Liver Transplantation
Number: 0596
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses liver transplantation.
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Medical Necessity
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Aetna considers liver transplantation medically necessary for the indications listed below in Section I.B. for the following members:
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Adolescents 12 years of age or older and adults with either:
- A Model of End-stage Liver Disease (MELD) score (see Appendix) greater than 10; or
- Who are approved for transplant by the United Network for Organ Sharing (UNOS) Regional Review Board; or
- Who meet the transplant institution's selection criteria; and
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Children less than 12 years of age who meet the transplanting institution's selection criteria.
In the absence of an institution's selection criteria, requests for liver transplantation are subject to medical necessity review for children, and for adolescents and adults with a MELD score of 10 or less who have not been approved by the UNOS Regional Review Board.
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Medically Necessary Indications (not an all-inclusive list)
Aetna considers orthotopic (normal anatomical position) liver transplantation (with cadaveric organ, reduced-size organ, living related organ, and split liver) medically necessary for members with end-stage liver disease (ESLD) due to any of the following conditions who meet medical necessity criteria in Section I.A.:
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Acute liver failure
- Hepatitis A, acetaminophen, autoimmune hepatitis
- Hepatitis B
- Hepatitis C, cryptogenic
- Drugs, hepatitis D
- Wilson's disease, Budd-Chiari syndrome
- Fatty infiltration (i.e., acute fatty liver of pregnancy, Reye's syndrome)
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Cholestatic diseases
- Biliary atresia;
- Familial cholestatic syndromes (e.g., Alagille syndrome, Byler's disease);
- Primary biliary cirrhosis;
- Primary sclerosing cholangitis with development of secondary biliary cirrhosis;
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Hepatocellular diseases
- Alcoholic cirrhosis;
- Chronic active hepatitis with cirrhosis (hepatitis B or C);
- Cryptogenic cirrhosis;
- Idiopathic autoimmune hepatitis;
- Post-necrotic cirrhosis due to hepatitis B surface antigen negative state;
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Malignancies
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Primary hepatocellular carcinoma confined to the liver when all of the following criteria are met:
- Any lung metastases that have been shown to be responsive to chemotherapy; and
- Member is not a candidate for subtotal liver resection; and
- Member meets UNOS criteria for tumor size and number; and
- There is no identifiable extra-hepatic spread of tumor to surrounding lymph nodes, abdominal organs, bone or other sites; and
- There is no macrovascular involvement;
Note: These criteria are intended to be consistent with UNOS guidelines for selection of liver transplant candidates for hepato-cellular carcinoma (HCC).
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Hepatoblastomas in members less than 12 years of age when all of the following criteria are met:
- Member is not a candidate for subtotal liver resection; and
- Member meets UNOS criteria for tumor size and number; and
- There is no identifiable extra-hepatic spread of tumor to surrounding lungs, abdominal organs, bone or other sites; Note: Spread of hepatoblastoma to veins and lymph nodes does not disqualify a member for coverage of a liver transplant;
- Epithelioid hemangioendotheliomas;
- Intra-hepatic cholangiocarcinomas (i.e., cholangiocarcinomas confined to the liver);
- Large, unresectable fibrolamellar HCCs;
- Metastatic neuroendocrine tumors (carcinoid tumors, apudomas, gastrinomas, glucagonomas) in persons with severe symptoms and with metastases restricted to the liver, who are unresponsive to adjuvant therapy after aggressive surgical resection including excision of the primary lesion and reduction of hepatic metastases;
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Vascular diseases
- Budd-Chiari syndrome;
- Veno-occlusive disease;
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Metabolic disorders and metabolic liver diseases with cirrhosis (not an all-inclusive list)
- Alpha 1-antitrypsin deficiency;
- Hemochromatosis;
- Inborn errors of metabolism;
- MASLD/MASH (metabolic dysfunction-associated steatotic liver disease);
- Protoporphyria;
- Wilson's disease;
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Miscellaneous
- Drug and Toxin-induced fulminant hepatic failure (e.g., acetaminophen overdose, mushroom toxicity);
- Familial amyloid polyneuropathy;
- Polycystic disease of the liver;
- Porto-pulmonary hypertension (pulmonary hypertension associated with liver disease or portal hypertension) in persons with a mean pulmonary artery pressure by catheterization of less than 35 mmHg;
- Trauma;
- Hepato-pulmonary syndrome when the following selection criteria are met:
- Arterial hypoxemia (PaO2 less than 60 mm Hg or AaO2 gradient greater than 20 mmHg in supine or standing position); and
- Chronic liver disease with non-cirrhotic portal hypertension; and
- Intrapulmonary vascular dilatation (as indicated by contrast-enhanced echocardiography, technetium-99 macroaggregated albumin perfusion scan, or pulmonary angiography).
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Retransplantation
Aetna considers retransplantation following a failed liver transplant medically necessary if the initial transplant was performed for a covered indication.
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Normothermic Machine Perfusion of Transplanted Liver
Aetna considers normothermic machine perfusion medically necessary for liver transplantation.
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Compatibility Testing
Aetna considers compatibility testing of prospective liver donors medically necessary for living donor liver transplantation. Note: Compatibility testing and related services of the prospective live donor, as well as inpatient care of a compatible live donor for the donation procedure, may be covered under the member's medical benefit.
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Contraindications
Aetna considers liver transplantation not medically necessary for members with any of the following absolute contraindications to liver transplantation:
- Active sepsis outside the biliary tract;
- Inability to adhere to the regimen necessary to preserve the transplant including homelessness, active substance abuseFootnote1* (e.g., alcohol, cocaine, crystal meth, heroin, methadone, and/or narcotics, etc.), and/or unstable psychiatric disease/ psychosocial problem"
- Other effective medical treatments or surgical options are available;
- Presence of significant organ system failure other than kidney, liver or small bowel.
Footnote1* Exception to this contraindication will be allowed with supporting documentation (within 4 weeks) demonstrating 3 months of stability from treating addiction medical professional or psychiatrist.
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Experimental, Investigational, or Unproven
The following interventions are considered experimental, investigational, or unproven because their safety and effectiveness has not been established:
- Bioartificial liver transplantation;
- Biomarkers (acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood T-cell activation, interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens) for diagnosis of acute allograft rejection following liver transplantation;
- Ectopic or auxiliary liver transplantation;
- Factor V Leiden and F2 testing for member scheduled to receive partial liver transplant for primary sclerosing cholangitis;
- Hepatocellular (hepatocyte) transplantation;
- HepatoTrack for prediction of acute allograft rejection following liver transplantation;
- Hypothermic machine perfusion for reduction of the incidences of early allograft dysfunction and biliary complications after LT;
- Liver elastography and Doppler examination of the portal veins and hepatic arteries for routine yearly surveillance following liver transplantation;
- Liver transplantation for malignancies other than those listed as medically necessary above;
- Measurements of plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL) for predicting acute kidney injury following orthotopic liver transplantation;
- Molecular Adsorbent Recirculating System (MARS) for the treatment of progressive familial intrahepatic cholestasis;
- Normothermic machine perfusion of donor liver;
- OmniGraf Liver for prediction of acute allograft rejection following liver transplantation;
- OrganOx metra System for transportation and preservation of the liver prior to transplantation;
- Peri-operative use of vasopressin in liver transplantation;
- Peri-operative use of sorafenib in liver transplantation;
- Scaffold-based transplantation (combination of xeno-organ and cell transplantations) as an alternative for orthotopic LT;
- Testing of high mobility group box protein 1 (HMGB1) gene polymorphisms for prediction of morbidity and mortality after liver transplantation;
- Transient elastography for diagnosis of acute cellular rejection following liver transplantation;
- Ursodeoxycholic acid (UDCA), adjuvant use to prevent acute cellular rejection after liver transplantation;
- Xenotransplantation.
Note: For policy on hepatitis B immune globulin for prophylaxis of recurrent hepatitis B infection in HbsAg positive liver transplant recipients, see CPB 0544 - Immune Globulins for Post-Exposure Prophylaxis.
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Related Policies
Background
Progressive liver diseases that lead to death, either in the short term or long term, are referred to as end-stage liver disease (ESLD). This condition is characterized by irreversible, progressive liver dysfunction, which may manifest as variceal bleeding, encephalopathy, synthetic dysfunction, poor growth, or poor nutritional status. The most common causes of ESLD include infections (e.g., acute or chronic hepatitis), toxic effects (e.g., alcohol, medications), metabolic disorders (e.g., hemochromatosis, Wilson's disease), tumors (both primary and metastatic), and malformations (e.g., primary biliary atresia). Liver transplantation is an effective treatment for fulminant (acute) hepatic failure and for many chronic liver diseases.
A liver transplant is typically positioned in the normal anatomical position (orthotopic) following a total hepatectomy of the recipient. In auxiliary liver transplantation, a second liver is implanted ectopically while the recipient's own liver remains in situ. A major concern with ectopic transplantation is that the recipient's diseased liver may harbor bacterial, fungal, or viral infections, or cancer. Advances in surgical techniques and immunosuppressive drugs have led to increased survival rates, with 1-year survival rates in the range of 85% to 90%, and 5-year survival rates exceeding 70%. Currently, 10% to 20% of liver transplant patients undergo retransplantation, with a success rate of greater than 50%.
Hepatitis C cirrhosis is the most common indication for liver transplantation. Alcoholic liver disease remains a controversial indication for liver transplantation; however, carefully selected patients tend to do well. Some of the common indications for liver transplantation include the following:
- Alcoholic liver disease (after a period of abstinence)
- Chronic active hepatitis (usually secondary to hepatitis B and C)
- Cryptogenic cirrhosis
- Primary biliary cirrhosis
- Primary sclerosing cholangitis.
Hepatocellular carcinoma (HCC) complicates many chronic liver diseases. However, a small tumor is not a contraindication to transplantation, as tumors rarely recur in these patients. In contrast, most patients with large tumors (greater than 5 cm in diameter) or multiple hepatomas, as well as most other types of cancer, are not considered for transplantation due to the rapid recurrence of tumors. Currently, there is insufficient evidence to support liver transplantation as an effective treatment for other malignancies affecting the liver, such as metastatic disease, bile duct carcinoma, and epithelioid hemangioendothelioma, among others. An assessment by the Agency for Healthcare Research and Quality (Beavers et al., 2001) on liver transplantation for malignancies other than HCC concluded that “[t]he available evidence does not provide a clear profile of patients who might be optimal candidates for such therapy.” Contraindications to liver transplantation include extra-hepatic malignancy, severe cardiopulmonary disease, systemic sepsis, and an inability to comply with regular pharmacotherapy.
Liver transplantation is an effective treatment for a variety of acute and chronic liver diseases in the pediatric population (less than 18 years of age). Approximately 15% of liver transplantations performed yearly in the United States are in pediatric patients. Most children who require liver transplantation are young (under 3 years of age) and small (weighing less than 45 pounds). Size-matched organs are given preference in organ allocation. However, due to the severe scarcity of pediatric donor livers, techniques such as reduced size (“cut down”) and split liver transplantations (where a liver is split between two recipients) are employed to adapt adult donor livers for pediatric recipients. Donation of the left lobe of the liver by a living adult relative (“living related donor”) is also an option. Liver transplantation in children is indicated for end-stage liver disease (ESLD) from any etiology in the absence of contraindications. The most common indication for pediatric liver transplantation is biliary atresia, often following failure to respond to a porto-enterostomy. Additionally, unresectable tumors and liver-based metabolic deficiencies may also warrant liver transplantation.
The Model for End-Stage Liver Disease (MELD) is a numerical scale ranging from 6 (less ill) to 40 (gravely ill) used for adult liver transplant candidates. It assigns each individual a 'score' based on how urgently they need a liver transplant within the next three months. The score is calculated using a formula that incorporates bilirubin, prothrombin time, and creatinine levels. Candidates under the age of 12 are categorized according to the Pediatric End-stage Liver Disease (PELD) scoring system. PELD is similar to MELD but uses different criteria to address the specific growth and development needs of children. PELD scores may range higher or lower than MELD scores. The PELD scoring system considers the patient's bilirubin, prothrombin time, albumin levels, growth failure, and whether the child is under 1 year old. A liver transplantation is rarely necessary for individuals with a MELD score of less than 10. According to data from the United Network for Organ Sharing (UNOS), of nearly 5,000 liver transplants performed in 2002, only 181 transplants were conducted on patients with a MELD score of less than 10.
The MELD/PELD score is a well-validated measure of short-term mortality from liver disease; however, referring physicians who believe a patient faces a greater mortality risk than predicted by the MELD/PELD score can request accelerated listing. UNOS Regional Review Boards can approve or deny these requests, and a study by Voight et al. (2004) concluded that these boards fairly and accurately distinguish between high- and low-risk patients. The study found that denials of physicians' requests for accelerated listings did not increase mortality for those patients. To determine the effect of UNOS Regional Review Board decisions on the mortality of physician-referred patients, investigators analyzed 1,965 nationwide referrals to UNOS Regional Review Boards. They noted which cases were approved and which were denied, and gathered information about patient deaths while awaiting transplantation. The investigators found no significant difference in survival to transplantation, whether accelerated listing was approved or denied for adult or pediatric cases. Additionally, the researchers examined whether referring physicians predicted death better than the MELD/PELD score. They found that physicians had poor predictive capacity and added no additional information to the risk assessment provided by the MELD/PELD score. The investigators concluded that the MELD-PELD score is a better predictor of mortality than the judgment of the referring physician, but the UNOS Regional Review Board process adds additional information (e.g., Voight et al., 2004).
Dimmock et al. (2008) noted that deoxyguanosine kinase (DGUOK) deficiency is the most common type of mitochondrial DNA depletion associated with a hepato-cerebral phenotype. These researchers assessed predictors of survival and therapeutic options in patients with DGUOK deficiency. A systematic search of MEDLINE, LILAC, and SCIELO was performed to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other studies of clinical relevance. Deoxyguanosine kinase deficiency was searched using the terms dGK, DGUOK, mitochondrial DNA depletion, mtDNA, and hepatocerebral. Bibliographies of identified articles were reviewed for additional references. A total of 13 studies met the inclusion criteria and were used in this analysis. The findings revealed that DGUOK deficiency is associated with a variable clinical phenotype. Long-term survival is best predicted by the absence of profound hypotonia, significant psychomotor retardation, or nystagmus. In the presence of these features, there is increased mortality, and liver transplantation does not confer increased survival. The authors concluded that liver transplantation appears to be futile in the presence of specific neurological signs or symptoms in patients affected by DGUOK deficiency. Conversely, in the absence of these neurological features, liver transplantation may be considered a potential treatment.
