REVIEW Abnormal Liver Tests After Liver Transplantation Andrew Fedoravicius, M.D., and Michael Charlton, M.D., F.R.C.P. GENERAL CONSIDERATIONS After liver transplantation (LTx), nearly every recipient will have an elevation of injury tests (aminotransferases and/or bilirubin and alkaline phosphatase). The timing, magnitude, and context of abnormal liver tests are always important considerations in determining the likely cause (Table 1). Because of the risk, implications, and high degree of variability in clinical and laboratory presentation of vascular thrombosis of the allograft, particularly of the hepatic artery, we recommend obtaining an abdominal ultrasound with Doppler examination of the hepatic and portal vessels as a routine component of evaluating clinical and liver test changes at any time point after LTx, particularly in the early postoperative period. PRIMARY GRAFT INJURY Some degree of elevated liver chemistry tests secondary to organ preservation injury, through combined cold and warm ischemia, is nearly ubiquitous and occurs immediately after LTx. Abnormal liver tests secondary to preservation injury are typically hepatocellular in pattern initially. Severity can range from mild transaminase elevations to a pattern akin to fulminant hepatic failure, with coagulopathy and encephalopathy, designated as primary nonfunction (PNF). Prepreservation injury can also occur because of donor liver disease, for example, caused by viral hepatitis or cardiac arrest with preprocurement hypotension. In donation after cardiac death, preprocurement warm ischemia tends to be more profound. In mild and moderately severe preservation injury, aspartate aminotransferase (AST) and alanine aminotransferase should peak within 48 hours of LTx, followed by consistent decline. Canalicular enzymes (alkaline Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; ESBL, extended-spectrum beta-lactamase producing organism; HAT, hepatic artery thrombosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HHV, human herpes virus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; LTx, liver transplantation; MRSA, methicillin-resistant Staphylococcus aureus; PML, progressive multifocal leukoencephalopathy; PNF, primary nonfunction; PTLD, posttransplant lymphoproliferative disorder; VRE, vancomycin-resistant enterococcus. From the Transplant Center, Intermountain Medical Center, Salt Lake City, UT 84107. Potential conflict of interest: Nothing to report. Received 6 November 2015; accepted 8 February 2016 View this article online at wileyonlinelibrary.com VC 2016 by the American Association for the Study of Liver Diseases 73 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
TABLE 1. CAUSES OF ELEVATED LIVER BIOCHEMISTRIES AFTER LIVER TRANSPLANTATION Primary Parenchymal Immune Rejection (acute, chronic, antibody mediated) Recurrence of autoimmune hepatitis, primary biliary cholangiopathy, primary sclerosing cholangitis Nonimmune Preservation injury, from mild to primary nonfunction Primary infection, including procedure related, donor derived, recipient derived, and nosocomial Recurrent infection, for example, hepatitis B and C Drug induced, for example, secondary to antibiotics or immunosuppression Recurrence of primary liver disease, for example, alcohol and nonalcoholic steatohepatitis Biliary Anastomotic stricture Ischemic-type nonanastomotic strictures Bile leak (intrahepatic or perihepatic) Choledocholithiasis Biliary casts, for example, following donation after cardiac death Other Causes Hemolysis Gilbert syndrome Space-occupying lesions, for example, posttransplant lymphoproliferative disease, recurrence of hepatocellular carcinoma, or cholangiocarcinoma Diabetic hepatopathy PNF occurs in approximately 2% to 5% of adult recipients. When PNF arises in a patient with a percutaneous biliary drain, bile flow is either absent or consists of colorless or very pale yellow bile. The prognosis is typically poor, most commonly leading to mortality or retransplantation. For the purposes of being designated as status 1 (highest priority) for relisting, PNF is technically defined by AST greater than 3000 within 7 days of LTx and INR 2.5, and/or acidosis (arterial ph 7.3 or venous ph 7.25, or lactate 4 mmol/l). A diagnosis of preservation injury or PNF requires that hepatic artery, portal venous, hepatic venous, and caval outflow abnormalities have all been ruled out. FIG 1 HAT is demonstrated on this angiogram obtained on the first postoperative week after LTx. The presentation was with severe, sudden elevation in aminotransferases with duplex ultrasound failing to identify a hepatic artery signal. phosphatase, gamma-glutamyltransferase, bilirubin) are typically slower to rise and fall than aminotransferases, sometimes peaking at days 7 to 14. 1 Risk factors for PNF include donor quality (affected by donor age, steatosis >30%, hypotension, small for size allograft, and possibly hypernatremia, among others) and prolonged cold (>12 hours) and warm (>90 minutes) ischemia time. 2 VASCULAR Hepatic artery thrombosis (HAT; Figure 1) occurs in 2% to 6% of recipients, with arterial reconstruction, delayed 74 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
FIG 2 (A) Hematoxylin and eosin stain of liver biopsy obtained on the seventh postoperative day. Cholangitis with intraductular macrophage and endotheliitis on a background of predominantly lymphocytic portal hepatitis are shown. (B) Hematoxylin and eosin stain of liver biopsy obtained on forty-second postoperative week. In addition to lymphocytic portal hepatitis, arteriolar and venular inflammation is shown with arteriolar fibrosis and intraluminal foam cell changes. Bile ducts are absent. 75 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
Hepatic vein stenosis/vena caval stenosis can result from technical complications at the anastomosis or from rotation of the liver graft. Presentation is frequently characterized by manifestations of outflow obstruction. Surgical reconstruction and/or venous stent placement with subsequent anticoagulation are frequently required. 3 IMMUNE-MEDIATED GRAFT DYSFUNCTION: REJECTION FIG 3 (A) Extravasation of contrast material is shown in the region of the choledochocholedochostomy (duct-to-duct) anastomosis on endoscopic retrograde cholangiopancreatography. (B) Anastomotic duct stricture after liver transplant. arterial reperfusion, aortic conduit use, multiple anastomoses, and pediatric recipients all being risk factors for HAT. HAT may present with any biochemical profile of abnormal liver tests but is more likely to present with profound elevation of aminotransferases in the early postoperative period. Initial investigation for suspicion of HAT is with duplex ultrasound, with immediate angiogram or surgical exploration being required when suspicion of HAT is high. In the early postoperative period this requires urgent relisting for transplant. Patients with HAT in a transplanted liver within 7 days of implantation, with evidence of severe liver injury as defined by AST greater than 3000 and INR 2.5, and/or acidosis (arterial ph 7.3 or venous ph 7.25, or lactate 4 mmol/l), are granted status 1. Candidates with HAT in a transplanted liver within 14 days of implantation not meeting the earlier criteria will be listed at a Model for End-Stage Liver Disease score of 40. Later HATs receive their laboratory-based Model for End-Stage Liver Disease score. Portal vein thrombosis can present similarly to HAT with respect to liver injury tests and has similar prognostic significance. Patients who develop portal vein thrombosis within 7 days of transplantation who meet criteria for PNF as described in the preceding section can be relisted for LTx as status 1. Acute cellular rejection (ACR; Figure 2A) severe enough to require treatment affects about one in four recipients, most common mostly occurring within 90 days of LTx, usually before the end of the first postoperative month. Patients with a history of immune-mediated liver disease, for example, autoimmune hepatitis, are at relatively greater risk for ACR. Early acute rejection episodes do not adversely affect graft or patient survival. Late cellular rejection episodes are often associated with low blood immunosuppression levels and are associated with reduced graft survival. Some degree of cholestasis is nearly ubiquitous in acute and chronic rejection, but rejection can present with any pattern of biochemical abnormality. Chronic rejection tends to be more cholestatic biochemically and is characterized by eventual arteriopathy and loss of bile ducts (Figure 2B). The diagnosis of rejection is histological, with biopsies typically obtained after a duplex ultrasound. Because causes other than rejection can present in an identical biochemical fashion, for example, viral hepatitis, empirical treatment of rejection is discouraged. Neither the serum biochemical profile nor immunosuppression drug levels are useful in predicting the presence or severity of rejection. 4,5 BILIARY COMPLICATIONS Bile Leaks Biliary complications affect 5% to 25% of recipients. Bile leaks occur most commonly in the first month after LTx (Figure 3A). Presentation varies from asymptomatic to severe abdominal pain with elevations in bilirubin and other liver test abnormalities. Any biliary leak can result in sepsis. Clinically significant bile leaks typically produce abdominal fluid collections. Suspected bile leaks should be evaluated with cross-sectional imaging and cholangiography (percutaneous or endoscopic as appropriate based on anastomosis type/anatomy). Management approaches include bile duct decompression and drainage of biloma. The diagnostic role of radionucleotide imaging (e.g., hepatobiliary iminodiacetic acid scan) is limited by sensitivity for smaller leaks. 76 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
TABLE 2. INFECTIOUS CAUSES OF ELEVATED LIVER BIOCHEMISTRIES AFTER LIVER TRANSPLANTATION <1 Month 1-6 Months >6 Months Transplant Procedure Related Infected intra-abdominal or intrahepatic fluid collections Infected intra-abdominal or intrahepatic fluid collections Biliary strictures with cholangitis with routine bacterial or and/or and/or VRE, MRSA, or fungal infections Biliary strictures with cholangitis caused by routine or Biliary strictures with cholangitis with routine bacterial or resistant bacteria, for example, MRSA, VRE, ESBL, or antimicrobial-resistant organisms, for example, Candida infections VRE, MRSA, ESBL, or fungal species infections Donor Derived LCMV, human immunodeficiency virus, West Nile virus, HCV, HBV, and CMV HCV, HBV, and CMV HCV, HBV, CMV, HSV, EBV Recipient, Nosocomial, or Community Derived Clostridium difficile, HBV, HCV, CMV, candidal fungal Pneumocystis, HCV, HBV, CMV, candidal fungal species, HCV, HBV, HSV, HEV, CMV, adenovirus, HHV 6 and 7, species, HSV, EBV, adenovirus, HHV, aspergillus, Pseudomonas, Listeria, HEV, EBV, adenovirus, HHV, aspergillus, histoplasmosis, blastomycosis, Cryptococcus, histoplasmosis, Pseudomonas, blastomycosis, aspergillus, histoplasmosis, blastomycosis, and PML, lymphoma (PTLD) and Cryptococcus Cryptococcus Abbreviations: ESBL, extended-spectrum beta-lactamase--producing organism; HBV, hepatitis B virus; HEV, hepatitis E virus; HHV, human herpes virus; LCMV, lymphocytic choriomeningitis virus; MRSA, methicillin-resistant Staphylococcus aureus; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disorder; VRE, vancomycin-resistant enterococcus. 77 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
Strictures About 1 in 10 patients experience a biliary stricture of some magnitude after LTx. The primary types of stricture are anastomotic (Figure 3B) and nonanastomotic. Most anastomotic strictures are amenable to endoscopic treatment (e.g., stenting and ballooning), with about 25% requiring eventual surgical revision to a Roux-en-Y anastomosis. Nonanastomotic strictures/cholangiopathy can be focal or diffuse, mimicking primary sclerosing cholangitis. Diagnosis is with cholangiography. Nonanastomotic strictures are commonly a consequence of global hypoperfusion, for example, after HAT and in recipients who receive a donation after cardiac death donor organ, or who have an original diagnosis of primary sclerosing cholangitis. Ultrasound examination of the bile ducts is unreliable in LTx recipients. Presentation of biliary strictures is highly variable but most frequently presents with a predominantly cholestatic biochemical profile. 6,7 INFECTIONS AS A CAUSE OF ABNORMAL LIVER BIOCHEMISTRIES There are four primary potential sources of infections in LTx recipients: donor derived, nosocomial, community acquired, and recipient derived. A list of timing and types of infection that occur in LTx recipients is provided in Table 2. 8 Activation and exacerbation of latent or chronic infections in the donor and/or the recipient can occur at any time after LTx. Although a thorough history and physical is a cornerstone of evaluating patients with possible infectious causes of elevated liver biochemistries, immunosuppression can dramatically alter the presentation of infections in LTx recipients. Infections should be part of the differential diagnosis for all magnitudes and patterns of abnormal liver biochemistries. Bacterial Infections Bacterial infections occur most commonly in the first days after transplant up to 2 months, although they can be seen throughout the lifetime of an LTx recipient. 9 Fungal Infections Fungal infections occur in up to 10% of LTx patients who are on fungal prophylaxis; they are associated with substantial chronicity and mortality. Candida species are the most common source of fungal infection after LTx and can range from local infection to candidemia with multiple organ/visceral spaces involved. Candida infection is most common in the first 6 weeks after transplant. Less common infections include aspergillosis, cryptococcal, and regional mycosis. Pneumocystis jiroveci usually occurs at 2 to 6 months after LTx and usually manifests with a nonproductive cough, fever, and chest radiograph with an interstitial pattern often described as bat-wing appearance. Elevated liver injury tests from this infection can occur up to 12 weeks after transplant and should be differentiated from other causes of an acute rise of liver injury tests. Viral Infections These are common in LTx patients from 1-6 months after transplant but patients are at increased risk throughout their lives especially if immune suppression is increased as can happen with acute cellular rejection or retransplantation. Recurrence of HCV infection is universal, 10 and is managed with high efficacy and safety with direct acting antiviral agents, typically initiated after the second postoperative month. Because of the potential for important drug-drug interactions with direct acting antiviral agents, treatment choice should be reviewed with a transplant pharmacologist when possible. Common infections are cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus, and Epstein- Barr virus (EBV). Less common viral infections are influenza, adenovirus, papovaviruses, human immunodeficiency virus, parvovirus, and hepatitis A and B. Viral infections can be locally tissue invasive or systemic. RECURRENCE OF DISEASE Many of the liver diseases that led to the need for LTx can recur after LTx. These include hepatitis B and C, nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, alcoholic liver disease, among others. Timing is highly variable. Diagnostic criteria are broadly similar to the nontransplant setting. 1 CORRESPONDENCE Michael Charlton, M.D., F.R.C.P., Chief of Hepatology, Medical Director of Liver Transplantation, Intermountain Medical Center, Salt Lake City, UT 84107. E-mail: michael.charlton@imail.org REFERENCES 1) Busutil R., Klintmalm G. Transplantation of the Liver. Philadelphia: Elsevier Saunders; 2015:870. 78 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD
2) Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6: 783-790. 3) Duffy JP, Hong JC, Farmer DG, Ghobrial RM, Yersiz H, Hiatt JR, et al. Vascular complications of orthotopic liver transplantation: experience in more than 4,200 patients. 2009;208: 896-903. 4) Abraham SC, Furth EE. Receiver operating characteristic analysis of serum chemical parameters as tests of liver transplant rejection and correlation with histology. Transplantation 1995;59: 740. 5) Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658-663. 6) Dunham DP. Receiver operating characteristic analysis for biliary complications in liver transplantation. Liver Transplant Surg 1997;3:374-378. 7) Guichelaar MM, Benson JT, Malinchoc M, Krom RA, Wiesner RH, Charlton MR. Risk factors for and clinical course of non-anastomotic biliary strictures after liver transplantation. Am J Transplant 2003;3: 885-890. 8) Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601-2614. 9) Romero FA, Razonable RR. Infections in liver transplant recipients. World J Hepatol 2011;3:83-92. 10) Garcia-Retortillo M, Forns X, Feliu A, Moitinho E, Costa J, Navasa M, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 2002;35:680-687. 79 CLINICAL LIVER DISEASE, VOL 7, NO 4, APRIL 2016 An Official Learning Resource of AASLD