© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Clin Transplant 2014: 28: 585–589 DOI: 10.1111/ctr.12352

Clinical Transplantation

Safety and performance of liver biopsies in liver transplant recipients Alten TA, Negm AA, Voigtl€ ander T, Jaeckel E, Lehner F, Brauner C, Wedemeyer H, Manns MP, Lankisch TO. Safety and performance of liver biopsies in liver transplant recipients. Abstract: Background: Liver biopsy in patients after liver transplantation (OLT) serves as a diagnostic tool to establish the cause of liver pathology. However, liver biopsy may cause life-threatening complications. Very limited information is available about complications and success rates of liver biopsies in patients after OLT. Our aim was to investigate biopsy-related complications and quality of specimen obtained by liver biopsy after OLT and to evaluate risks and benefits of this procedure. Methods: Retrospective analysis of patients after OLT presenting for liver biopsy between January 2000 and October 2012. All patients were observed for 24 h after intervention. Twelve or more portal tracts were required for liver biopsy specimens to be considered as adequate. Results: Of 703 liver biopsies were performed in 409 patients. Thirteen (1.9%) liver biopsies did not have an adequate number of portal tracts. Only 10 (1.4%) liver biopsies caused complications. Five patients suffered from pain, three patients developed post-procedural fever, and three patients had subcapsular/intercostal bleeding. One patient suffered from a vasovagal reaction. Pain was treated by analgesics; none of the patients required blood transfusion or surgery. Conclusions: Liver biopsy is a safe and adequate diagnostic tool in patients after OLT.

Tim A. Altena, Ahmed A. Negmb,c, €nderb,c, Elmar Torsten Voigtla b,c Jaeckel , Frank Lehnerd, Christin Braunerc, Heiner Wedemeyerb,c, Michael P. Mannsb,c and Tim O. Lankischb,c a

Department of Radiology, bDepartment of Gastroenterology, Hepatology and Endocrinology, cIntegrated Research and Treatment Center – Transplantation (IFB-Tx), and dDepartment of Visceral Surgery, Hannover Medical School, Hannover, Germany Key words: complication – liver biopsy – liver transplantation – quality Corresponding author: Tim Lankisch, MD, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Tel.: +49 511 532 2406; fax: +49 511 532 3351; e-mail: [email protected] Conflict of interest: None. Accepted for publication 5 March 2014

Orthotopic liver transplantation (OLT) is a lifesaving procedure in patients with end-stage liver disease or acute liver failure. After transplantation, graft survival plays a crucial role in the management of patients. Graft survival may be limited by rejection, recurrence of the underlying disease, infection, ischemia, or biliary disorders (1). All of them may result in fibrosis to cirrhosis leading to graft failure, retransplantation, or death. Thus, early diagnosis of those harmful conditions is of major importance in patients after OLT (2, 3). Percutaneous liver biopsy has been performed over decades to diagnose liver diseases and remained part of the clinical routine in managing patients with liver diseases until now (2). Frequently, liver biopsy is performed after OLT for diagnosis, staging, prognosis, and management of the liver diseases. However, as liver biopsy is an

invasive method, it harbors potentially life-threatening complications. Consequently, non-invasive tests such as serum marker tests or liver stiffness measurements play an increasing role to detect liver diseases after transplantation (4–8). However, so far such indirect tests are not capable of completely replacing liver histology. In contrast, liver biopsy provides histology and thus remains the gold standard for diagnosing liver diseases. The procedure of liver biopsy and the quality of histology in patients after OLT may be influenced by scaring due to surgery, change of anatomy as well as an increase in liver stiffness after surgery. A few older studies showed severe complications after biopsy such as bleeding requiring surgery in a majority of patients and fever leading to sepsis (9– 11). Although non-invasive methods have been established to diagnose liver pathology after OLT,

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it is our belief that they probably will not replace liver histology in a considerable number of patients. However, before recommending liver biopsy in selected patients, more data on procedural safety and diagnostic value are required. Therefore, our aim was to analyze complications of liver biopsy and to evaluate the quality of obtained histology in patients after OLT. Methods

A retrospective chart review was performed between January 2000 and October 2012 to identify patients after OLT presenting to percutaneous liver biopsy at a single tertiary-care center (Hannover Medical School). The local institutional review board approved the study protocol. Procedure