Varma et al. (2011) described indications for liver transplantation in the context of assessing need based on disease severity and projected mortality. The review described that patients with chronic liver disease and selected cases of acute liver failure required transplantation as a life-saving measure, with allocation guided by objective scoring systems. The model for end-stage liver disease score was calculated using serum creatinine, total bilirubin, and international normalized ratio, with higher scores indicating greater urgency, and patients with a score ≥30 categorized as higher priority for transplantation. The Child-Turcotte-Pugh classification and PELD score were also used to stratify risk and predict short-term mortality. Referral criteria included MELD score >10 or Child-Turcotte-Pugh score >7, along with decompensated liver disease features such as ascites, variceal hemorrhage, encephalopathy, and jaundice. The review further described that patients qualifying for transplantation generally had an expected survival ≤90% at 1 year without transplantation. In acute liver failure, criteria such as the King’s College criteria were used to identify patients requiring urgent transplantation, noting that selected patients had 100% mortality without intervention. For chronic liver disease, a projected 1-year mortality of at least 10% without transplantation supported listing. Additional frameworks, including tumor-specific criteria such as the Milan criteria for hepatocellular carcinoma, defined eligibility based on tumor size and number, with a single lesion <5 cm or up to three lesions each <3 cm in the absence of vascular invasion or metastases. The authors included the following indications for liver transplantation (not an all-inclusive list) — acute liver failure due to hepatitis A, acetaminophen toxicity, autoimmune hepatitis, hepatitis B, hepatitis C, cryptogenic causes, drugs, hepatitis D, Wilson’s disease, Budd-Chiari syndrome, and fatty infiltration such as acute fatty liver of pregnancy and Reye’s syndrome. Cirrhosis from chronic liver disease included chronic hepatitis B virus infection, chronic hepatitis C virus infection, alcoholic liver disease, autoimmune hepatitis, cryptogenic liver disease, and nonalcoholic fatty liver disease. Malignant diseases of the liver included hepatocellular carcinoma, carcinoid tumor, islet cell tumor, epithelioid hemangioendothelioma, and cholangiocarcinoma. Metabolic liver diseases included Wilson’s disease, hereditary hemochromatosis, alpha-1 antitrypsin deficiency, glycogen storage disease, cystic fibrosis, Crigler-Najjar syndrome, galactosemia, type 1 hyperoxaluria, familial homozygous hypercholesterolemia, and hemophilia A and B. Vascular diseases included Budd-Chiari syndrome and veno-occlusive disease. Cholestatic liver diseases included primary biliary cirrhosis, primary sclerosing cholangitis, secondary biliary cirrhosis, biliary atresia, Alagille syndrome, and Byler’s disease.
Acute In-Patient Rehabilitation After Liver Transplantation
Mina et al. (2022) noted that the indication and surgical complexity of OLT underscore the need for strategies to optimize the recovery for transplant recipients. In a systematic review, these researchers identified, evaluated, and synthesized the evidence examining the effect of in-patient rehabilitation for LT recipients and provided related practice recommendations. Health research databases were systematically reviewed for studies that included adults who received LT and participated in acute, post-transplant rehabilitation. Post-operative morbidity, mortality, hospital LOS, ICU LOS, and other markers of surgical recovery were extracted. Practice recommendations were provided by an international panel using GRADE. A total of 12 studies were included in the review (including 3,901 participants). Rehabilitation interventions varied widely in design and composition; however, details regarding intervention delivery were poorly described in general. The quality of evidence was rated as very low largely owing to “very serious” imprecision, poor reporting, and limited data from comparative studies. Overall, the studies suggested that in-patient rehabilitation for recipients of LT was safe, tolerable, and feasible, and may benefit functional outcomes. The authors concluded that 2 practice recommendations related to in-patient rehabilitation following LT were yielded from this review. First, it was safe, tolerable, and feasible. Second, it improved post-operative functional outcomes. Each of the recommendations was weak and supported by low-quality of evidence. These investigators stated that no recommendation could be made related to benefits or harms for clinical, physiological, and other outcomes. They stated that adequately powered and high-quality RCTs are needed in this area.
Anti-Thrombotic Therapy for Prevention of Graft Thrombosis in Liver Transplant Recipients
Surianarayanan and colleagues (2021) noted that graft thrombosis is a well-recognized complication of solid organ transplantation and is one of the leading causes of graft failure. Currently, there are no standardized protocols for thrombo-prophylaxis, and many transplant units utilize unfractionated heparin (UFH) and low molecular weight heparin (LMWH) as prophylactic measures against thrombosis. Antiplatelet agents, such as aspirin, are routinely used to prevent other thrombotic conditions and may also play a role in preventing graft thrombosis. However, any pharmacological thrombo-prophylaxis carries the theoretical risk of increasing major blood loss following transplantation. In a Cochrane review, these investigators examined the benefits and harms of instituting thrombo-prophylaxis in patients undergoing solid organ transplantation. They searched the Cochrane Kidney and Transplant Register of Studies up to November 10, 2020, using relevant search terms. Studies in the Register are identified through searches of CENTRAL, Medline, Embase, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. The researchers included all randomized controlled trials (RCTs) and quasi-RCTs designed to evaluate interventions aimed at preventing thrombosis in solid organ transplant recipients, encompassing all donor types (donor after circulatory death [DCD], donor after brain death [DBD], and live transplantation). There was no upper age limit for recipients in the search. The results of the literature search were screened, and data were collected by two independent authors. Dichotomous outcome results were expressed as risk ratios (RR) with 95% confidence intervals (CI), and random effects models were employed for data analysis. The risk of bias was independently assessed by two authors using a risk of bias assessment tool, and confidence in the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
The investigators identified nine studies involving 712 participants; seven studies (544 participants) included kidney transplant recipients, while the remaining studies involved liver transplant recipients. No studies were found that enrolled heart, lung, pancreas, bowel, or other solid organ transplant recipients. Selection bias was high or unclear in eight of the nine studies, and five studies were at high risk of bias for performance and/or detection bias. Attrition and reporting biases were generally low or unclear. Three studies (180 participants) primarily examined heparinization in kidney transplantation, with only two studies reporting on graft vessel thrombosis in kidney transplantation (144 participants). These small studies were at high risk of bias in several domains and reported only two graft thromboses between them, leaving it unclear whether heparin decreased the risk of early graft thrombosis or non-graft thrombosis (very low certainty). UFH may make little or no difference compared to placebo regarding the rate of major bleeding events in kidney transplantation (3 studies, 155 participants: RR 2.92, 95% CI: 0.89 to 9.56; I² = 0%; low certainty evidence). Sensitivity analysis using a fixed-effect model suggested that UFH may increase the risk of hemorrhagic events compared to placebo (RR 3.33, 95% CI: 1.04 to 10.67, p = 0.04). Compared to control, any heparin (including LMWH) may make little or no difference in the number of major bleeding events (3 studies, 180 participants: RR 2.70, 95% CI: 0.89 to 8.19; I² = 0%; low certainty evidence) and had an unclear effect on the risk of re-admission to intensive care (3 studies, 180 participants: RR 0.68, 95% CI: 0.12 to 3.90, I² = 45%; very low certainty evidence). The effect of heparin on other outcomes, including death, patient and graft survival, and transfusion requirements, remained unclear (very low certainty evidence). Three studies (144 participants) examined antiplatelet interventions in kidney transplantation: one study compared aspirin versus dipyridamole, and two studies assessed Lipo-PGE1 plus low-dose heparin in patients diagnosed with acute rejection. None of these studies reported on early graft thromboses, and the effects of aspirin, dipyridamole, and Lipo-PGE1 plus low-dose heparin on any outcomes were unclear (very low certainty evidence). Two studies (168 participants) examined interventions in liver transplants, with one comparing warfarin versus aspirin in patients with pre-existing portal vein thrombosis and the other investigating plasmapheresis plus anticoagulation. Both studies were abstract-only publications, had a high risk of bias in several domains, and no outcomes could be meta-analyzed. Overall, the effects of these interventions on any outcomes remained unclear, with no evidence to guide anti-thrombotic therapy in standard liver transplant recipients (very low certainty evidence).
The authors concluded that there is a significant lack of research in the field of graft thrombosis prevention. Due to the absence of high-quality evidence, it remains unclear whether any therapy can effectively reduce the rate of early graft thrombosis in any type of solid organ transplant. UFH may increase the risk of major bleeding in kidney transplant recipients; however, this conclusion is based on low certainty evidence. There is no evidence from RCTs to guide anti-thrombotic strategies in liver, heart, lung, or other solid organ transplants. The researchers emphasized the need for further studies to compare anticoagulants and antiplatelets to placebo in solid organ transplantation, focusing on outcomes such as early graft thrombosis, major hemorrhagic complications, return to the operating room, and patient/graft survival.
Bioartificial Liver Transplantation
Artificial and bioartificial livers have been developed for use as a bridge to transplant in patients with liver failure or to facilitate recovery in individuals with acute liver failure. Liu et al. (2004) conducted a meta-analysis of 12 trials comparing artificial or bioartificial support systems to standard medical therapy, involving 483 patients, as well as 2 trials comparing different artificial support systems, involving 105 patients. Most trials exhibited unclear methodological quality. Compared to standard medical therapy, support systems showed no significant effect on mortality (relative risk [RR] 0.86; 95% confidence interval [CI]: 0.65 to 1.12) or bridging to liver transplantation (RR 0.87; 95% CI: 0.73 to 1.05), but demonstrated a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI: 0.52 to 0.86). Subgroup analysis indicated that artificial and bioartificial livers may reduce mortality by one-third in acute-on-chronic liver failure (RR 0.67; 95% CI: 0.51 to 0.90), but not in acute liver failure (RR 0.95; 95% CI: 0.71 to 1.29). The authors noted that the incidence of adverse events was inconsistently reported. They concluded that, although artificial support systems may reduce mortality in acute-on-chronic liver failure, “considering the strength of the evidence, additional randomized clinical trials are needed before any support system can be recommended for routine use.”
More recently, Demetriou et al. (2004) reported on the first prospective, randomized controlled trial of a bioartificial liver, the HepatAssist Liver Support System, involving 171 patients with severe acute liver failure, including both fulminant/sub-fulminant hepatic failure and primary non-function following liver transplantation. For the entire patient population, survival at 30 days was 71% for patients assigned to the bioartificial liver compared to 62% for patients in the control group (p = 0.26). After excluding patients with primary non-function, survival was 73% for those assigned to the bioartificial liver versus 59% for those in the control group (p = 0.12). When survival was analyzed while accounting for confounding factors, there was no difference between the two groups in the entire patient population (risk ratio = 0.67; p = 0.13). However, differences in survival between bioartificial liver and control patients with fulminant/sub-fulminant hepatic failure reached marginal statistical significance (risk ratio = 0.56; p = 0.048). The authors concluded that this study demonstrated improved survival in patients with fulminant/subfulminant hepatic failure, but emphasized that these results would need to be confirmed in additional prospective randomized studies before definitive conclusions can be drawn about the effectiveness of the bioartificial liver.
Biomarkers for Diagnosis of Acute Allograft Rejection following Liver Transplantation
Krenzien and colleagues (2019) stated that non-invasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection following liver transplantation. However, none has been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard. These investigators performed a systematic review and meta-analysis of diagnostic biomarkers for non-invasive diagnosis of acute allograft rejection following liver transplantation. Systematic literature searches of Medline, Cochrane and Embase were conducted up to February 2019 to identify studies evaluating the use of non-invasive markers in diagnosing allograft rejection following liver transplantation. Meta-analysis was performed using a random effects model with DerSimonian-Laird weighting and the hierarchical summary receiver operating curve. Of 560 identified studies, 15 studies (1,445 patients) met the inclusion criteria. The following markers were tested: acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood eosinophil count, peripheral blood T-cell activation and interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens. Only eosinophil count was tested in multiple studies, and they demonstrated high heterogeneity (I 2 = 72% [95% CI: 0.5 to 0.99]). IL-2 receptor demonstrated the highest sensitivity (89% [95% CI: 0.78 to 0.96]) and specificity (81% [95% CI: 0.69 to 0.89]). The authors concluded that IL-2 receptor expression demonstrated the highest diagnostic accuracy, while the peripheral eosinophil count was the only marker tested in more than 1 study. These researchers stated that currently, liver biopsy remains superior to non-invasive diagnostic biomarkers as most studies exhibited inferior designs, hindering possible translation into clinical application at this time.
Epstein-Barr Viral Load Monitoring
Ruijter et al. (2023) stated that primary infection with or reactivation of Epstein-Barr virus (EBV) can occur following LT and can lead to post-transplant lymphoproliferative disease (PTLD). In pediatric LT, an EBV-DNA viral load (EBV VL) monitoring strategy, including the reduction of immunosuppression, has led to a lower incidence of PTLD. For adult LT recipients with less primary infection and more EBV reactivation, it is unknown whether this strategy is effective. In a retrospective, cohort study, these researchers examined the effect of an EBV VL monitoring strategy on the incidence of PTLD following LT in adults. Adult recipients of 1st LT in Leiden between September 2003 and January 2017 with an EBV VL monitoring strategy formed the monitoring group (M1), recipients of 1st LT in Rotterdam between January 2003 and January 2017 without such a strategy formed the contemporary control group (C1), and those who had transplants in Leiden between September 1992 and September 2003 or Rotterdam between 1986 and January 2003 formed the historical control groups (M0 and C0, respectively). Measurements entailed influence of EBV VL monitoring on incidence of PTLD. After inverse probability of treatment weighting of the 4 groups to achieve a balance among the groups for important patient characteristics, differences within hospitals between the historical and recent era in cumulative incidences -- expressed as the number of events per 1,000 patients measured at 5-, 10-, and 15-year follow-up-showed fewer events in the contemporary era in both centers. This difference was considerably larger in the monitoring center, whereas the 95% CI included the null value of 0 for point estimates. The authors concluded that monitoring EBV VL may reduce PTLD incidence after LT in adults; however, larger studies are needed. The drawbacks of this study included retrospective design, low statistical power, and incompletely balanced groups, and non-EBV PTLD could not be prevented.
Factor V Leiden and F2 Testing is for Individuals Scheduled to Receive Partial Liver Transplant for Primary Sclerosing Cholangitis
Perez-Pujol and colleagues (2012) noted that limited information is available regarding the impact of factor V Leiden (FVL) on clinical events characterized by prevalent inflammation. Conditions such as uremia, cirrhosis, liver transplantation, sepsis (a generalized inflammatory state also known as systemic inflammatory response syndrome [SIRS]), infection, and inflammatory bowel disease (IBD) result in a chronic inflammatory state. Although the mechanisms of action and clinical management of these conditions are well established, a final consensus has not been reached on whether FVL modifies the outcomes of these events.
Fan and associates (2013) stated that hepatic artery thrombosis (HAT) following orthotopic liver transplantation (OLT) is associated with significant morbidity and mortality, with the FVL mutation being the most common genetic defect predisposing individuals to thrombosis. The reconstruction of the hepatic artery with an arterial graft is a documented risk factor for HAT; however, the relationship among the FVL mutation, arterial grafts, and HAT remains to be determined. These researchers randomly genotyped 485 patients who underwent OLT from April 2002 to January 2011 and studied the incidence of HAT in the presence of the FVL mutation. Among the 485 patients, 21 (4.3%) developed HAT (13 men and 8 women), with 10 patients (4 men and 6 women) being heterozygous for the FVL mutation. The incidences of HAT in patients without versus with the FVL mutation were 3.8% and 30%, respectively (p = 0.007). Of the patients with HAT, 8 hepatic arteries were reconstructed with infra-renal aortic conduits. All 3 patients (100%) with FVL who received arterial grafts developed HAT, compared to 5 (28%) without FVL (p = 0.042). The authors concluded that their findings suggest that the FVL mutation may be a risk factor for HAT in liver transplantation, with the risk being augmented in the presence of an arterial graft.
Kupeli and co-workers (2015) noted that solid-organ transplant recipients can develop chronic hyper-coagulation, which increases the incidence of pulmonary embolism (PE). These investigators evaluated the frequency of PE in solid-organ transplant recipients during the first 10 years after transplantation and assessed the risk factors for its development. They retrospectively reviewed the medical records of solid-organ transplant recipients treated between 2003 and 2013, including demographics, type of transplant, co-morbidities, pro-coagulation factors, thrombo-embolism prophylaxis, and the timing and extent of PE. A total of 999 solid-organ transplant recipients were included in the study (661 renal and 338 liver transplant recipients), with a male-to-female ratio of 665:334. PE was diagnosed in 12 renal (1.2%) and 1 liver transplant recipient (0.3%), with PE developing 1 year after transplantation in 10 patients. One patient developed PE less than 3 months after transplantation, while the other 9 developed PE within 3 to 6 months. None of the patients had a prior history of deep venous thrombosis (DVT) or PE. Among the patients, 5 received tacrolimus, 7 received sirolimus, and 1 received cyclosporine; 10 patients received prednisolone, and 8 received mycophenolate mofetil. All patients were homozygous normal for FVL and prothrombin genes; 1 patient was homozygous abnormal, and 1 had a heterozygous mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Two patients were treated with low-molecular-weight heparin (LMWH), while the remaining patients received warfarin, with 8 patients treated for 6 months and the others receiving longer treatments. The authors concluded that the incidence of PE in solid-organ transplant recipients was 1.2%, with renal transplant recipients at a higher risk of developing PE than liver transplant recipients. The factors increasing the risk of PE in solid-organ transplant recipients appeared to be multifactorial, including genetic predisposition.
