Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model.

BACKGROUND AND AIMS: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. APPROACH AND RESULTS: We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. CONCLUSIONS: After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.

5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial.

BACKGROUND & AIMS: ß-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase coupling. It also converts homocysteine (tHcy) into methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide bioavailability markers in patients with cirrhosis and portal hypertension. METHOD: Sixty patients with cirrhosis and HVPG ≥12 mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of nitric oxide bioavailability (BH4, ADMA and tHcy) were measured again at the end of treatment. RESULTS: Groups were similar in terms of baseline clinical and hemodynamic data and nitric oxide bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p = 0.028), without differences in hepatic blood flow. At the end of treatment, 5-MTHF+propranolol (vs. placebo+propranolol) was associated with higher BH4 (1,101.4 ± 1,413.3 vs. 517.1 ± 242.8 pg/ml, p <0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7 µmol/L, p = 0.027) and lower tHcy (µmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2 µmol/L, p = 0.010) plasma levels. CONCLUSION: In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation. CLINICAL TRIAL EUDRACT NUMBER: 2014-002018-21. IMPACT AND IMPLICATIONS: Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of ß-blockers, but some patients still present with acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to ß-blockers is more effective in reducing portal pressure than ß-blockers alone. This finding could represent the basis for validation studies in larger cohorts, which could impact the future prophylactic management of variceal bleeding in cirrhosis. Enhancing the benefit of ß-blockers with a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis, which in turn could translate into a reduction in the rates and costs of hospitalization, and ultimately into improved survival.

Portosystemic shunt is an effective treatment for complications of portal hypertension in hepatic myeloid metaplasia and improves nutritional status.

In patients affected by myelofibrosis with hepatic myeloid metaplasia (HMM), portal hypertension (PHT) complications may develop. In this case series, we analysed the efficacy and safety of transjugular portosystemic shunt (TIPS) in the treatment of PHT-related complications and its effects on the nutritional status. Six patients were evaluated and the average follow-up period after TIPS was 33 (IQR 5) months. None of the patients developed hepatic failure, nor any recurrence of variceal bleeding was recorded. No additional paracentesis or endoscopic prophylactic treatment for PHT-related complications were required. In all subjects, the average dose of diuretics was almost halved three months after TIPS. Three patients died during the follow-up, but none for liver-related causes. All patients showed an improvement in the global nutritional status. In conclusion, TIPS represent an effective and safe treatment option for patients affected by complications of PHT secondary to HMM and drives to an improvement of the nutritional status.

Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study.

BACKGROUND: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. METHODS: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. RESULTS: We analysed data from 511 patients observing significant associations between quality of life's physical score and both age and adherence to Mediterranean diet (p < .01). A significant negative correlation was observed between mental score and the sedentary activity (p < .05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. CONCLUSIONS: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.

Predictors of solid extra-hepatic non-skin cancer in liver transplant recipients and analysis of survival: A long-term follow-up study.

INTRODUCTION AND OBJECTIVES: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. PATIENTS: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. RESULTS: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n = 47) more often developed post-LT diabetes mellitus (DM) (57.4% versus 35,9%, p = 0.004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p = 0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p = 0.023). CONCLUSIONS: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients.

Relevance of Spontaneous Portosystemic Shunts Detected with CT in Patients with Cirrhosis.

