Post-Liver Transplant Intrahepatic Cholestasis: Etiology, Clinical Presentation, Therapy

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European Review for Medical and Pharmacological Sciences 2017; 21 (1 Suppl): 23-36 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy

F.R. PONZIANI1, S. BHOORI2, M. POMPILI1, M.A. ZOCCO1, M. BIOLATO1, G. MARRONE1, A. GASBARRINI1, V. MAZZAFERRO2, A. GRIECO1

1Internal Medicine, Gastroenterology, Hepatology, Agostino Gemelli Hospital, Rome, Italy 2Liver Transplant, Hepatobiliary and Gastrointestinal Surgery, Istituto Nazionale Tumori, Milan, Italy

Abstract. – Post-liver transplant intrahepatic rum bilirubin, alkaline phosphatase (ALP), and cholestasis is consequent to the impairment of gamma-glutamyl transpeptidase (GGT), with or bile flow or formation. It may develop in the ear- without increased transaminases levels. ly (within 6 months) or in the late (more than 6 In the liver transplant (LT) setting, cholestasis months) post-liver transplant period and differ- may be classified as extrahepatic, due to mecha- ent causes may be recognized according to the time elapsed from a liver transplant. The raise nical impairment of bile flow (e.g. anastomotic at various degrees of serum bilirubin, alkaline strictures, bile stones), or as intrahepatic, associa- phosphatase, and gamma-glutamyl transpep- ted with impairment of liver cells or ductular dy- tidase, with or without increased transaminas- sfunction. Post LT cholestasis may develop early es levels, are common hematochemical find- (within 6 months after LT) or late (more than 6 ings. Liver histology is helpful for diagnostic months after LT), with different etiology accor- assessment, and sometimes crucial to differen- tiate among possible causes of cholestasis. Al- ding to the time elapsed from LT (Table I). though timely treatment of underling conditions In this review, the main causes of post LT in- as well as supportive care may resolve post-liv- trahepatic cholestasis are discussed, focusing on er transplant intrahepatic cholestasis, the risk of clinical presentation and therapeutic approach. graft loss and retransplantation are remarkable. For this reason, post-liver transplant intrahepatic cholestasis should be managed in collabora- Early Post-Liver Transplant tion with the LT center, and treatment should be devolved to expert hepatologists. Intrahepatic Cholestasis In the early post LT period intrahepatic chole- Key Words: stasis is common, usually subclinical and self-li- Cholestasis, Liver transplant, Ischemia reperfusion, miting. However, some patients may develop pro- Rejection, Small for size, Immunosuppression, Drug in- longed cholestasis and irreversible liver injury, duced liver injury, DILI. leading to re-LT. Initial poor graft function (IPGF) and primary graft non-function (PNF) may manifest with ear- Introduction ly post LT cholestasis. PNF is an irreversible graft dysfunction requiring emergency liver replacement Cholestasis is a condition characterized by de- within the first 10 days after LT2. It is characterized fective bile flow or formation1. It may result from by rapidly rising transaminases, absence of bile pro- an altered uptake, transfer and secretion of bile duction, severe coagulation deficit, hypoglycemia, components, mainly caused by liver injury in the high lactate levels, and hemodynamic instability. absence of mechanical obstruction. According to the united network of organ sharing The histological features of cholestasis are bile (UNOS) criteria, PNF is defined by the presence of stasis in liver parenchyma and bile ducts plugs; aspartate transaminase (AST) ≥ 5000 IU/L, inter- bilirubin accumulation into hepatocytes, Kupffer national normalized ratio (INR) ≥ 3.0, and acidosis cells, and canaliculi in zone 3 as well as ductu- (pH ≤ 7.3 and/or lactate concentration ≥ 2× normal). lar proliferation in zone 1, or bile acid retention Conversely, there is no agreement on the diagnostic (“cholate stasis”) may be present1. Blood exami- criteria of IPGF, which is mainly characterized by nations show the raise at various degrees of se- elevation of serum transaminases3-5.

Corresponding Author: Francesca R. Ponziani, MD; e-mail: [email protected] 23 F.R. Ponziani, S. Bhoori, M. Pompili, M.A. Zocco, M. Biolato, G. Marrone, A. Gasbarrini, et al.