Bagheri Lankarani and colleagues (2015) stated that portal vein thrombosis (PVT) is a relatively common and potentially life-threatening complication in patients with liver cirrhosis. The risk factors for PVT in these patients are not fully understood. These investigators examined the associations between various risk factors in cirrhotic patients and the development of PVT. In this case-control study, they studied 219 patients (aged over 18 years) with liver cirrhosis who were awaiting liver transplantation. The patients were evaluated through history, physical examination, and laboratory tests, including assessments for FVL, prothrombin gene mutation, Janus Kinase 2 (JAK2) mutation, and serum levels of protein C, protein S, anti-thrombin III, homocysteine, factor VIII, and anti-cardiolipin antibodies. The study found no statistically significant difference in the assessed hyper-coagulable states between patients with or without PVT. However, a history of previous variceal bleeding followed by endoscopic treatment was significantly higher in patients with PVT compared to those without (p = 0.013, OR: 2.526, 95% CI: 1.200 to 5.317). The authors concluded that in this population of cirrhotic patients, treatment of variceal bleeding predisposed patients to PVT, while hyper-coagulable disorders alone were not associated with PVT.
Hepatic Glycogen Storage Disease
Beyzaei et al. (2023) noted that LT is the choice of therapeutic option for end-stage hepatic glycogen storage disease (GSD) patients; however, reports regarding the long-term outcome of LT in these patients have remained controversial. In a systematic review and meta-analysis, observational studies published until December 31, 2021 were examined regarding the long-term outcome of LT in hepatic GSD patients. They carried out a literature search in the Medline/PubMed, Embase, Cochrane Library, Scopus and Web of Science Core Collection databases was performed. A total of 14 studies with 210 patients were included in this analysis. As the results showed, the pooled proportion of GSD patients with complications following LT (e.g., hemorrhagic shock, biliary complications, tacrolimus encephalopathy, chronic hepatitis, hepatic artery thrombosis, hepatic adenoma, sepsis, liver dysfunction, chronic rejection, ACR, and cytomegalovirus (CMV) infection) was 27.7% (95% CI: 20.42 to 35.67) without heterogeneity (I2 = 24.04%), as calculated by the random-effect model. The pooled proportion of GSD patients with complications related to GSD following LT, including HCC, renal complication, muscle problems, delayed menarche, persistent neutropenia, pneumonitis, renal failure, and hepatic adenoma was 22.2% (95% CI: 7.97 to 40.01) with high heterogeneity (I2 = 82.47%). Subgroup analysis including the age of patients (adult/pediatric), duration of follow-up, and type of donor was performed to examine the resources of heterogeneity. The authors concluded that according to their investigation and review analysis, most GSD patients showed significant outcome improvement following LT. Overall, these findings showed an excellent outcome of LT in GSD patients; however, further investigations are needed to confirm these findings.
HepatoTrack
HepatoTrack by LuminoDx is a CLIA-certified liquid biopsy test that utilizes a panel of microRNA (miRNA) biomarkers to predict acute cellular rejection (ACR) following liver transplantation (LT). This test is designed for early monitoring and personalized management of immunosuppressive therapy (IST). However, there is a lack of published evidence regarding HepatoTrack in the peer-reviewed literature.
Morsiani et al. (2023) emphasized the importance of blood-circulating sensitive biomarkers for monitoring patients after LT, aiming to reduce the reliance on standard invasive protocols such as liver biopsy. These researchers examined changes in circulating microRNA (c-miR) levels in recipients' blood before and after LT, correlating these levels with gold standard biomarkers and outcomes such as rejection or complications post-graft. An initial miR profile was established, and the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT, compared to a control group of 24 non-transplanted healthy subjects. The validated miRs included miR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, which were further analyzed with an additional 19 serum samples from LT recipients at different follow-up times. The results indicated significant follow-up-related changes in c-miRs, particularly showing that miR-122-5p, miR-92a-3p, and miR-18a-5p exhibited similar trends post-LT, with increased levels observed in patients experiencing complications, regardless of follow-up times. In contrast, variations in standard hematobiochemical parameters for assessing hepatic function were not significant during the same follow-up period, underscoring the potential of c-miRs as non-invasive biomarkers for monitoring outcomes after LT.
Vidal-Correoso et al. (2024) noted that while LT is crucial for patients with end-stage liver disease (ESLD), organ shortages continue to be a challenge. Donation after circulatory death (DCD) aims to expand the donor pool but presents complications such as acute rejection, hepatic artery thrombosis, and biliary issues that affect post-transplant prognosis. Biomarkers, including extracellular vesicles (EVs) and microRNAs (miRNAs), have shown promise in understanding and monitoring post-transplant events. These researchers investigated the role of EVs and their miRNA cargo in LT, assessing their potential as diagnostic tools. They detected EVs from intra-hepatic end-ischemic organ preservation solution (eiOPS) in 79 donated livers using various techniques (nano-sight tracking analysis, transmission electron microscopy, and flow cytometry). EV-derived miRNAs were identified through quantitative real-time polymerase chain reaction (RT-PCR), and bioinformatics analysis was conducted using the R platform. The study found different-sized and origin-specific EVs in eiOPS, with significantly higher concentrations in DCD compared to donation after brain death organs. Several EV-associated miRNAs, including let-7d-5p, miR-28-5p, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, were over-expressed in DCD-derived eiOPS and exhibited differential expression patterns in liver tissue biopsies. Pathway analysis revealed enrichment in signaling pathways related to extracellular matrix organization and various cellular processes. Additionally, specific EVs and miRNAs correlated with clinical outcomes, including survival and early allograft dysfunction. A predictive model combining biomarkers and clinical variables showed promise in detecting acute rejection following LT. The authors concluded that these findings provide new insights into the use of EVs and miRNAs as biomarkers, potentially enhancing diagnostic approaches and personalized treatment strategies in LT.
Koch et al. (2024) stated that while LT is a life-saving treatment for patients with ESLD, acute cellular rejection (ACR) and graft complications remain significant postoperative challenges. Early and accurate diagnosis is crucial for timely intervention and improved patient outcomes; however, current diagnoses rely on invasive biopsy sampling, prompting the search for non-invasive biomarkers. MicroRNAs (miRNAs) have emerged as promising biomarkers in various pathological conditions, and their potential application in diagnosing ACR following LT has garnered significant interest. These investigators conducted a systematic review of PubMed, Web of Science, and the ClinicalTrials.gov registry to analyze studies examining miRNAs as biomarkers for ACR and graft dysfunction in LT. The Cochrane Collaboration tool for assessing risk of bias was utilized. Population data identified miRNAs and their dynamic regulation, as well as event prediction, which were compared. Data extraction and quality assessment were performed independently by two reviewers, resulting in the inclusion of 13 studies in the systematic review. Various miRNAs, such as miR-122, miR-155, miR-181, miR-483-3p, and miR-885-5p, were found to be up-regulated in association with ACR, indicating their potential as biomarkers. Additionally, several studies conducted target gene analysis, providing insights into cellular mechanisms linked to ACR. Moreover, various miRNAs were capable of predicting different organ complications following transplantation, highlighting their versatility. Remaining challenges include the standardization of miRNA profiling, the need for functional validation, and the necessity for long-term studies. The authors concluded that the findings of this systematic review underscore the potential of miRNAs as specific, non-invasive biomarkers for ACR and graft dysfunction following LT. They also emphasized the need for further investigations to validate these findings and establish standardized diagnostic panels for clinical practice, as well as to explore miRNA-based therapies in the future.
Julian et al. (2025) noted that identifying non-invasive biomarkers for monitoring LT recipients is essential for the early detection of graft dysfunction and rejection. Donor-derived cell-free DNA (dd-cfDNA) and microRNAs (miRNAs) have emerged as promising biomarkers for evaluating graft integrity. While dd-cfDNA levels have been validated for use in kidney and heart transplantation, data regarding its potential in liver graft monitoring are limited. Similarly, the expression levels of miRNAs, which are key regulators of immune responses and liver injury, may help distinguish between rejection and other causes of graft dysfunction. In a prospective observational study, these researchers monitored the levels of dd-cfDNA and miRNAs by analyzing 437 plasma samples from 64 LT recipients over a 12-month period, measuring dd-cfDNA levels and signature miRNAs at predefined time points and during episodes of graft dysfunction. The diagnostic performance of dd-cfDNA levels and signature miRNAs was assessed using ROC curve analysis and logistic regression models. The study found that dd-cfDNA levels were significantly elevated during acute rejection (AR) episodes, with a median 3.9-fold increase compared to stable patients. A diagnostic cut-off value of 9.88% yielded an area under the ROC curve (AUROC) of 0.812, with a sensitivity of 100%, specificity of 66.7%, positive predictive value (PPV) of 17.5%, and negative predictive value (NPV) of 100%. Interestingly, patients with cholestasis also exhibited increased dd-cfDNA levels (3.0-fold compared to stable patients), suggesting it could serve as a potential confounder in diagnosing transplant rejection. Plasma miRNA analysis revealed significant up-regulation of miR-155-5p, miR-122-5p, and miR-181a-5p during rejection episodes, and incorporating these factors improved diagnostic accuracy when combined with dd-cfDNA levels. The authors concluded that dd-cfDNA and miRNA profiling represent promising non-invasive biomarkers for diagnosing liver graft rejection and dysfunction. The combined use of these biomarkers may enhance diagnostic accuracy, reduce unnecessary biopsies, and facilitate personalized immunosuppressive management. They also stated that further investigations with larger cohorts are needed to validate the clinical applicability of these biomarkers.
Yang et al. (2025) stated that non-coding RNAs (ncRNAs) are a class of RNAs that primarily lack the capacity to encode proteins. They have gained significant attention due to their central regulatory functions across numerous cellular and physiological processes at transcriptional, post-transcriptional, and translational levels. Over the past decade, ncRNA-based therapies have garnered considerable interest in the diagnosis, treatment, and prevention of diseases, with many studies reporting significant relationships between ncRNAs and various conditions. Concurrently, due to their tissue specificity, an increasing number of projects have focused on applying ncRNAs as biomarkers in diseases, as well as designing and developing novel ncRNA-based vaccines and therapies for clinical use. These ncRNAs may also drive research into the potential molecular mechanisms and complex pathogenesis of related diseases. However, new biomarkers need to be validated for their clinical effectiveness. The researchers noted that plasma miRNAs, including miR-181a-5p, miR-155-5p, and miR-122-5p, are significantly up-regulated in patients with acute T-cell-mediated rejection (TCMAR) and sub-clinical rejection (SCR) following LT. Before transplantation, the expression levels of miR-155-5p and miR-181a-5p exhibited different trends between the two groups: miR-155-5p was significantly higher in TCMAR patients than in SCR patients, while miR-181a-5p was significantly higher in SCR patients than in TCMAR patients. This difference provides valuable insights for diagnosis and prognosis before and after LT, making these miRNAs potential candidates for a biomarker panel in liver injury following LT.
High Mobility Group Box Protein 1 (HMGB1) Gene Polymorphisms Testing for Prediction of Morbidity and Mortality after Liver Transplantation
Tsukiyama et al. (2025) examined the effect of single-nucleotide polymorphisms (SNPs) in the high mobility group box 1 (HMGB1) gene on morbidity and mortality following LT. Among 120 LT recipients and their living donors, the genotypes of HMGB1, and the SNPs rs2249825, rs1045411, rs1412125, and rs1360485 were determined. There were no significant associations between these 4 SNPs and the incidence of rejection or mortality. However, the incidence of early allograft dysfunction (EAD) (n = 43), which presents as functional insufficiency within 1 week of LT, was significantly higher in recipients with the GC + CC allele of rs2249825 (n = 17/34) than in those with the GG allele (n = 26/86) (p = 0.044). Although the impact of donor HMGB1 SNPs on the incidence of EAD was not statistically significant, recipients with the GC + CC allele of rs2249825 who received liver grafts from donors with the same genotype had the highest incidence of EAD (p = 0.052). In contrast, the donor TC + CC allele of rs1412125 was an independent risk factor for the development of sepsis (n = 33) in LT recipient (OR = 3.05, 95% CI: 1.18 to 7.87, p = 0.021). The authors concluded that the SNPs of the HMGB1 gene in either recipients or donors were not associated with mortality but influenced the incidence of EAD and sepsis, likely being a predictive biomarker for the risk of serious complications following LT.
Furthermore, UpToDate reviews on “Liver transplantation in adults: Initial and maintenance immunosuppression” (Vierling and Brandman, 2025), and “Liver transplantation in adults: Long-term management of transplant recipients” (Gaglio and Cotler, 2025) do not mention testing of high mobility group box 1 (HMGB1) gene as a management tool.
Hypothermic Machine Perfusion for Reduction of the Incidences of Early Allograft Dysfunction and Biliary Complications after Liver Transplantation
Bellini and associates (2019) noted that to address the current disparity between organ demand and availability from the donor pool, there has been a shift towards accepting extended criteria donors (ECD), which are often associated with longer ischemic times. Novel dynamic preservation techniques, such as hypothermic or normothermic machine perfusion (HMP or NMP), are increasingly being adopted, particularly for organs from ECDs. In a systematic review, these researchers compared the viability and incidence of reperfusion injury in kidneys and livers preserved with machine perfusion versus static cold storage (SCS). They conducted a systematic review and meta-analysis between February and March 2019, searching Medline, Embase, and Transplant Library via OvidSP, as well as the Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL). An English language filter was applied, resulting in 10,585 studies, ultimately leading to a total of 30 studies included in the meta-analysis for kidneys and livers. The analysis found that HMP significantly reduced the incidence of primary non-function (PNF, p = 0.003) and delayed graft function (DGF, p < 0.00001) in kidneys compared to SCS, although it did not affect the duration of DGF. No differences were observed in serum creatinine or estimated glomerular filtration rate (eGFR) post-transplantation; however, kidneys preserved with HMP had a significantly longer 1-year graft survival (OR: 1.61, 95% CI: 1.02 to 2.53, p = 0.04). In contrast, for livers, there was no significant difference in PNF between those stored using SCS and those preserved by HMP and NMP. Machine perfusion demonstrated superior outcomes in early allograft dysfunction (EAD) and post-transplantation AST levels compared to SCS, but only HMP significantly decreased serum bilirubin and the incidence of biliary stricture compared to SCS. The authors concluded that machine perfusion improved DGF and 1-year graft survival in kidney transplantation and appeared to mitigate EAD in livers; however, more clinical studies are needed to verify these findings with homogeneous parameters to measure the outcomes of interest and to establish the potential superiority of these novel technologies regarding PNF in livers.