Background Cirrhosis leads to portal hypertension and to the consequent formation of spontaneous portosystemic shunts (SPSSs), leading to complications related to the diversion of portal blood into the systemic circulation, which is called portosystemic shunt syndrome. Purpose To investigate the characteristics of patients with cirrhosis and an SPSS and secondarily to assess the prognostic impact of SPSSs on portal hypertension-related complications and transplant-free survival. Materials and Methods A retrospective database review of patients with cirrhosis (observed from March 2015 to July 2019) was performed to identify patients with CT imaging and outcomes data. For each patient, clinical and biochemical data were collected, and the presence, types, and sizes of SPSSs were investigated with CT. Patients were followed for a mean of 27.5 months ± 22.8. Multivariable logistic analysis was used to identify the clinical characteristics associated with the presence of SPSSs (any size) and presence of SPSSs 1 cm or larger. Competitive risk analysis (Fine and Gray model) was used to identify the association between SPSSs and complications and mortality. Results Two hundred twenty-two patients with cirrhosis (157 male, 65 female; mean age, 62 years ± 12 [standard deviation]) were evaluated. An SPSS was found in 141 of 222 patients (63.5%), and 40 of 222 (18%) had a shunt diameter of at least 1 cm. At presentation, variables independently associated with the presence of SPSSs (any size) were portal vein thrombosis (odds ratio, 5.5; P = .008) and Child-Pugh class C (odds ratio, 3.0; P = .03). Previous hepatic encephalopathy (odds ratio, 4.4; P = .001) and portal vein thrombosis (odds ratio, 5.3; P = .001) were the only variables associated with SPSSs larger than 1 cm. Patients with SPSSs of any size had higher mortality (subdistribution hazard ratio, 1.9; P < .001) and higher frequency of hepatic encephalopathy (subdistribution hazard ratio, 2.3; P = .023), gastrointestinal bleeding (subdistribution hazard ratio, 2.9; P = .039), and portal vein thrombosis (subdistribution hazard ratio, 7.6; P = .005). Conclusion The presence of spontaneous portosystemic shunts on CT images in patients with cirrhosis was associated with higher mortality and complications, including portal vein thrombosis, hepatic encephalopathy, and gastrointestinal bleeding. © RSNA, 2021 See also the editorial by Reeder in this issue.

Assessment of Liver Fibrosis With Elastography Point Quantification vs Other Noninvasive Methods.

BACKGROUND & AIMS: Elastography point quantification (ElastPQ) is a non-invasive method for assessing liver fibrosis based on liver stiffness. We evaluated the accuracy of ElastPQ for the staging of liver fibrosis in patients with chronic liver disease (CLD) compared with aspartate transaminase to platelet ratio index, fibrosis-4 index, and transient elastography (TE), using liver biopsy as reference standard. METHODS: We performed a retrospective study of 406 patients with CLD of any etiology who underwent liver biopsy analysis from September 2012 through June 2017 at a clinic in Bologna, Italy. We obtained liver stiffness measurements, made by ElastPQ and TE, for 361 patients. Liver fibrosis stage was assessed by the METAVIR scoring system. Areas under the receiver operating characteristic curve (AUROC) were used to assess the diagnostic performance of ElastPQ. RESULTS: ElastPQ values correlated with histologic detection of fibrosis (r = 0.718; P < .001). The AUROC values were 0.856 for detection of significant fibrosis (F≥2), 0.951 for advanced fibrosis (F≥3), and 0.965 for cirrhosis. The best cut-off values identified for classifying patients with F≥2, F≥3, or cirrhosis were 6.0 kPa, 6.2 kPa, and 9.5 kPa, respectively: these were lower than those for TE. Comparison of ElastPQ with TE data resulted in superimposable diagnostic accuracy of both methods for each stage of liver fibrosis. Both elastography techniques performed better than aspartate transaminase to platelet ratio index or fibrosis-4 index scores (P < .05 for all AUROC comparisons). CONCLUSIONS: ElastPQ has good to excellent performance for the non-invasive staging of liver fibrosis in patients with CLD. ElastPQ identified patients with fibrosis or cirrhosis with levels of accuracy that were not inferior to those of TE, and outperformed serum fibrosis indexes in identifying each stage of liver fibrosis.

Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B.

The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a "grey" zone. Hepatitis B core-related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg-negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment-naive HBeAg-negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV-DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow-up of at least 1 year. In the overall population of 160 HBeAg-negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV-DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut-off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long-term clinical evaluation, a single measurement of HBcrAg at the established cut-off was optimally consistent with clinical outcome. Conversely, the HBsAg cut-off performed well in the true quiescent phase and less in more difficult-to-categorize patients. In conclusion, single-point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.

Impact of psychosocial status on liver transplant process.

