Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.

Immunosuppression optimization is central to graft function in liver transplant recipients. Post-transplantation patients develop new onset or worsening metabolic syndrome, are prone to atypical infections, and are at higher risk of developing cardiac and brain-related clinical events. In this context, liver transplant recipients are at risk of using multiple comedications alongside immunosuppressants. It is imperative for the transplant physician to understand the various drug-drug interactions that potentially reduce or promote toxicity of immunosuppression, as well as associated synergistic or antagonistic effects on extrahepatic organ systems. This comprehensive review discusses drug-drug interactions in liver transplant recipients and the impact and role of complementary and alternative medicines among individuals on immunosuppression.

The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at reducing the risk of disease recurrence and complications related to immunosuppressive therapy. Such approaches will include strategies aiming to promote stable long-term immunological tolerance of the liver graft.

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1-, 3- and 5-year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per-operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni- and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri-operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.

The influence of crossmatching in liver transplantation is still controversial, and at present, our unit does not alter management according to the result of standard lymphocytotoxicity testing. This study retrospectively assessed outcome of grafts transplanted in the presence of preformed antidonor cytotoxic antibody. One hundred twelve patients undergoing their first orthotopic liver transplantation had results available (mean follow-up: 18 months). Twelve patients had a positive crossmatch and 100 negative. The 1-year graft survival was 58% in the positive crossmatch group, compared with 81% in the negative crossmatch group (P = .02). The 1-year patient survival was 83% in the positive crossmatch group compared with 90% in the negative group (P = .41). Acute cellular rejection occurred in 6 of 7 (86%) grafts surviving more than 7 days in the positive crossmatch group compared with 46 of 88 (52%) grafts in the negative group (P = .09). However, episodes of further acute cellular rejection requiring treatment occurred in 4 of the 6 grafts in the positive crossmatch group but in only 4 of the 46 grafts with a negative crossmatch (P = .0006). The authors conclude that evidence exists in our population that preformed antidonor antibodies adversely affect the outcome of hepatic allografts but not patient survival.

Liver transplantation has been accepted as a successful therapeutic tool for irreversible liver diseases such as primary biliary cirrhosis. However, removal of the diseased liver may not eliminate this autoimmune disease, and recurrence of primary biliary cirrhosis in the liver graft has been reported as early as within the first posttransplant year. We studied whether or not primary biliary cirrhosis recurs after liver transplantation in follow-up biopsies of 19 primary biliary cirrhosis patients. Biopsies of 14 non-primary biliary cirrhosis patients served as controls. The median follow-up period was 5 years (range 1-11 years). Both groups of patients were selected according to strict criteria which excluded pre- and posttransplant diseases which could mimic primary biliary cirrhosis. The follow-up biopsies were taken according to a protocol at yearly intervals. Established histologic criteria for primary biliary cirrhosis were assessed semi-quantitatively in 119 biopsies in a coded fashion. A longitudinal study was performed after decoding the biopsies, to document the course of morphological changes in time per patient. In addition to data on liver tests and immunosuppression, anti-mitochondrial antibodies including the primary biliary cirrhosis specific subtypes (anti-PDH-E2 and BCKD-E2) were determined in freeze-stored serum samples. The biopsies showed a striking concordance between the primary biliary cirrhosis and non-primary biliary cirrhosis groups and few overt histologic abnormalities. There was no significant difference in liver-test results and immunosuppression. Overall anti-mitochondrial antibodies remained present in decreased titers.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple and fast HPLC method for the determination of porphyrins in bile without extraction is described. Porphyrins were determined in bile from control subjects and from patients after orthotopic liver transplantation, including three patients with erythropoietic protoporphyria. It was found that: 1) coproporphyrin I is the predominant porphyrin in bile of controls, accompanied by some coproporphyrin III and protoporphyrin, whereas protoporphyrin mostly but not always is the predominant porphyrin in the bile of erythropoietic protoporphyria patients. In two of the three erythropoietic protoporphyria patients, the bile contained a hundred times more protoporphyrin than that of non-porphyric orthotopic liver transplantation patients. The third erythropoietic protoporphyria patient remained cholestatic and was unable to excrete sufficient amounts of protoporphyrin. 2) All investigated bile samples contained no secondary porphyrins derived from protoporphyrin, i.e. no deutero-, pempto-, or mesoporphyrin. Even when extracts of bile and serum were concentrated fifty to a hundred times, no traces of deutero-, pempto- and mesoporphyrin were detected. This complete absence of secondary porphyrins suggests that an enterohepatic circulation of dicarboxylic porphyrins from the distal gastrointestinal tract does not exist. 3) The HPLC chromatograms contain peaks from unknown compounds. No correlation between porphyrins and these compounds was found. Porphyrin profiles were followed in the bile of some orthotopic liver transplantation patients. Three episodes are recognizable. During the first three days after orthotopic liver transplantation there is a very high coproporphyrin excretion. There is then a lag of one to three weeks, in which no or very low porphyrin concentrations are detectable, followed by the restoration of normal biliary porphyrin patterns.