The incidence rates are variable, up to 11.8% sion of inflammatory cells to the endothelium, for PNF and to 36% for IPGF, respectively; PNF increased interstitial fluid and endothelial vaso- is responsible for 81% of re-transplantations du- constriction18. The activation of the immune sy- ring the first week after surgery6. stem leads to a massive production of cytokines, The most frequent causes of early post LT cho- chemokines, adhesion molecules, reactive oxygen lestasis, which sometimes lead to PNF and IPGF, species (ROS), to the activation of the comple- are mainly related to liver graft preservation ment system and to the promotion of autoimmune and size match, infectious complications, acute injury, as well as of mitochondrial dysfunction rejection, and drugs. triggering cell death programs17. This sustains the pro-inflammatory process and produces liver da- Ischemia/Reperfusion Injury mage. Ischemia reperfusion injury (IRI) is the consequence of the inflammatory response triggered Treatment by the procedures of organ procurement and pre- Liver susceptibility to IRI depends on organ servation. Thus, IRI is a kind of “sterile inflam- preservation techniques and is increased by do- mation”, which develops in the absence of any nor starvation, age, and graft steatosis19. Several microorganism7. measures can be adopted to reduce the risk of IRI Two major types of IRI can be recognized. in predisposed organs20. Surgical interventions, “Warm” IRI develops in situ during LT surgery pharmacological agents, and gene therapy are when hepatic blood supply is temporarily inter- the main treatment strategies, which have been rupted, and is consequent to hepatocellular dama- extensively reviewed elsewhere19. On the whole, ge. “Cold” IRI, occurs ex vivo during liver graft the use of a vasoprotectors, modulators of the preservation, is caused by hepatic sinusoidal en- renin-angiotensin system, β-blockers, antioxi- dothelial cells damage and is coupled with warm dants, growth factors, tyrosine kinase inhibitors, IRI8,9. Other causes of IRI may be sepsis, shock, angiotensin II blockers, hydroxy-methylglutaryl and trauma, which are pathological conditions eli- (HMG)-Coenzyme A (CoA) reductase inhibitors, citing systemic and liver hypoperfusion that may calcium channel blockers, peroxisome prolifera- occur in the setting of LT. tor-activated receptors (PPAR-α) agonists are the In both warm and cold IRI, two stages of liver most innovative approaches reported in literatu- damage can be recognized. The first one is the re, to be distinguished form surgical measures ischemic injury phase, which initiates the process widely used in everyday practice (e.g. minimiza- of cell death and is characterized by glycogen tion of cold and warm ischemia time, intermittent consumption, lack of oxygen, and ATP depletion. clamping, ischemic preconditioning, the use of The subsequent reperfusion injury phase is the preservation solutions with specific additives). consequence of the metabolic derangement associated with inflammatory damage. Reperfusion Small-For-Size Syndrome injury phase can be further distinguished in early Living donor LT (LDLT) is a common practice (or acute), occurring within the first 3 to 6 hours for Asian transplant Centers. It has been imple- post-reperfusion and characterized by the activa- mented in selected cases to increase the number tion of Kupffer cells, and late (or subacute), with of available organs in Western Countries and to massive neutrophil infiltration beginning at 18-24 reduce the waiting list period. In practice, donor’s hours post-reperfusion9-12. liver is splitted in two parts, one of them being IRI is caused by the innate immune respon- used as transplantable graft. This procedure may se mediated by pattern recognition receptors be adopted for deceased donors too. To obtain (PRR)13-16, including Toll-like receptor (TLR) 4, an adequate equilibrium between the amount of TLR9 and the inflammasome17. Different cells of transplanted (recipient) and residual (donor) liver the immune system (T lymphocytes and natural tissue, in adult-to-adult LDLT graft size should killer lymphocytes, polymorphonuclear cells) are cover 30-40% of the expected recipient’s liver vo- involved in the promotion of IRI, and recent data lume or 0.8-1.0% of the recipient’s body weight21. have reported a stimulation of adaptive immune Therefore, the right liver lobe is usually prefer- response. The “no reflow” phenomenon observed red. Living donor liver volumes are calculated after liver reperfusion is a common feature of IRI based on three-dimensional CT scan; the most resulting from inflammation; in particular, blood useful estimated parameters are graft volume to flow mechanical obstruction is caused by adhe- standard liver volume (SLV) ratio, and graft wei-