Liver transplant candidates and recipients are at high risk of psychological distress. Social, psychological and psychiatric patterns seem to influence morbidity and mortality of patients before and after transplant. An accurate organ allocation is mandatory to guarantee an optimal graft and recipient survival. In this context, the pre-transplant social, psychological and psychiatric selection of potential candidates is essential for excluding major psychiatric illness and for estimating the patient compliance. Depression is one of the most studied psychological conditions in the field of organ transplantation. Notably, an ineffectively treated depression in the pre-transplant period has been associated to a worst long-term recipient survival. After transplant, personalized psychological intervention might favor recovery process, improvement of quality of life and immunosuppressant adherence. Active coping strategy represents one of the most encouraging ways to positively influence the clinical course of transplanted patients. In conclusion, multidisciplinary team should act in three directions: prevention of mood distress, early diagnosis and effective treatment. Active coping, social support and multidisciplinary approach might improve the clinical outcome of transplanted patients.

Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis.

BACKGROUND & AIMS: Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy. We also studied whether under-dilated TIPS self-expand to nominal diameter over time. METHODS: We performed a prospective, non-randomized study of 42 unselected patients with cirrhosis who received under-dilated TIPS (7 and 6 mm) and 53 patients who received PTFE-SGs of 8 mm or more (controls) at referral centers in Italy. After completion of this study, dilation to 6 mm became the standard and 47 patients were included in a validation study. All patients were followed for 6 months; Doppler ultrasonography was performed 2 weeks and 3 months after TIPS placement and every 6 months thereafter. Stability of PTFE-SG diameter was evaluated by computed tomography analysis of 226 patients with cirrhosis whose stent grafts increased to 6, 7, 8, 9, or 10 mm. The primary outcomes were incidence of at least 1 episode of PSE grade 2 or higher during follow up, incidence of recurrent variceal hemorrhage or ascites, incidence of shunt dysfunction requiring TIPS recanalization, and reduction in porto-caval pressure gradient. RESULTS: PSE developed in a significantly lower proportion of patients with under-dilated TIPS (27%) than controls (54%) during the first year after the procedure (P = .015), but the proportions of patients with recurrent variceal hemorrhage or ascites did not differ significantly between groups. No TIPS occlusions were observed. These results were confirmed in the validation cohort. In an analysis of self-expansion of stent grafts, during a mean follow-up period of 252 days after placement, none of the PTFE-SGs self-expanded to the nominal diameter in hemodynamically relevant sites (such as portal and hepatic vein vascular walls). CONCLUSIONS: In prospective, non-randomized study of patients with cirrhosis, we found under-dilation of PTFE-SGs during TIPS placement to be feasible, associated with lower rates of PSE, and effective.

Low molecular weight heparin does not increase bleeding and mortality post-endoscopic variceal band ligation in cirrhotic patients.

BACKGROUND & AIMS: Anticoagulants are commonly indicated in cirrhotic patients due to high rate of (pro)thrombotic conditions. Low molecular weight heparin (LMWH) is safe in patients with esophageal varices. However, the safety of LMWH is unknown in patients undergoing prophylactic endoscopic variceal ligation (EVL). To define the 4-week risk of bleeding and death after prophylactic EVL in cirrhotic patients continuously treated with LMWH. METHODS: All EVLs performed at a tertiary Italian Center from 2009 to 2016 were retrospectively reviewed. Patients treated with LMWH were classified as on-LMWH; the remaining as no-LMWH. Endoscopic characteristics at first and index EVL (that preceding an endoscopy either showing a bleeding episode or the absence of further treatable varices) and clinical events within 4 weeks from the procedures were recorded. RESULTS AND CONCLUSIONS: Five hundred fifty-three EVLs were performed in 265 patients (in 215 as a primary prophylaxis): 169 EVLs in 80 on-LMWH and 384 in 185 no-LMWH (4.9 ± 1.1 vs 4.8 ± 1.0 bands/session, respectively; P = .796). Six patients bled (2.2%) without between-groups difference (3.8% on-LMWH vs 1.6% no-LMWH, Log-rank P = .291). Large varices with red marks (100% vs 51.4%, P = .032), number of bands (5.6 ± 0.5 vs 4.6 ± 1.2, P = .004), underlying portal vein thrombosis (66.7% vs 23.6%, P = .033), and creatinine (2.2 ± 2.7 vs 1.0 ± 0.8 mg/dL, P = .001) at index EVL were significantly different between bleeders and non-bleeders. Six patients died within 4-week from index EVL, without between-groups difference (2.5% on-LMWH vs 2.2% no-LMWH, Log-rank P = .863). LMWH does not increase the risk of post-procedural bleeding and does not affect survival of cirrhotic patients undergoing prophylactic EVL.