Four antimitochondrial antibody profiles (A-D) have been defined in primary biliary cirrhosis according to the presence of antibodies to M2, M4, M8, and M9 in ELISA and the complement fixation test: A: anti-M9 positive in ELISA and western blot, B: anti-M9 and/or anti-M2 positive in ELISA, C: anti-M2, -M4 and/or -M8 positive in ELISA, D: anti-M2, -M4, and/or -M8 positive in ELISA and complement fixation test. These profiles predict the outcome of primary biliary cirrhosis in the early stages and reflect differences in the natural course of the disease (benign versus progressive). In this study sera from 29 patients with advanced primary biliary cirrhosis who had received liver transplant were retested before and after orthotopic liver transplantation. Twenty-eight were antimitochondrial antibody/anti-M2 positive, and one patient had only antibodies to nuclear dots in the immunofluorescence test on cell cultures. When the antimitochondrial antibody-profiles in these 28 anti-M2 positive patients were analysed, it became evident that 26 of them belonged to subgroup C or D before orthotopic liver transplantation. Two patients had profile B; one had high titres of antinuclear and smooth muscle antibodies indicating an overlap syndrome between primary biliary cirrhosis and autoimmune chronic active hepatitis. The other patient had antibodies to nuclear dots in association with anti-M2. None of the patients had profile A. Antibody titres were studied after orthotopic liver transplantation in 23 of the 28 patients who survived for 1 to 13 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Pediatric liver transplantation has advanced remarkably over the past three decades. One-year survival has progressively increased to nearly 90% in patients transplanted for most forms of liver disease. Parallel advances in organ procurement, operative technique, immunosuppression, and infection control are responsible for improved patient survival. Among the most important advances are use of the University of Wisconsin (UW) organ preservation solution, the employment of venovenous bypass and/or "piggyback" operative technique, the development of cyclosporine A (CyA) and FK506, and the emergence of acyclovir, ganciclovir, foscarnet, and alpha interferon to combat life-threatening viral infections. The current organ shortage is being addressed by "cutdown" liver transplantation, "split liver" transplantation, and living-related donations. The next decade is likely to see advances in multi-visceral transplantation, induction of chimerism by simultaneous bone marrow-solid organ transplantation, and performance of cross-species xenografting.

The initial enthusiasm for orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) soon vanished as early recurrences appeared. OLT in HCC remains a controversial issue. We evaluated the efficacy of preoperative studies to select No-Mo patients and determined whether pT stage and histopathological grade (G) have a prognostic significance. A group of 25 patients, all previously thoroughly studied to rule out extrahepatic disease, underwent OLT for HCC. All patients were pNo after pathological study and none of the six patients who died in the postoperative period showed extrahepatic dissemination at necropsy (pMo). The recurrence rate was 43%. The 2 and 5 years actuarial survival was 62% and 43% respectively. The pT and G were not prognostic factors for long-term survival. We think that HCC is still a good indication for OLT because almost 50% of patients have good survival prospects.

The role of hepatic transplantation in patients with nonresectable liver or bile duct cancer remains a controversial issue. An analysis of 95 consecutive cases was undertaken to evaluate retrospectively the pathological tumor stage--in accordance with the TNM system--and outcome after transplantation. Included were patients with the following diagnoses: hepatocellular carcinoma (n = 52), cholangiocellular carcinoma (n = 10), hepatoblastoma (n = 2), hemangiosarcoma (n = 2), bile duct carcinoma (n = 20), and liver metastases from different primary tumors (n = 9). The overall actuarial survival rate at 5 years was 20.4%. Median survival improved significantly within the last 4 years as compared to the preceding era (18.06 vs. 4.0 months). Currently 27 patients are alive, with the longest follow-up more than 12 years. The incidences of residual or recurrent tumor were 27 and 28, respectively. Particularly in patients who underwent transplantation for hepatocellular or bile duct carcinoma without extra-hepatic tumor spread, the results were significantly better; median survival time achieved for these two groups were 120 (p less than 0.01) and 35 months (p less than 0.05). Prolonged survival without tumor recurrence was not seen in patients with cholangiocellular carcinoma or liver metastases. These results demonstrate clearly that liver transplantation for hepatobiliary malignancy is still justified on the premises of careful patient selection by adequate tumor staging.

Surgical resection offers the only realistic hope of cure in hepatocellular carcinoma (HCC) but is usually not possible, either because the tumour is widespread throughout the liver at diagnosis, or because liver function is adversely affected by concomitant cirrhosis. The results of operation in early asymptomatic disease are, however, encouraging and efforts should be made to screen regularly the cirrhotic population at risk of HCC development. The prognosis for inoperable patients remains gloomy, though exciting new treatment methods exist which require extensive evaluation. An anthracycline given as single agent intravenous therapy is probably the current treatment of choice for inoperable patients, though only 20-30% will show a response. Intra-arterial therapy has not yet been convincingly shown to have any advantages over intravenous therapy. The evaluation of clinical trials in HCC would be made easier if response criteria were standardized and universally adopted, and if trials were properly controlled and of sufficient sample size to test adequately the hypothesis in question. This review deals only with the specific treatment of HCC. HCC prevention, the early diagnosis of HCC, and the relief of symptoms in HCC, though areas of obvious importance, are outside the scope of this review.

In 20 adult patients undergoing orthotopic liver transplantation (OLT), we studied longitudinally for the first 3 weeks after OLT the composition of bile with regard to differences between surviving and non-surviving patients and between patients with more or less rejection and the relation between bile and serum concentrations. The analyzed biliary components were bilirubin, cholesterol, bile acids, phospholipids, copper, iron, glucose, urea, creatinine, ammonia, protein, sodium, potassium, chloride, pH, bicarbonate, calcium and phosphate. After the 1st day the composition of bile was often different from reference values. In most patients deviations of the hepatic excretion function were found. Especially, a sharp fall was noticed in the biliary concentrations of cholesterol and copper. The composition of bile was not helpful in predicting the histologic degree of rejection or the ultimate outcome of the patients. Changes in bile glucose, electrolyte, urea, and creatinine concentrations were positively related to serum concentrations. We conclude that for the compounds analyzed the composition of bile after OLT is not only influenced by the state of the liver but also by the overall metabolic state of the patient.

Antimitochondrial antibodies are markers for primary biliary cirrhosis and probably reflect a specific defect in immunoregulation underlying this disease. Antimitochondrial antibodies and their primary biliary cirrhosis-specific subtypes were tested before and up to 6 years after orthotopic liver transplantation. Sera from 31 consecutive patients were tested, 15 patients had primary biliary cirrhosis and 16 non-primary biliary cirrhosis. Antimitochondrial antibodies were investigated under code by immunofluorescence, and primary biliary cirrhosis-specific subtypes were determined by radioimmunoassay (anti-p62, anti-p48) and complement fixation test (anti-M2, anti-M4, anti-M8). Before orthotopic liver transplantation, antimitochondrial antibodies were detected by immunofluorescence in 13 of 15 patients with primary biliary cirrhosis. Of these patients, 12 were positive for anti-p62 and 8 for anti-p48. Ten patients were positive for anti-M2, 4 patients for anti-M4 and 7 patients for anti-M8. Two primary biliary cirrhosis patients and all non-primary biliary cirrhosis patients were negative with all tests. One month after orthotopic liver transplantation, antimitochondrial antibodies titers declined or became negative by antimitochondrial antibodies immunofluorescence, 3 patients became negative by radioimmunoassay for anti-p62 and 1 for anti-p48. With complement fixation test, 4 patients became negative for anti-M2, 2 for anti-M4 and 4 for anti-M8. Antimitochondrial antibody titer reduction observed 1 month after orthotopic liver transplantation remained unchanged in most sera during the following years. A rise was observed in two patients after 4 and 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

