CACS, CCTA and mCAD-LT score in the pre-transplant assessment of coronary artery disease and the prediction of post-transplant cardiovascular events.

BACKGROUND: The optimal cardiovascular assessment of liver transplant (LT) candidates is unclear. We aimed to evaluate the performance of CT-based coronary tests (coronary artery calcium score [CACS] and coronary CT angiography [CCTA]) and a modification of the CAD-LT score (mCAD-LT, excluding family history of CAD) to diagnose significant coronary artery disease (CAD) before LT and predict the incidence of post-LT cardiovascular events (CVE). METHODS: We retrospectively analysed a single-centre cohort of LT candidates who underwent non-invasive tests; invasive coronary angiography (ICA) was performed depending on the results of non-invasive tests. mCAD-LT was calculated in all patients. RESULTS: Six-hundred-and-thirty-four LT candidates were assessed and 351 of them underwent LT. CACS, CCTA and ICA were performed in 245, 123 and 120 LT candidates, respectively. Significant CAD was found in 30% of patients undergoing ICA. The AUROCs of mCAD-LT (.722) and CCTA (.654) were significantly higher than that of CACS (.502) to predict the presence of significant CAD. Specificity of the tests ranged between 31% for CCTA and 53% for CACS. Among patients who underwent LT, CACS ≥ 400 and mCAD-LT were independently associated with the incidence of CVE; in patients who underwent CCTA before LT, significant CAD at CCTA also predicted post-LT CVE. CONCLUSION: In this cohort, mCAD-LT score and CT-based tests detect the presence of significant CAD in LT candidates, although they tend to overestimate it. Both mCAD-LT score and CT-based tests classify LT recipients according to their risk of post-LT CVE and can be used to improve post-LT risk mitigation.

IgG4-related disease mimicking a liver abscess.

IgG4-related disease (IGRD) is a complex medical condition affecting multiple organs, including the liver. The condition is characterized by excessive production of IgG4 antibodies, leading to chronic inflammation and tissue damage. We present a case of a 37-year-old man with a history of chronic pancreatitis was diagnosed with a liver mass. Initial treatment included piperacillin and tazobactam, but the patient's condition worsened. An ultrasound-guided biopsy revealed increased IgG4 positive cells, leading to the diagnosis of an inflammatory pseudotumor associated with IGRD. The patient was treated with prednisone taper therapy, and the liver mass resolved after six months of corticoid treatment.

Results of a multidisciplinary strategy to improve the management of cardiovascular risk factors after liver transplantation.

Although liver transplantation (LT) recipients are at high cardiovascular risk (CVR), the management of CVR factors (CVRF) after LT is far from optimal and needs to be improved. For this reason, we developed a multidisciplinary protocol to standardize the identification, risk stratification, management, and targets of therapy of CVRF during the first post-LT year. The grade of identification and control of CVRF 12 months after LT in the postintervention cohort (LT January 2018-January 2020, n = 150) were compared with a control cohort who underwent LT between July 2015 and December 2016 (n = 100). Before LT, the prevalence of metabolic-associated fatty liver disease as the indication of LT and the presence of obesity were significantly higher in the postintervention cohort, whereas the prevalence of other CVRF and renal dysfunction tended to be higher. Cyclosporine A was used less frequently in the postintervention cohort, whereas everolimus tended to increase. At 12 months after LT, the proportion of patients with measured blood pressure (88% vs. 56%), glycosilated hemoglobin (HbA1c; 96% vs. 72%), and high-density lipoprotein/low-density lipoprotein cholesterol (67% vs. 33%) was higher in the postintervention than in the control cohort (all p < 0.001). Blood pressure (64% vs. 36%, p = 0.02) and HbA1c (85% vs. 70%, p = 0.1) were within target in more individuals with hypertension and diabetes mellitus, respectively, in the postintervention cohort. Median total cholesterol levels were lower in the postintervention (184 mg/dl; interquartile range [IQR], 160-210 mg/dl) than in the control cohort (212 mg/dl; IQR, 186-240 mg/dl; p = 0.02). At 2 years after LT, the incidence of cardiovascular events was 14% in the control cohort and 6% in the postintervention cohort (p = 0.063). In conclusion, a multidisciplinary, multiprofessional strategy can achieve a higher grade of assessment and management of post-LT CVR despite a worsening metabolic profile of LT recipients.

