronic GVHD may present outside of these classic time cutoffs have led to use of clinical findings instead of a set time period to differentiate acute from chronic GVHD. GVHD arises

Fig. 2. Sinusoidal obstruction syndrome. In the inner parts of hepatic acini, sinusoidal dilatation occurs with endothelial damage along the sinusoids and lining of terminal hepatic vein segments. Fibrin forms in the sinusoidal lumina centrally, and over time, fibrointimal obliteration of the lumina of terminal hepatic veins occurs (trichrome stain). Figure courtesy of Thomas E. Rogers, MD.

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ducts. Liver biopsies are important to exclude other etiologies and variably show lobular hepatitis, chronic persistent hepatitis, and ductopenia with cholestasis [33]. There has been a declining incidence of acute GVHD due to widespread use of prophylactic immunosuppressive [34]. Although its use is controversial, studies have supported 12–15 mg/kg/day of ursodeoxycholic acid (UDCA) as prophylaxis which is well-tolerated. A recent study of 242 HCT recipients randomized to receive UDCA for the first 90 days after HCT had significantly reduced rates of hyperbilirubinemia, severe GVHD, and had significantly improved overall survival after 10 years of follow-up [5]. Once the diagnosis of GVHD has been established and infectious causes excluded, treatment involves immunosuppressive therapy which usually includes steroids with or without a calcineurin inhibitor. Improvement in liver function tests is usually observed within 4 weeks of treatment. However, only 30–50% of patients with hepatic GVHD have resolution of liver abnormalities after initial immunosuppressive treatment, and over half will develop chronic GVHD [24]. Of those with chronic GVHD, 40% have been reported to die without resolution of chronic GVHD [35].

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SOS

DILI

HSV Sepsis associated cholangitis Early GVHD

HBV reactivation

Late GVHD

Iron Overload

0

2

4

6

8

10

12

14

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Months after HCT Fig. 3. Timing of hepatic complications after hematopoietic cell transplantation.

3.2. Infectious complications Infectious complications often involve the liver after HCT and are a major source of morbidity and mortality. The types of infections are related to the degree of immunosuppression and exposures and in general divided into three periods: pre-engraftment (less than 3 weeks), immediate post-engraftment, and late post-engraftment (over 3 months). However, any period of increased immunosuppression, such as during treatment for GVHD, can predispose the host for a variety of pathogens. 3.2.1. Hepatitis B virus Hepatitis B virus (HBV) is one of the most important causes of hepatitis flares after HCT, and screening with a HBV profile prior to HCT is essential to prevent reactivation in the setting of immunosuppression [36]. The risk of reactivation can be as high as 20–50% among HBsAgpositive carriers after HCT. While most cases are asymptomatic, hepatic decompensation can occur with reported mortality ranging from 3 to 60% [37,38]. The risk of HBV reactivation is related to patient factors, presence of HBsAg, and type of immunosuppression. The greatest risk factors for reactivation are treatment with monoclonal anti-CD20 monoclonal antibodies such as rituximab and a high HBV DNA load (N 10 5 copies/mL) [39,40]. Although evidence-based guidelines are still being formulated, antiviral prophylaxis in patients at risk should start prior to immunosuppression and extend for at least 6 months after completion with careful monitoring of HBV parameters and LFTs [36]. Patients with high baseline HBV DNA (N2000 IU/mL) should continue treatment until they reach treatment endpoints as in immunocompetent patients [36]. This strategy prevents HBV reactivation, decreases morbidity and mortality, and interruptions in cancer treatment. Although HBV reactivation can occur in patients that are HBsAg negative but with isolated anti-HBc or even anti-HBc and anti-HBs positive, the occurrence is very rare and there are not enough data at this time to make recommendations regarding routine prophylaxis for these individuals but certainly warrant close monitoring [36,41]. Lamivudine has been shown to be effective prophylaxis [42] although its prolonged use is associated with the emergence of resistant HBV mutants. In patients with prior lamivudine exposure or the need for prolonged therapy, treatment with newer potent nucelos(t)ide analogues such as entecavir is recommended [36]. 3.2.2. Hepatitis C virus Although there is little initial post-HCT morbidity, HCV in HCT survivors has almost always resulted in chronic hepatitis and is the most common cause of cirrhosis after HCT. Studies have shown that HCT recipients with chronic HCV infection have significantly worse nonrelapse mortality, even in patients with normal or minimally elevated

LFTs [43]. Some studies have identified HCV infection with elevated ALT or AST levels as a risk factor for severe SOS [44] and drug-induced liver injury [44] after HCT. Since liver injury in patients with HCV infection is T-cell response dependent, hepatitis is usually only seen after immune reconstitution and symptomatic and fulminant HCV is rarely seen [44,45]. Although antiviral treatment with interferon-based therapy has proved difficult in this patient population due to thrombocytopenia, GVHD, concurrent immunosuppression, and poor viral clearance rates, the recently-approved oral direct-acting antiviral agents for HCV are revolutionizing our ability to effectively treat these patients to prevent long-term sequelae and should decrease HCV-related morbidity and mortality. 3.2.3. Other viral hepatitides: hepatitis E virus, hepatitis G virus, adenovirus Hepatitis E virus (HEV) has become an increasingly acknowledged cause of viral hepatitis. While most cases in immunocompetent patients resolve spontaneously, it has become a recognized source of significant morbidity and mortality in immunocompromised patients. A recent study of 328 HCT recipients found that while there is a relatively low 2.4% incidence of acute HEV, the risk of acute infection developing into chronic HEV infections in these immunocompromised patients was high at 63% [46,47]. Half of the patients died with HEV viremia and ongoing hepatitis and the surviving patients took a median of 6.3 months to achieve viral clearance. Therefore all cases of hepatitis after HCT even in low-endemic countries must raise the question of HEV infection. However the diagnosis remains challenging as the serologies are often misleading and only a few specialized labs process HEV PCR assays. Treatment is mostly supportive although some centers have treated with ribavirin. Hepatitis G virus RNA has been observed in high prevalence in HCT and is associated with prior blood transfusions [48]. However its clinical significance remains uncertain and its role as a contributor to liver dysfunction remains unclear. Studies have demonstrated viral clearance even during chemotherapy but nonetheless can experience exacerbation when subsequently immunosuppressed [49]. Adenovirus infections are becoming increasingly recognized after HCT and represent a very wide spectrum of severity of disease including asymptomatic viremia, gastrointestinal and respiratory disease, hemorrhagic cystitis, and rarely severe disseminated disease which is often fatal [50]. Cidofovir is the agent with the strongest in vitro and in vivo data supporting its use in patients with documented adenovirus disease, although it has significant toxicity risk including nephrotoxicity. Patients with significant end-organ damage (other than hemorrhagic cystitis) are likely to benefit to from treatment with cidofovir; data are too limited to recommend universal prophylaxis [51].

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3.2.4. Herpesviridae: HSV, CMV, EBV, VZV, HHV-6 Hepatic herpesvirus infections are now rare due to acyclovir prophylaxis for herpes simplex (HSV) and varicella zoster viruses (VZV) during the immediate post-HCT period. Almost all HSV infections in HCT recipients are caused by viral reactivation. With a median time to onset of 2–3 weeks after HCT [52], herpes hepatitis is a severe infection with high mortality of over 70%. Prompt recognition and diagnosis with liver biopsy and PCR are essential as herpes hepatitis is effectively treated with early initiation of acyclovir. Herpes hepatitis commonly presents with fever, coagulopathy, encephalopathy, and ALT and AST over 500 U/L; the classic vesicular rash is noted in less than half of the patients [53]. Patients with VZV hepatitis can present similarly to HSV hepatitis with abdominal pain, aminotransferase elevation, fever, also often lack the characteristic rash, and is effectively treated with early intravenous acyclovir [54]. Prophylactic acyclovir has been effective and some centers are extending low-dose prophylaxis for over a year after HCT [55]. While use of the live attenuated VZV vaccine in immunocompromised patients is contraindicated, there are recent reports of its safe use in patients over 2 years after HCT not on immunosuppression [56]. Clinically significant hepatitis due to Epstein–Barr virus (EBV) alone after HCT is uncommon and rarely severe. When present, it is usually accompanied by other clinical signs such as lymphadenopathy and splenomegaly. Elevated serum EBV levels may predict the development of posttransplant lymphoproliferative disorder (PTLD) as described in Section 4.5 on hepatic malignancy. The clinical presentation of cytomegalovirus (CMV) hepatitis after HCT is variable, ranging from asymptomatic viremia to symptoms due to tissue-invasive disease. Risk factors for CMV after HCT include lymphocyte depletion therapy, donor-positive/ recipient-negative serologic mismatching, and transfusions without CMV reduction or leukocyte depletion [57,58]. Widespread antiviral prophylaxis after HCT has effectively reduced the incidence of CMV infection; newly diagnosed infections are treated with intravenous ganciclovir followed by long-term prophylaxis. Human herpesvirus-6 (HHV-6) has become recognized in recent years to have reactivation in over 40% of HCT recipients within 2 to 4 weeks after HCT. While there have been reports of fulminant liver failure after HCT due to HHV-6 (presenting with simultaneous HHV-6 encephalitis), most patients with HHV-6 viremia do not develop clinically significant disease. [59,60].