The Birmingham liver transplant programme started in 1982. Forty-six patients have been transplanted with a follow-up of 3 months or longer. Twenty-seven patients are still alive, of whom sixteen have lived for more than one year. The 30 day hospital mortality was 30.4 per cent and the actuarial predicted one year survival 55.5 per cent. Four patients have been regrafted for chronic rejection and graft failure. Thirteen patients have required surgery in the postoperative period for: bleeding (two), removal of abdominal packs (four), biliary leaks and obstruction (five), duodenal perforation (one) and small bowel obstruction (one). Acute rejection was common, occurring in 30 patients and progressing to chronic rejection in 4. Ten patients developed renal failure with an 80 per cent mortality and eleven patients developed grand mal fits. Severe bleeding (greater than 70 units) was associated with previous abdominal surgery and a high mortality (88.9 per cent). Opportunistic fungal infection carried a 100 per cent mortality. Although more than half of all transplanted patients will survive for more than one year, the postoperative period is still one of high morbidity and mortality.

Cyclosporin A is a novel, powerful immunosuppressive agent. It is a cyclic polypeptide and is one of several metabolites of a number of soil fungi. Its main effect is directed against the helper T lymphocyte. Thus, cyclosporin A represents the first of a new generation of immunosuppressive agents that are capable of selective rather than broad spectrum activity. The immunosuppressive properties of cyclosporin A have been applied successfully to prevent the rejection of transplanted organs both in animals and humans. Clinically, it has been used in the management of transplanted kidneys, hearts, lungs, livers and, to some degree, pancreases and bone marrow. It is also finding some application in the control of various autoimmune conditions. The clinical use of cyclosporin A is still in an early phase and several aspects have not been defined optimally. The most common and troublesome side-effect is nephrotoxicity. Other adverse effects include hirsutism, gum hypertrophy and mild psychiatric disturbances as well as involvement of the gastrointestinal tract, liver and central nervous system.

In a prospective study involving 25 consecutive adult orthotopic liver transplantation (OLT) patients, of whom 23 had cirrhosis, we have related pretransplantation recipient parameters to blood loss during transplantation. In phase 1 (explantation of diseased liver) blood loss was 0.1-7.2 1, in phase 3 (following restoration of the portal blood flow after implantation) 0.1-39.7 1, and total blood loss was 1.6-47.2, median 9.2 1. Five patients (20%) died from causes directly related to defective haemostasis during the operation. Pretransplantation cholinesterase, antithrombin III and albumin correlated most strongly with blood loss in phase 1; a history of ascites, antithrombin III and cholinesterase levels correlated with blood loss in phase 3, and a history of ascites, urinary sodium and antithrombin III with total blood loss. Cholestasis did not influence blood loss. Portal hypertension per se presumably played only a restricted role. A pretransplant 24-h urinary sodium excretion of 10 mmol or less and a serum sodium of 132 mmol/l or less were highly predictive of blood loss exceeding 10 1 during OLT. Urinary sodium determination under test conditions and serum sodium measurement should already be part of the assessment of potential OLT candidates by the referring hospital.

Trained specialists in hepatology, liver and biliary surgery, anesthesiology and pathology must form the core of a team for liver transplantation. The hospital must be a center for organ transplantation to provide the essential infrastructure to manage specific aspects of transplantation. A well-organized blood bank is essential to cope with acute requests for large amounts of donor blood. Because of the extremely high costs, liver transplantation has to be approved medically and politically before it can be considered as a generally accepted modality of treatment.