24 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy ght-to-recipient body weight ratio (GWBWR)22-25. and related to other post-LT factors (mechanical A GWBWR of 0.8% is a widely accepted cut-off ventilation, level and type of immunosuppres- for minimizing the risk of graft failure26. In the sion [e.g. monoclonal and polyclonal antibodies], case of deceased donors, the body surface area PNF, vascular complications [e.g. hepatic artery index (BSAi) is adopted27. thrombosis and portal vein thrombosis], biliary Small-for-size syndrome (SFSS) occurs when complications [e.g. ischaemic cholangitis, bi- the partial liver graft fails to fulfill the functio- liary strictures and fistulae])36-43. nal demand of the recipient28. If the hepatocyte The type of infection is associated with the cellular mass is inadequate for the recipient size, time from LT. In the first month after surgery the small vascular network of the graft causes a (early period) opportunistic, donor-derived and discrepancy between accelerated liver regenera- surgical site infections are usual, whereas at 2-12 tion and inadequate supply of oxygen and growth months after LT (intermediate period) opportuni- factors. This leads to hyperafflux in the portal stic (Mycobacterium tuberculosis, Pneumocystis, system (portal hyperperfusion), reduction in ar- Listeria, Cryptococcus, Toxoplasma, Rhodococ- terial perfusion (hepatic arterial buffer respon- cus, Nocardia, Legionella, etc.) and community se) and sinusoidal microcirculatory disturbances acquired infections (flu, urinary tract infections) causing liver damage and inflammation29-32. are more frequent. After the first year post LT SFSS encompasses various clinical presenta- (late period) community acquired infections are tions, ranging from mild hepatic dysfunction and more likely to occur, whereas opportunistic in- isolated hyperbilirubinemia, to coagulopathy, fections are generally rare44. ascites, portal hypertension, prolonged cholesta- Cytomegalovirus (CMV) infection is one of sis, encephalopathy, and irreversible graft failure the most common viral complications of the ear- leading to death of the patient in the absence of an ly-intermediate post LT period, involving about available organ for re-transplantation. 30-50% of LT recipients although a delayed on- Liver biopsy shows diffuse ischemic damage, set can also be observed44. Either new or reacti- cellular ballooning, and features of cholestasis33. vated infection may occur. It is characterized by virus replication in blood, which can be defined Treatment as “CMV disease” in the presence of the fol- Treatment is mainly aimed at reducing portal lowing associated manifestations: fever >38°C, hyperperfusion by mechanic procedures (splenic for at least 2 days within a 4-day period, neutro- artery ligation, splenectomy, portosystemic shun- penia or thrombocytopenia, and tissue invasion ts, extracorporeal continuous portal diversion with organ dysfunction, including lung, liver, ki- [ECPD]), or medical therapy (splanchnic vaso- dney and central nervous system45. According to constrictors such as: terlipressin, somatostatin, donor and recipient previous contact with CMV, octreotide)34. the infection can be defined as primary (donor positive/recipient negative) or as superinfection Infections (donor positive/recipient negative). In the case of Infectious complications are a common cause primary infection, in the absence of prophyla- of morbidity and mortality among LT recipients. xis, over 90% of the recipients develop CMV in- Bacterial infections are the most frequent (80%), fection compared to about 25% of the recipients followed by viral (20%) and fungal (8%) ones35- in the case of superinfection; in the case of re- 37. Both the reactivation of previous infections activation of previous infection (donor positive/ or the exposition to new infectious agents is recipient negative), around 15% of the recipients possible. Concomitant factors may contribute become ill. to the onset and the evolution of the infective The liver is a regulatory organ in the host de- episode; they can be recipient-related (advanced fense system, acting as a firewall against syste- age, MELD score >30 at LT, acute liver failure, mic diffusion of bacteria and pathogens; during malnutrition, > 48 hours stay in intensive care infections, several proinflammatory cytokines unit [ICU], prolonged hospital stay, previous in- (tumor necrosis factor alpha [TNF-α], interleukin fections, diabetes), donor-related (prolonged ICU [IL]-1, IL-6, and IL-8) are released, altering bile stay, previous infections, marginal graft), sur- acid transport at the sinusoidal and canalicular gery-related (choledochojejunostomy, prolonged membrane domains46-49. surgery [> 12 h], re-operation or re-transplanta- Cholestasis may precede the development of tion, transfusion of more than 15 blood units), septic complications; bacterial infections usually