Zhang and colleagues (2019) stated that the global shortage of organs remains the primary limitation of liver transplantation (LT). To bridge the gap between the demand and supply of liver grafts, it is necessary to utilize extended criteria for donor livers. Hypothermic machine perfusion is designed to enhance the quality of preserved organs before implantation. In clinical LT, HMP is still in its early stages. These researchers conducted a systematic search of the PubMed, Embase, Springer, and Cochrane Library databases to identify studies comparing outcomes in patients with HMP versus SCS of liver grafts. The parameters analyzed included incidences of PNF, EAD, vascular complications, biliary complications, length of hospital stay (LOS), and 1-year graft survival. A total of 6 studies qualified for the review, involving 144 liver grafts preserved with HMP and 178 with SCS. The incidences of EAD and biliary complications were significantly reduced with HMP, showing an OR of 0.36 (95% CI: 0.17 to 0.77, p = 0.008) and 0.47 (95% CI: 0.28 to 0.76, p = 0.003), respectively. Additionally, 1-year graft survival was significantly increased with HMP, with an OR of 2.19 (95% CI: 1.14 to 4.20, p = 0.02). However, there was no difference in the incidence of PNF (OR 0.30, 95% CI: 0.06 to 1.47, p = 0.14), vascular complications (OR 0.69, 95% CI: 0.29 to 1.66, p = 0.41), or LOS (MD -0.30, 95% CI: -4.10 to 3.50, p = 0.88) between HMP and SCS preservation. The authors concluded that HMP was associated with a reduced incidence of EAD and biliary complications, as well as increased 1-year graft survival; however, it was not associated with the incidence of PNF, vascular complications, or LOS. They also noted that due to the limitations of this meta-analysis, further large, multi-center randomized controlled trials (RCTs) are needed to confirm these findings.
The authors acknowledged several potential drawbacks to this meta-analysis, which may have increased the possibility of publication bias and affected the final results. First, the meta-analysis included only 6 studies, and the number of cases was limited for this specific subject. Second, all included studies were cohort studies. Although they provided the best available evidence on this topic, the non-randomized nature of these studies might have led to an unbalanced selection of patients. Third, there was heterogeneity in graft quality or donor status, including variations in warm ischemic time, cold ischemic time, donor age, steatosis, types of machine perfusion solution, perfusion route, perfusion pressure, and whether active oxygenation was used, which were correlated with study design and individual hospital preferences.
Patrono et al. (2022) noted that prolonged warm ischemia time (WIT) has a negative prognostic value in liver transplantation using grafts procured after donation after circulatory death (DCD). These investigators examined the value of abdominal normothermic regional perfusion (A-NRP) combined with dual hypothermic oxygenated machine perfusion (D-HOPE) in controlled DCD liver transplantation. They prospectively analyzed data on liver transplants performed between January 2016 and July 2021, comparing outcomes of controlled DCD liver transplants using A-NRP + D-HOPE (n = 20) to those performed with grafts procured after donation after brain death (DBD) (n = 40), selected using propensity-score matching. The DCD utilization rate was 59.5%. In the DCD group, the median functional WIT, A-NRP, and D-HOPE times were 43, 246, and 205 minutes, respectively. Early outcomes for DCD graft recipients were comparable to those of matched DBD liver transplants. In the DCD and DBD groups, the incidence of anastomotic biliary complications and ischemic cholangiopathy was 15% versus 22% (p = 0.73) and 5% versus 2% (p = 1), respectively. One-year patient survival and graft survival rates were 100% versus 95% (p = 0.18) and 90% versus 95% (p = 0.82), respectively. The authors concluded that the combination of A-NRP + D-HOPE in DCD liver transplantation with prolonged WIT achieved outcomes comparable to DBD liver transplantation. They also stated that larger studies are needed to confirm these findings, refine the evaluation process, and establish when and by which modality machine perfusion is indicated in this context.
The authors acknowledged several drawbacks of this study, including its retrospective, single-center design and limited sample sizes. Due to the exploratory nature of the analysis, a formal sample size calculation was not performed. Additionally, since most DCD liver transplants were conducted between 2020 and 2021, follow-up was shorter in the DCD group. Although a minimum follow-up of 6 months should have captured the majority of biliary complications, late-onset complications may have been missed. The investigators recognized that an updated definition of functional WIT has recently been introduced; however, all cases included in this study predated this update, and a retrospective recalculation of functional WIT was not feasible. Finally, as all grafts included in this study were treated with D-HOPE, the researchers could not assess the additional value of D-HOPE following A-NRP. They argued that machine perfusion could potentially be omitted in selected cases, while additional viability assessment through normothermic machine perfusion might be indicated in others. In their experience, the use of D-HOPE has been systematic for grafts meeting all viability criteria during A-NRP, which were included in this series. Thus far, the use of normothermic machine perfusion has been limited to cases characterized by uncertain evaluations during A-NRP or where logistical constraints necessitated prolonged preservation times. The investigators stated that well-designed and adequately powered randomized studies are needed to define when and by which modality machine perfusion after A-NRP is indicated in DCD liver transplantation.
Verstraeten and Jochmans (2022) stated that predicting organ viability before transplantation remains one of the most challenging objectives in transplant surgery. Wait-list mortality is high while transplantable organs are often discarded. Currently, approximately 20% of deceased donor kidneys and livers are discarded due to "poor organ quality." Decisions to discard organs are primarily based on subjective judgment, as there are limited reliable tools available to predict outcomes. Organ perfusion technology has been proposed as a platform for pre-transplant organ viability assessment. Markers of graft injury and function, as well as perfusion parameters, have been examined as potential viability markers during ex-situ hypothermic and normothermic perfusion. These investigators provided an overview of the available evidence regarding the use of kidney and liver perfusion as a tool to predict post-transplant outcomes. Although existing evidence suggests that post-transplant outcomes could be predicted by both injury markers and perfusion parameters during hypothermic kidney perfusion, the predictive accuracy is insufficient to warrant clinical decision-making based solely on these parameters. In the case of liver perfusion, further evidence is needed to establish the usefulness of hypothermic perfusion as a predictive tool. Normothermic perfusion, during which the organ remains fully metabolically active, appears to be a more promising platform for true viability assessment. Although the researchers do not yet fully understand the behavior of "on-pump" organs at normothermia, initial data in both kidney and liver transplantation are promising. The authors concluded that while good quality evidence indicates that injury markers and perfusion parameters during hypothermic kidney perfusion can predict graft outcomes, these markers lack the necessary predictive accuracy for clinical practice. They also noted that little is known about the association of liver perfusate injury markers and perfusion parameters during hypothermic perfusion, which warrants further investigation.
Hypothermic / Sub-Normothermic Machine Perfusion for Organ Preservation During Liver Transplantation
Bellini and associates (2019) stated that to address the current disparity between organ demand and availability from the donor pool, there has been a shift towards accepting extended criteria donors (ECD), which are often associated with longer ischemic times. Novel dynamic preservation techniques, such as hypothermic or normothermic machine perfusion (MP), are increasingly being adopted, particularly for organs from ECDs. In a systematic review and meta-analysis, these researchers compared the viability and incidence of reperfusion injury in kidneys and livers preserved with MP versus static cold storage (SCS). They conducted a literature search between February and March 2019, utilizing Medline, Embase, and Transplant Library via OvidSP, as well as the Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL), applying an English language filter. The search yielded a total of 10,585 studies, resulting in 30 papers included in the meta-analysis for kidneys and livers. Hypothermic MP (HMP) significantly reduced the incidence of primary non-function (PNF, p = 0.003) and delayed graft function (DGF, p < 0.00001) in kidneys compared to SCS, although it did not affect the duration of DGF. No differences were observed in serum creatinine or estimated glomerular filtration rate (eGFR) post-transplantation; however, kidneys preserved with HMP had a significantly longer 1-year graft survival (OR: 1.61, 95% CI: 1.02 to 2.53, p = 0.04). In contrast, for livers, there was no significant difference in PNF between those stored using SCS and those preserved by HMP and normothermic machine perfusion (NMP). Machine perfusion demonstrated superior outcomes in early allograft dysfunction and post-transplantation AST levels compared to SCS; however, only HMP significantly decreased serum bilirubin and the incidence of biliary stricture compared to SCS. The authors concluded that MP improved DGF and 1-year graft survival in kidney transplantation and appeared to mitigate early allograft dysfunction in livers; however, more studies are needed to establish the potential superiority of these novel technologies regarding PNF in livers.
The researchers noted that, contrary to the findings in kidneys, no difference in PNF was observed in livers preserved via HMP or NMP compared to SCS. In liver preservation, both HMP and NMP showed superior outcomes in mitigating early allograft dysfunction and post-transplantation AST levels compared to SCS; however, only HMP was able to significantly lower serum bilirubin and the incidence of biliary strictures compared to SCS. Furthermore, the value of AST as an endpoint is controversial, as there can be a release of AST in the perfusate during MP; thus, a more reliable marker should be considered in future studies. These conflicting results may be attributed to the relatively small number of RCTs, leading to insufficient evidence to conclude a clear superiority of one modality over the other.
Horvath and colleagues (2021) noted that allograft ischemia during liver transplantation (LT) negatively affects mitochondrial function, impairing oxidative phosphorylation and compromising post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. These researchers examined the available evidence on the mitochondrial effects of graft preservation methods in pre-clinical models of LT. Additionally, they conducted a network meta-analysis to determine if any of these treatments provide superior benefits that could be applicable to human patients. The investigators performed a systematic search using electronic databases (Embase, Medline via PubMed, the Cochrane Central Register of Controlled Trials [CENTRAL], and Web of Science) for controlled animal studies utilizing preservation methods for LT. The primary outcome was the ATP content of the graft, serving as an indicator of overall mitochondrial function. Secondary outcomes included the respiratory activity of mitochondrial complexes, cytochrome c, and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were employed. After a comprehensive search, 25 studies were included in the analysis. Treatments that exhibited the most significant protective effects on ATP content included HMP and sub-normothermic machine perfusion (SNMP) (MD = -1.0, 95% CI: -2.3 to 0.3; and MD = -1.1, 95% CI: -3.2 to 1.02), while the effects of warm ischemia (WI) without cold storage and normothermic machine perfusion (NMP) were less pronounced (MD = -1.8, 95% CI: -2.9 to -0.7; and MD = -2.1, 95% CI: -4.6 to 0.4). The subgroup of SCS with shorter preservation times (less than 12 hours) yielded better results than SCS of 12 hours or more, NMP, and WI in terms of ATP preservation and the respiratory capacity of mitochondrial complexes. HMP and SNMP stood out in terms of mitochondrial protection compared to other treatments for LT in animal models. The authors concluded that shorter storage times at lower temperatures, combined with dynamic preservation, provided superior protection for grafts regarding mitochondrial function. They emphasized the need for additional clinical studies involving human patients, including marginal donors and longer ischemia times, to confirm any superiority of preservation methods concerning mitochondrial function.
van Rijn and co-workers (2021) stated that transplantation of livers obtained from donors after circulatory death is associated with an increased risk of non-anastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited. In a controlled, multi-center trial, these researchers randomly assigned patients undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional SCS alone (control group). The primary endpoint was the incidence of non-anastomotic biliary strictures within 6 months following transplantation, while secondary endpoints included other graft-related and general complications. A total of 160 patients were enrolled, with 78 receiving a machine-perfused liver and 78 receiving a liver after SCS only (4 patients did not receive a liver in this trial). Non-anastomotic biliary strictures occurred in 6% of patients in the machine-perfusion group and in 18% of those in the control group (RR, 0.36; 95% CI: 0.14 to 0.94; p = 0.03). Post-reperfusion syndrome occurred in 12% of recipients of a machine-perfused liver and in 27% of those in the control group (RR, 0.43; 95% CI: 0.20 to 0.91). Early allograft dysfunction occurred in 26% of machine-perfused livers, compared to 40% of control livers (RR, 0.61; 95% CI: 0.39 to 0.96). The cumulative number of treatments for non-anastomotic biliary strictures was lower by a factor of almost four following machine perfusion compared to control. The incidence of adverse events (AEs) was similar in both groups. The authors concluded that hypothermic oxygenated machine perfusion resulted in a lower risk of non-anastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death compared to conventional SCS. Moreover, they noted that in the present trial, machine perfusion did not affect patient or graft survival; given the high percentage of patients who survive following transplantation and the relatively low risk of graft loss, much larger trials are needed to detect an effect on these outcome measures.
The authors also stated that despite the restoration of ATP, hepatic metabolism remains suppressed, and livers did not produce bile during this type of machine perfusion. Although the release of mitochondrial flavin mononucleotide into the perfusate has been correlated with hepatic function following LT, it remains unclear whether this also predicts the risk of cholangiopathy. In contrast to normothermic machine perfusion, hypothermic machine perfusion is currently not considered a viable tool for assessing organ viability before transplantation. Furthermore, these investigators indicated that the potential benefits of hypothermic machine perfusion in the transplantation of livers obtained from brain-dead donors are the subject of ongoing clinical trials.
Liver Elastography and Doppler Examination for Surveillance Following Liver Transplantation
An UpToDate review on “Liver transplantation in adults: Long-term management of transplant recipients” (Gaglio and Cotler, 2024) does not mention elastography / Fibrosure / FirboScan as a management option. However, it notes that “Complications of Immunosuppression -- An abdominal ultrasound with Doppler examination is performed in patients with cholestatic laboratory abnormalities or known biliary disease to evaluate for evidence of biliary obstruction and for hepatic artery thrombosis. We proceed to an MRCP or endoscopic retrograde cholangiopancreatography when there is clinical suspicion of a biliary stricture”.
The American Association for the Study of Liver Diseases (AASLD) and the American Society of Transplantation (AST) 2026 Practice Guideline on adult liver transplantation explicitly states: "Due to insufficient data, routine use of transient elastography to monitor allograft health cannot be recommended in adult liver transplant recipients" (Weak recommendation, Level 3 evidence).
The ACR Appropriateness Criteria (2026) rates duplex Doppler as the optimal initial imaging modality for suspected vascular or biliary complications post-transplant. However, for the long-term surveillance variant, the ACR states there is "no relevant literature comparing the performance characteristics of the different imaging modalities for surveillance in posttransplant patients," and notes only anecdotally that "some experts suggest that US duplex Doppler abdomen may be performed after transplant for surveillance in certain scenarios".
Liver Transplantation as a Rescue Therapy for Severe Neurologic Forms of Wilson Disease
Poujois and colleagues (2020) examined the effects of liver transplantation (LT) in patients with Wilson disease (WD) who experienced severe neurological worsening that was resistant to active chelation therapy. The study involved a retrospective analysis of French patients with WD who underwent LT for purely neurological indications. Neurological impairment was assessed using the Unified Wilson's Disease Rating Scale (UWDRS) score, disability was measured with the modified Rankin Scale (mRS) score, and hepatic function was evaluated using the MELD score. Additionally, the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance were also examined. The co-primary outcomes were the survival rate and disability at the last follow-up, while the evolution of KFR and brain MRI scores were considered secondary outcomes. Prognostic factors were further assessed. A total of 18 patients underwent LT, all of whom were highly dependent prior to the procedure, with a median mRS score of 5. Neurological symptoms were severe, with a median UWDRS score of 105, predominantly characterized by dystonia and parkinsonism. The cumulative survival rates were 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive, and their mRS and UWDRS scores showed significant improvement (p < 0.0001 and p = 0.0003, respectively). Eight patients experienced major improvement (a 78% decrease in UWDRS score), four had moderate improvement (a 41% decrease), and two maintained a stable status. Improvements were also noted in KFR and brain MRI scores (p = 0.0007). Severe sepsis (p = 0.011) and admission to the intensive care unit (ICU) (p = 0.001) prior to LT were significantly associated with mortality. The authors concluded that LT is a potential rescue therapeutic option that should be carefully considered for selected patients with neurological WD who are resistant to anti-copper therapies (such as chelators or zinc salts), as it may enable patients to achieve physical independence with a reasonable risk.
The researchers acknowledged that while this study represents the largest series published using objective scores, it has several limitations: a small sample size (n = 18), a retrospective evaluation of patients, and the absence of a control group. The rarity of the disease contributed to these limitations, as only 906 prevalent cases were identified in France. Furthermore, they noted that the enrolled subjects were highly selected, indicating that larger prospective studies are needed to validate these preliminary findings.
