Development and validation of pFIB scores for exclusion of significant liver fibrosis in pediatric MASLD.

BACKGROUND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking. APPROACH RESULTS: Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established non-invasive fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, HOMA-IR index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values (NPV) were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels. CONCLUSIONS: Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in non-selected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

Adipose Tissue Insulin Resistance Correlates with Disease Severity in Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease: A Prospective Cohort Study.

OBJECTIVES: To assess the role of adipose tissue insulin resistance (Adipo-IR) in the pathogenesis of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and to determine Adipo-IR evolution during a lifestyle intervention program. STUDY DESIGN: In this prospective cohort study, children and adolescents with severe obesity were recruited between July 2020 and December 2022 at an inpatient pediatric rehabilitation center. Treatment consisted of dietary intervention and physical activity. Liver steatosis and fibrosis were evaluated using ultrasound examination and transient elastography with controlled attenuation parameter and liver stiffness measurement. Every 4-6 months, anthropometric measurements, serum biochemical analysis, ultrasound examination, and elastography were repeated. Adipo-IR was estimated by the product of the fasting serum insulin times the fasting free fatty acid concentration, and hepatic IR by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), respectively. RESULTS: Of 200 patients with obesity, 56% had evidence of steatosis on ultrasound examination and 26% were diagnosed with fibrosis (≥F2). Adipo-IR increased progressively from lean controls to patients with obesity to patients with MASLD and MASLD with fibrosis. Adipo-IR was already increased in patients with only mild steatosis (P = .0403). Patients with more insulin-sensitive adipose tissue exhibited a lower liver fat content (P < .05) and serum alanine transaminase levels (P = .001). Adipo-IR correlated positively with visceral adipose tissue weight, waist circumference, and the visceral adipose tissue/gynoid adipose tissue ratio (P < .001), but not with total body fat percentage (P = .263). After 4-6 months of lifestyle management, both MASLD and Adipo-IR improved. CONCLUSIONS: Our data suggest that Adipo-IR is associated with the presence of pediatric MASLD, particularly steatosis.

Etiology, risk factors and management of hypertension post liver transplantation.

BACKGROUND: Cardiovascular events are one of the most important causes of morbidity and mortality in the long-term follow-up of liver transplant recipients. Hypertension is a significant cardiovascular risk factor that occurs frequently after pediatric liver transplantation. Chronic use of immunosuppressants - mainly calcineurin inhibitors - plays a major role in the development of post-transplant hypertension and circadian disturbances such as flattening of the nocturnal blood pressure dip. This requires special attention in children given the long timeframe during which immunosuppressive therapy is necessary. Careful and structured blood pressure monitoring and adequate treatment of hypertension are essential to optimize the quality of life and life expectancy of pediatric liver transplant patients. However, evidence-based guidelines for monitoring and management of post-transplant hypertension and its complications are lacking. METHODS: We conducted a comprehensive review of the current knowledge and practices concerning post-transplant hypertension. The databases Pubmed, Embase, Web of Science and Google Scholar were scanned with the following keywords: pediatric liver transplantation, immunosuppression, tacrolimus, cardiovascular effects, hypertension, heart function, kidney function, circadian rhythm, mechanism, monitoring, and management. RESULTS: In this review, we describe the incidence and etiology of hypertension in pediatric liver transplant recipients, the underlying mechanisms and characteristics of calcineurin inhibitor-induced hypertension, and the consequences of and risk factors for post-transplant hypertension. We hereby present an overview of the current practices in blood pressure monitoring and antihypertensive treatment as well as an algorithm for the evaluation and management of hypertension post liver transplantation. Finally, we discuss knowledge gaps and suggestions for future research.

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

EASL-ERN position paper on liver involvement in patients with Fontan-type circulation.

Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.

Transjugular Intrahepatic Portosystemic Shunts in Pediatric Portal Hypertension: A Systematic Review and Meta-Analysis.

PURPOSE: To investigate the technical outcome, clinical outcome, and patency of transjugular intrahepatic portosystemic shunt (TIPS) in pediatric portal hypertension (PHT). METHODS: A systematic search of MEDLINE/PubMed, EMBASE, Cochrane databases, ClinicalTrials.gov, and WHO ICTRP registries was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. An a priori protocol was registered at the PROSPERO database. Original full-text articles on pediatric patients (sample size of ≥5 patients with upper age limit of 21 years) with PHT who underwent TIPS creation for any indication were included. RESULTS: Seventeen studies with 284 patients (average-weighted age of 10.1 years) were included, with an average-weighted follow-up of 3.6 years. TIPS was technically successful in 93.3% (95% confidence interval [CI], 88.5%-97.1%) of patients, with a major adverse event rate of 3.2% (95% CI, 0.7-6.9) and adjusted hepatic encephalopathy rate of 2.9% (95% CI, 0.6-6.3). The pooled 2-year primary and secondary patency rates were 61.8% (95% CI, 50.0-72.4) and 99.8% (95% CI, 96.2%-100.0%), respectively. Stent type (P = .002) and age (P = .04) were identified as a significant source of heterogeneity for clinical success. In subgroup analysis, the clinical success rate was 85.9% (95% CI, 77.8-91.4) in studies with a majority of covered stents, and 87.6% (95% CI, 74.1-94.6) in studies with a median age of 12 years or older. CONCLUSIONS: This systematic review and meta-analysis demonstrates that a TIPS is a feasible and safe treatment for pediatric PHT. To improve clinical outcome and patency on the long term, the use of covered stents should be encouraged.

'A radical operation' - a thematic analysis of newspaper framing of bariatric surgery in adolescents.

BACKGROUND: Obesity in adolescents is a growing public health issue. Bariatric surgery is an effective, yet controversial treatment option for adolescents. The moral acceptability of this procedure by health-care professionals as well as the general public can be influenced by its portrayal in the news media. Our objective was to analyze how newspaper articles portrayed adolescent bariatric surgery, with attention to the language used and moral arguments made. METHODS: Using an inductive thematic analysis approach, we analyzed 26 UK and 12 US newspaper articles (2014-2022) on adolescent bariatric surgery for implicit or explicit moral evaluations and use of normative language. Coding was performed after immersive reading, assisted by NVivo. Themes were identified and refined iteratively through consecutive auditing cycles to enrich the depth and rigor of our analysis. RESULTS: The major themes identified related to (1) defining the burden of adolescent obesity, (2) sparking moral outrage, (3) sensation-seeking, and (4) raising ethical issues. The articles employed moral language, specifically non-neutral and negative discourse regarding surgery. Blame was attributed to adolescents or their parents. Sensationalist wording often reinforced the normative content, drawing the attention of the reader and contributing to stigmatization of adolescents with severe obesity as lacking will power and being lazy. Further moral issues that stood out were the challenges in obtaining an informed consent, and the unequal access to surgery for socially disadvantaged groups. CONCLUSIONS: Our findings provide insights into how adolescent bariatric surgery is represented in the print news media. Despite frequent citing of experts and studies on the efficacy, safety and unmet need for bariatric surgery, obesity and surgery in adolescents are often stigmatized and sensationalized, with (prospective) patients depicted as looking for an easy way out in the form of a solution brought by others (health systems, society, tax payers). This may increase the stigma surrounding adolescent obesity, and therefore limit the acceptability of specific treatments such as bariatric surgery.

Maternal and Perinatal Risk Factors for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The intrauterine and early life environment can have an important impact on long-term metabolic health. We investigated the impact of maternal prepregnancy obesity, (pre)gestational diabetes, breastfeeding, and birth anthropometrics/preterm birth on the development of NAFLD in children and adolescents. METHODS: A comprehensive search was performed in MEDLINE, PubMed Central, EMBASE, and grey literature databases through August 2020. The primary outcome was the prevalence of pediatric NAFLD, whereas the histologic severity of steatohepatitis and/or fibrosis were secondary outcomes. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. RESULTS: Our systematic review included 33 articles. Study heterogeneity regarding patient populations, diagnostic tools, and overall quality was considerable. Eight studies determined the impact of maternal prepregnancy overweight/obesity and identified this as a possible modifiable risk factor for pediatric NAFLD. Conversely, 8 studies investigated (pre)gestational diabetes, yet the evidence on its impact is conflicting. Breastfeeding was associated with a reduced risk for NAFLD, steatohepatitis, and fibrosis, especially in studies that evaluated longer periods of breastfeeding. Being born preterm or small for gestational age has an unclear impact on the development of NAFLD, although an early catch-up growth might drive NAFLD. CONCLUSIONS: In a systematic review, we found that maternal prepregnancy overweight and obesity were associated with an increased risk of pediatric NAFLD. Breastfeeding might be protective against the development of NAFLD when the duration of breastfeeding is sufficiently long (≥6 months).

Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Childhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. METHODS: Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium, De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle, and psychosocial support. At baseline, 6 months, and 12 months, liver ultrasound and transient elastography with controlled attenuation parameter were performed to assess liver steatosis and fibrosis. RESULTS: A total of 204 patients (median age, 14.0 y; body mass index Z-score, +2.8) were evaluated at admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had controlled attenuation parameter values of 248 dB/m or greater. A total of 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography of 9 kPa or greater. After 6 months, the median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P < .001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. Seventy-nine patients had reached the 1-year time point. The improvements were sustained because fibrosis regressed at least 1 stage in all patients with baseline fibrosis. Fasting serum alanine aminotransferase and homeostasis model assessment of insulin resistance decreased significantly over the 1-year period (P < .001). CONCLUSIONS: NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program that causes significant weight loss not only improves liver steatosis, but also fibrosis.

Non-invasive assessment of liver abnormalities in pediatric Fontan patients.

Liver abnormalities are well known among long-term survivors of Fontan palliation, which remains the definite surgery for complex congenital heart disease and single ventricle physiology. Pediatric data however are scarce. We assessed the prevalence and degree of liver abnormalities in pediatric Fontan patients through non-invasive investigations suitable for longitudinal follow-up. Thirty-five patients with a median age of 11.8 years (5.2-16.6) and median time since Fontan of 6 years (1.17-13.83) were studied. Each child underwent a blood test, liver Doppler ultrasound (US), and transient elastography (TE). Healthy children were used as controls for TE measurement. AST, ALT, γGT, and direct bilirubin were abnormal in respectively 12 (34%), 5 (14%), 24 (69%), and 7 (20%) patients, while platelet count was decreased in 7 (20%). Splenomegaly was present in 7 (20%) patients. Portal vein mean flow velocity was < 15 cm/s in 19 (54%) patients indicative of portal hypertension. Twenty-two patients (63%) showed inferior vena cava collapsibility index values below 17%, indicating venous congestion. Hepatic artery and superior mesenteric artery resistance index were inversely correlated with time post Fontan (p < 0.05). TE values in Fontan patients were significantly higher than controls, with a median of 12.6 versus 4.6 kPa (p < 0.001) and were already increased shortly after Fontan completion. Conclusion: Liver abnormalities are frequently observed in pediatric Fontan patients. The non-invasive investigations used were not able to confirm liver fibrosis or differentiate hepatic congestion from fibrosis. Based on our findings, we propose a prospective screening protocol with serial measurements of laboratory, (Doppler) US, and TE parameters. What is Known: • Hepatic dysfunction is a well-known consequence of the Fontan circulation. • The natural history of Fontan-associated liver disease in the pediatric age group remains unclear. What is New: • Liver abnormalities are frequently observed in pediatric Fontan patients; however, differentiating liver fibrosis and hepatic congestion with non-invasive investigations remains challenging. Sonographic Doppler measurements may improve our insight in both Fontan-associated liver disease development and the functioning of the Fontan circulation. • A prospective screening protocol is proposed to improve our ability to detect Fontan-associated liver disease early on and understand its natural history.

Two cases of DCDC2-related neonatal sclerosing cholangitis with developmental delay and literature review.

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have further been reported in the context of nephronophthisis and non-syndromic recessive deafness. Polymorphisms in DCDC2 have also been associated with dyslexia and DCDC2 has a role in neuronal development. We report on two unrelated patients with DCDC2-related NSC with additional central nervous system impairment manifesting as microcephaly, global developmental delay, and axial hypotonia. Histological findings of our patients can mimic biliary atresia or congenital hepatic fibrosis. We further show that transmission electron microscopy in patients with NSC does not always show absence of primary cilia. Hence patients with DCDC2 pathogenic variants should also undergo an evaluation of neuromotor development. Review of all reported patients further reveals a risk for supra-aortic arterial aneurysms.

Successful liver transplantation in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Case report.

BACKGROUND: HHH syndrome is a rare autosomal recessive disorder of the urea cycle, caused by a deficient mitochondrial ornithine transporter. We report the first successful liver transplantation in HHH syndrome performed in a seven-year-old boy. The patient presented at 4 weeks of age with hyperammonemic coma. The plasma amino acid profile was suggestive of HHH syndrome, and the diagnosis was confirmed when sequencing of the SLC25A15 gene identified two mutations p.R275Q and p.A76D. Although immediate intervention resulted in normalization of plasma ammonia levels within 24 hours, he developed cerebral edema, coma, convulsions, and subsequent neurological sequelae. Metabolic control was difficult requiring severe protein restriction and continued treatment with sodium benzoate and L-arginine. Despite substantial developmental delay, he was referred to our center for liver transplantation because of poor metabolic control. Following cadaveric split liver transplantation, there was complete normalization of his plasma ammonia and plasma amino acid levels under a normal protein-containing diet. This excellent metabolic control was associated with a markedly improved general condition, mood and behavior, and small developmental achievements. Twelve years after liver transplantation, the patient has a stable cognitive impairment without progression of spastic diplegia. CONCLUSION: This first case of liver transplantation in HHH syndrome demonstrates that this procedure is a therapeutic option for HHH patients with difficult metabolic control.

Autoantibodies and Donor-specific Antibodies are Associated With Graft Dysfunction in Pediatric Liver Transplantation.

OBJECTIVES: Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. METHODS: We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. RESULTS: AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P = 0,032) and deceased donor LT (P = 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P < 0,001), and an association was found with the presence of nonspecific histologic alterations (P = 0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P < 0,001), ALT (P < 0,001), AST (P < 0,001), γ-GT (P = 0,001), IgG (P = 0,011) and lower albumin (P = 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P = 0,019), higher total (P = 0,033), and direct (P = 0,012) bilirubin and γ-GT (P < 0,001). CONCLUSIONS: The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.

Primum non nocere: lingual frenotomy for breastfeeding problems, not as innocent as generally accepted.

The frenotomy or surgical release of the lingual frenulum is performed with increasing frequency. Restricted tongue mobility, ankyloglossia, is the main indication for this procedure. This clinical diagnosis is often used as synonym for tongue-tie which is blamed for many feeding difficulties resulting in an increase in performed frenotomies. Until recently, little was known about the anatomical structure and normal variation of the tongue-tie. Different grading systems have been developed. Some are exclusively based on appearance of the tongue-tie; others also include functional elements. There is, however, no established relation between the tongue-tie score and the observed feeding problems or outcomes following frenotomy. Therefore, caution is warranted before submitting babies to this procedure.Conclusion: This narrative review aims to give an overview of current knowledge and concerns regarding the tongue-tie, which need to be considered before referral for a frenotomy. What is Known: • The presence of a tongue-tie is associated with a higher frequency of breastfeeding problems. • Hence, frenotomy is advocated and increasingly performed in infants with breastfeeding problems. Current tongue-tie classifications do not allow to predict breastfeeding problems. What is New: • New anatomy insights caution for possible complications resulting from this seemingly innocent practice of frenotomy. • Frenotomy should only be performed after multidisciplinary evaluation of feeding problems, following exclusion and remediation of other causative factors.

Benign anastomotic biliary strictures untreatable by ERCP: a novel percutaneous balloon dilatation technique avoiding indwelling catheters.

OBJECTIVE: To evaluate long-term patency rates of a novel percutaneous threefold balloon dilatation protocol in benign anastomotic biliary strictures. METHODS: Patients with a benign biliary stricture after hepatobiliary surgery or liver transplantation, untreatable with endoscopy, underwent a percutaneous treatment cycle consisting of a 20-min balloon dilatation session on day one, repeated on days three and five. No catheters were left behind after the last dilatation session. Technical and clinical success as well as complications were analysed. Mean primary and secondary patency times were assessed. Cumulative primary and secondary patency rates at 6 months and 1, 2 and 3 years were determined. RESULTS: Seventy patients underwent 135 dilatation treatment cycles (mean 1.9) with a technical success rate of 99%. Clinical success was achieved in 87% of the patients. Fifty-eight of 135 (43%) patients had minor and 15/135 (11%) had major complications. Mean primary and secondary patency times were 26 months and 46 months, respectively, with a median follow-up of 69 months. Cumulative primary patency rate at 6 months was 67%, at 1 year 56%, at 2 years 41% and at 3 years 36%. The cumulative secondary patency rate at 6 months was 83%, at 1 year 79%, at 2 years 70% and at 3 years 64%. CONCLUSION: In benign anastomotic biliary strictures, a percutaneous threefold balloon dilatation treatment is effective. As long indwelling catheters are avoided, patient comfort improves. KEY POINTS: • Percutaneous threefold balloon dilatation treatment is effective in benign anastomotic biliary strictures. • As indwelling catheters after dilatation are avoided, patient comfort improves. • The dilatation protocol can be repeated efficiently in case of recurrent stricture.

Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes.

BACKGROUND: This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. METHODS: This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. RESULTS: We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. CONCLUSIONS: Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.