25 F.R. Ponziani, S. Bhoori, M. Pompili, M.A. Zocco, M. Biolato, G. Marrone, A. Gasbarrini, et al. present with high fever, cholestasis, and positive tended as the detection of antibodies in the re- blood cultures. Liver biopsy specimens show bi- cipient’s serum binding to the surface of donor’s liary tract inflammation with neutrophil infiltra- lymphocytes, is associated with an increased tes, bile duct proliferation, and bile plugs50. risk of hyperacute rejection of the kidney allo- CMV hepatitis usually presents with fever, ja- graft64. undice and increased cholestasis blood test. Liver The liver is relatively resistant to antibodies histology shows cholestatic features, microab- mediated injury due to its wide sinusoidal en- scesses and typical intranuclear “owl’s eye” in- dothelial surface allowing the absorption of clusions51. Persistence of CMV has been demon- circulating antibodies, to its intrinsic ability to strated in liver grafts developing vanishing bile regenerate and also for the secretion of soluble duct syndrome and chronic rejection52. Although HLA I that binds and inactivate circulating an- CMV infection may increase alloantigens expres- tibodies65-68. These mechanisms of protection al- sion, making bile ducts more vulnerable to im- low the clearance of preexisting DSAs in 90% munologic damage53, large studies have failed to of presensitized LT-recipients69. However, in pa- demonstrate any significant association between tients with rejection or inflammatory conditions CMV infection and the development of graft cho- involving the liver the exposure of alloantigen langiopathy54. secondary to tissue injury may trigger the production of “de novo” DSAs, similary to what re- Treatment ported for kidney transplant recipients70,71. The treatment of the infectious complication The association between a positive cross-ma- usually resolves cholestasis. tching and ACR in LT recipients is not constant among published studies and is, therefore, diffi- Acute Cellular Rejection cult to draw firm conclusions69,72-77. Although the Although the prevalence of acute cellular presence of inflammation in biopsy specimens rejection (ACR) is declining, the current inciden- from patients with a positive cross-match has ce of clinically significant acute rejection is 10- been reported78, no significant difference in tran- 40%55. saminases and bilirubin levels, as well as in graft ACR may be early, usually occurring within 3 and recipient’s survival, was proven compared to months post LT, or late, occurring after 3 mon- cross-match negative patients78-81. ths post LT56. In any case, it is triggered by a T Histologically, ACR is classified according to cells-driven immune response against major hi- Banff criteria82,83. Portal, bile duct and venous en- stocompatibility complex (MHC) alloantigens in dothelial inflammation are the three main featu- the liver graft. CD4+ and CD8+ T cells but also res of ACR, and at least two of them are required myeloid cells and innate lymphoid cells are ini- for the diagnosis. Inflammatory cells in the portal tially involved, but hepatic inflammation leads to spaces are represented by a mixed population of further recruitment of leukocytes from circula- lymphocytes (T cells), blast cells, macrophages, tion55,57. Inflammation results in hepatocytes, en- neutrophils, and eosinophils. Bile ducts appear dothelial cells, and bile ducts damage58-62. inflamed, with degenerative changes or focal lu- The association between antibody-mediated minal disruption. Centrilobular perivenulitis con- rejection and ACR has also been a controver- sists in hepatic venous and perivenular inflam- sial issue in the LT setting. Antibody-mediated mation with perivenular hepatocyte loss. In late rejection is a hyperacute rejection characterized ACR this “typical” picture is less prominent, but by graft endothelial damage by complement acti- central perivenulitis is more marked56,84,85. vation, with direct injury to the capillary endothe- ACR is as always asymptomatic, but jaundice lium and activation of inflammatory cells, such as can be present. The diagnosis is supposed based natural killer (NK) lymphocytes, macrophages, on the increase in transaminases, bilirubin and and neutrophils63. cholestasis enzymes levels and is confirmed by ACR should be distinguished from hype- liver biopsy findings. ractue rejection. Donor-specific human alloantibodies (DSAs) against leukocyte antigen (HLA) Treatment and ABO antibodies are involved in hyperacute Advances in immunosuppressive therapy have rejection. DSAs are a well-known risk factor for significantly increased the success of LT, mini- decreased graft survival after kidney and heart mizing the risk of ACR. Histological evidence of transplantation. A positive “cross-match”, in- ACR without any biochemical alteration does not