Worsening of Serum Lipid Profile after Direct Acting Antiviral Treatment.

INTRODUCTION: Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA). MATERIAL AND METHODS: We considered patients consecutively treated between January and November 2015 recording clinical data at baseline and week 24 of follow-up. Frozen serum samples were used for apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to estimate trends and Logistic Regression for predictors of lipid changes. RESULTS: We enrolled 100 patients, mostly cirrhotic (81%) and with genotype 1b (59%). Ninety-three patients achieved sustained virological response (SVR), while 7 relapsed. Homeostasis model assessment of insulin resistance declined (from 3 to 2.7, p < 0.001); non-high density lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35 (p < 0.001), and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dL (p < 0.001). Rise of low-density lipoprotein/HDL and apoB/apoA1 ratio were registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18 to 0.53 ± 0.18 mg/dL, p < 0.001). We conducted a subanalysis on patients with relapse. In this subgroup, no change of lipid profile was recorded. At multivariate analysis emerged that the addition of ribavirin to DAA, represented an independent predictor of increased Lp(a) (OR 3.982, 95% CI 1.206-13.144, p = 0.023). CONCLUSION: DAA therapy led to reduction of insulin resistance. In contrast, pro-atherogenic lipid changes were observed in patients with SVR. Further studies will be necessary to evaluate the cardiovascular balance between amelioration of glucose metabolism and negative changes of lipid profile.

NS5A inhibitors for the treatment of hepatitis C infection.

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV-NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.

Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant.

Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis.

A new prognostic model to predict dropout from the waiting list in cirrhotic candidates for liver transplantation with MELD score <18.

BACKGROUND & AIMS: The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD < 18 awaiting LT, finding prognostic variables to identify a high dropout risk. METHODS: Training set consisted of 277 patients and validation cohort of 292 patients. Competing risk regression analysis, taking into account LT, was used for univariate/multivariate analysis. RESULTS: Ascites, sodium, bilirubin, albumin and glomerular filtration rate were independently associated with a 12-month dropout risk in the training set. Combining these five prognostic parameters, we calculated a new score named liver-renal-risk (LIRER). In the validation set, the 12-month LIRER concordance index showed a discrimination power [0.798, 95% confidence interval (95% CI) 0.793-0.803] better than MELD (0.582, 95% CI 0.575-0.588), Child-Turcotte-Pugh (0.687, 95% CI 0.681-0.693), MELD-sodium (0.721, 95% CI 0.715-0.727) and MELD-ascites-sodium (0.729, 95% CI 0.724-0.735), with a remarkable calibration (Hosmer-Lemeshow test: P = 0.91; R(2) = 0.911). Considering all study patients, the risk of wait list dropout increased with the rise in LIRER. The survival benefit analysis comparing the wait list dropout risk with the mortality of the 216 transplanted patients with same LIRER showed an important benefit for LT in patients with LIRER > 15.9. CONCLUSIONS: In patients with low MELD (<18), combination of ascites, sodium, albumin, bilirubin and renal function in a new score (LIRER) discriminates patients at high risk of medium-term adverse outcome from those in whom LT may be safely deferred.

Metabolic Disorders in Liver Transplant Recipients: The State of the Art.