Liver Transplantation for the Treatment of Hilar Cholangiocarcinoma
Moris and associates (2019) noted that hilar cholangiocarcinoma (hCCA) is a rare and aggressive malignancy, with R0 resection currently being the only option for long-term survival. As outcomes of liver transplantation (LT) have improved, the indications for LT have expanded to include other malignant tumors, such as hCCA. These researchers critically examined the outcomes of LT compared to resection with curative intent in patients with hCCA. They systematically searched the literature for articles published up to May 2018, applying the following algorithm: ((hilar cholangiocarcinoma) or (perihilar cholangiocarcinoma) or klatskin$ or (bile duct neoplasm) or cholangiocarcinoma) and (transplant$ OR graft$). Neoadjuvant treatment with chemotherapy and radiation therapy was significantly more common in the LT group, with very few patients in the resection group receiving pre-operative therapy (p = 0.0005). Additionally, the length of hospital stay (LOS) was shorter after LT than after resection (p < 0.00001). However, no difference was found between the two methods regarding post-operative mortality (p = 0.57). There was a trend towards longer overall survival (OS) following LT compared to resection, which was not evident in the first year post-operatively but became significant at 3 years after the operation (p = 0.02). The authors concluded that in cases of non-disseminated unresectable tumors, LT appeared to provide non-inferior survival. They suggested that neoadjuvant chemoradiotherapy and/or strict selection criteria may contribute to superior survival outcomes compared to curative-intent resection. However, the researchers cautioned that due to the lack of level 1 evidence, it remains unclear whether LT should be increasingly considered for technically resectable early-stage hCCA.
The authors acknowledged several drawbacks of this study. First, all included studies were non-randomized, retrospective analyses, making them subject to inherent biases. In particular, there was heterogeneity regarding neoadjuvant treatment and whether tumors were associated with underlying primary sclerosing cholangitis (PSC) or arose de novo. Specifically, only one study provided data for patients with and without PSC, while the other studies lacked sufficient detail on this aspect. Including PSC patients in the analysis may skew results towards longer OS with LT, as they are generally diagnosed at an earlier stage, leading to improved outcomes. Furthermore, patients in the LT arm had locally unresectable disease, while those in the resection arm had resectable disease. There was also heterogeneity among studies concerning staging and evaluating the extent of the disease. Additionally, the median follow-up times across studies were all below 5 years, and few patients were followed up for 5 years or more post-operatively. Therefore, conclusions regarding 5-year survival rates should be interpreted with caution. Finally, the small number of studies and patients included in the analysis underscored the need for follow-up comparative studies.
Machairas and colleagues (2020) stated that patients with hCCA often present with advanced disease, limiting curative therapeutic options. Liver transplantation, in cases of unresectable disease, is theoretically an attractive option as it provides the maximum resection margin while also addressing the underlying parenchymal liver disease. In recent years, several studies have explored the potential benefits of neoadjuvant therapy followed by LT for treating patients with unresectable hCCA. In a systematic review, these investigators examined the long-term outcomes of patients with hCCA undergoing LT. They conducted a systematic search of four electronic databases (Medline, Scopus, Google Scholar, and ClinicalTrials.gov) for articles published between January 2000 and May 2019. A total of 13 studies involving 698 patients were included in this systematic review. Among the patients, 74.4% received a combination of chemotherapy and radiation as part of their neoadjuvant therapy. The 1-, 3-, and 5-year OS rates varied significantly among the included studies, ranging from 58% to 92%, 31% to 80%, and 20% to 74%, respectively. Recurrence rates ranged from 16% to 61%, while peri-operative mortality varied from 0% to 25.5%. The authors concluded that LT could provide acceptable long-term outcomes in the context of neoadjuvant chemoradiation and strict patient selection criteria. They emphasized that given the organ shortage and the lack of level I evidence, more prospective, randomized trials are needed to establish clear indications, rigorous criteria, and standardized protocols for LT in hCCA to maximize potential benefits for these patients.
Liver Transplantation for the Treatment of Methylmalonic Acidemia / Propionic Acidemia
Zhou and associates (2021) noted that the global experience of liver transplantation (LT) in treating propionic acidemia (PA) remains limited and fragmented. In a systematic review and meta-analysis, these investigators aimed to provide a comprehensive and quantitative understanding of post-transplant clinical outcomes in PA patients. They searched the Medline, Embase, and Cochrane Library databases for studies focusing on PA patients who underwent LT. The pooled estimate rates and 95% confidence intervals (CIs) were calculated using a random-effects model with Freeman-Tukey double arcsine transformation. A total of 21 studies involving 70 individuals were included in the analysis. The pooled estimate rates indicated a patient survival rate of 0.95 (95% CI: 0.80 to 1.00) and an allograft survival rate of 0.91 (95% CI: 0.72 to 1.00). The rates for complications included rejection at 0.20 (95% CI: 0.05 to 0.39), hepatic artery thrombosis at 0.08 (95% CI: 0.00 to 0.21), cytomegalovirus/Epstein-Barr virus infection at 0.14 (95% CI: 0.00 to 0.37), and biliary complications at 0.03 (95% CI: 0.00 to 0.15). Additionally, the pooled estimate rates for metabolic stability were 0.98 (95% CI: 0.88 to 1.00), for reversal of pre-existing cardiomyopathy were 1.00 (95% CI: 0.79 to 1.00), and for improvement of neurodevelopmental delay were 0.97 (95% CI: 0.78 to 1.00). A significant proportion of patients achieved liberalization of protein intake post-transplant, with a pooled estimate rate of 0.66 (95% CI: 0.35 to 0.93). The authors concluded that despite the risk of transplant-related complications, LT is a viable therapeutic option for PA patients, demonstrating satisfactory survival rates and clinical outcomes. They emphasized the need for consensus on neurological evaluation methods and post-transplant protein intake due to the diversity in assessment methods and the inconsistency in achieving dietary protein liberalization across different studies. Furthermore, they called for additional studies to evaluate the long-term clinical outcomes of LT for PA.
Jiang and colleagues (2021) stated that LT and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for patients with methylmalonic aciduria (MMA). In a systematic review and meta-analysis, these investigators examined the available evidence regarding the safety and efficacy of these procedures. They searched Medline, Embase, and the Cochrane Library to identify studies reporting post-LT/CLKT clinical outcomes for MMA from their inception to February 1, 2020. The pooled rates were calculated using a random-effects model with Freeman-Tukey double arcsine transformation. A total of 32 studies involving 109 patients were included in the analysis. The pooled estimate rates indicated a patient survival rate of 99.9% (95% CI: 95.3 to 100.0) and a graft survival rate of 98.5% (95% CI: 91.5 to 100.0) after LT/CLKT. The combined incidence of biliary complications, vascular complications, and rejection were 0.2% (95% CI: 0.0 to 6.6), 7.7% (95% CI: 0.1 to 22.1), and 18.4% (95% CI: 4.6 to 36.3), respectively. The pooled estimate rates for metabolic eradication were 100.0% (95% CI: 99.4 to 100.0) and for normalization of kidney function were 61.5% (95% CI: 33.4 to 87.0). Chronic kidney disease (CKD) remission was more promising after CLKT (70.3%) compared to the LT group (37.6%). The pooled estimate rates for neurodevelopmental status improvement and protein intake liberalization were 52.0% (95% CI: 2.8 to 98.8) and 36.3% (95% CI: 6.3 to 71.7), respectively. The authors concluded that this first quantitative systematic review confirmed favorable survival outcomes and partially improved disease-related complications in transplanted MMA patients, although some results should be interpreted with caution. They also suggested that future studies should provide detailed descriptions of long-term outcomes and establish consensus on neurodevelopmental evaluation methods to offer a more accurate picture.
The authors acknowledged several drawbacks in their study. First, due to substantial heterogeneity in two endpoints (improvement in neurodevelopmental status and protein intake), the statistical pooling may be misleading. Although subgroup analyses were conducted, the investigators were unable to explain the heterogeneity due to the limited and invalidated data. Furthermore, they could not perform further analysis because the data provided by individual studies were insufficient. For other endpoints, the results were robust. Second, this systematic review was primarily based on case studies. Given that case reports confirming clinical study conclusions are more likely to be published, a publication bias cannot be ruled out. Third, the relatively short follow-up periods of these studies made them unsuitable for evaluating the long-term outcomes of transplantation. Based on these findings, the researchers suggested that future independent studies examining the efficacy of LT/CLKT for MMA should involve a relatively large sample size with more detailed information and utilize standardized tools to assess clinical outcomes.
Molecular Adsorbent Recirculating System (MARS)
Khuroo and colleagues (2004) stated that the molecular adsorbent recirculating system (MARS), a non-cell-based device, is an important option for patients with liver failure, providing them additional time for recovery or serving as a "bridge" to transplantation. However, its effect on survival for such patients is not well established. The researchers evaluated the treatment effects of MARS on patients with acute and acute-on-chronic liver failure, focusing on survival as the outcome measure. They conducted a comprehensive search of Medline (1966 to 2002) and Embase (1974 to 2002) using terms such as liver failure, liver support systems, and MARS. The search was extended to include the Cochrane Controlled Trials Registry Database, published abstracts from five international conferences, Teraklin (the manufacturer of MARS), known contacts, and bibliographies from each full published report. Eligible studies included randomized and non-randomized controlled trials comparing MARS treatment with standard medical treatment. Of the 206 articles screened, four randomized controlled trials (RCTs) involving 67 patients were analyzed, along with two non-randomized trials with 61 patients for exploratory analysis. The methodology, population, intervention, and outcomes of each selected trial were evaluated through independent review, with disagreements resolved by consensus. In the primary meta-analysis, MARS treatment did not significantly reduce mortality compared to standard medical treatment (relative risk [RR], 0.56; 95% confidence interval [CI]: 0.28 to 1.14; p = 0.11). Only one of the four randomized trials showed a significant reduction in mortality. Sensitivity analysis of three peer-reviewed trials also did not show a significant reduction in mortality with MARS treatment (RR, 0.72; 95% CI: 0.37 to 1.40; p = 0.33). Subgroup analysis of two trials for acute liver failure and two for acute-on-chronic liver failure did not reveal any survival benefits with MARS treatment. In contrast, exploratory analysis of two non-randomized trials indicated a significant survival benefit with MARS treatment (risk ratio [RR], 0.36; 95% CI: 0.17 to 0.76; p = 0.007), possibly due to bias in patient selection. The authors concluded that MARS treatment had no significant survival benefit for patients with liver failure compared to standard medical therapy. However, they noted the limited number of trials and small patient populations, which could lead to false negatives and erroneous conclusions. They strongly recommended well-conducted randomized trials to define the role of MARS in treating liver failure.
Vaid and associates (2012) noted that MARS is an artificial liver support system developed for patients with liver failure, intended to support liver function until recovery or as a bridge to transplantation. These researchers conducted a meta-analysis to examine the effectiveness of this promising therapy. They searched Medline, Embase, and the Cochrane Registry of Controlled Trials databases, as well as abstracts from several scientific meetings. Patients with acute, acute-on-chronic, and hyper-acute liver failure were included, and the investigators compared MARS with standard medical therapy. Both randomized and non-randomized controlled trials were included, with MARS as the intervention. They evaluated net changes in total bilirubin levels, improvements in hepatic encephalopathy, and mortality; nine RCTs and one non-randomized controlled study met the criteria for inclusion. The meta-analysis revealed that MARS resulted in a significant decrease in total bilirubin levels (net change -7.0 mg/dL; 95% CI: -10.4 to -3.7; p < 0.001) and an improvement in the West-Haven grade of hepatic encephalopathy (odds ratio [OR] 3.0; 95% CI: 1.9 to 5.0; p < 0.001). However, there was no beneficial effect on mortality (OR 0.91; 95% CI: 0.64 to 1.31; p = 0.62). Limitations of this study included a small sample size, inability to blind participants, significant heterogeneity among studies, and variable definitions of liver failure. The authors concluded that while MARS is associated with significant improvements in total bilirubin levels and hepatic encephalopathy, it has no impact on survival. They emphasized the need for larger studies to assess the efficacy of this promising therapy on patient-centered outcomes.
Saliba et al. (2013) stated that albumin dialysis with MARS (Gambro, Lund, Sweden), a non-cell artificial liver support device, may be beneficial in acute liver failure (ALF). In a randomized controlled trial, these investigators examined whether MARS improved survival in ALF. Subjects received either conventional treatment (n = 49) or MARS combined with conventional treatment (n = 53), stratified by whether paracetamol caused ALF. Outcome measures included 6-month survival, with secondary endpoints including adverse events. A total of 102 patients (mean age 40.4 years [SD, 13]) were included in the modified intention-to-treat (mITT) population. The per-protocol analysis (49 conventional, 39 MARS) included patients who underwent at least one session of MARS lasting 5 hours or more. Six-month survival was 75.5% (95% CI: 60.8% to 86.2%) with conventional treatment and 84.9% (CI: 71.9% to 92.8%) with MARS (p = 0.28) in the mITT population, and 75.5% (CI: 60.8% to 86.2%) with conventional treatment and 82.9% (CI: 65.9% to 91.9%) with MARS (p = 0.50) in the per-protocol population. In patients with paracetamol-related ALF, the 6-month survival rate was 68.4% (CI: 43.5% to 86.4%) with conventional treatment and 85.0% (CI: 61.1% to 96.0%) with MARS (p = 0.46) in the mITT population; 66 of 102 patients underwent transplantation (41.0% among paracetamol-induced ALF; 79.4% among non-paracetamol-induced ALF) (p < 0.001). Adverse events did not significantly differ between groups. The authors concluded that this randomized trial of MARS in patients with ALF was unable to provide definitive conclusions regarding safety or effectiveness, as many patients underwent transplantation before receiving the intervention; ALF not caused by paracetamol was associated with greater 6-month patient survival.
He and co-workers (2015) evaluated the treatment effects of MARS in patients with ALF and acute-on-chronic liver failure (AOCLF). They searched Medline, Embase, and the Cochrane Controlled Trials Registry database from January 1966 to January 2014. They included RCTs comparing the treatment effects of MARS with standard medical treatment, assessing study quality according to Consolidated Standards of Reporting Trials (CONSORT) criteria. The search strategy revealed 72 clinical studies, of which 10 RCTs met the criteria for inclusion; four addressed ALF (93 patients) and six addressed AOCLF (453 patients). The mean CONSORT score was 15 (range of 10 to 20). The meta-analysis indicated that MARS significantly improved survival in ALF (RR 0.61; 95% CI: 0.38 to 0.97; p = 0.04), but there was no significant survival benefit in AOCLF (RR 0.88; 95% CI: 0.74 to 1.06; p = 0.16). The authors concluded that MARS therapy can improve survival in patients with ALF, but there is no evidence that it improves survival in patients with AOCLF.
Tsipotis and colleagues (2015) stated that albumin dialysis is the best-studied extracorporeal non-biologic liver support system, serving as a bridge or destination therapy for patients with liver failure awaiting liver transplantation or recovery of liver function. These researchers performed a systematic review to examine the safety and effectiveness of three albumin dialysis systems (MARS, fractionated plasma separation, adsorption and hemodialysis [Prometheus system], and single-pass albumin dialysis) in randomized trials for the supportive treatment of liver failure. They searched PubMed, Ovid, EMBASE, Cochrane's Library, and ClinicalTrials.gov. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, efficacy, and safety endpoints. A total of 10 trials (seven of MARS and three of Prometheus) were identified, involving 620 patients. The meta-analysis showed that albumin dialysis achieved a net decrease in serum total bilirubin levels relative to standard medical therapy of 8.0 mg/dL (95% CI: -10.6 to -5.4) but did not significantly reduce serum ammonia or bile acids. Albumin dialysis improved hepatic encephalopathy relative to standard medical therapy, with a RR of 1.55 (95% CI: 1.16 to 2.08), but had no effect on survival (RR of 0.95; 95% CI: 0.84 to 1.07). Due to inconsistencies in reporting adverse events, the safety analysis was limited but did not reveal major safety concerns. The authors concluded that albumin dialysis is effective in removing albumin-bound molecules, such as bilirubin, and improving hepatic encephalopathy. They stated that additional experience is needed to guide its optimal use and address safety concerns.