26 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy require treatment; on the other hand, when ACR • Acute cholestatic hepatitis, characterized by is suspected liver biopsy is mandatory to grade the association of cholestasis, inflammation its severity and to exclude other causes of liver and sometimes hepatocellular necrosis; damage (e.g. drugs, IRI, infections, recurrent di- • Cholestasis with bile duct injury, when ductu- sease) before treatment. The increase of immu- lar, cholangiolar, or cholangiolytic damage is nosuppression alone is usually effective to treat prevalent and hepatocellular injury is minimal; mild ACR; the maintenance of increased levels • Vanishing bile duct syndrome. of immunosuppressive drugs associated with cor- Cholestatic DILI pattern is defined as an in- ticosteroid boluses is recommended in modera- crease in ALP >2 × the upper limit of normal te-severe ACR86. and/or with an alanine aminotransferase (ALT)/ ALP ratio <2, whereas a mixed (citonecrotic Drug Induced Liver Injury and cholestatic) DILI pattern as an ALT/alka- Despite data on the general population are line phosphatase ratio greater than 2 and less scarce, the prevalence of hepatotoxicity among than 5. However, these features are common in patients hospitalized for jaundice has been esti- the early post LT period97,98. The Roussel Uclaf mated to range between 2% and 10%87-91 and an Assessment model (RUCAM) may be useful to incidence as high as 2% has been reported in LT investigate the likelihood of DILI97,98. Further- recipients92. more, some drugs have a “signature pattern,” Drug induced liver injury (DILI) is an uncom- as a typical pattern of liver injury may be reco- mon cause of cholestasis, even if large studies gnized after a similar duration of drug intake. confirm that among patients with DILI 20-40% In the diagnostic workup, online archives and may have a cholestatic histological pattern and web sites are useful tools to investigate drugs 12-20% a mixed hepatocellular/cholestatic pat- hepatoxicity99. tern93-96. It is usually difficult to recognize DILI in the Several drugs necessary for LT recipients may LT setting due to the multiple factors potentially have hepatotoxic effects and may lead to cholesta- responsible for liver damage. However, in presen- sis. Therefore, drug induced liver injury (DILI) ce of unexplained cholestasis, after the exclusion may be a cause of cholestatic damage in both the of common causes of liver injury and after exten- early and the late post LT period. sive testing including liver biopsy, DILI should be The most common clinical presentation of cho- considered as a possible cause. lestatic DILI is the increase in ALP with or wi- In the same way as in the general population, thout jaundice and pruritus. Fever and abdominal histological assessment of DILI is challenging in pain may be present. Diagnosis of DILI is often LT recipients and may be confounding, due to the difficult after LT, especially in the early period, influence of several other factors, sometimes de- due to the coexistence of other causes of liver da- laying DILI diagnosis. Moreover, the investiga- mage. tion of medication history, which is mandatory to Histology is helpful in the differential diagno- estimate the time to DILI onset, may be difficult stic process and in the classification of cholestatic due to variations in treatment doses and duration DILI, which can be distinguished as follows93-95: as well as interruptions/re-start. Conversely, the • Acute pure cholestasis, presenting with hepa- strict biochemical monitoring to which LT reci- tocyte cholestasis, canalicular dilation, and bile pients are subjected is a potential advantage in the plugs in the absence of relevant inflammation; early detection of DILI.

Table I. Main causes of post LT intrahepatic cholestasis according to post LT period.

Early post LT period (<6 months) Late post LT period (≥6 months)

Primary non function Chronic rejection Ischemia/reperfusion injury Infections Small for size graft Drug induced liver injury Infections Recurrence of the original disease Acute rejecton Antibodies-mediated rejection Drug induced liver injury

27 F.R. Ponziani, S. Bhoori, M. Pompili, M.A. Zocco, M. Biolato, G. Marrone, A. Gasbarrini, et al.

Table II. Classification of medications associated with drug induced liver injury according to the number of reports and to the likelihood of use in liver transplant recipients98,123.

Drugs category A Drugs category B Drugs category C Drugs category D (≥ 50 Cases) (18-49 Cases) (4-11 Cases) (1-3 Cases)

Frequently used in LT: Frequently used in LT: Frequently used in LT: Frequently used in LT: Allopurinol* Celecoxib* Amlodipine* Acyclovir Atorvastatin* Clopidogrel* Candesartan* Atenolol* Diclofenac Enalapril* Gemfibrozil* Carvedilol* Ibuprofen* Esomeprazole Gilipizide* Clofibrate* Ticlopidine* Fenofibrate* Glimepiride* Enoxaparin Fluvastatin* Irbesartan* Fondaparinux Uncommonly/occasionally Glibenclamide* Ketoprofen* Hydrochlorotiazide* used in LT: Lisinopril Losartan* Glicazide* Amiodarone* Lovastatin* Lansoprazole* Propofol Amoxicillin+calvulanate* Metformin* Metronidazole Rabeprazole* Naproxen* Pravastatin* Raltegravir Rarely used in LT: Nifedipine Pantoprazole Repaglinide Busulfan* Omeprazole Ramipril* Spironolactone* Carbamazepin* Ranitidine* Tamsulosin Dantrolene Rosuvastatin* Uncommonly/occasionally Valsartan* Efavirenz* used in LT: Erythromycin* Uncommonly/occasionally Ampicillin* Uncommonly/Occasionally Floxuridine* used in LT: Alfuzosin* used in LT: Halothane Amoxicillin* Diltiazem* Cefaclor Infliximab* Azithromycin* Levocetirizine* Cefadroxi Ketoconazole* Captopril* Vancomycin Cefnidir Nevirapine* Cefazolin Verapamil* Cefepime Nimesulide* Ceftriaxone* Warfarin* Cefoperazone Phenytoin* Ciprofloxacin* Cefotaxime Quinidine* Clarithromycin* Rarely used in LT: Cefprozil Rifampin* Fluconazole Amphotericin B* Ceftazidime Simvastatin* Levofloxacin* Albendazole* Cefuroxime Sulfasalazine* Propafenone* Bosentan* Flecainide Sulfonamides* Cephalexin Fosfomycin* Sulindac* Rarely used in LT: Citalopram* Imipenem* Thioguanine* Clindamycin Cytarabine* Meropenem* Valproic Acid* Clozapine* Daptomycin Sitagliptin Doxorubicin Doxycycline* Valacyclovir* Duloxetine* Escitalopram* Etanercept* Fluoxetine* Rarely used in LT: Heparin Erlotinib Acetazolamide* Imatinib* Famotidine Aliskiren* Irinotecan Flavocoxid* Alosetron Itraconazole* Fluorouracil* Alprazolam* Moxifloxacin* Gabapentin* Anastrozole Olanzapine* Gemcitabine* Atazanavir* Ofloxacin* Hydroxyurea Bortezomib* Paroxetine* Indomethacin* Carbenicillin* Phenobarbital* Isotretinoin Carboplatin Quinine* Labetalol Chlorambucil* Rivaroxaban Levetiracetam Cisplatin Sertraline* Linezolid* Clomipramine* Tamoxifen* Mesalamines* Clonazepam* Thiabendazole* Mirtazapine* Dabigatran Venlafaxine* Mitomycin Dalteparin Voriconazole* Montelukast* Darbepoetin alfa Nafcillin Dasatinib Natalizumab* Deferoxamine Nefazodone* Donepezil Norfloxacin* Entacapone* Orlistat Ethambutol* Penicillin G* Pioglitazone* Pregabalin* Procainamide* Table continued