Liver transplantation represents a chief therapeutic approach for acute liver failure, end-stage liver disease and hepatocellular carcinoma. Despite witnessing advancements in short- and medium-term survival over recent decades, attributed to refinements in surgical techniques and immunosuppressive protocols, long-term mortality remains impervious to modification. Notably, cardiovascular disease emerges as a predominant cause of mortality among liver transplant recipients. This trend is accentuated by the increasing prominence of non-alcoholic steatohepatitis-related cirrhosis as an indication for liver transplantation. Moreover, the administration of immunosuppressive agents is intricately linked to the degradation of the metabolic profile in liver transplant recipients, thereby contributing to the initiation or exacerbation of cardiovascular risk factors, such as hypertension, diabetes, and dyslipidaemia. In addition, the post-liver transplantation period is marked by a decline in lifestyle quality and a failure to acknowledge the psychological distress experienced by patients throughout the transplant process. These factors can precipitate a deterioration in the patient's metabolic profile, exacerbated by suboptimal therapeutic compliance. This narrative review aims to comprehensively address the principal metabolic disorders intricately associated with liver transplantation.

Aging with a Liver Graft: Analysis of Very Long-Term Survivors after Liver Transplantation.

BACKGROUND: In Italy, data on long-term survivors after liver transplantation are lacking. MATERIALS AND METHODS: We conducted a hybrid design study on a cohort of 359 adult recipients who received transplants between 1996 and 2002 to identify predictors of survival and the prevalence of co-morbidities among long-term survivors. RESULTS: The actuarial (95% CI) patient survival was 96% (94.6-98.3%), 69% (64.2-73.6%), 55% (49.8-59.9%), 42.8% (37.6-47.8%), and 34% (29.2-38.9%) at 1, 5, 10, 15, and 20 years, respectively. The leading causes of death were hepatitis C virus recurrence (24.6%), extrahepatic malignancies (16.9%), infection (14.4%), and hepatocellular carcinoma recurrence (14.4%). The factors associated with the survival probability were younger donor and recipient ages (p = 0.001 and 0.004, respectively), female recipient sex (p < 0.001), absence of HCV (p < 0.01), absence of HCC (p = 0.001), and absence of diabetes mellitus at one year (p < 0.01). At the latest follow-up, the leading comorbidities were hypertension (53.6%), obesity (18.7%), diabetes mellitus (17.1%), hyperlipidemia (14.7%), chronic kidney dysfunction (14.7%), and extrahepatic malignancies (13.8%), with 73.9% of patients having more than one complication. CONCLUSIONS: Aging with a liver graft is associated with an increased risk of complications and requires ongoing care to reduce the long-term attrition rate resulting from chronic immunosuppression.

Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

Unsupervised Exercise Intervention vs. Adherence to a Mediterranean Diet Alone: The Role of Bioelectrical Impedance Vector Analysis and Cardiovascular Performance in Liver-Transplanted Recipients.

(1) Background: Cardiovascular disease is one of the leading causes of mortality after liver transplantation. Body composition and cardiovascular performance assessment represent a potential approach for modulating lifestyle correction and proper follow-up in chronic disease patients. This study aimed to verify the additional role of an unsupervised physical activity program in a sample of male liver transplant recipients who follow the Mediterranean diet. (2) Methods: Thirty-three male liver transplant recipients were enrolled. Sixteen subjects followed a moderate-intensity home exercise program in addition to nutritional support, and seventeen received advice on the Mediterranean diet. After six months, bioelectrical vector impedance analysis (BIVA) and cardiopulmonary exercise testing (CPET) were performed. (3) Results: No differences in CPET (VO2 peak: exercise 21.4 ± 4.1 vs. diet 23.5 ± 6.5 mL/kg/min; p = 0.283) and BIVA (Z/H: exercise 288.3 ± 33.9 vs. diet 310.5 ± 34.2 Ω/m; p = 0.071) were found. Furthermore, the BIVA values of resistance correlate with the submaximal performance of the Ve/VCO2 slope (R = 0.509; p < 0.05) and phase angle with the maximal effort of the VO2 peak (R = 0.557; p < 0.05). (4) Conclusions: Unsupervised physical exercise alone for six months does not substantially modify liver transplant recipients' cardiovascular performance and hydration status, despite their adherence to a Mediterranean diet. The body composition analysis is useful to stratify the risk profile, and it is potentially associated with better outcomes in transplanted subjects.