In a prospective, randomized, cross-over study, Sponholz et al. (2016) compared two devices (MARS and single-pass albumin dialysis [SPAD]), focusing on the reduction of bilirubin levels (primary endpoint) and the influence on para-clinical and clinical parameters (secondary endpoints) associated with liver failure. Patients presenting with liver failure were screened for eligibility and randomly assigned to receive either conventional MARS or SPAD (with 4% albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. A total of 69 cross-over cycles of extracorporeal albumin dialysis (ECAD) in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median -68 μmol/L, interquartile range [IQR] -107.5 to -33.5, p = 0.001; SPAD: -59 μmol/L, -84.5 to +36.5, p = 0.001). However, reductions in bile acids (MARS: -39 μmol/L, -105.6 to -8.3, p < 0.001; SPAD: -9 μmol/L, -36.9 to +11.4, p = 0.131), creatinine (MARS: -24 μmol/L, -46.5 to -8.0, p < 0.001; SPAD: -2 μmol/L, -9.0 to +7.0, p = 0.314), and urea (MARS: -0.9 mmol/L, -1.93 to -0.10, p = 0.024; SPAD: -0.1 mmol/L, -1.0 to +0.68, p = 0.523) were only achieved by MARS, which also increased albumin-binding capacity (MARS: +10%, -0.8 to +20.9%, p < 0.001; SPAD: +7%, -7.5 to +15.5%, p = 0.137). Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were not significantly altered by either MARS or SPAD. The authors concluded that both procedures were safe for temporary extracorporeal liver support. While plasma bilirubin levels were reduced by both systems, only MARS affected other para-clinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels).
Soo and associates (2016) noted that in children, acute liver failure (ALF) is a rare but life-threatening condition, with two-thirds of affected individuals not recovering with supportive therapy. Treatment options are limited by the availability of liver transplants. The molecular adsorbent recirculating system (MARS) dialysis serves as a bridge to transplantation, enhancing survival chances during the waiting period, although it cannot improve overall survival. Open albumin dialysis (OPAL) is a new mode of albumin dialysis developed to further improve dialysis efficiency. These investigators reported a pediatric case of acute-on-chronic liver failure (AOCLF) and compared the two modes of albumin dialysis, MARS and OPAL, used to treat the patient's cholestatic pruritus. Serial blood tests measured the removal of total and direct bilirubin, ammonia, and bile acids. The OPAL mode demonstrated increased removal of bile acids, while the removal of total and direct bilirubin and ammonia was similar in both modes. The patient reported better improvement in pruritus following OPAL compared to dialysis with MARS. The authors concluded that OPAL may offer a better solution than MARS for treating refractory pruritus in liver failure.
Additionally, a phase II clinical trial on “Molecular Adsorbent Recirculating System (MARS®) in Hypoxic Hepatitis (MARS in HH)” is currently recruiting participants (last verified September 2016).
Best et al. (2019) noted that hepatorenal syndrome is defined as renal failure in individuals with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogs or noradrenaline), renal vasodilator drugs (such as dopamine), trans-jugular intrahepatic portosystemic shunt (TIPS), and liver support with MARS. There is uncertainty regarding the best treatment regimen for hepatorenal syndrome. In a Cochrane review, these investigators compared the benefits and harms of different treatments for hepatorenal syndrome in individuals with decompensated liver cirrhosis. The authors concluded that based on very low-certainty evidence, there is no evidence of benefit or harm from any of the interventions for hepatorenal syndrome concerning the following outcomes: all-cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low-certainty evidence suggested that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low- or very low-certainty evidence also indicated that albumin plus midodrine plus octreotide and albumin alone had lower recovery rates from hepatorenal syndrome compared to albumin plus terlipressin. The researchers stated that future randomized clinical trials should be adequately powered, employ blinding, avoid post-randomization drop-outs or planned cross-overs (or perform an intention-to-treat [ITT] analysis), and report clinically important outcomes such as mortality, health-related quality of life (HR-QOL), adverse events, and recovery from hepatorenal syndrome. They suggested that albumin plus noradrenaline and albumin plus terlipressin should be the interventions compared in future trials.
Kade et al. (2020) examined the effectiveness of MARS in patients with alcohol-related acute-on-chronic liver failure (AoCLF) complicated by type 1 hepatorenal syndrome (HRS). So far, MARS efficacy and safety have been demonstrated in various acute liver failure scenarios. Data from 41 MARS procedures (10 patients with type 1 HRS in the context of alcohol-related AoCLF) were considered for this study. Biochemical tests of blood serum were performed before and after each procedure. The condition of patients was assessed before and after treatment using the model for end-stage liver disease - sodium (MELD-Na) and the stage of encephalopathy severity based on the West Haven criteria. During the observation period (20.5 ± 13.9 days), five patients died, while the remaining five were discharged from the hospital. In the group of 10, the 14-day survival rate starting from the first MARS treatment was 90%. The MARS procedure was associated with a 19% reduction in bilirubin (27.5 ± 6.1 versus 22.3 ± 4.0 mg/dL, p < 0.001), a 37% reduction in ammonia (44.1 ± 22.5 versus 27.6 ± 20.9, p < 0.001), a 27% reduction in creatinine (1.5 ± 1.0 versus 1.1 ± 0.6 mg/dL, p < 0.001), and a 14% reduction in urea (83.8 ± 36.1 versus 72.1 ± 33.3, p < 0.001) in blood serum samples, with stable hemodynamic parameters. In the group of patients discharged from the clinic (n = 5), MARS treatments resulted in an improvement in hepatic encephalopathy (West Haven; p = 0.043) and a reduction in the MELD-Na score (p = 0.015). The authors concluded that MARS is a hemodynamically safe method for supporting liver and kidney function, effectively reducing symptoms of encephalopathy in patients with alcohol-related type 1 HRS. However, they noted that the findings of this study were subject to limitations due to the small number of patients resulting from the selection of a homogeneous group.
Sparrelid et al. (2020) stated that post-hepatectomy liver failure (PHLF) remains a serious complication after major liver resection, associated with severe 90-day mortality. MARS is considered a potential therapeutic option for PHLF. In a systematic review, these investigators examined the experiences and results of MARS in PHLF. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, they conducted a systematic literature review using PubMed and Embase; non-randomized trials were assessed using the MINORS criteria. A total of 2,884 records were screened, and 22 studies were extracted (none were RCTs), involving 809 patients, including 82 patients with PHLF. Five studies (n = 34) specifically examined the role of MARS in patients with PHLF. In these patients, the overall 90-day survival rate was 47%. Patients with primary PHLF had significantly better 90-day survival compared to those with secondary PHLF (60% versus 14%, p = 0.03), and treatment was initiated earlier (median postoperative day [POD] 6 [range of 2 to 21] versus median POD 30 [range of 15 to 39]; p < 0.001). The number of treatments differed non-significantly between these groups. The safety and feasibility of early MARS treatment following hepatectomy were demonstrated in one prospective study, which reported no major adverse events (AEs). The authors concluded that early MARS treatment was safe and feasible in patients with PHLF, but currently, MARS cannot be recommended as standard care for these patients; further prospective studies are needed.
Soreide and Deshpande (2021) stated that PHLF is a relatively rare but feared complication following liver surgery, associated with high morbidity, mortality, and cost implications. Significant advances have been made in detailed pre-operative assessment, particularly of liver function, to predict and mitigate this complication. These researchers conducted a detailed search of PubMed and Medline using keywords such as "liver failure," "liver insufficiency," "liver resection," "postoperative," and "post-hepatectomy." Only full texts published in English were considered. A formal systematic review was deemed unfeasible, leading to a pragmatic review. The reported incidence of PHLF varies widely in the literature due to a historical lack of a universal definition. Incorporating the now-accepted definition and grading of PHLF suggests an incidence of 8% to 12%. Major risk factors include background liver disease, extent of resection, and intra-operative course. The majority of mortality associated with PHLF is related to sepsis, organ failure, and cerebral events. Despite multiple attempts, little progress has been made in the definitive and specific management of liver failure. The authors discussed recent advances in detailed pre-operative evaluation of liver function and evidence-based targeted approaches to managing PHLF. They concluded that PHLF remains a major cause of mortality following liver resection, and in the absence of a specific remedy, the best approach is to mitigate the risk of occurrence through detailed assessment of liver function, patient selection, and general care of critically ill patients. Artificial liver support was one of the keywords included in this review.
Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Predicting Acute Kidney Injury Following Orthotopic Liver Transplantation
Yeung and colleagues (2018) noted that acute kidney injury (AKI) is common following orthotopic liver transplantation (OLT) usually occurring early post-transplant. Multiple causes include graft preservation injury, blood loss, hypotension but also severity of recipient liver disease. Early intervention in AKI has both short- and long-term patient benefits. Unfortunately there are no current clinical biomarkers of early AKI. In a systemic review, these investigators examined the value of NGAL in predicting AKI following OLT. Ovid Medline and Embase were searched between the years of 2000 and 2017 for studies using keywords: Neutrophil gelatinase associated lipocalin or NGAL variants combined with synonyms for liver transplantation. A total of 96 studies were identified; 11 studies including 563 patients were considered suitable for analysis. Both urinary (uNGAL) and plasma NGAL (pNGAL) measurement were found to predict AKI following liver transplantation. Optimal reported area under the receiver-operator characteristics curve (AUROC) values of 0.5 to 0.83 and 0.54 to 0.86 respectively. The authors concluded that NGAL is a good predictor of early AKI following OLT although there was considerable variation in the published results. These researchers stated that further studies with prospectively defined cut-off values, standardized definitions of AKI and rigorous data reporting should be conducted to establish its clinical usefulness and limitations.
Normothermic Machine Perfusion for Liver Transplantation
Bral and co-workers (2017) reported that after extensive experimentation, the outcomes of the first clinical trial of normothermic machine perfusion of the liver (NMP-L) in the United Kingdom demonstrated feasibility and clear safety, with improved liver function compared to standard static cold storage (SCS). These researchers presented a preliminary single-center North American experience using the same NMP technology. A total of 10 donor liver grafts were procured, with 4 (40%) from donation after circulatory death (DCD), of which 9 were transplanted. One liver was discarded due to a technical failure with portal cannulation. The transplanted NMP grafts were matched 1:3 with transplanted SCS livers. The median duration of NMP was 11.5 hours (range of 3.3 to 22.5 hours), with one DCD liver perfused for 22.5 hours. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (the primary outcome) was not statistically different between groups on an intent-to-treat basis (p = 0.25). However, intensive care and hospital stays were significantly longer in the NMP group. The authors concluded that this preliminary experience demonstrated feasibility as well as potential technical risks of NMP in a North American setting, highlighting the need for larger, randomized studies.
Laing and associates (2017) noted that NMP-L is a novel technology recently introduced into liver transplantation practice. These researchers discussed the benefits of normothermic perfusion over conventional SCS and summarized recent publications in this area. The initial clinical trials have demonstrated both safety and feasibility of NMP-L, showing that machine perfusion can entirely replace cold storage or be initiated following a period of cold ischemia. The technology currently allows transplant teams to extend the period of organ preservation for up to 24 hours. Results from the first randomized controlled trial (RCT) comparing NMP-L with SCS are expected soon. One major advantage of NMP-L technology over other parallel technologies is the ability to assess liver function during NMP-L. Several case series have suggested parameters for liver viability testing during NMP-L, including bile production and clearance of lactic acidosis. NMP-L allows for the viability testing of high-risk livers and has the potential to increase the utilization of donor organs and improve transplant procedure logistics. The authors concluded that NMP-L is likely to become an important technology that will enhance organ preservation and improve the utilization of extended criteria donor livers.
Ceresa and colleagues (2017) stated that the preservation of the liver via NMP is rapidly gaining attention in both academic and clinical settings. These investigators described the benefits and limitations of NMP and discussed the potential role of SCS. Recent clinical studies have reported the use of NMP in liver preservation for transplantation, indicating that the technology is well-tolerated and feasible, with potentially improved post-transplant outcomes. NMP facilitates extended preservation times and the potential to increase organ utilization through viability assessment and regeneration. However, this technology is considerably more expensive than cold storage and presents significant logistical challenges. Cold storage remains the gold standard for preserving standard criteria livers, ensuring good long-term patient and graft survival. The authors concluded that NMP represents an exciting technological advancement in liver preservation, likely to have a positive impact on liver transplantation. However, they emphasized that RCTs are needed to justify its inclusion in standard practice and to provide evidence supporting its effectiveness.
The OCS Liver PROTECT RCT (n=300) demonstrated significant reductions in early allograft dysfunction (18% vs 31%, p=0.01) and ischemic biliary complications at 12 months (2.6% vs 9.9%, p=0.02). The OCS Liver PROTECT trial was a multicenter randomized controlled study (2016–2019) across 20 U.S. transplant centers that demonstrated the clinical benefits of normothermic machine perfusion (NMP) using the OCS Liver device compared with conventional ischemic cold storage (ICS) in higher-risk donor livers. Among 300 randomized recipients, NMP significantly reduced early allograft dysfunction (18% vs 31%, P=.01), decreased ischemia-reperfusion injury as evidenced by lower rates of moderate-to-severe inflammation on biopsy, and markedly lowered ischemic biliary complications at both 6 and 12 months. The device, which preserves livers in a warm, oxygenated, metabolically active state, also enabled greater utilization of donation-after-cardiac-death (DCD) organs (51% vs 26%), suggesting expanded donor pool potential. Importantly, safety outcomes, including graft-related serious adverse events within 30 days, were comparable between groups, supporting NMP as a clinically effective and safe advancement in liver preservation.
A meta-analysis of 7 RCTs (1,017 patients) confirmed significant reductions in early allograft dysfunction with both normothermic and hypothermic perfusion. Parente et al. (2023) conducted the first RCT-only systematic review and meta-analysis comparing machine perfusion to static cold storage (SCS) in liver transplantation, analyzing 7 trials (1,017 patients) and evaluating hypothermic oxygenated perfusion (HOPE) and normothermic machine perfusion (NMP) separately. Both techniques significantly reduced early allograft dysfunction versus SCS (NMP RR 0.50; HOPE RR 0.48), but HOPE demonstrated broader clinical benefits, including reductions in major complications, retransplantation (79% reduction), and graft loss (60% reduction), whereas NMP did not significantly improve these harder outcomes. Both approaches likely reduce overall biliary complications and non-anastomotic strictures, though neither improved patient survival at 1 year, likely due to insufficient power. The analysis highlighted a key distinction: HOPE offers more consistent improvements in graft-related outcomes with higher-quality evidence, while NMP’s primary advantage appears to be enhanced organ utilization, particularly for marginal donors. Limitations included short follow-up, modest sample size, and absence of direct HOPE vs NMP comparisons, but subsequent meta-analyses have reinforced the finding that HOPE delivers broader outcome benefits while NMP’s impact remains more limited to early graft function and logistical advantages.