28 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy

Table II. Continued. Classification of medications associated with drug induced liver injury according to the number of reports and to the likelihood of use in liver transplant recipients98,123.

Drugs category A Drugs category B Drugs category C Drugs category D (≥ 50 Cases) (18-49 Cases) (4-11 Cases) (1-3 Cases) Quetiapine* Hydroxychloroquine Risperidone* Lopinavir* Ritonavir* Mebendazole Rosiglitazone* Mefloquine* Sorafenib Metoprolol Thalidomide* Micafungin Tolcapone* Nelfinavir Topiramate Ondasetron Trazodone* Oxcarbazepine* Vincristine Rifabutin* Zafirlukast Rilpivirine Rivastigmine Saquinavir* Sildenafil* Terbutaline Thyroxine Tobramycin Tolvaptan* Triamterene* Zileuton

*mixed or cholestatic pattern of drug induced liver injury.

The optimization of tailored immunosuppres- Among other drugs that may cause a cholesta- sive drugs regimens have significantly minimized tic syndrome in LT recipients, antifungal agents the incidence of DILI in LT recipients, but the as well as antibiotics have been reported as the risk is not completely absent and increases when most common agents of DILI in LT recipients92. complications or other concomitant medical con- Pharmacological therapies for cardiovascular ditions require treatment. diseases are frequently employed in LT recipients Cyclosporine may have cholestatic effects interfe- as well as analgesics and antinflammatory anti- ring with bile formation and leading to hyperbiliru- diabetic neurologic, anticoagulant, antiaggregant, binemia and to the formation of biliary sludge100-108. gastroenterologic and psychotropic medications. The inhibition of ATP-dependent export carriers The main drugs potentially causing DILI, inclu- and of the bile salts export pumps in the canalicu- ding the cholestatic type, are reported in Table lar membrane of hepatocytes, together with impair- II, and are stratified according to the frequency ment of biliary secretion of glutathione, are involved of hepatic adverse effects124. Medical therapies in cyclosporine-related impairment of canalicular should not be avoided only for concerns regar- bile flow105-107. Similarly to cyclosporine but at a les- ding their potential hepatotoxicity, but thorough ser extent, tacrolimus has been reported to inhibit patient evaluation is mandatory to avoid under- canalicular bile acids transport and glutathione se- recognized cases of DILI. Particular attention cretion105,109,110. However, Ericzon et al. reported that should be paid to the use of herbal and dietary tacrolimus was able to recover bile acid secretion supplements too, which may be hepatotoxic by after LT more rapidly than cyclosporine111,112. As re- itself or due to the presence of other ingredients gards other immunosuppressive agents, two cases of and adulterants125,126. cholestatic liver damage have been reported in two Only 6% of patients with DILI develop chronic renal transplant recipients receiving mycophenolate liver injury127. However, patients with cholestatic and sirolimus, respectively112,113. DILI seem to be more prone to experience chro- Azathioprine, a purine analogue rarely used as nic liver disease; in a minor part of them, ducto- immunsosuppressant in the LT setting today, may penia and vanishing bile duct syndrome with the cause damage to the hepatic sinusoidal and venu- progression to biliary cirrhosis may also occur, lar endothelial cells, resulting in a variety of cli- especially in association with specific drugs128-134. nical, biochemical, and histologic manifestations, Reversal of drug-related vanishing bile duct syn- including cholestasis115-123. drome has also been reported135,136.

29 F.R. Ponziani, S. Bhoori, M. Pompili, M.A. Zocco, M. Biolato, G. Marrone, A. Gasbarrini, et al.

DILI-related mortality ranges between 5% and for routine histological assessment138,139. It tipical- 14%93-95. However, in a recent study focused only ly occurs during the first 12 months after LT but a on LT recipients, DILI did not affect the post LT delayed diagnosis is possible, since CR may have outcome as patients did not require re-transplan- an indolent course over years140. CR may occur tation and no death was reported92. in patients with previous episodes of ACR, even if this is not a strict requirement141. As like as for Treatment ACR, a positive cross-matching has been demon- Immediate withdrawal of the suspected drug strated in patients with CR80,142-144. Notably, even is the core principle of DILI management. In if data from published studies are contrasting, the case of immunosuppressive drugs, dose re- circulating DSAs have been associated with an duction or conversion to other regimens may be increased risk of developing rejection in patients considered. Specific therapies may be adopted who have weaned immunosuppression. for few toxic agents, such as N-acetylcysteine Loss of bile ducts (vanishing bile duct syn- for acetaminophen overdose137. N-acetylcysteine drome) at liver histology and obliteration of has been empirically administered to adults with large and medium size arteries are the main- DILI due to other agents too, reporting favorable stay of CR. These pathological alterations are results. Corticosteroids may be used in case of due to the infiltration of macrophages (foam tyrosine kinase inhibitors-related DILI or in cells) and inflammatory cells into the vessel case of drug-induced autoimmune-like hepati- wall, leading to fibrosis and, finally to the tis, especially when liver injury does not resolve obliteration of arterial lumen with consequent after withdrawal of the offending agent. Ursode- ischemic damage. oxycholic acid administration has obtained be- Histologically, ductopenia should be present neficial results in the setting of cholestatic DILI, in more than 50% of portal tracts to make a re- as well as cholestyramin alone or in association liable diagnosis of CR145-147. Bile ducts inflam- with antihistamines as regards pruritus relief. mation can be present in the early stages, sub- Silibinin use in the setting of DILI has obtained siding during time, and bile ducts degeneration contrasting results, whereas few data on methio- leads to dysplastic and athrophic features. In the nine and glutathione are available. centrilobular zone, bilirubinostasis, hepatocyte Gastric decontamination (aspiration by lavage, ballooning and loss may be present, evolving in charcoal) should be considered in selected cases centrilobular fibrosis and cirrhosis during time. of DILI, such as those related to acteminophen Fibrosis pattern may be veno-centric, which is overdose, toxic mushrooms, salicylate or to the associated with the obliteration of hepatic and ingestion of other toxic substances. portal vein branches, periportal/biliary, when bile duct inflammation and loss is predominant, or centrilobular, which is associated with central Late Post-Liver Transplant Intrahepatic perivenulitis. Bile duct proliferation and peri- Cholestasis portal fibrosis are more frequent in cases of late presentation, and are suggestive of a prolonged The main causes of intrahepatic cholestasis in course of CR. the late post LT period are chronic rejection (CR), Microscopic vascular abnormalities can be pre- infections and DILI, which have been extensively sent and the small portal tracts may show a reduced discussed above. number of small arterial branches and of other mi- Exclusion of the recurrence of the original liver crovascular channels145-147. disease (e.g. hepatitis C virus infection, primary CR may have a long asymptomatic course; pro- sclerosing cholangitis, primary biliary cholangi- gressive jaundice, with or without ascites, is the tis) and of extrahepatic conditions inducing cho- typical clinical manifestation. lestasis, such as hepatic artery thrombosis and mechanical obstruction, is mandatory to guide Treatment treatment. Switch of immunosuppressive therapy or its potentiation (combination of two or 3 drugs) are Chronic Rejection the most commonly used approaches. Although The prevalence of CR (otherwise called “ducto- chronic rejection is sometimes irreversible, re- penic rejection”) is 2% in LT recipients, although transplantation is necessary in only 5% of ca- probably underestimated for the lack of protocols ses138,139.

