Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2017; 21 (1 Suppl): 23-36 Post-liver transplant intrahepatic cholestasis: etiology, clinical presentation, therapy F.R. PONZIANI 1 , S. BHOORI 2 , M. POMPILI 1 , M.A. ZOCCO 1 , M. BIOLATO 1 , G. MARRONE 1 , A. GASBARRINI 1 , V. MAZZAFERRO 2 , A. GRIECO 1 1 Internal Medicine, Gastroenterology, Hepatology, Agostino Gemelli Hospital, Rome, Italy 2 Liver Transplant, Hepatobiliary and Gastrointestinal Surgery, Istituto Nazionale Tumori, Milan, Italy Abstract. – Post-liver transplant intrahepatic rum bilirubin, alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), with or cholestasis is consequent to the impairment of bile fmow 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 classifjed as extrahepatic, due to mecha - ent causes may be recognized according to the nical impairment of bile fmow (e.g. anastomotic time elapsed from a liver transplant. The raise strictures, bile stones), or as intrahepatic, associa - at various degrees of serum bilirubin, alkaline ted with impairment of liver cells or ductular dy - phosphatase, and gamma-glutamyl transpep - tidase, with or without increased transaminas - sfunction. Post LT cholestasis may develop early es levels, are common hematochemical fjnd - (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 - ding to the time elapsed from LT (Table I). tiate among possible causes of cholestasis. Al - In this review, the main causes of post LT in - though timely treatment of underling conditions trahepatic cholestasis are discussed, focusing on as well as supportive care may resolve post-liv - clinical presentation and therapeutic approach. er transplant intrahepatic cholestasis, the risk of graft loss and retransplantation are remarkable. For this reason, post-liver transplant intrahepat - ic cholestasis should be managed in collabora - Early Post-Liver Transplant tion with the LT center, and treatment should be Intrahepatic Cholestasis devolved to expert hepatologists. In the early post LT period intrahepatic chole - stasis is common, usually subclinical and self-li - Key Words: miting. However, some patients may develop pro - Cholestasis, Liver transplant, Ischemia reperfusion, 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 fjrst 10 days after LT 2 . It is characterized fective bile fmow or formation 1 . It may result from by rapidly rising transaminases, absence of bile pro - an altered uptake, transfer and secretion of bile duction, severe coagulation defjcit, 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 defjned 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 present 1 . Blood exami - criteria of IPGF, which is mainly characterized by nations show the raise at various degrees of se - elevation of serum transaminases 3-5 . Corresponding Author: Francesca R. Ponziani, MD; e-mail: francesca.ponziani@yahoo.it 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 infmammatory cells to the endothelium, for PNF and to 36% for IPGF, respectively; PNF increased interstitial fmuid and endothelial vaso - is responsible for 81% of re-transplantations du - constriction 18 . The activation of the immune sy - ring the fjrst week after surgery 6 . 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 programs 17 . This sustains the pro-infmammatory process and produces liver da - Ischemia/Reperfusion Injury mage. Ischemia reperfusion injury (IRI) is the con - sequence of the infmammatory 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 infmam - preservation techniques and is increased by do - mation”, which develops in the absence of any nor starvation, age, and graft steatosis 19 . Several microorganism 7 . measures can be adopted to reduce the risk of IRI Two major types of IRI can be recognized. in predisposed organs 20 . 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 elsewhere 19 . 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, IRI 8,9 . 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 fjrst 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 specifjc additives). consequence of the metabolic derangement asso - Small-For-Size Syndrome ciated with infmammatory damage. Reperfusion injury phase can be further distinguished in early Living donor LT (LDLT) is a common practice (or acute), occurring within the fjrst 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 infjltration beginning at 18-24 reduce the waiting list period. In practice, donor’s hours post-reperfusion 9-12 . 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 infmammasome 17 . 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 weight 21 . have reported a stimulation of adaptive immune Therefore, the right liver lobe is usually prefer - response. The “no refmow” 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 infmammation; in particular, blood useful estimated parameters are graft volume to fmow mechanical obstruction is caused by adhe - standard liver volume (SLV) ratio, and graft wei - 24
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