A NEJM review describes machine perfusion as an established clinical approach. The review describes normothermic machine perfusion (NMP) as an ex vivo preservation strategy in which donor livers are perfused at physiologic temperature (~37 °C) with oxygenated, ABO-compatible blood via the hepatic artery and portal vein, thereby maintaining near‑normal metabolism and function. Compared with traditional static cold storage, NMP can reduce ischemia–reperfusion injury, enable real‑time assessment of organ viability through functional markers (e.g., oxygen consumption, lactate clearance, enzyme release), and facilitate use of higher‑risk or marginal grafts by improving tissue quality and lowering rates of early allograft dysfunction and ischemic biliary complications. The approach also creates opportunities for therapeutic intervention and organ “reconditioning” before transplantation, potentially expanding the donor pool, although it is more complex, costly, and logistically demanding, and evidence is still evolving regarding optimal implementation and comparative effectiveness versus other perfusion methods.
Lai et al. (2025) noted that LT is the gold standard for ESLD; however, ischemic cholangiopathy (IC) remains a significant complication. Ex-situ normothermic machine perfusion (ES-NMP) has emerged as a potential strategy to mitigate ischemic injury. However, the effect of ESNMP on reducing post-LT IC remains controversial. These investigators carried out an updated meta-analysis to examine the impact of ES-NMP on the incidence of IC. They conducted a systematic review and meta-analysis following PRISMA guidelines. The literature search included studies from 2015 to 2025 comparing LT outcomes using ES-NMP versus SCS. The primary outcome was the incidence of IC. Risk of bias was evaluated using the ROBINS-E tool. Statistical analysis, including random-effects meta-analysis, sensitivity analysis, and meta-regression, was carried out to assess heterogeneity, potential confounders, and the impact of follow-up duration. A total of 17 studies, including 76,045 patients (4,843 ES-NMP; 71,202 SCS), were analyzed. No statistically significant difference in IC incidence was found between ES-NMP and SCS (1.3% versus 0.6%; RR = 0.68, 95% CI: 0.41 to 1.13; p = 0.14). Sensitivity analysis excluding 1 outlier study showed a reduction in IC risk with ES-NMP (RR = 0.62, 95% CI: 0.38 to 1.01; p = 0.054). Two sub-analyses of studies with 12 months or longer of follow-up (RR = 0.51, 95% CI: 0.26 to 0.99; p = 0.049) and DCDs (RR = 0.33, 95% CI: 0.16 to 0.67; p = 0.002) demonstrated risk reduction. The meta-regression showed that the back-to-base perfusion approach was associated with the occurrence of IC, with an OR of 1.03 (95% CI: 1.00 to 1.07, p = 0.035). The authors concluded that there appeared a correlation between ES-NMP use and IC reduced risk, especially with longer follow-up periods and DCDs, although further high-quality studies are needed to confirm benefits and refine clinical use.
OmniGraf Liver
OmniGraf Liver by Eurofins Transplant Genomics is a non-invasive blood test that employs gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) to assist in monitoring the health of liver transplantation recipients and guiding the optimization of their immunosuppressive therapy (IST). The test aims to help clinicians evaluate the stability of the liver graft, differentiate between rejection and other forms of graft injury, and rule out rejection, potentially reducing the need for invasive liver biopsies. However, there is currently a lack of published evidence regarding OmniGraf Liver in the available literature.
Teszak et al. (2024) stated that solid organ transplant rejection is a major cause of graft dysfunction, hospitalization, and mortality. While invasive biopsy remains the gold standard for monitoring rejection, it is associated with hospitalization, complications, and high inter-observer variability. Therefore, non-invasive methods for monitoring allograft injury are critically important. Donor-derived cell-free DNA is a marker of graft injury that can be isolated from the recipient’s serum. Elevated levels of dd-cfDNA can precede the diagnosis of rejection on biopsy and have a high negative predictive value (NPV). These researchers examined the role of dd-cfDNA testing following solid organ transplantation (including heart, kidney, liver, lung, and pancreas) and presented the first Hungarian results from a dd-cfDNA-based routine cardiac allograft rejection surveillance program. Since October 2022, dd-cfDNA testing has been performed on 264 occasions in 46 heart transplant recipients. The dd-cfDNA level was measured relative to the total amount of cell-free DNA in a plasma sample, with a level of 0.20% or greater indicating injury and a severe injury threshold set at 0.35% or greater. A total of 80% of dd-cfDNA data points were below the injury threshold. Elevated dd-cfDNA values prompted 20 for-cause endomyocardial biopsies (EMBs), resulting in the diagnosis of 6 heart allograft rejection episodes. Based on dd-cfDNA levels, 232 EMBs—88% of routine surveillance biopsies that would have otherwise been performed over 16 months—were safely avoided. The authors concluded that dd-cfDNA has the potential to detect early signs of graft injury, facilitating earlier and more personalized titration of immunosuppressive therapy, thereby avoiding toxicities, more severe allograft rejection, and irreversible graft dysfunction.
Sorbini et al. (2025) noted that liver transplantation (LT) is still constrained by organ shortages and challenges in post-transplant monitoring. While machine perfusion techniques enhance organ preservation, biomarkers such as dd-cfDNA and mitochondrial cfDNA (mt-cfDNA) may provide insights into graft injury and viability before and after LT. In a prospective observational study involving 45 LT recipients, these researchers examined the use of dd-cfDNA as a biomarker for graft dysfunction during the first 6 months following LT. Dd-cfDNA was quantified from blood samples collected pre- and post-LT using droplet digital PCR. In livers undergoing dual hypothermic oxygenated machine perfusion (D-HOPE), total cfDNA and mt-cfDNA levels were measured from perfusate samples collected at 30-minute intervals. The study assessed correlations with graft function and clinical outcomes. Dd-cfDNA levels peaked post-LT and correlated with transaminase levels and histological injury severity. Longitudinal assessments revealed that postoperative complications and rejection were associated with increased dd-cfDNA levels. Mt-cfDNA levels in D-HOPE perfusate correlated with graft function parameters post-LT and were higher in patients with early allograft dysfunction and severe complications. The authors concluded that the findings confirmed dd-cfDNA as a marker of graft injury following LT and suggested that mt-cfDNA levels in perfusate during D-HOPE correlated with graft function and post-transplant clinical outcomes. They stated that integrating these tests into clinical practice may enhance transplant management and viability assessment during hypothermic perfusion.
Zhong et al. (2025) stated that while liver transplantation (LT) has become an effective treatment for end-stage liver disease (ESLD), issues such as immune rejection and graft damage continue to significantly influence the success rate of LT and patients' quality of life (QOL). In recent years, advancements in genetic testing technologies have drawn attention to the study and application of dd-cfDNA in the diagnosis and treatment of LT. These investigators reviewed research advancements in dd-cfDNA within LT management, assessing its potential applications throughout the LT process while examining the challenges faced by current studies and outlining future research directions. The authors concluded that dd-cfDNA shows promising potential as a strategic tool for postoperative monitoring in LT, particularly in areas such as immune rejection, graft damage, immunosuppressant adjustment, complication monitoring, and personalized treatment, positioning it to become a reliable biomarker in the management of patients following LT.
OrganOx Metra System for Transportation and Preservation of the Liver Prior to Transplantation
The OrganOx Metra System is a transportable medical device designed for the normothermic perfusion of donor transplant livers for up to 24 hours. It is intended to sustain donor livers destined for transplantation in a functioning state for a total preservation time of up to 12 hours. The device is suitable for liver grafts from donors after brain death (DBD) or liver grafts from donors after circulatory death (DCD) who are 40 years of age or younger, with less than or equal to 20 minutes of functional warm ischemic time (the time from when the donor's systolic blood pressure drops below 50 mmHg) and macro-steatosis of less than or equal to 15%. The system aims to maintain the liver in a near-physiologic, normothermic, and functioning state for potential transplant recipients.
Gaurav et al. (2022) noted that livers donated after circulatory death are associated with an increased risk of primary non-function, poor function, and non-anastomotic strictures (NAS), which leads to their under-utilization. In a retrospective, single-center study, these researchers compared the outcomes of livers donated after circulatory death (DCD) that underwent either in-situ normothermic regional perfusion (NRP) or ex-situ normothermic machine perfusion (NMP) with livers undergoing static cold storage (SCS). They prospectively collected data on 233 DCD liver transplants performed using SCS, NRP, or NMP between January 2013 and October 2020. A total of 97 SCS, 69 NRP, and 67 NMP DCD liver transplants were performed, with 6-month and 3-year transplant survival (graft survival non-censored for death) rates of 87%, 94%, 90%, and 76%, 90%, and 76%, respectively. NRP livers exhibited a lower 6-month risk-adjusted Cox proportional hazard for transplant failure compared to SCS (hazard ratio [HR] 0.30, 95% confidence interval [CI]: 0.08 to 1.05, p = 0.06). NRP and NMP livers showed a risk-adjusted estimated reduction in the mean model for early allograft function score of 1.52 (p < 0.0001) and 1.19 (p < 0.001), respectively, compared to SCS. Acute kidney injury (AKI) was more common with SCS (55% versus 39% NRP versus 40% NMP; p = 0.08), with a lower risk-adjusted peak-to-baseline creatinine ratio in the NRP group (p = 0.02). No NRP liver had clinically significant NAS, in contrast to SCS (14%) and NMP (11%, p = 0.009), with lower risk-adjusted odds of overall NAS development compared to SCS (odds ratio [OR] = 0.2, 95% CI: 0.06 to 0.72, p = 0.01). The authors concluded that NRP and NMP were associated with better early liver function compared to SCS, with NRP showing superior preservation of the biliary system. They also emphasized the need for randomized comparisons of all new technologies, particularly comparing hypothermic oxygenated machine perfusion (HOPE) with NRP and NMP.
The authors acknowledged several limitations in their study. First, the retrospective design of the study, despite the data being prospectively recorded. Second, NRP was predominantly performed in loco-regional donors (86%), while NMP livers were often sourced from remote hospitals outside the authors’ region (78%), typically after being declined by at least one other center. This selection bias favored NRP for locally procured livers and did not favor NMP, which often involved less than ideal DCDs. Third, the long cold ischemia time (CIT) for all groups in the study, with the SCS group having a CIT that was 30 minutes longer than that of NMP and NRP. To counter this, NRP had significantly longer asystolic and functional warm ischemia than the other two groups, with more NRP livers categorized as “high risk” (SCS 43%, NRP 64%, NMP 37%) as defined in a recent benchmarking paper. Notably, the superior outcomes of NRP livers were maintained even after adjusting for CIT and other risk factors.
Peri-Operative Immuno-Nutrition
Lei and colleagues (2015) stated that no consensus has been reached concerning the effects of peri-operative immuno-nutrition in patients undergoing liver transplantation. These researchers conducted a meta-analysis to evaluate the effects of peri-operative immuno-nutrition on clinical outcomes and liver function in patients undergoing liver transplantation. The PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and google scholar were searched to identify all available RCTs that compared peri-operative immuno-nutrition support (arginine, glutamine, ribonucleic acids, and ω-3 polyunsaturated fatty acids) with standard nutrition. The data analysis was performed using Revman 5.2 software. A total of 7 RCTs involving 501 patients were included. Peri-operative immuno-nutrition significantly reduced the risk of infectious complications (RR: 0.51; 95% CI: 0.27 to 0.98, p = 0.04) and shortened the post-operative hospital stay [weighted mean difference (WMD): -3.89; 95% CI: -7.42 to -0.36; p = 0.03]. Furthermore, peri-operative immuno-nutrition improved liver function by decreasing the levels of aspartate aminotransferase (AST) in the blood (WMD: -25.4; 95% CI: -39.9 to -10.9, p = 0.0006). However, these investigators did not find statistically significant differences in serum alanine aminotransferase (ALT), total bilirubin (TB) and direct bilirubin (DB) levels. There were no statistically significant differences in mortality and rejection reaction. The authors concluded that peri-operative nutrition support adding immuno-nutrients like arginine, glutamine, ribonucleic acids, and ω-3 polyunsaturated fatty acids may improve outcomes in patients undergoing liver transplantation. Moreover, they stated that due to the limited sample size of the included trials, further large-scale and rigorously designed RCTs are needed to confirm these preliminary findings.
Pre-Operative Neutrophil-to-Lymphocyte Ratio
Xu and co-workers (2018) stated that many recent reports showed that the pre-transplant neutrophil-to-lymphocyte ratio (NLR) may be correlated with the prognosis of patients undergoing liver transplantation for HCC. However, their results still remained controversial. These researchers performed a meta-analysis of 13 studies to estimate the prognostic value of pre-transplant NLR. Databases including PubMed, Embase, Cochrane Library and Web of Science were searched to September 2017. Hazard ratio (HR) or OR with its 95% CI was used to evaluate the association between elevated NLR and the prognosis or clinical features of liver cancer patients. A total of 13 studies including 1,936 patients were included in this meta-analysis. Elevated pre-transplant NLR had a close association with the overall survival (OS) (HR: 2.22; 95% CI: 1.34 to 3.68), recurrence-free survival (RFS) (HR: 3.77; 95% CI: 2.01 to 7.06) and disease-free survival (DFS) (HR: 2.51; 95% CI: 1.22 to 5.15) of patients undergoing LT for HCC, respectively. In addition, elevated NLR was associated with the presence of vascular invasion (OR: 2.39; 95% CI: 1.20 to 4.77) and Milan criteria (OR: 0.26; 95% CI: 0.17 to 0.40). The authors concluded that the results of this meta-analysis showed that elevated pre-transplant NLR may be used as a new prognostic predictor after liver transplantation for HCC.
Pre-Operative Platelet-to-Lymphocyte Ratio
Lai and colleagues (2018) performed a systematic review and meta-analysis on platelet-to-lymphocyte ratio (PLR) as a risk factor for post-transplant HCC recurrence. A systematic literature search was performed using PubMed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following the following criteria: studies comparing pre-transplant low versus high PLR values; studies reporting post-transplant recurrence rates; and if more than 1 study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases (80.0%) were males; 3 studies coming from European countries and 1 from Japan presented HCV as the main cause of cirrhosis. On the opposite, 1 Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart 1, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation (OR = 3.33; 95%CI: 1.78 to 6.25; p < 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I2 statistic value. The authors concluded that pre-transplant high PLR values were connected with an increased risk of post-operative recurrence of HCC. Moreover, they stated that although the reported data suggested an effective biological correlation between platelets and tumor aggressive behavior, they underlined that further clinical studies trying to univocally demonstrate the biological role of platelets in the HCC oncogenesis are needed. The authors stated that this study had 2 main drawbacks. First, moderate heterogeneity was observed among the studies investigated, as clearly shown by the reported Higgins I2 statistic value (26.8%). Such a phenomenon was surely caused by the broad eligibility criteria for HCC and the different PLR cut-off values used in the different centers. It was, in fact, clear that a meta-regression weighted for the geographical area, HCV versus HBV as the main cause of liver failure, living-donor versus deceased-donor LT, and markers of tumor aggressiveness should represent a more accurate way for better clarify the role of PLR in this setting. Unfortunately, the limited number of cases reported did not consent these investigators to perform more sophisticated analyses. Secondly, no information was reported in the different series on the presence and grade of portal hypertension, a very well known cause of thrombocytopenia in cirrhosis.
Peri-Operative Use of Sorafenib
Qi and colleagues (2015) examined if the application of sorafenib during the peri-operative period of liver transplantation (LT) improves prognosis in liver cancer patients. These investigators searched PubMed, EMBASE and MEDLINE for eligible articles. A total of 4 studies were found that fulfilled the previously agreed-upon standards. They then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria. Out of the 104 studies identified in the database, 82 were not clinical experiments, and 18 did not fit the inclusion standards. Among the remaining 4 articles, only 1 was related to the pre-operative use of sorafenib, whereas the other 3 were related to its post-operative use. As the heterogeneity among the 4 studies was high, with an I(2) of 86%, a randomized effect model was applied to pool the data. The application of sorafenib before LT had a hazard ratio (HR) of 3.29 (95% CI: 0.33 to 32.56). The use of sorafenib after LT had an HR of 1.44 (95%CI: 0.27 to 7.71). The overall pooled HR was 1.68 (95%CI: 0.41 to 6.91). The authors concluded that the results showed that the use of sorafenib during the peri-operative period of LT did not improve patient survival significantly. In fact, sorafenib could even lead to a worse prognosis, as its use may increase the hazard of poor survival.