The Role of Arterial Stiffness in the Estimation of Cardiovascular Risk in Liver Transplant Recipients.

BACKGROUND: Long-term cardiovascular (CV) events are a frequent cause of death and disability after liver transplant (LT). Although a more in-depth, risk-adapted control of CV risk factors may result in improved post-LT CV outcomes, an accurate stratification of the CV risk of LT recipients to better implement preventive strategies is lacking. Aortic pulse wave velocity (aPWV) is a surrogate of arterial stiffness that has been suggested as a biomarker of CV risk; it has never been evaluated in adult LT recipients. METHODS: In a single-center prospective study, we included 122 LT recipients at 12 (n = 39), 60 (n = 45), or 120 (n = 38) mo after LT. aPWV estimation by oscillometry, clinical assessment of CV risk factors, and CV risk estimation by standard clinical scores (systematic coronary risk evaluation and pooled cohort equation) were performed. The incidence of CV events during prospective follow-up was registered. RESULTS: aPWV was independently associated with age and the grade of control of blood pressure. After a median follow-up of 35 mo, 15 patients (12%) presented a CV event. Higher aPWV, diabetes, past or present smoking habit, previous CV events, lower eGFR, being in systematic coronary risk evaluation or pooled cohort equation high-risk groups, and higher levels of total cholesterol, LDL-cholesterol, creatinine, and triglycerides were associated with the incidence of CV events at univariate analysis; aPWV, past or present smoking habit, and triglycerides were independent predictors of CV events. CONCLUSIONS: According to our results, aPWV mirrors CV risk in LT recipients and thus may be a useful CV risk biomarker in this population. Considering these preliminary results, its accuracy in stratifying risk requires confirmation in further studies.

Liver and kidney transplantation in polycystic liver and kidney disease. / Trasplante hepático y renal en la enfermedad poliquística hepatorrenal.

OBJECTIVE: To evaluate the results of isolated liver and combined liver and kidney transplantation in a retrospective series of 32 patients with hepatorenal liver and kidney disease. MATERIALS AND METHODS: A retrospective observational study that enrolled patients with polycystic liver disease (PLD) and polycystic liver and kidney disease (PLKD) who were evaluated for transplantation between January 1999 and December 2019 at Hospital Clínic de Barcelona [Clinical Hospital of Barcelona]. RESULTS: We included a total of 53 patients enrolled, 32 (60.3%) had indication for transplantation, of which 12 received a single liver transplant and 20 received a double liver and kidney transplant. The mean age was 52 years and 83.9% of the recipients were women. The main indication for liver transplantation was disabling symptomatic hepatomegaly (93.5%). Among the postoperative complications, in the combined liver and kidney transplant group, hepatic artery thrombosis in one case and renal artery thrombosis in other were detected. In both groups there was one case of inferior vena cava lesion. Three patients presented acute cellular rejection responding to corticosteroids and one presented humoral rejection which was treated with plasmapheresis. During the follow-up period of 80 (27-121) months, the liver transplant survival rate was 100% and the kidney transplant survival rate was 90%. Two patients in the combined liver and kidney transplant group died (one due to cardiovascular causes and the other due to intestinal adenocarcinoma). CONCLUSIONS: Isolated liver transplantation or combined liver and kidney transplantation in selected patients with polycystic disease yields excellent results, with few complications, very good transplant survival and excellent patient survival (93.8%).

Improvement of sexuality after hepatitis C cure with direct acting antivirals.

Despite rarely assessed, sexuality is a relevant domain in Quality of Life. We prospectively evaluated the impact of direct-acting antiviral therapy on sexuality in a cohort of 186 patients with chronic hepatitis C (HCV). Sexual dysfunction was assessed by validated scales CSFQ-14/CSFQ-VAS at baseline and one year after treatment finalization. Median age was 55 years and 87% had mild liver disease. Basal prevalence of sexual dysfunction (62%) and fear of HCV transmission (25%) were high. After HCV cure, both sexual dysfunction prevalence and CSFQ-VAS improved (P = .058 and P < .01, respectively), and fear of HCV transmission dropped to 16% (P = .02). These changes were especially relevant in young men (<55), where sexual dysfunction decreased from 48.6% to 29.7% (P = .04) and among non-depressed patients in whom sexual dysfunction decreased from 54.6% to 47% (P < .01). Age and major depression remained as independent factors of sexual dysfunction persistence after HCV cure. Our data suggest that HCV eradication is associated with an improvement in sexuality, in those patients without depression.

