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Abstract
Biliary complications (BCs) remain one of the most outstanding factors influencing long-term results after orthotopic liver transplantation. The authors carried out a systematic overview of 1720 papers since 2008, and focused on 45 relevant ones. Among 14,411 transplanted patients the incidence of BCs was 23%. Biliary leakage occurred in 8.5%, biliary stricture in 14.7%, mortality rate was 1–3%. Risk factors: preoperative sodium level; p = 0.037, model of end-stage liver disease score >25; p = 0.048, primary sclerosing cholangitis; p = 0.001, malignancy; p = 0.026, donor age >60, macrovesicular graft steatosis; p = 0.001, duct-to-duct anastomosis; p = 0.004, long anhepatic phase; p = 0.04, cold ischemic time >12 h; p = 0.043, use of T-tube; p = 0.032, insufficient flush of bile ducts; p = 0.001, acute rejection; p = 0.003, cytomegalovirus infection; p = 0.004 and hepatic artery thrombosis; p = 0.001. The management was surgical in case of biliary leakage, and interventional radiology or endoscopic retrograde cholangiopancreatography in case of biliary stricture. Mapping of miRNA profile is a new field of research. Nemes–Doros score is a useful tool in the estimation of hepatic artery thrombosis. Management of BCs requires a multidisciplinary expert team.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Along with cadaveric donor organ shortage, the proportion of extended criteria organs increases. Advanced donor age and macrovesicular steatosis are two proven independent risk factors for the development of BCs. Whenever these factors are already given, facts at organ harvesting extra challenges must be avoided. Preservation injury is underestimated. Bile ducts must be carefully flushed.
If possible, an extended criteria organ must never be given to a recipient with extensive risk factors. Extended criteria donors (age older >70 years, cardiocirculatory death donors), steatotic liver, prolonged cold ischemic time (CIT) are independent risk factors for biliary complications (BC). The risk will even be higher, when additive risk factors are present on the recipient side, like high model of end-stage liver disease score.
Some centers argue for a simultaneous portal and arterial revascularization at implantation. That has its benefits in easy cases. Surgery has its subjective factors also. This is proven that the incidence of hepatic artery thrombosis (HAT) is higher when the arterial anastomosis is performed on tiny vessels, after a heavy hepatectomy, made overnight. To avoid HAT/HAS, a sequential revascularization is suggested, and a change for a relaxed new team or a short break is suggested, before arterial anastomosis.
In the past few years, microsurgical technique has become the most favored technique in biliary reconstruction, especially in living-related liver transplantation (LRLT) cases. The benefit of performing an anastomosis under microscopy is not only the better vision, but the prevention of ischemic damage on vulnerable small ducts.
The use of T-tubes had been abandoned in the last 10 years in vast majority of centers.
According to our increasing knowledge, bile ducts are permanently under a demolishing and reconvalescing balance. It suggests that the ‘future’ of bile ducts after liver transplantation is already determined at the time of harvesting: a certain proportion of them are actually devastated. Therefore, the capacity to recover will be the key factor. It might be determined by the integrity of the peribiliary plexus and glands. This is in accordance with the previous key point. Further studies are needed.
Vanishing bile duct syndrome and chronic rejection are still not completely defined entities, their causes are under debate. Immunological reasons are supported by papers that described macrophage activated syndrome, where histologically, liver involvement was characterized by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury similar to the vanishing bile duct syndrome. Inflammatory changes and bile duct lesions were dominated by the presence of activated macrophages and T cells, in particular CD8+ lymphocytes, and in part NK cells.
A high pre- and post-surgery hepatitis C virus (HCV)-RNA serum load were independent risk factors for anastomotic strictures. HCV positivity and BCs alone did not alter graft loss. HCV-positive patients with BCs, however, had a significantly worse graft outcome (p = 0.02).
The experience is limited, in relation to distinguishing the recurrent primary sclerosing cholangitis from other entities affecting the bile ducts (such as ischemic-type biliary lesion [ITBL], vanishing bile ducts, etc.).
The results of miRNA studies are summarized as: miR-517a, miR-892a, and miR-106a*, which are increased in the bile fluid of patients with ITBL versus patients with anastomotic BC. This is a fact that the ratio of cholangiocyte-derived miRNAs over hepatocyte-derived miRNAs taken from the graft perfusate solution correlates with ITBL. This is also proven that recurrence of HCV and after antiviral therapy revealed distinct HCV-related miR expression profiles, with significant dysregulation of those miRNAs potentially targeting mRNAs of HCV receptors. In particular, miR-194 and miR-21 might be involved in the regulation of HCV receptor proteins’ expression during HCV infection and antiviral therapy.
The role of bile salts is also under intensive research. Unparalleled secretion of bile salts and phospholipids results in cytotoxic bile formation. Longer donor liver preservation time will increase graft bile cytotoxicity. This suggests that endogenous bile salts play a role in the pathogenesis of bile duct injury.