- male gender (p = 0.001);
- time to progression (p = 0.038); and adverse drug events, divided in
- gastrointestinal (p = 0.038),
- cardiovascular (p = 0.029), and
- dermatological (p = 0.014).
The authors concluded that additional data from multi-center prospective studies are needed to clearly determine if sorafenib is a safe and acceptable treatment in hepatocellular carcinoma recurrence after LT. Nevertheless, its association with m-Tor inhibitors should be discouraged.
Peri-Operative Use of Vasopressin
In a meta-analysis, Won and associates (2015) evaluated the effect of peri-operative terlipressin (an analog of vasopressin) on post-operative renal function in patients who have undergone living donor liver transplantation (LDLT) and analyzed the hemodynamic data during transplantation surgery. These investigators assessed the post-operative peak serum creatinine level and changes in the hemodynamic data (e.g., the mean arterial pressure, heart rate, and systemic vascular resistance). They collected RCTs from PubMed, Embase Drugs and Pharmacology, Cochrane Controlled Trials Register, and Cochrane Database on Systematic Reviews. Analysis was conducted using RevMan 5.2. Data from each trial were pooled and weighted by their mean differences and corresponding 95% CI. A heterogeneity assessment was performed. A total of 3 trials (151 patients) were included. The difference in the mean (95% CI) peak serum creatinine (mg/dL) levels post-operatively was not significant between the intervention and control groups (WMD: -0.27; CI: -0.55 to 0.01; p = 0.06). Terlipressin significantly decreased heart rate during the anhepatic phase (WMD: -6.58; 95% CI: -8.85 to -4.31; p < 0.00001) with a low heterogeneity (I(2) = 41%) and significantly decreased heart rate during the neohepatic phase (WMD: -9.82; 95% CI: -11.96 to -7.68; p < 0.00001), although the heterogeneity was high (I(2) > 50%). The authors concluded that an iv infusion of terlipressin peri-operatively for LDLT had no effect on the creatinine values post-operatively. Moreover, they stated that larger RCTs on terlipressin infusions during liver transplantation are needed.
Routine Use of Endobiliary Stent in Liver Transplantation
Elkomos et al. (2023) stated that biliary complications are a significant cause of morbidity following transplantation, and the routine use of biliary stents in liver transplantation (LT) to mitigate these complications remains a topic of debate. In a systematic review and meta-analysis, these investigators compared the incidence of biliary complications in patients with and without the use of trans-anastomotic biliary stents during LT. They conducted searches in PubMed, Scopus, Web of Science, and the Cochrane Library for eligible studies from inception to February 2022. A total of 17 studies involving 2,623 patients were included in the analysis. The pooled results indicated that there was no significant difference in the rate of biliary complications (including strictures, leaks, and cholangitis) between stented and non-stented patients following LT. However, patients with stents experienced higher costs and increased rates of biliary interventions. Furthermore, subgroup analyses revealed no significant reduction in the incidence of biliary complications associated with the use of trans-anastomotic biliary stents in living donor liver transplantation (LDLT), deceased donor liver transplantation (DDLT), Roux-en-Y hepaticojejunostomy (RYHJ), duct-to-duct anastomosis, or in pediatric and adult LT. The authors concluded that the routine use of endobiliary stents in LT does not provide additional benefits, and stented patients were at a higher risk of requiring multiple endoscopic retrograde cholangiopancreatographies (ERCPs). They emphasized the need for further investigations to compare the use of stents versus stentless techniques in pediatric LT and RYHJ.
The authors acknowledged several limitations in their study. First, not all the included studies were randomized controlled trials (RCTs). Second, significant heterogeneity in some outcomes could not be adequately explained by subgroup analyses. Third, none of the included studies compared the rates of acute rejection (AR) or graft loss due to biliary complications between the two groups. Fourth, most of the studies were conducted in Asia, with only a few performed in North America and Europe. Fifth, only one study was identified that compared the use of bio-absorbable stents versus stentless techniques in biliary reconstruction.
Scaffold-Based Transplantation
Furuta and colleagues (2020) noted that OLT is the only treatment for end-stage liver failure; however, graft shortage impedes its applicability. Hence, studies examining alternative therapies are plenty. However, no study has comprehensively analyzed these therapies from different perspectives. These researchers summarized the current status of alternative transplantation therapies for OLT and to support future research. They carried out a systematic literature search using PubMed, Cochrane Library and Embase for articles published between January 2010 and 2018, using the following MeSH terms: “liver transplantation and cell”, or “liver transplantation and differentiation”, or “liver transplantation and organoid”, or “liver transplantation and xenotransplantation”. Various types of studies describing therapies to replace OLT were retrieved for full-text evaluation. Among them, these investigators selected articles including in-vivo transplantation. A total of 89 studies were selected. There were 3 principle forms of treatment for liver failure: Xeno-organ transplantation, scaffold-based transplantation, and cell transplantation. Xeno-organ transplantation was covered in 14 articles, scaffold-based transplantation was discussed in 22 articles, and cell transplantation was discussed in 53 articles. Various types of alternative therapies were discussed: Organ liver, 25 articles; adult hepatocytes, 31 articles; fetal hepatocytes, 3 articles; mesenchymal stem cells (MSCs), 25 articles; embryonic stem cells, 1 article; and induced pluripotent stem cells, 3articles and other sources. Clinical applications were discussed in 12 studies: Cell transplantation using hepatocytes in 4 studies, 5 studies using umbilical cord-derived MSCs, 3 studies using bone marrow-derived MSCs, and 2 studies using hematopoietic stem cells. The authors concluded that clinical applications are present only for cell transplantation. Scaffold-based transplantation is a comprehensive treatment combining organ and cell transplantations; future research on the clinical application of scaffold-based transplantation is expected.
Split Liver Transplantation versus Whole Liver Transplantation
Wan and colleagues (2015) noted that split liver transplantation (SLT) has proven to be an effective technique to reduce the mortality of children on the waiting list, but whether creating 2 split grafts from 1 standard-criteria whole liver would compromise outcomes of adult recipients remains uncertain. These investigators conducted this meta-analysis to compare outcomes of right lobe SLT and whole liver transplantation (WLT) in adult patients. PubMed, Embase, and the Cochrane Library were searched for relevant articles published before December 2014. Outcomes assessed were patient survival, graft survival and major surgical complications after transplantation. Pooled odds ratios (OR) with 95% CI were calculated to synthesize the results. A total of 17 studies with a total of 4,8457 patients met the full inclusion criteria. Patient survival and graft survival rates were all found to be equivalent between SLT and WLT recipients. However, SLT was associated with higher rates of overall biliary complications (OR = 1.66, 95% CI: 1.29 to 2.15, p < 0.001), bile leaks (OR = 4.30, 95% CI: 2.97 to 6.23, p < 0.001), overall vascular complications (OR = 1.81, 95% CI:1.29 to 2.53, p < 0.001), hepatic artery thromboses (OR = 1.71, 95% CI: 1.17 to 2.50, p = 0.005) and outflow tract obstructions (OR = 4.17, 95% CI: 1.75 to 9.94, p = 0.001). No significant difference was observed in incidences of biliary stricture, portal vein complications, post-operative bleeding requiring surgical treatments, primary non-function and re-transplantations. In subgroup analyses, biliary and vascular complications only increased after ex-vivo SLT rather than in-situ SLT, and SLT recipients had more re-transplantations if they matched with WLT recipients in terms of urgent status. The authors concluded that adult right lobe SLT was associated with increased biliary and vascular complications compared with WLT, but it did not show significant inferiority in patient and graft survivals.
Transient Elastography in Acute Cellular Rejection Following Liver Transplantation
Bhat and associates (2017) reported that recurrent fibrosis after liver transplantation significantly impacts long-term graft and patient survival. These investigators conducted a meta-analysis to compare the accuracy of non-invasive methods for diagnosing significant recurrent fibrosis (stages F2 to F4) following liver transplantation. They systematically identified studies comparing serum fibrosis biomarkers, specifically the AST-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), and transient elastography (TE) with liver biopsy in liver transplantation recipients through electronic databases. In the meta-analysis, the researchers calculated the weighted pooled odds ratios (OR) using a fixed-effect model, as there was no significant heterogeneity between studies. A total of 8 studies were included for APRI, 4 for FIB-4, and 12 for TE. The mean prevalence of significant liver fibrosis was found to be 37.4%. The summary OR was significantly higher for TE (21.17, 95% CI: 14.10 to 31.77, p = 1X10^-30) compared to APRI (9.02, 95% CI: 5.79 to 14.07; p = 1X10^-30) and FIB-4 (7.08, 95% CI: 4.00 to 12.55; p = 1.93X10^-11). The authors concluded that TE was the most effective method for diagnosing recurrent fibrosis in liver transplantation recipients, while APRI and FIB-4 could be used as estimates of significant fibrosis in centers where TE is unavailable. They suggested that longitudinal assessment of fibrosis using these non-invasive tests may reduce the need for liver biopsy.
The authors acknowledged several drawbacks in their study, including a higher proportion of hepatitis C virus patients represented. They also included pediatric studies with various reasons for the development of fibrosis post-transplant. Additionally, the reported range of cut-off values for TE was wide (from 7.3 kPa to 12.3 kPa) in liver transplantation recipients, complicating its clinical application for individual patients. This variability was likely due to the heterogeneous study populations, differing etiologies of liver disease, various post-liver transplantation time points for assessing liver fibrosis, study design, sample size, and the variable interval between liver biopsy and non-invasive assessment of liver fibrosis. The researchers could not account for these different cut-offs for TE across various chronic liver disease etiologies in their meta-analysis, as this information was not provided in the studies. Nonetheless, the validity of their findings across this heterogeneous population suggested the usefulness of these non-invasive tools for assessing fibrosis, even in the complex context of liver transplantation.
Moreover, the researchers noted that due to their non-invasive nature and feasibility for serial measurements, non-invasive tests for liver fibrosis could be utilized in the post-transplant clinical setting as an additional tool for suspected recurrent or de novo liver disease. The high accuracy found in this meta-analysis, particularly for TE, indicated that these tests have similar diagnostic value as in the pre-transplant setting. It is important to emphasize that liver biopsy remains a cornerstone in the clinical management of liver transplantation recipients, as non-invasive tests cannot differentiate between various liver pathologies that may coexist in this setting, such as acute or chronic rejection. However, once the etiology of recurrent or de novo disease is established, these non-invasive tests can be valuable for monitoring fibrosis progression over time and implementing preventive therapies promptly. The authors stated that further studies are needed to define optimal cut-off values for identifying significant liver fibrosis.
Nacif and colleagues (2018) noted that transient elastography (TE) is a non-invasive technique that measures liver stiffness, which increases in the presence of an inflammatory process. Acute cellular rejection (ACR) results from an inflammatory response directed at endothelial and bile epithelial cells and is diagnosed through liver biopsy. This systematic review assessed the viability of TE in detecting ACR following liver transplantation. The researchers searched the Cochrane Library, Embase, and Medline PubMed databases, updating their search to November 2016. The MESH terms used included "liver transplantation," "graft rejection," "elasticity imaging techniques" (PubMed), and "elastography" (Cochrane and Embase). A total of 70 studies were retrieved and selected based on the PICO (patient, intervention, comparison or control, outcome) criteria; three prospective studies were included in the meta-analysis. A total of 33 patients with ACR were assessed using TE. One study identified a cut-off point of greater than 7.9 kPa to define graft damage and less than 5.3 kPa to exclude graft damage (receiver operating characteristic [ROC] of 0.93; p < 0.001). Another study reported elevated liver stiffness levels in ACR patients but did not suggest a specific cut-off point for ACR. The final prospective study included 27 patients with ACR confirmed by liver biopsy, defining cut-off points as TE greater than 8.5 kPa for moderate-to-severe ACR, with a specificity of 100% and ROC of 0.924. TE measurements less than 4.2 kPa excluded the possibility of any ACR (p = 0.02). The authors concluded that TE may be an important tool for assessing the severity of ACR in patients following liver transplantation. They also emphasized the need for further studies to better define cut-off points and the applicability of this examination.
Ursodeoxycholic Acid for Prevention of Acute Cellular Rejection after Liver Transplantation
Deng et al. (2014) noted that acute cellular rejection (ACR) after LT is one of the most common problems faced by transplant recipients in spite of advances in immunosuppressive therapy. Recently, clinical trials reported that ursodeoxycholic acid (UDCA) reduced the incidence of ACR significantly. However, others have shown contradictory conclusion. Therefore, these investigators performed a meta-analysis of rigorous randomized controlled trials (RCTs) to determine the effectiveness of UDCA in reducing ACR after LT. All RCTs that evaluated effectiveness of UDCA as an adjuvant treatment to prevent ACR after LT were searched from PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ScienceDirect databases and Web of Science (from January 1981 to March 2012). There was no language limitation in these searches. Relevant abstracts of international meetings were also searched. References of each included study were searched manually. A total of 234 patients from 4 high-quality RCTs (Jadad score 4 to 5) were included in this meta-analysis. Prophylactic use of UDCA did not decrease the incidence of ACR (RR: 0.94, 95% CI: 0.77 to 1.16, p > 0.05), steroid-resistant rejection (RR: 0.77, 95% CI: 0.47 to 1.27, p > 0.05) and the number of patients with the multiple episodes of ACR (RR: 0.60, 95% CI: 0.28 to 1.30, p > 0.05). Different intervention programs (high-dose versus low-dose UDCA; early versus delayed UDCA treatment) also did not alter the outcomes. The authors concluded that UDCA, as an adjuvant treatment, was not able to prevent ACR and steroid-resistant rejection after LT. They stated that further trials should be done to determine whether higher dose of UDCA will be beneficial.
Xenotransplantation
The success of transplantation has resulted in a significant increase in the number of candidates, with over 16,000 individuals on the national waiting list. However, there has been little growth in the supply of available cadaveric organs, leading to an organ shortage crisis. With waiting times often exceeding 1 to 2 years, the death rate on the waiting list now exceeds 10% in most regions. Researchers have explored novel approaches such as xenotransplantation, hepatocellular transplantation, and bioartificial liver to address the growing disparity between the limited supply and excessive demand for suitable organs. However, all these approaches are currently considered investigational.
Studies on xenotransplantation are conducted using primates, such as baboons and smaller monkeys. Major concerns in xenotransplantation include the transmission of diseases that can be passed from animals to humans under natural conditions (zoonoses) and the risk of hyper-acute rejection. Hepatocellular transplantation is employed to temporarily or permanently replace the diseased liver. In this process, hepatocytes are seeded onto a biodegradable polymer that serves as a temporary extracellular matrix and promotes vascular in-growth. The seeded polymer is then implanted into a vascular-rich area, such as the mesentery of the small intestine, with other techniques including direct injection into the spleen or liver. A bioartificial liver is designed to treat liver disease in a manner similar to how a dialysis machine treats renal disease. Investigators utilize porcine hepatocytes or a transformed line of hepatocytes housed in a bioreactor, allowing plasma from patients with liver failure to perfuse through it. This system can be used either as a bridge to liver transplantation or to facilitate the recovery of the native liver.
Glossary of Terms
| Term | Definition |
|---|---|
| Orthotopic | Normal anatomical position |
Appendix
A tool to calculate MELD score is available at the following website: MELD Calculator - OPTN.
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