MicroRNAs 155-5p, 122-5p, and 181a-5p Identify Patients With Graft Dysfunction Due to T Cell-Mediated Rejection After Liver Transplantation.

MicroRNAs (miRNAs) are small noncoding RNAs that can be detected in plasma and whose expression is associated with pathological processes. The role of miRNAs in the noninvasive diagnosis of T cell-mediated rejection (TCMR) after liver transplantation (LT) is unclear. Thus, we aimed to assess the effectiveness of a panel of 4 miRNAs (155-5p, 122-5p, 181a-5p, and 148-3p) in diagnosing TCMR in LT recipients with graft dysfunction (GD), and we compared its accuracy with previously published tests for diagnosing TCMR based on routine laboratory parameters. From a prospective cohort of 145 patients followed during the first year after transplant, 49 developed GD and underwent a liver biopsy and plasma collection for miRNA analysis using quantitative real-time polymerase chain reaction. Patients with GD due to TCMR (n = 21) exhibited significantly higher (P < 0.001) expression of miRNA 155-5p (2.05 versus 0.07), 122-5p (19.36 versus 1.66), and 181a-5p (1.33 versus 0.37) compared with those with GD from other causes (n = 28). The area under the receiver operating characteristic curve of miRNAs 155-5p, 122-5p, and 181a-5p for the diagnosis of TCMR was 0.87, 0.91, and 0.89, respectively, significantly higher than those of the other noninvasive tests (P < 0.001). Furthermore, miRNA 155-5p identified all patients who presented TCMR during the first 2 weeks after transplant. miRNA plasmatic expression differentiates TCMR from other causes of GD in patients who have undergone LT and may be a useful tool in clinical practice.

Resolution of subclinical porphyria cutanea tarda after hepatitis C eradication with direct-acting anti-virals.

BACKGROUND: Hepatitis C virus (HCV) is a risk factor for porphyria cutanea tarda (PCT), a rare disease originating in the liver characterised by overproduction of porphyrins. Although hepatitis C infection is highly prevalent among patients with porphyria, only a minority of hepatitis C patients develop PCT. AIMS: To explore the presence of porphyrin abnormalities in a cohort of asymptomatic hepatitis C-infected patients and the impact of anti-viral therapy. METHODS: Eighty-four consecutive patients with HCV infection treated with direct-acting antivirals after 1 January 2018 were longitudinally evaluated for the presence of porphyrin abnormalities. Those patients with biochemical abnormalities at baseline were additionally evaluated at follow-up. Porphyrins in urine were screened by fluorometry and isomer separation was performed by liquid chromatography. RESULTS: In five patients, all of them asymptomatic, porphyrin profile abnormalities were detected: three presented significant increased urinary porphyrins with a typical PCT profile, and two showed normal levels of urinary porphyrins, but abnormal porphyria-like profiles. Urine evaluation after hepatitis C cure showed complete normalisation of the urinary porphyrins in all patients, confirming the biochemical cure of the disease. CONCLUSIONS: We document the existence of rare cases of hepatitis C-infected patients with significant uroporphyrinuria in the absence of dermatological manifestations. Anti-viral therapy normalises the biochemical disorder, preventing patients from presenting PCT associated complications.

Incidence, Predictors, and Impact on Survival of Long-term Cardiovascular Events After Liver Transplantation.