Before liver biopsy, a full blood count, an activated partial thromboplastin time (aPTT) and prothrombin time were required for all patients. As a precondition for biopsy, a platelet count of more than 50 000/mm3, aPTT of less than 50 s, and prothrombin time of more than 50% were mandatory. A severe coagulopathy and/or thrombopenia was defined as the presence of a platelet count of less than 50 000/mm3 and/or aPTT of more than 50 s and/or prothrombin time of less than 50%. In rare cases, patients with coagulopathy and/or thrombopenia received fresh frozen plasma and/or platelet concentrates before liver biopsy. In those patients, coagulation status was not repeated after substitution before liver biopsy. In patients with anticoagulation, medication was discontinued for at least five d before intervention. In patients on oral anticoagulation, a bridge with heparin was performed. Heparin was stopped 12 h before biopsy. Antiplatelet therapy was then again started two d after biopsy. Contraindications for liver biopsy were ascites, severe coagulopathy, or the absence of written informed consent. Since 2010, all patients undergoing OLT were included in a protocol liver biopsy program with approval of the ethical committee of the Hannover Medical School after informed consent has been obtained. Liver biopsies were performed at the time of transplantation, at six months, 12 months, and yearly, thereafter until year three. Afterward, biopsies were performed every 24 months. Patients were fasting over night before the procedure. Transthoracic ultrasound-guided biopsy was performed with a core aspiration needle (Menghini needle 17 G) in all patients without any sedation. The most appropriate site for liver biopsy was

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determined by ultrasound, followed by local anesthesia of the subcutaneous tissue and liver capsule. After biopsy, patients were placed in a right lateral decubitus position for two h and were confined to bed for 24 h. Blood count was performed after four h of liver biopsy to exclude bleeding. Hemoglobin drop of more than 1 g/dL was regarded as potential bleeding, and another blood count was performed after two h. Blood transfusion would have been taken into consideration in case of clinical symptoms and/or drop below 8 g/dL. All patients were monitored for at least 24 h in the hospital. The occurrence and intensity of pain (mild 1– 3 on an analog scale of 0–10, moderate [4–6], and severe [7–10]) was recorded by the examining doctor and by the doctor who was responsible for the discharge of the patient. If neither clinical symptoms of complications nor any decrease in hemoglobin were present, the patient was discharged 24 h after liver biopsy. Patients were seen in the outpatient clinic one to two wk after liver biopsy. Patients were again examined and asked for potential complications of the liver biopsy. Quality of histology

The quality of histology obtained by liver biopsy was determined by the presence of portal tracts. Twelve or more portal tracts were regarded as adequate for histologic examination.

Results Patients and liver graft characteristics

During the study period, 703 liver biopsies were performed in 409 patients, who were transplanted between December 1983 and August 2011. Patients were predominantly men (68%), median age was 50 yr old (interquartile range [IQR 42–58], and the median body mass index was 23.99 kg/m2 (IQR 21.45–27.06); Table 1). Three hundred and twelve (76.3%) received a duct-to-duct anastomosis, whereas biliodigestive anastomosis was performed in 97 (23.7%) transplantations, mainly in patients with primary sclerosing cholangitis (PSC). Most of the patients (87%) received a complete liver graft. Nine patients had a severe coagulopathy and/or thrombopenia. Therefore, five patients with severe coagulopathy received fresh frozen plasma and four patients with thrombopenia received platelet concentrates before liver biopsy. Mean hemoglobin levels before liver biopsy were 12.36 g/dL and after liver biopsy 11.99 g/dL. A second blood count was required after 55 (7.8%) liver biopsies, but none of the patients needed blood transfusion.

Liver biopsy after OLT Table 1. Patients and liver graft characteristics

Table 3. Indication for liver biopsy

Patients Age (median) Sex (male/female) Body mass index kg/m2 (median) Primary liver graft Liver graft Duct-duct anastomosis Biliodigestive anastomosis Complete graft Split graft

Indication for biopsy related to

Number of biopsies (703) (%)

Rejection Protocol biopsy Recurrence of primary disease Cholestasis Cytomegalovirus infection

449 (63.9) 161 (22.9) 58 (8.3) 25 (3.6) 10 (1.4)

409 50 yr (IQR 42–58) 277 (68%)/132 (32%) 23.99 (IQR 21.45–27.06) 365 (87%) 312 (76.3%) 97 (23.7%) 371 (90.7%) 38 (9.3%)

IQR, Interquartile range.

Table 2. Indication for liver transplantation Indication for liver transplantation

Number of patients (%)

Hepatitis C/+HCC Hepatitis B/+Hepatitis D/+HCC Alcohol-induced liver cirrhosis/+HCC Autoimmune hepatitis Wilson’s disease Hemochromatosis Cryptogenic cirrhosis PSC PBC Budd-Chiari syndrome Liver cystic diseases Cystic fibrosis Acute liver failure NASH-associated cirrhosis Others

78 (19.1)/53 (13) 26 (6.4)/11(2.7)/24 (5.9) 17 (4.2)/7 (1.7) 15 (3.7) 14 (3.4) 3 (0.7) 18 (4.4) 60 (14.7) 14 (3.4) 13 (3.2) 7 (1.7) 6 (1.5) 21 (5.1) 2 (0.5) 20 (4.9)

HCC, hepatocellular carcinoma; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; NASH, non-alcoholic steatohepatitis.

Main indications for OLT were viral hepatitis, acute liver failure, PSC, alcoholic and autoimmune hepatitis (Table 2). The median time interval from OLT to liver biopsy was 468 d (IQR 175–1455 d). Liver biopsy was performed to diagnose suspected rejection (63.9%), disease recurrence (8.3%), unexplained cholestasis (3.6%), cytomegalovirus infection (1.4%), or as part of a protocol biopsy program (22.9%) (Table 3). Patients with complications after liver biopsy

Only 10 (1.4%, three females and seven males) of 709 liver biopsies were followed by complications (Table 4). Five patients suffered from pain, three patients developed post-procedural fever, and three patients had subcapsular/intercostal bleeding. One patient suffered from a vasovagal reaction. Intensity of the pain was mild in two patients, moderate in two patients, and severe in one patient. Pain was treated with analgesics (for details please see Table 4). None of the patients needed blood transfusion or surgical treatment. In

addition, no patient experienced a life-threatening complication. None of the patients with a complication had an abnormal coagulation status. The main indication for liver biopsy causing a complication was suspected rejection (nine rejections, one recurrence of viral infection). The number of liver biopsies performed before index liver biopsy of the examiner ranged from 10 to 294 procedures. Quality of liver histology

Insufficient biopsy material was obtained only in rare cases. Only 13 (1.9%) of 703 liver biopsies displayed less than 12 portal tracts. Discussion

Liver biopsy is still the most specific diagnostic test for liver diseases (2). However, this procedure remains highly invasive harboring potentially life-threatening complications. Other noninvasive tests such as liver stiffness measurement or serum fibromarker tests have been developed in hope of replacing invasive liver biopsy in patients after OLT. We therefore investigated the present role of liver biopsy with regard to complications and histologic quality to assess risks and benefits. At present, only scarce data about complications of liver biopsy in patients after OLT exist. One large study from Germany showed bleeding associated with liver biopsy in 1.41% of patients (11). Fifty-three percent of those required major surgical interventions. Interestingly, we detected no major complications among 703 biopsies performed in our study. Major complication rates of liver biopsies varied in other studies, depending on the procedure, number of patients, and patient cohort (0– 0.33%) (2, 12–16). However, most of the studies were performed in non-transplanted patients with liver diseases. The lack of major complications may be due to various reasons. Bleeding appears to be a common complication after liver biopsy. Different bleeding rates have been reported classified as mild bleedings (0.4–18%), and moderate-to-severe bleedings

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Rejection Rejection Rejection Rejection 197 2668 592 300 Hep. C Hep. C + HCC PBC PSC 51 63 50 40 F M M M 7 8 9 10

41 M 6

F, female; M, male; AIH, autoimmune hepatitis; Hep., hepatitis; HCC, hepatocellular carcinoma; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis.

145 290 10 61 Conservative: Tazobactam (five d) Conservative: Tazobactam (five d) Conservative: i.v. fluids Conservative: Ceftriaxone (five d)

99 Rejection 240

Rejection 271

Hep. B +Hep. D PSC M 5

48

M 4

57

Hep. C

317

Relapse

Mild local pain at the puncture site directly after biopsy; no pneumothorax in chest radiography Severe post-interventionell pain; small subcapsular hematoma detected by ultrasound, fever Moderate increasing pain directly after biopsy for 24 h. Small liver hematoma in ultrasound. No hemoglobin decrease Intercostal bleeding directly after biopsy with small perihepatic hematoma. Stable hemoglobin levels and normal blood pressure Two-d fever episode 36 h after biopsy Post-punctional fever and shivering 12 h after biopsy Vegetative reaction directly after biopsy Fever after biopsy Rejection 924 Hep. B M 3

27

Rejection 71 ALF F 2

27

Conservative

72

136

172

294

Conservative: Dimenhydrinate Piritramide (one d) Conservative: Metamizole Piritramide (one d) Conservative: Tazobactam (five d) Piritramide (two d) Conservative: Piritramide (one d)

97 Conservative: Metamizole (one d)

Mild breath-dependent right hemithoracic pain two d after biopsy No pathology in chest radiography and ultrasound Moderate pain and nausea directly after biopsy Rejection 2470 AIH F 1

31

Indication for biopsy Days after OLT Disease Age Sex Patient

Table 4. Patients with complications related to liver biopsy

Complication

Management

No. of liver biopsies performed by the examiner

Alten et al.

requiring either transfusion or intervention (1.2– 5.3%). After OLT, the liver is encapsulated in the right upper abdominal quadrant which is due to adhesions to the right lateral abdominal wall, the diaphragm as well as to the transverse colon. Consequently, in case of bleeding, there is no blood spread to other abdominal compartments and the bleeding tamponades itself in the defined compartment. This situation was found in two of our patients with minor complications, who only developed a hematoma that was strictly confined to the subcapsular space. In addition, the consequent use of the Menghini needle may also explain the low incidence of bleeding compared with the Tru-Cut needle, which causes more bleeding in comparison (12, 17, 18). Moreover, the strength of this retrospective study is that in contrast to other liver units, patients were observed in hospital for 24 h and hemoglobin tests were performed four h after the procedure, which means that even slight decreases in hemoglobin levels could have been detected. However, our data indicate that a 24-h observation period after liver biopsy in patients after OLT may not be reasonable given the lack of serious complications. A main complication remains biliary peritonitis caused by puncture of large bile ducts or the gallbladder (2). This complication appears to be low in patients after OLT as they do not have a gallbladder. In addition, two studies showed higher infection rates caused by liver biopsy in patients with choledochocholedochostomy and choledochojejunostomy after OLT (9,10). However, in our study, only one patient with biliodigestive anastomosis after OLT developed fever indicating a low risk of infection in those patients. Pain was the most common minor complication caused by liver biopsy. All patients were successfully treated by analgesics. This is in accordance with previous studies that reported pain occurring in up to 84% of patients including also those with relatively mild discomfort (19). The difference between the findings of Eisenberg et al. and our and other findings may be explained using different thresholds. In addition, patients after OLT may experience less frequent pain because of the neural denervation. Moreover, in our cohort, more male patients developed complications, whereas other studies observed more pain-related complications in females. Experience of the examiner does not appear to be a major risk factor for complications after liver biopsy. Twenty-one examiners with different levels of experience performed liver biopsies and minor complications were observed independently from the level of experience. However, similar to other

Liver biopsy after OLT studies, our analysis is limited, because a subgroup analysis is impossible due to the small number of complications. The patients who developed biopsy complications were the patients who more likely underwent liver biopsy for a suspicion of rejection, although the proportion within the collective is only 64%. As the number of complications is very low, this might be a coincidence and we cannot draw further conclusion. Secondly, we investigated the quality of liver histology in patients after OLT. Interestingly, almost all liver biopsies resulted in a representative liver histology with more than 12 portal tracts assessed by the pathologist. This is somehow surprising as we expected that scarring between peritoneum and liver might cause an insufficient aspiration by the needle resulting in reduced liver tissue suction. Due to the retrospective nature of the study, documentation of needle passes was not well performed in all patients. However, our findings indicate that the histologic quality of liver biopsy in patients after OLT is excellent. Due to the absence of major complications and with regard to the good quality of histology, we conclude that liver biopsy is a safe and reliable diagnostic tool supporting the clinician in the management of patients after OLT. Authors’ contributions

Tim Alten performed acquisition of data, statistical analysis, analysis and interpretation of data, and drafting of the manuscript; Ahmed A. Negm performed acquisition of data and data bank design; Torsten Voigtl€ander carried out acquisition of data, statistical analysis, and drafting of the manuscript; Elmar Jaeckel carried out acquisition of data and critical revision of the manuscript for important intellectual content; Frank Lehner carried out acquisition of data; Christin Brauner performed acquisition of data; Heiner Wedemeyer performed critical revision of the manuscript for important intellectual content and drafting of the manuscript; Michael P. Manns carried out critical revision of the manuscript for important intellectual content and drafting of the manuscript; Tim O. Lankisch carried out study concept and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript. References 1. Banff Working Group. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology 2006: 44: 489.

2. ROCKEY DC, CALDWELL SH, GOODMAN ZD, NELSON RC, SMITH AD. Liver biopsy. Hepatology 2009: 49: 1017. 3. SEBAGH M, SAMUEL D, ANTONINI TM et al. Twenty-year protocol liver biopsies: invasive but useful for the management of liver recipients. J Hepatol 2012: 56: 840. 4. AL KNAWY B, SHIFFMAN M. Percutaneous liver biopsy in clinical practice. Liver Int 2007: 27: 1166. 5. SANDRIN L, FOURQUET B, HASQUENOPH J-M et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003: 29: 1705.   JA, FERNANDEZ -VARO G, BRUGUERA M et al. 6. CARRION Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation. Gastroenterology 2010: 138: 147. 7. RIGAMONTI C, DONATO MF, FRAQUELLI M et al. Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation. Gut 2008: 57: 821. 8. MARTINEZ SM, CRESPO G, NAVASA M, FORNS X. Noninvasive assessment of liver fibrosis. Hepatology 2011: 53: 325. 9. LARSON AM, CHAN GC, WARTELLE CF et al. Infection complicating percutaneous liver biopsy in liver transplant recipients. Hepatology 1997: 26: 1406. 10. BUBAK ME, PORAYKO MK, KROM RA, WIESNER RH. Complications of liver biopsy in liver transplant patients: increased sepsis associated with choledochojejunostomy. Hepatology 1991: 14: 1063. € AR, BECHSTEIN WO, 11. LANG M, NEUMANN UP, MULLER NEUHAUS R, NEUHAUS P. Complications of percutaneous liver biopsy in patients after liver transplantation. Z Gastroenterol 1999: 37: 205. 12. SZYMCZAK A, SIMON K, INGLOT M, GLADYSZ A. Safety and effectiveness of blind percutaneous liver biopsy: analysis of 1412 procedures. Hepat Mon 2012: 12: 32. 13. HUANG J-F, HSIEH M-Y, DAI C-Y et al. The incidence and risks of liver biopsy in non-cirrhotic patients: an evaluation of 3806 biopsies. Gut 2007: 56: 736. 14. PICCININO F, SAGNELLI E, PASQUALE G, GIUSTI G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986: 2: 165. 15. MCGILL DB, RAKELA J, ZINSMEISTER AR, OTT BJ. A 21year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology 1990: 99: 1396. 16. SEEFF LB, EVERSON GT, MORGAN TR et al. DIENSTAG JL; HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010: 8: 877. 17. GILMORE IT, BURROUGHS A, MURRAY-LYON IM, WILLIAMS R, JENKINS D, HOPKINS A. Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut 1995: 36: 437. 18. DE GROEN PC, RAKELA J, MOORE SC et al. Diagnostic laparoscopy in gastroenterology. A 14-year experience. Dig Dis Sci 1987: 32: 677. 19. EISENBERG E, KONOPNIKI M, VEITSMAN E, KRAMSKAY R, GAITINI D, BARUCH Y. Prevalence and characteristics of pain induced by percutaneous liver biopsy. Anesth Analg 2003: 96: 1392.

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Safety and performance of liver biopsies in liver transplant recipients.

Liver biopsy in patients after liver transplantation (OLT) serves as a diagnostic tool to establish the cause of liver pathology. However, liver biops...
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