3.2.5. Fungal hepatic infections Due to intense immunosuppression regimens, HCT recipients are at risk of disseminated fungal infections which can infect the liver. The most common hepatic fungal organisms are Candida and Aspergillus species although other mycoses (such as Cryptococcus) and endemic mycoses (histoplasmosis, blastomycosis, and coccidiomycosis) have been observed after HCT. Hepatic candidal infections typically present by multiple liver abscesses and granulomas while Aspergillus species can invade local blood vessels resulting in hepatic infarction [58]. In addition to imaging, tissue culture, and histologic examination, assays can be helpful such as serum β-D-glucan assay for Candida infection and galactomomannan assay for mold infection [61,62]. Mucormycosis is a devastating invasive fungal disease which often occurs relatively late (over 3 months) after HCT with variable reports of incidence estimated between 0.1–2% of HCT recipients; the highest incidence is in patients with GVHD [63]. Widespread prophylaxis has effectively reduced the rate of fungal abscesses and associated morbidity and mortality after HCT; one study found prophylactic fluconazole reduced hepatic fungal infections from 16 to 3% [64]. Given prophylaxis use, most fungi present in the liver are likely to be molds or resistant Candida species requiring prolonged therapy and may present with fever, tender hepatomegaly and increased alkaline phosphatase levels. Some experts recommend cautioning patients prior to full immune reconstitution to avoid ingestion of mold such as cheese or herbal remedies due to the concern of introduction of yeast to the portal circulation [24,65].

4. Late complications As overall survival after HCT continues to improve, there has been increased recognition of morbidity and mortality associated to longterm complications of HCT. The overall prevalence of chronic liver disease in recipients who had survived over 2 years after HCT has been estimated to be 58% [66].

4.1. Iron overload Secondary iron overload is frequently observed in long-term HCT survivors due to multiple red blood cell transfusions and dyserythropoiesis leading to increased iron absorption in the intestine. Iron overload is particularly severe in patients who have undergone HCT with underlying thalassemia. Data show that elevated pretransplant serum ferritin levels are significantly associated with a lower overall survival rate and higher incidence of treatment-related complications [67,68]. While there may be an increased incidence of chronic liver disease and sinusoidal obstruction syndrome in HCT survivors [69], the most concerning consequences of extreme iron overload in HCT survivors are cardiac, pituitary, and pancreatic dysfunction [29]. Although observed in approximately 50% of HCT survivors [66], hepatic iron overload is rarely the single cause of serious liver disease [29]. In cases in which hepatic iron overload is felt to be the cause of liver disease, mobilization of iron by phlebotomy or chelation therapy has been shown to improve both enzyme levels and liver histology [66,70]. Treatment recommendations are extrapolated from data on thalassemia patients. Phlebotomy is indicated when liver iron content is 7000–15,000 μg/g dry weight; combination therapy with phlebotomy and chelation if the liver iron content is greater than 15,000 μg/g dry weight [12,71]. Accurate non-invasive quantification of hepatic iron levels can be problematic. Elevated serum ferritin levels are common in other liver-related conditions such as GVHD and viral hepatitis but may not be reflective of hepatic tissue iron stores. Although there is no accurate serum or plasma marker to accurately monitor body iron overload, iron-specific quantitative magnetic resonance imaging has been shown to accurately measure iron, not only in the liver but also in other relevant organs such as the heart and pancreas [72]. 4.2. Nodular regenerative hyperplasia Patients who receive high-dose chemotherapy rarely develop idiopathic hepatic nodules, or nodular regenerative hyperplasia (NRH), that can lead to portal hypertension without fibrosis or liver dysfunction. The condition is usually clinically silent unless portal hypertension develops, and its management is similar to that of cirrhosis [12,58]. Although its development is thought to be rare, one retrospective study reported a rate of 22.5% after HCT [73] and there is concern that it may be misdiagnosed as VOD, GVHD, drug toxicity, or cirrhosis. Its pathogenesis is not well understood and probably results from sinusoidal lesions causing local hypoperfusion with regenerative hyperplasia in the normally perfused surrounding areas; no particular cause or myeloablative agent is known to be responsible [74,75].

4.3. Focal nodular hyperplasia An increased rate of focal nodular hyperplasia (FNH) lesions has been described in HCT survivors. One prospective study including 138 HCT patients found 12.3% of the patients developed FNH, a rate significantly higher than the general population. All patients were children at the time of HCT and had a median delay of 6.4 years (range: 2.2–13.6 years) until development. The presumed cause is due to sinusoidal injury due to myeloablative condition regimens [76].

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4.4. Cirrhosis Long-term survivors of HCT have multiple risk factors for development of chronic liver disease and ultimately cirrhosis, including chronic hepatitis B and C viral infection, chronic GVHD, and iron overload. HCV is the most common cause of cirrhosis in HCT recipients, found in 81% of cases [77]. An accelerated rate of progression to cirrhosis has been described in HCT recipients with chronic hepatitis C [78,79] with and estimated incidence of cirrhosis to be as high as 24% after 20 years of survival after HCT [78]. In 2004 a patient with decompensated cirrhosis due to HCV infection underwent a living-donor liver transplantation from the same original hematopoietic cell donor which resulted in an excellent outcome with complete withdrawal of immunosuppression after 6 months without evidence of “isograft” rejection [80]. In addition to hepatitis C virus, there are other recognized etiologies of cirrhosis in long-term HCT survivors. Nonalcoholic steatohepatitis is an increasing cause of cirrhosis and is reported to be the cause of cirrhosis in 5% of HCT recipients; risk factors associated with the development are likely type 2 diabetes, obesity, and long-term steroid use and total parenteral nutrition [66]. While hepatic GVHD is not known as a fibrogenic process, cirrhosis has been rarely reported as a result of chronic hepatic GVHD [81]. Liver transplantation for cirrhosis secondary to chronic hepatic GVHD been performed and one study of over 70 patients described impressive 1- and 5-year actuarial patient survival rates of 72.4 and 62.9%, respectively, without any allograft re-transplantation or patient deaths due to recurrent hepatic GVHD [82]. 4.5. Hepatic malignancies HCT recipients that survive over 10 years have been shown to have 8.3 times higher risk than expected to develop new solid cancers relative to the general population, likely related to immune suppression and as a sequela of treatment with TBI and high-dose chemotherapy [83]. One study found a 28-fold increase in the development of hepatocellular carcinoma after HCT compared to expected with age under 34 at time of HCT and hepatitis C virus as risk factors [84]. EBV-mediated PTLD usually occurs in the first year after allogeneic HCT with half of the cases involving the liver, resulting in hepatosplenomegaly and increased alkaline phosphatase. The rate has decreased due to EBV surveillance and preemptive treatment [85]. 4.6. Biliary complications Long-term HCT survivors have an increased incidence of gallstones and biliary complications, likely related to formation of biliary sludge. Formation of calcium bilirubinate micoliths resulting in biliary sludge is common after myeloablative conditioning therapy and can be identified by sonogram in 70 and 100% on autopsy of HCT survivors [86,87]. Passage of biliary sludge can cause epigastric pain, nausea, and elevation of liver function tests although endoscopic sphincterotomy is rarely indicated [24]. Microliths serve to develop mixed pigment and cholesterol gallstones which may be exacerbated by calcineurin inhibitor use and can result in choledocholithiasis and biliary pancreatitis. 5. Evaluation of pre-transplant liver conditions Patient selection and screening are essential because underlying liver disease is common in the population of patients being considered for HCT, and liver-related morbidity and mortality largely affect postHCT outcomes. Improved patient selection is likely an important reason for improved post-transplant survival despite older and more seriously ill patients [1]. Patients referred for HCT should undergo careful evaluation with history and physical exam, labs, and imaging and by focusing on identification of patients at risk, prior drug-related liver injury, and hepatic infections. Patients with clearly decompensated cirrhosis are likely not candidates for any anti-cancer therapies; compensated

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cirrhotics are at some risk for liver injury from regimens that cause direct liver injury [45]. Patients with recent liver dysfunction following chemotherapy or radiation prior to HCT are at risk for worse post-HCT outcomes [45]. It is essential to identify patients at high-risk of hepatic complications such as hepatic decompensation or increased risk of SOS after HCT. Recent treatment with imatinib can lead to hepatic fibrosis after resolution of acute hepatocellular necrosis [88]. The underlying disease may also affect outcomes; HCT performed for myelofibrosis has been shown to have significantly elevated risk of hepatotoxicity in the first 6 weeks, perhaps to previously silent portal hypertension in these patients due to extramedullary hematopoiesis causing stimulation of stellate cells resulting in sinusoidal fibrosis [89]. Pre-transplant levels of gamma-glutamyl transpeptidase (GGT) and bilirubin levels are strongly associated with worse post-HCT mortality but pre-transplant levels of alkaline phosphatase, ALT, and AST have no apparent impact on post-HCT outcomes [90]. Prevention of SOS may be more effective than treating it and attention must be paid to patients at high-risk. As many as 15–40% of patients treated with myeloablative conditioning regimen within 3 months of receiving gemtuzumab ozogamicin will develop SOS post-HCT [91]. Assessment of underlying hepatic infection is essential prior to proceeding with HCT. The recommendations for pre-HCT screening and evaluation for HBV and HCV are discussed above in Sections 3.2.1 and 3.2.2. As our ability to treat and manage these viruses improve, there are some recent data showing no significant differences in liverrelated morbidity or survival in donor or recipient HBV or HCV status after related donor allogeneic HCT [92]. Therefore, exposure or infection to HBV or HCV prior to HCT should not itself be considered an absolute contraindication to HCT. Finally, identification of hepatic fungal infection should be sought in pre-HCT patients with pain, imaging with magnetic resonance imaging, and suggestive serum tests. 6. Conclusion It is essential for the treating clinician to be familiar with the many possible hepatic complications after HCT since it is a major source of morbidity and mortality in this special population. Prevention of complications by improved patient screening, antimicrobial prophylaxis, and appropriate alterations in conditioning therapy has effective decreased hepatic complications. Early recognition and swift therapy are essential to continue to improve outcomes. The author does not have any financial relationships in the subject matter or materials discussed in this article. References [1] Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010;363:2091–101. [2] Locasciulli A, Alberti A, de Bock R, et al. Impact of liver disease and hepatitis infections on allogeneic bone marrow transplantation in Europe: a survey from the European Bone Marrow Transplantation (EBMT) Group–Infectious Diseases Working Party. Bone Marrow Transplant 1994;14:833–7. [3] McDonald GB, Shulman HM, Wolford JL, Spencer GD. Liver disease after human marrow transplantation. Semin Liver Dis 1987;7:210–29. [4] Gooley TA, Rajvanshi P, Schoch HG, McDonald GB. Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation. Hepatology 2005;41:345–52. [5] Ruutu T, Juvonen E, Remberger M, et al. Improved survival with ursodeoxycholic Acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study. Biol Blood Marrow Transplant 2014;20:135–8. [6] Essell JH, Schroeder MT, Harman GS, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:975–81. [7] McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003;101:2043–8. [8] Bornhauser M, Storer B, Slattery JT, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood 2003;102: 820–6.

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