BACKGROUND: Information on the risk factors, particularly kidney function, and impact of long-term cardiovascular events (CVE) after liver transplantation (LT) remains scarce. METHODS: This is a retrospective, single-center study that included consecutive LT recipients between 2007 and 2017. The incidence of CVE, their risk factors, and their impact on patient survival were investigated. RESULTS: We included 627 LT recipients. The incidence of CVE was 8% and 20% at 12 and 60 months after LT, respectively. The independent risk factors of long-term (beyond 12 mo) CVE were age at LT (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.07), male gender (HR, 2.48; 95% CI, 1.21-5.05), history of pre-LT cardiovascular disease (HR, 2.19; 95% CI, 1.2-3.98), and immunosuppression with cyclosporine A (HR, 1.93; 95% CI, 1.14-3.3). In patients with pre-LT cardiovascular disease, creatinine levels 12 months after LT significantly impacted the risk of long-term CVE. Long-term CVE (HR, 2.12; 95% CI, 1.24-3.61), hepatitis C as the etiology of liver disease (HR, 2.18; 95% CI, 1.29-3.67), cytomegalovirus infection (HR, 1.89; 95% CI, 1.08-3.3), and donor age (HR, 1.02; 95% CI, 1.01-1.04) were independent factors associated with post-LT patient death. CONCLUSIONS: Age, male gender, cardiovascular disease before LT, and cyclosporine A were associated with the risk of long-term CVE. The impact of serum creatinine was restricted to patients with pre-LT cardiovascular disease. In these patients, preservation of kidney function early after LT may lessen the incidence of CVE, which are an independent predictor of post-LT death.

Severe hepatitis B reactivation during direct-acting antiviral treatment in "the absence" of hepatitis B surface antigen.

Hepatitis C virus (HCV) treatment with direct-acting antivirals (DAA) can be associated with reactivation of hepatitis B (HBV). We report a case of a kidney transplant recipient who had a fatal severe HBV reactivation during treatment for chronic hepatitis C with DAA. Diagnosis of HBV reactivation was delayed due to undetectable surface antigen (HBsAg) by standard assays. The latter was explained by the presence of HBsAg escape mutants. The case illustrates the relevance of HBV-DNA testing in transplant recipients with previous exposure to HBV, even in the absence of HBsAg, and particularly when liver test abnormalities are present.

Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation.

The development of noninvasive biomarkers that reflect the state of immunosuppression (IS) remains an unmet need in liver transplantation (LT). Torque Teno virus (TTV) is a highly prevalent, nonpathogenic DNA virus whose plasma levels may be associated with the immune status of the host. The aim of this study was to assess the role of TTV as a biomarker of IS in LT recipients. TTV DNA in plasma was quantified by real-time polymerase chain reaction at different time points during the first year after transplant in a prospectively followed cohort of 63 de novo LT recipients, and any correlation between TTV DNA and biopsy-proven acute cellular rejection (ACR) and opportunistic infections was then evaluated. In addition, TTV DNA was studied in 10 longterm LT recipients in monotherapy with tacrolimus, 10 tolerant recipients, and 10 healthy controls. TTV was detected in the plasma of all patients. Among the 63 LT recipients, 20 episodes of ACR were diagnosed, and there were 28 opportunistic infections, 26 of them being cytomegalovirus (CMV) infections. TTV viremia was significantly lower during ACR (4.41 versus 5.95 log10 copies/mL; P = 0.002) and significantly higher during CMV infections (5.79 versus 6.59 log10 copies/mL; P = 0.009). The area under the receiver operating characteristic curve of TTV viral load for the diagnosis of moderate ACR was 0.869, with a sensitivity and negative predictive value of 100%, respectively, for a cutoff point of 4.75 log10 copies/mL. There were no statistically significant differences in TTV DNA in either longterm or tolerant patients and healthy controls. In conclusion, plasma TTV DNA levels are associated with immune-related events after LT and could constitute a potential biomarker of the state of IS during the first months after transplant.

Primary adrenal insufficiency due to hereditary apolipoprotein AI amyloidosis: endocrine involvement beyond hypogonadism.