30 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy

Conclusions stein RM, Klintmalm GB. Liver retransplantation for primary nonfunction: analysis of a 20-year single-center Intrahepatic cholestasis in LT recipients is a experience. Liver Transpl 2007; 13: 227-233. challenge for clinicians, as multiple conditions 3) Ploeg RJ, D’Alessandro AM, Knechtle SJ, Stegall may alter the clinical picture. In the early post LT MD, Pirsch JD, Hoffmann RM, Sasaki T, Sollinger HW, Belzer FO, Kalayoglu M period, cholestasis may be a manifestation of graft . Risk factors for primary dysfunction after liver transplantation--a dyfunction, and a rapid assessment of the possible multivariate analysis. Transplantation 1993; 55: cause is mandatory to start the correct treatment 807-813. rapidly and to avoid the loss of liver graft or its 4) Gonzalez FX, Rimola A, Grande L, Antolin M, Gar- irreversible damage. The improvement in surgi- cia-Valdecasas JC, Fuster J, Lacy AM, Cugat E, Visa J, cal techniques and organ preservation methods as Rodes J. Predictive factors of early postoperative well as the progressive shortening of both donor graft function in human liver transplantation. He- and recipient surgical procedures times, have si- patology 1994; 20: 565-573. Nanashima A, Pillay P, Verran DJ, Painter D, Nakasuji gnificantly reduced the incidence of early post-LT 5) M, Crawford M, Shi L, Ross AG. Analysis of initial cholestasis. Likewise, the optimization of immu- poor graft function after orthotopic liver transplan- nosuppressive regimens has minimized the inci- tation: experience of an australian single liver dence of rejection, of early and late infections and transplantation center. Transplant Proc 2002; 34: of immunosuppressive drugs-related cholestasis. 1231-1235. In this scenario, DILI remains the most com- 6) Chen Hao XJ, Shen Baiyong, Deng Xiaxing, Tao Ran, mon cause of post LT cholestasis, especially in Peng Chenghong, Li Hongwei. Initial Poor Graft Dy- sfunction and Primary Graft Non-Function After the late period. Thorough investigation of me- Orthotopic Liver Transplantation, Liver Biopsy in dical history is mandatory to exclude a possible Modern Medicine. In: D. Y. Mizuguchi, ed., 2011. DILI; while the identification of a drug respon- 7) Chen GY, Nunez G. Sterile inflammation: sensing sible for cholestasis may be very difficult in the and reacting to damage. Nat Rev Immunol 2010; early postoperative period, it can be easier in the 10: 826 - 837. late phase, when pharmacological therapy is al- 8) Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver most stable. However, most of the medications ischemia and reperfusion injury: new insights into are necessary and treatment modifications should mechanisms of innate-adaptive immune-media- be done considering potential drug-to-drug inte- ted tissue inflammation. Am J Transplant 2011; 11: 1563-1569. ractions and under close clinical monitoring. 9) Ikeda T, Yanaga K, Kishikawa K, Kakizoe S, Shimada Liver biopsy maintains a crucial role in the dif- M, Sugimachi K. Ischemic injury in liver transplan- ferential diagnosis of cholestasis in the LT setting. tation: difference in injury sites between warm However, as protocol biopsies in asymptomatic and cold ischemia in rats. Hepatology 1992; 16: recipients with normal or near-normal liver tests 454-461. after years from LT are not universally performed, 10) Jaeschke H, Farhood A. Neutrophil and Kupffer liver histology is frequently obtained only when cell-induced oxidant stress and ischemia-reper- ematochemical parameters become abnormal. fusion injury in rat liver. Am J Physiol 1991; 260: G355-362. For these reasons, the management of cholesta- Fondevila C, Busuttil RW, Kupiec-Weglinski JW sis in the post LT setting is a complex medical 11) . He- patic ischemia/reperfusion injury--a fresh look. issue, and should be performed in collaboration Exp Mol Pathol 2003; 74: 86-93. with the LT center and devolved to expert hepa- 12) Ardizzone G, Stratta C, Valzan S, Crucitti M, Gal- tologists. lo M, Cerutti E. Acute blood leukocyte reduction after liver reperfusion: a marker of ischemic injury. Transplant Proc 2006; 38: 1076-1077. Conflict of interest 13) Takeuchi O, Akira S. Pattern recognition receptors The authors declare no conflicts of interest. and inflammation. Cell 2010; 140: 805-820. 14) Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4: 499-511. References 15) Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Im- munol 2007; 7: 179-190. Sherlock S, Dooley J. 1) Diseases of the liver and bi- 16) Baccala R, Gonzalez-Quintial R, Lawson BR, Stern liary system. Blackwell Science, 2002. ME, Kono DH, Beutler B, Theofilopoulos AN. Sen- 2) Uemura T, Randall HB, Sanchez EQ, Ikegami T, Nara- sors of the innate immune system: their mode of simhan G, McKenna GJ, Chinnakotla S, Levy MF, Gold- action. Nat Rev Rheumatol 2009; 5: 448-556.

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