Lymphoma and Hematological Conditions: I. Lymphoma and Liver Complications of Bone Marrow Transplant

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1 REVIEW Lymphoma and Hematological Conditions: I. Lymphoma and Liver Complications of Bone Marrow Transplant Oliver Tavabie, M.R.C.P., and Abid R. Suddle, M.D. Liver abnormalities are frequently seen in patients with hematological diseases, because of: (1) liver involvement by the hematological disorder, (2) as a result of measures used to treat the hematological disorder, or (3) a concurrent or independent disease. On occasion, clinical liver disease is the first manifestation of a primary hematological condition, for example, cholestasis in Hodgkin s disease. 1 This review summarizes the important hepatic abnormalities found in the lymphomas and liver complications related to bone marrow transplantation. initial manifestation but is relatively frequent in late stages, usually resulting from either extensive infiltration by tumor or biliary obstruction caused by hilar lymphadenopathy. A few patients exhibit a syndrome of idiopathic intrahepatic cholestasis, for which a paraneoplastic hormonal effect has been suggested. Hodgkin s disease should be among the differential diagnoses when liver biopsy demonstrates an unexplained bland cholestasis. In some patients with cholestasis, ductopenia unassociated with tumour infiltration is demonstrated. 1,2 HODGKIN S DISEASE The prevalence rate of liver involvement in Hodgkin s disease varies widely: from 5% of liver biopsies obtained at diagnosis to as high as 60% in autopsy series. 1,2 Patients with liver involvement often remain asymptomatic. An enlarged liver is a common finding but does not necessarily infer hepatic infiltration. Jaundice is rare as an NON-HODGKIN S LYMPHOMAS Liver involvement in non-hodgkin s lymphoma is more common than in Hodgkin s disease: Liver biopsies obtained at diagnosis show infiltration in about 15% of cases. Primary lymphomas of the liver account for 0.4% of extranodal lymphomas; approximately 20% of these patients have chronic viral hepatitis. 3,4 Abbreviations:, acute graft versus host disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase;, chronic graft versus host disease; CMV, cytomegalovirus; GVHD, graft versus host disease; HCV, hepatitis C virus; HSCT, hematopoietic stem cell transplantation; HVPG, hepatic venous pressure gradient; PAI-1, plasminogen activator inhibitor type 1; PCR, polymerase chain reaction; SOS, sinusoidal obstruction syndrome; TPN, total parenteral nutrition. From the Institute of Liver Studies, King s College Hospital, London, SE5 9RS, United Kingdom. Potential conflict of interest: Nothing to report. Received 8 January 2016; accepted 4 May 2016 View this article online at wileyonlinelibrary.com VC 2016 by the American Association for the Study of Liver Diseases 1 CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD

2 Liver infiltration in non-hodgkin s lymphoma is often clinically silent. Mild-to-moderate elevation in serum alkaline phosphatase (ALP) may be present. Jaundice is uncommon; when it occurs it is more likely as a consequence of extrahepatic biliary obstruction by nodal disease as opposed to hepatic infiltration. Rarely, jaundice with acute liver failure is the first clinical manifestation of lymphoma. This diagnosis must be considered in the patient with acute liver failure and an enlarged liver, an infiltrative pattern of abnormality in liver function tests (predominant increase in ALP as opposed to serum transaminases), and lactic acidosis. This clinical phenotype of acute liver failure is one of the few in which liver biopsy is mandated. Primary lymphoma of the liver presents with abdominal pain and B-type symptoms. There is a consistent increase in ALP, with a less consistent abnormality of transaminases. Jaundice and ascites are rare. Findings on liver-specific imaging are nonspecific. Biopsy is required for diagnosis. HEPATIC COMPLICATIONS RELATED TO BONE MARROW TRANSPLANT Liver dysfunction after hematopoietic stem cell transplantation (HSCT) is common, and differentiating between the potential causes (Table 1) can be challenging. 5-7 In assessing the patient with liver dysfunction in this context, certain clinical, laboratory, and imaging data can be helpful in the diagnostic evaluation (Table 2). Liver biopsy may be required to make a definitive diagnosis. This intervention is associated with a high risk for bleeding during the cytopenic phase after HSCT, and the transjugular approach should be considered. Biopsy of the liver is not usually required when liver function test abnormalities consistent with graft versus host disease (GVHD) are associated with skin or intestinal involvement confirmed by histology, or if diagnostic criteria for sinusoidal obstruction syndrome (SOS) are met. GVHD GVHD results from an inflammatory response of donor immunocompetent cells when introduced into a foreign environment. HSCT is a clinical context associated with a high risk for development of GVHD. Incidence, timing, and severity of GVHD are very variable depending on several patient-, donor-, and transplant-related variables. The term acute graft versus host disease () TABLE 1. CAUSES FOR LIVER DYSFUNCTION AFTER HSCT Drug toxicity SOS Parenteral nutrition Biliary sludge syndrome Bacterial, fungal, and viral infections of the liver Cholecystitis Nodular regenerative hyperplasia Extrahepatic biliary obstruction describes a distinct syndrome of dermatitis, hepatitis, and enteritis, usually occurring within the first 100 days after HSCT. Chronic graft versus host disease () describes a more polymorphic syndrome resembling an autoimmune disease that usually develops after day 100. Liver is characterized by a gradual increase in bilirubin and ALP up to 20 times the upper limit of normal and transaminases up to 10 times the upper limit of normal. Usually, the increase in bilirubin is of a greater magnitude than the increase in enzymes. The most usual manifestation of dermal is a maculopapular exanthema. Gastrointestinal manifestations can include diarrhea, abdominal pain, bleeding, and ileus if the distal bowel is involved, and anorexia and dyspepsia if the more proximal bowel is involved. The majority of patients will have had prior. Several organs can be affected, with the skin and liver most commonly affected. Liver involvement is present in 80% of patients. The most characteristic manifestation is a slowly progressive cholestasis. A hepatitic variant has been described. In addition to intensification of immunosuppression for extensive forms of, ursodeoxycholic acid can be helpful in treating hepatic. SINUSOIDAL OBSTRUCTION SYNDROME (PREVIOUSLY VENO-OCCLUSIVE DISEASE) SOS is characterized by initial, acute damage to endothelial cells; this is followed by their detachment and 2 CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD

3 TABLE 2. EVALUATION OF THE DIFFERENTIAL DIAGNOSIS OF LIVER DYSFUNCTION AFTER HSCT 5 Data Evaluated Finding Consider Day of onset (day 0 5 day of HSCT) Before day 15 Day 15 to engraftment After engraftment (days 115 to 150) Days 160 to 1100 Drug toxicity Severe SOS Mild-to-moderate SOS Hemolysis TPN/biliary sludge Early After day 1100 NRH Biliary obstruction Clinical features Weight gain, edema, ascites, painful hepatomegaly SOS Fever during neutropenia Prolonged TPN TPN/sludge Skin rash, diarrhea Persistent fever despite antibiotics and neutrophil recovery Skin lesions, Sicca syndrome Laboratory investigations Increased PAI-1 SOS " Bilirubin, normal ALP Cyclosporine toxicity """ Bilirubin, "ALP ""Bilirubin, " ALP GVHD Cholestasis 1 " ALT/AST Viral hepatitis Hepatitic form of GVHD Positive blood cultures CMV DNA positive by PCR CMV infection Imaging Ascites, hepatomegaly, reverse flow in portal vein VOD Nodules Fungal infection NRH Other infections Hemodynamic data HVPG >15 mm Hg Severe SOS Chronic liver disease HVPG >10 mm Hg SOS Chronic liver disease HVPG <10 mm Hg Not SOS Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; HVPG, hepatic venous pressure gradient; PAI-1, plasminogen activator inhibitor type 1; PCR, polymerase chain reaction; TPN, total parenteral nutrition. embolization into the central area of the lobule where they cause a postsinusoidal outflow block. Myeloablative therapy for HSCT has become the major cause of SOS. Depending on the myeloablative conditioning regimen, the incidence rate varies from 0% to 50%; prevalence is highest with regimens of cyclophosphamide and total body irradiation. Risk factors associated with SOS are outlined in Table 3. 3 CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD

4 TABLE 3. RISK FACTORS FOR SOS Patient Related Age Malignant disease Disease relapse Status of the liver (e.g., cirrhosis, fibrosis) High AST/ALT ratio Previous liver radiation Chronic viral hepatitis, especially HCV Iron overload Abbreviation: HCV, hepatitis C virus. SOS usually occurs early after conditioning (within the first 21 days), but cases have been reported after day 30. Clinically, the diagnosis is suspected when jaundice, painful hepatomegaly, and unexplained weight gain, with or without ascites, occur soon after HSCT. Diagnostic criteria have been formulated (Table 4). The differentiation between SOS and can be difficult, especially because they can coexist. The presence of ascites and fluid retention, and absence of evidence for GVHD affecting other organs, helps exclude GVHD. Severe SOS is associated with high morbidity and mortality. Management includes supportive measures for fluid overload. Defibrotide, a mixture of oligonucleotides derived from porcine intestinal mucosa, is one of the most promising drug treatments for SOS. It is approved in the European Union, but not yet in the United States, for the treatment of severe SOS in patients undergoing stem cell transplantation. Two British societies also recommend the drug as prophylaxis against SOS. 8,9 SUMMARY Transplant Related Allogenic transplant Donor type Bone marrow--derived stem cell origin Fever in conditioning Second transplant Abdominal irradiation Prior treatment with gemtuzumab Conditioning regimen Hepatotoxic drugs Assessing liver dysfunction in the context of lymphoma or after HSCT requires an understanding of the pathophysiology of the underlying hematological disorder and measures used to treat the condition. Investigation and management are best coordinated in a multidisciplinary manner with input from hepatology, hematology, radiology, and pathology. It is particularly important for the hepatologist to be cognizant of the TABLE 4. DIAGNOSTIC CRITERIA FOR SOS Original Seattle criteria Presentation before day 30 post-hsct of two or more of the following: Jaundice Hepatomegaly and right upper quadrant pain Ascites 6 unexplained weight gain Modified Seattle criteria Presentation before day 20 post-hsct of two of the following: Bilirubin >2 mg/dl (34 lmol/l) Hepatomegaly or right upper quadrant pain of liver origin Unexplained weight gain of >2% baseline caused by fluid accumulation Baltimore criteria Bilirubin 2 mg/dl (34 lmol/l) before day 21 post-hsct and at least two of the following: Hepatomegaly Ascites Weight gain 5% from baseline possibility of lymphoma causing acute liver failure if the liver is enlarged and to have a logical, consistent approach to investigation of abnormal liver function after bone marrow transplant. 10 CORRESPONDENCE Abid R. Suddle, M.D., Institute of Liver Studies, King s College Hospital, London, SE5 9RS United Kingdom. abid.suddle@nhs.net REFERENCES 1) Liberman DA. Intrahepatic cholestasis due to Hodgkin s disease. An elusive diagnosis. J Clin Gastroenterol 1986;8: ) Colby TV, Hoppe RT, Warnke RA. Hodgkin s disease: a clinicopathologic study of 659 cases. Cancer 1982;49: ) Santos ES, Raez LE, Salvatierra J, Morgensztern D, Shanmugan N, et al. Primary hepatic non-hodgkin s lymphomas: case report and review of the literature. Am J Gastroenterol 2003;98: ) Bronowicki JP, Bineau C Feugier P, et al. Primary lymphoma of the liver: clinical-pathological features and relationship with HCV patients in French patients. Hepatology 2003;37: ) Carreras E, Martnez C, Bruguera M. The liver in graft-vs.-host disease. In: Textbook of Hepatology. Oxford, UK: Blackwell; 2007: ) Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol 2003;78: ) Carreras E. Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol 2000;64: CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD

5 8) Richardson PG, Corbacioglu S, Ho VT, Kernan NA, Lehmann L, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf 2013; 12: ) Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives---a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2015;50: ) Flowers MED, Vogelsang GB. Clinical manifestations and natural history. In: Vogelsang GB, Pavletic SZ, eds. Chronic Graft Versus Host Disease: Interdisciplinary Management. New York, NY: Cambridge University Press; 2009: CLINICAL LIVER DISEASE, VOL 8, NO 1, JULY 2016 An Official Learning Resource of AASLD