Several mutations in the gene encoding apolipoprotein AI (apoAI) have been described as a cause of familial amyloidosis. Individuals with apoAI-derived (AApoAI) amyloidosis frequently manifest with liver, kidney, laryngeal, skin and myocardial involvement. Although primary hypogonadism (PH) is considered almost pathognomonic of this disease, until now, primary adrenal insufficiency (PAI) has not been described as a common clinical feature. Here, we report the first kindred with AApoAI amyloidosis in which PAI is well-documented. All family members with the Leu60_Phe71delins60Val_61Thr heterozygous mutation who were regularly followed-up at our centre were considered. Nineteen individuals had the confirmed APOA1 deletion/insertion mutation, with detailed medical records available in 11 cases. Of these, 6 had PAI and 3 (all males) had PH. Among them, one 47-year-old man, not previously diagnosed with PAI, developed adrenal crisis after liver transplantation, precipitated by an opportunistic infection. Transplantation due to organ failure, which necessitates use of immunosuppressive medication such as corticosteroids, is frequently required during the course of hereditary amyloidosis. Consequently, PAI can remain masked, being discovered only when an adrenal crisis develops. Therefore, according to the present evidence, patients with AApoAI amyloidosis should be submitted to regular testing of corticotrophin and cortisol levels in order to avoid delaying corticosteroid replacement.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). CONCLUSION: In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694).

Increased risk of portal vein thrombosis in patients with autoimmune hepatitis on the liver transplantation waiting list.

Liver transplantation (LT) is indicated in autoimmune hepatitis (AIH) for both acute presentation with liver failure and end-stage chronic liver disease. Few studies have suggested an association between AIH and coagulation disorders and a higher incidence of portal vein thrombosis (PVT) in patients with AIH listed for LT. The aim of this study was to determine the incidence of thrombotic complications, particularly PVT, in a cohort of 37 patients undergoing LT because of AIH. PVT was present before transplantation in 30% (n=11) of these patients compared to 11% in the whole population transplanted in our center (P=.002). On comparing only patients with cirrhosis, PVT was present in 55% of the AIH group, being 12% in the whole cohort (P<.001). Among patients with PVT before LT, no patient receiving anticoagulation therapy early after LT developed recurrence of PVT, whereas two patients (33%) without anticoagulation therapy did. The increased incidence of PVT in the pretransplant period and the possibility of thrombosis recurrence after LT suggest that patients with AIH and PVT could benefit from anticoagulation therapy after transplantation. However, further studies are needed to recommend anticoagulation in these patients in clinical practice.

Clinical course and short-term mortality of cirrhotic patients with infections other than spontaneous bacterial peritonitis.

BACKGROUND & AIMS: Clinical course and risk factors of death in non-spontaneous bacterial peritonitis (SBP) infections are poorly known. We assessed the prevalence of acute kidney injury (AKI) and type-1 hepatorenal syndrome (HRS), hospital, 30-day and 90-day mortality and risk factors of death in 441 decompensated patients. METHODS: Analysis of 615 non-SBP infections (161 urinary infections (UTI), 95 cellulitis, 92 suspected infections, 92 bacteraemias, 84 pneumonias, 21 bronchitis, 18 cholangitis, 15 spontaneous empyema, 13 secondary peritonitis, 24 other). RESULTS: Ninety-six percent of infections solved. AKI and type-1 HRS were developed in 37% and 9% of infections respectively. Overall hospital, 30-day and 90-day mortality rates were 11%, 12% and 18% respectively. Clinical course and mortality differed markedly across infections. Endocarditis, osteoarticular infections, pneumonia, spontaneous bacteraemia, cholangitis, secondary peritonitis and UTI showed higher rates of AKI. Prevalence of type-1 HRS was not significantly different among infections. Endocarditis, secondary peritonitis, pneumonia and bacteraemia showed lower rates of renal impairment resolution and higher hospital mortality associated with AKI (42% vs 12%, P<.0001) or type-1 HRS (71% vs 27%, P=.003) than the rest of infections. Age (HR: 1.04), serum sodium (HR: 0.91), serum bilirubin (HR: 1.06), INR (HR: 1.91), hepatic encephalopathy (HR: 2.44), ascites (HR: 3.06) and multidrug-resistant isolation (HR: 2.27) at infection diagnosis were independent predictors of death during hospitalization. CONCLUSIONS: Non-SBP infections constitute a heterogeneous group regarding clinical course and prognosis. Endocarditis, secondary peritonitis, pneumonia and bacteraemia show worse prognosis. The combination of data of liver and renal dysfunction and of the type of infection allows the identification of patients with poor prognosis.

Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation.

Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post-liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy-proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)-infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment.