Cardiac risk stratification of the liver transplant candidate: A comprehensive review

Cardiovascular diseases (CVD) form a principal consideration in patients with end-stage liver disease (ESLD) undergoing evaluation for liver transplant (LT) with prognostic implications in the peri- and post-transplant periods. As the predominant etiology of ESLD continues to evolve, addressing CVD in these patients has become increasingly relevant. Likewise, as the number of LTs increase by the year, the proportion of older adults on the waiting list with competing comorbidities increase, and the demographics of LT candidates evolve with parallel increases in their CVD risk profiles. The primary goal of cardiac risk assessment is to preemptively reduce the risk of cardiovascular morbidity and mortality that may arise from hemodynamic stress in the peri- and post-transplant periods. The complex hemodynamics shared by ESLD patients in the pre-transplant period with adverse cardiovascular events occurring in only some of these recipients continue to challenge currently available guidelines and their uniform applicability. This review focusses on cardiac assessment of LT candidates in a stepwise manner with special emphasis on preoperative patient optimization. We hope that this will reinforce the importance of cardiovascular optimization prior to LT, prevent futile LT in those with advanced CVD beyond the stage of optimization, and thereby use the finite resources prudently.     

Liver transplantation and aging

An increase in the average life expectancy, paralleled by a demographic shift in the population with end-stage liver disease lies behind the rising demand for liver transplantation (LT) among the elderly. Some of the most common indications for LT including hepatocellular carcinoma, alcohol-related liver disease, chronic hepatitis C and non-alcoholic fatty liver disease tend to affect older patients. Transplant professionals are faced with an increasing demand for LT among elderly patients in an age of organ shortage and it is important that risk and benefits are carefully weighed in order to achieve the optimum use of precious liver grafts.     

Pediatric metabolic liver diseases: Evolving role of liver transplantation

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis’, arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.     

Noninvasive markers of liver steatosis and fibrosis after liver transplantation – Where do we stand?

In the last two decades, advances in immunosuppressive regimens have led to fewer complications of acute rejection crisis and consequently improved short-term graft and patient survival. In parallel with this great success, long-term post-transplantation complications have become a focus of interest of doctors engaged in transplant medicine. Metabolic syndrome (MetS) and its individual components, namely, obesity, dyslipidemia, diabetes, and hypertension, often develop in the post-transplant setting and are associated with immuno-suppressive therapy. Nonalcoholic fatty liver disease (NAFLD) is closely related to MetS and its individual components and is the liver manifestation of MetS. Therefore, it is not surprising that MetS and its individual components are associated with recurrent or “de novo” NAFLD after liver transplantation (LT). Fibrosis of the graft is one of the main determinants of overall morbidity and mortality in the post-LT period. In the assessment of post-LT steatosis and fibrosis, we have biochemical markers, imaging methods and liver biopsy. Because of the significant economic burden of post-LT steatosis and fibrosis and its potential consequences, there is an unmet need for noninvasive methods that are efficient and cost-effective. Biochemical scores can overestimate fibrosis and are not a good method for fibrosis evaluation in liver transplant recipients due to frequent post-LT thrombocytopenia. Transient elastography with controlled attenuation parameter is a promising noninvasive method for steatosis and fibrosis. In this review, we will specifically focus on the evaluation of steatosis and fibrosis in the post-LT setting in the context of de novo or recurrent NAFLD.     

Intracranial pressure monitoring in the perioperative period of patients with acute liver failure undergoing orthotopic liver transplantation

Acute liver failure (ALF) may result in severe neurological complications caused by cerebral edema and elevated intracranial pressure (ICP). Multiple pathogenic mechanisms explain the elevated ICP, and newer hypotheses have been described. While invasive ICP monitoring (ICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage. ICPM is the subject of much debate, and significant heterogeneity exists in clinical practice regarding its use. Contemporary ICPM techniques and coagulopathy reversal strategies may be associated with a lower risk of hemorrhage; however, most of the evidence is limited by its retrospective nature and relatively small sample size.     

Volume of malignant melanoma is superior to thickness as a prognostic indicator. Preliminary observation

There are many clinical and histologic factors that are known to be valuable in predicting survival rates for patients with cutaneous malignant melanomas. Breslow thickness is considered to be the most reliable prognostic factor; however, thickness is a unidimensional measurement. A more accurate mensuration to predict biologic behavior might be one that takes into account the three-dimensional volume of the neoplasm. In a study of 35 primary malignant melanomas, the volumes of the dermal components of the tumors were calculated. Those patients with tumor volumes of 200 mm3 or less had a 91.4% 5-year disease-free survival rate, compared with survival rate of only 16.7% for those patients whose lesions had tumor volumes exceeding 200 mm3. On multivariate analysis, tumor volume exceeded thickness as a prognostic indicator. Thus, measurement of tumor volume proved to be of greater significance than thickness in predicting the outcome for patients with malignant melanomas.     

Impact of body mass index on outcomes of 48281 patients undergoing first time cadaveric liver transplantation

AIM: To investigate possible disparities in perioperative morbidity and mortality among different body mass index (BMI) groups and to simulate the impact that these differences might have had on the cohort of patients undergoing cadaveric liver transplantation (LT). METHODS: All adult recipients undergoing first time LT for benign conditions and receiving a whole graft from brain-dead donors were selected from the united network of organ sharing registry. From January 1994 to June 2013, 48281 patients satisfied the inclusion criteria and were stratified by their BMI. The hypothesis that abnormal BMIs were independent predictors of inferior outcomes was tested with univariate and multivariate regression analyses. RESULTS: In comparison to normal weight recipients, underweight and morbidly obese recipients had increased 90-d mortality (adjusted OR = 1.737; 95%CI: 1.185-2.548, P = 0.005) (adjusted OR = 1.956; 95%CI: 1.473-2.597, P = 0.000) respectively and inferior patients’ survivals (adjusted HR = 1.265; 95%CI: 1.096-1.461, P = 0.000) (adjusted HR = 1.157; 95%CI: 1.031-1.299, P = 0.013) respectively. Overall, patients’ 5-year survival were 73.9% for normal-weight, 71.1% for underweight, 74.0% for overweight, 74.4% for class I obese, 75.0% for class II obese and 71.5% for class III obese recipients. Analysis of hypothetical exclusion of underweight and morbidly obese patients from the pool of potential LT candidates would have improved the overall survival of the entire cohort by 2.7% (95%CI: 2.5%-3.6%). CONCLUSION: Selected morbidly obese patients undergoing LT for benign conditions had 5-year survival rates clinically comparable to normal weight recipients. Impact analysis showed that exclusion of high-risk recipients (underweight and morbid obese patients) would not significantly improve the overall survival of the entire cohort of patients requiring LT.     

Management of biliary atresia: To transplant or not to transplant

Kasai procedure (KP) and liver transplantation (LT) represent the only therapeutic options for patients with biliary atresia (BA), the most common indication for LT in the pediatric population. However, KP represents by no means a radical option but rather a bridging one, as nearly all patients will finally require a liver graft. More and more experts in the field of transplant surgery propose that maybe it is time for a paradigm change in BA treatment and abandon KP as transplantation seems inevitable. Inadequacy of organs yet makes this option currently not feasible, so it seems useful to find ways to maximize the efficacy of KP. In previous decades, multiple studies tried to identify these factors which opt for better results, but in general, outcomes of KP have not improved to the level that was anticipated. This review provides the framework of conditions which favor native liver survival after KP and the ones which optimize a positive LT outcome. Strategies of transition of care at the right time are also presented, as transplantation plays a key role in the surgical treatment of BA. Future studies and further organization in the transplant field will allow for greater organ availability and better outcomes to be achieved for BA patients.     

Factors affecting complications development and mortality after single lung transplant

Lung transplantation (LT) is a life-saving therapeutic procedure that prolongs survival in patients with end-stage lung disease. Furthermore, as a therapeutic option for high-risk candidates, single LT (SLT) can be feasible because the immediate morbidity and mortality after transplantation are lower compared to sequential single (double) LT (SSLTx). Still, the long-term overall survival is, in general, better for SSLTx. Despite the great success over the years, the early post-SLT period remains a perilous time for these patients. Patients who undergo SLT are predisposed to evolving early or late postoperative complications. This review emphasizes factors leading to post-SLT complications in the early and late periods including primary graft dysfunction and chronic lung allograft dysfunction, native lung complications, anastomosis complications, infections, cardiovascular, gastrointestinal, renal, and metabolite complications, and their association with morbidity and mortality in these patients. Furthermore, we discuss the incidence of malignancy after SLT and their correlation with immunosuppression therapy.     

Pre-and-post transplant considerations in patients with nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is currently the third most common indication for liver transplantation in the United States. With the growing incidence of obesity, NAFLD is expected to become the most common indication for liver transplantation over the next few decades. As the number of patients who have undergone transplantation for NAFLD increases, unique challenges have emerged in the management and long-term outcomes in patients. Risk factors such as obesity, hypertension, diabetes, and hyperlipidemia continue to play an important role in the pathogenesis of the disease and its recurrence. Patients who undergo liver transplantation for NAFLD have similar long-term survival as patients who undergo liver transplantation for other indications. Research shows that post-transplantation recurrence of NAFLD is commonplace with some patients progressing to recurrent non-alcoholic steatohepatitis and cirrhosis. While treatment of comorbidities is important, there is no consensus on the management of modifiable risk factors or the role of pharmacotherapy and immunosuppression in patients who develop recurrent or de novo NAFLD post-transplant. This review provides an outline of NAFLD as indication for liver transplantation with a focus on the epidemiology, pathophysiology and risk factors associated with this disease. It also provides a brief review on the pre-transplant considerations and post-transplant factors including patient characteristics, role of obesity and metabolic syndrome, recurrence and de novo NAFLD, outcomes post-liver transplantation, choice of medications, and options for immunosuppression.     

The applicability and prognostic value of the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: results on a large cohort of primary cutaneous B-cell lymphomas and comparison with the system used by the Dutch Cutaneous Lymphoma Group

BACKGROUND: Recently, a consensus proposal was published for a TNM classification system for all primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome, meant to document extent of disease in a consistent manner. The applicability and the prognostic significance of this system have not been investigated thus far. OBJECTIVES: To test the applicability and prognostic relevance of the proposed TNM classification system on a cohort of primary cutaneous B-cell lymphomas (CBCL). METHODS: The study group included 71 primary cutaneous marginal zone lymphomas (PCMZL), 171 primary cutaneous follicle centre lymphomas (PCFCL) and 58 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL, LT). As only patients with primary cutaneous lymphoma were included (T1-3, N0M0), only the T-rating was scored. The results were compared with the scoring as applied by the Dutch Cutaneous Lymphoma Group. RESULTS: The system was easily applicable to all cases. In PCMZL and PCFCL no correlation was found between T-score and survival (5-year disease-specific survival: T1, 100% and 98%; T2, 94% and 93%; T3, 100% and 88%, respectively). In PCLBCL, LT there was a clear, although statistically not significant, association between increasing T-score and reduced survival (5-year disease-specific survival: T1, 75%; T2, 49%; T3, 0%; P = 0.077). Comparing the TNM system with the Dutch Cutaneous Lymphoma Group system, there was a discrepancy in the classification of 20 cases. CONCLUSIONS: The new TNM system is a useful tool to document disease extent in patients with CBCL and provides prognostic information in the group of patients with PCLBCL, LT.     

Renal transplantation, immunosuppression and the skin: an update

Transplant medicine has seen many innovations over past decades and continues to evolve into the 21st century. Newer immunosuppressive strategies in renal transplantation are associated with better patient and graft survival rates; however, the adverse toxicities and long-term side effects associated with these agents present a number of challenges. Certain immunosuppressants are commonly used in dermatologic disorders, however, dermatologists may be less familiar with the clinical efficacy, side-effect profile, and dosage of newer immunosuppressive agents. A knowledge of the molecular and cellular mechanisms of action of these agents gives us a better understanding of how these agents contribute to the cutaneous and mucosal complications frequently seen post-transplant. With the advent of new immunosuppressive therapies and different treatment regimens, there is an increasing need for a multidisciplinary approach to balancing the risks and benefits of these medications to the individual transplant recipient. This review will highlight the different immunosuppressive agents and their effect on the skin while focusing on the evidence base to support the commonly used immunosuppressive regimes, newer protocols aimed at achieving maximum graft survival with minimal side effects, and important drug interactions with which all dermatologists should be familiar.     

Growing challenge of post-liver transplantation non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide, with an estimated prevalence of 25%. Post-liver transplantation (LT) recurrent or de novo hepatic steatosis is a common complication in recipients, irrespective of transplantation indication. Risk factors for graft steatosis mainly include obesity, immunosuppression, donor steatosis, and genetic factors. Liver transplant recipients are at high risk of developing insulin resistance, new-onset diabetes, and post-transplantation metabolic syndrome that is highly associated with immunosuppressive treatment. Post-LT NAFLD is often underdiagnosed due to the poor sensitivity of most routine imaging methods. The gold standard for the diagnosis of hepatic steatosis is liver biopsy, which is, however, limited to more complex cases due to its invasive nature. There is no approved pharmacotherapy in NAFLD. Lifestyle modification remains the cornerstone in NAFLD treatment. Other treatment strategies in post-LT NAFLD include lifestyle modifications, pharmacotherapy, bariatric surgery, and tailored immunosuppression. However, these approaches originate from recommendations in the general population, as there is scarce data regarding the safety and efficacy of current management strategies for NAFLD in liver transplant patients. Future prospective studies are required to achieve tailored treatment for these patients.     

Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation

Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to published clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab–bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of rejection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we summarize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.     

Loco-regional therapies for patients with hepatocellular carcinoma awaiting liver transplantation: Selecting an optimal therapy

Hepatocellular carcinoma (HCC) is a common, increasingly prevalent malignancy. For all but the smallest lesions, surgical removal of cancer via resection or liver transplantation (LT) is considered the most feasible pathway to cure. Resection - even with favorable survival - is associated with a fairly high rate of recurrence, perhaps since most HCCs occur in the setting of cirrhosis. LT offers the advantage of removing not only the cancer but the diseased liver from which the cancer has arisen, and LT outperforms resection for survival with selected patients. Since time waiting for LT is time during which HCC can progress, loco-regional therapy (LRT) is widely employed by transplant centers. The purpose of LRT is either to bridge patients to LT by preventing progression and waitlist dropout, or to downstage patients who slightly exceed standard eligibility criteria initially but can fall within it after treatment. Transarterial chemoembolization and radiofrequency ablation have been the most widely utilized LRTs to date, with favorable efficacy and safety as a bridge to LT (and for the former, as a downstaging modality). The list of potentially effective LRTs has expanded in recent years, and includes transarterial chemoembolization with drug-eluting beads, radioembolization and novel forms of extracorporal therapy. Herein we appraise the various LRT modalities for HCC, and their potential roles in specific clinical scenarios in patients awaiting LT.     

Journey of a patient with scleroderma from renal failure up to kidney transplantation

The increased awareness of systemic sclerosis (SS) and its pathogenetic background made the management of this disease more amenable than previously thought. However, scleroderma renal crisis (SRC) is a rarely seen as an associated disorder that may involve 2%-15% of SS patients. Patients presented with earlier, rapidly progressing, diffuse cutaneous SS disease, mostly in the first 3-5 years after non-Raynaud clinical manifestations, are more vulnerable to develop SRC. SRC comprises a collection of acute, mostly symptomatic rise in blood pressure, elevation in serum creatinine concentrations, oliguria and thrombotic microangiopathy in almost 50% of cases. The advent of the antihypertensive angiotensin converting enzyme inhibitors in 1980 was associated with significant improvement in SRC prognosis. In a scleroderma patient maintained on regular dialysis; every effort should be exerted to declare any possible evidence of renal recovery. A given period of almost two years has been suggested prior to proceeding in a kidney transplant (KTx). Of note, SS patients on dialysis have the highest opportunity of renal recovery and withdrawal from dialysis as compared to other causes of end-stage renal disease (ESRD). KTx that is the best well-known therapeutic option for ESRD patients can also be offered to SS patients. Compared to other primary renal diseases, SS-related ESRD was considered for a long period of poor patient and allograft survivals. Pulmonary involvement in an SS patient is considered a strong post-transplant independent risk factor of death. Recurrence of SRC after transplantation has been observed in some patients. However, an excellent post-transplant patient and graft outcome have been recently reported. Consequently, the absence of extrarenal manifestations in an SS-induced ESRD patient can be accepted as a robust indicator for a successful KTx.     

Sentinel lymph node biopsy in extramammary Paget disease: A 13-year institutional experience

Whether sentinel lymph node biopsy status is a prognostic factor or effective in determining treatment strategies in extramammary Paget disease remains unclear. This study aimed to investigate the significance of sentinel lymph node biopsy in extramammary Paget disease. We retrospectively reviewed the clinical information of previously untreated patients with invasive extramammary Paget disease who underwent wide local excision of the primary tumor and sentinel lymph node biopsy at our hospital between April 2008 and March 2021. Clinical data including the baseline neutrophil-to-lymphocyte ratio and recurrence-free survival were analyzed. Sentinel lymph node metastases were classified as macrometastases and micrometastases, with a cut-off value for sentinel lymph node tumor burden of 2 mm. Univariate and multivariate analyses of factors affecting sentinel lymph node biopsy positivity and recurrence-free survival rates were performed. Overall, 85 patients were included in the analysis. Patients in the sentinel lymph node biopsy-positive group (n = 26) had a significantly higher invasion level and neutrophil-to-lymphocyte ratio. According to multivariate analyses, invasion level and a high neutrophil-to-lymphocyte ratio were independent predictive factors for sentinel lymph node biopsy positivity, and the sentinel lymph node biopsy status was an independent prognostic factor for recurrence-free survival. In conclusion, sentinel lymph node biopsy provides an accurate risk classification and clinical indication for postoperative follow-up in patients with invasive extramammary Paget disease.     

Acral keratotic graft versus host disease simulating warts

A 55-year-old man experienced persistent oral graft versus host disease after receiving an HLA-matched allogeneic stem cell peripheral blood transplant for chronic myeloid leukaemia. Twelve months post-transplant, multiple keratotic lesions resembling warts developed on his fingers, on his palms and on the soles of his feet. Skin biopsy showed a lichenoid reaction under a hyperplastic and hyperkeratotic epidermis lacking signs of papillomavirus infection. The lesions partially regressed when the patient's oral prednisone was increased. This instance of acral keratotic lesions may represent an unusual expression of chronic graft versus host disease; however, the the hydroxychloroquine which had been used for 8 months to control the patient's oral graft versus host disease cannot be excluded as a cofactor.     

Plantar malignant melanoma in a white Caucasian population

Fifty-one white Caucasian patients from the west of Scotland, with stage I primary malignant melanoma arising on the plantar surface were studied. Subungual lesions were excluded from the study. Clinical and pathological features were related to survival, and compared with a group of 239 cases of clinical stage 1 melanoma of the lower limb, excluding the foot, collected in the same geographical area over the same period of time (1979–84). The average age of patients with plantar melanoma was 67 years and was significantly older than those with leg melanomas, in whom the mean age was 53 years.
Twenty patients with plantar lesions had superficial spreading melanomas, 27 had acral lentiginous melanomas, and four had nodular lesions. The female: male ratio was 3:2 which was significantly different from the 7:1 female:male ratio for leg lesions. Plantar melanomas were more commonly ulcerated (57%) than were melanomas on the leg (29%) [P<0.001]. There was no significant difference between the mean thickness of melanomas on the plantar surface and those on the leg. Nine (17%) of the patients with plantar melanomas gave a clinical history of pre-existing naevus and in 27% there was pathological evidence of a pre-existing naevus.
Disease-free survival at 5 years for the population with plantar melanomas was 82, 51 and 0%, respectively, for melanomas 0–1.49,1.5–3.49 and over 3–5 mm in thickness. This compares with 95, 71 and 46%, respectively, for leg lesions. In each thickness category patients with leg melanomas have a significantly better survival. In analysis of multiple prognostic features using a stepwise proportional hazards model, tumour thickness was the major prognostic indicator, and thickness alone provided all prognostic information on recurrence of stage I plantar melanoma. For survival, however, ulceration complemented tumour thickness. These were the only two significant factors for modelling time of death due to melanoma.     

Female gender in the setting of liver transplantation

The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Women’s access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a woman’s physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause.