Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Neurodegeneration in Hepatic and Neurologic Wilson's Disease.

Clinical presentation of Wilson disease (WD) includes hepatic and neurologic manifestations. This study compares subcortical brain regions by magnetic resonance imaging in patients with WD and without neurological symptoms. Distinct atrophy affecting the basal ganglia, accumbens, and hippocampus was present in neurological WD. Cerebellar atrophy was observed in hepatic WD without neurological symptoms.

MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes.

BACKGROUND AND AIMS: High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia. APPROACH AND RESULTS: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 µg/L for women and ≥300 µg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s-1 ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s-1 ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified. CONCLUSIONS: In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.

Afamin predicts the prevalence and incidence of nonalcoholic fatty liver disease.

OBJECTIVES: In the general population, increased afamin concentrations are associated with the prevalence and incidence of metabolic syndrome as well as type 2 diabetes. Although metabolic syndrome is commonly associated with nonalcoholic fatty liver disease (NAFLD), there exist no information on afamin and NAFLD. METHODS: Afamin concentrations were cross-sectionally measured in 146 Austrian patients with NAFLD, in 45 patients without NAFLD, and in 292 age- and sex-matched healthy controls. Furthermore, the feasibility of afamin to predict incident NAFLD was evaluated in 1,434 adult participants in the population-based Cardiovascular Risk in Young Finns Study during a 10-year follow-up. RESULTS: Median afamin concentrations were significantly higher in NAFLD patients (83.6 mg/L) than in patients without NAFLD (61.6 mg/L, p<0.0001) or in healthy controls (63.9 mg/L, p<0.0001). In age- and sex-adjusted logistic regression analyses a 10 mg/L increase of afamin was associated with a 1.5-fold increase of having NAFLD as compared with patients without NAFLD and the risk was even two-fold when compared with healthy controls. In the population-based cohort, afamin concentrations at baseline were significantly lower in participants without NAFLD (n=1,195) than in 239 participants who developed NAFLD (56.5 vs. 66.9 mg/L, p<0.0001) during the 10-year follow up, with highest afamin values observed in individuals developing severe forms of NAFLD. After adjustment for several potentially confounding parameters, afamin remained an independent predictor for the development of NAFLD (OR=1.37 [95% CI 1.23-1.54] per 10 mg/L increase, p<0.0001). CONCLUSIONS: Afamin concentrations are increased in patients with NAFLD and independently predict the development of NAFLD in a population-based cohort.

Charting the Path Forward for Risk Prediction in Liver Transplant for Hepatocellular Carcinoma: International Validation of HALTHCC Among 4,089 Patients.

Prognosticating outcomes in liver transplant (LT) for hepatocellular carcinoma (HCC) continues to challenge the field. Although Milan Criteria (MC) generalized the practice of LT for HCC and improved outcomes, its predictive character has degraded with increasing candidate and oncological heterogeneity. We sought to validate and recalibrate a previously developed, preoperatively calculated, continuous risk score, the Hazard Associated with Liver Transplantation for Hepatocellular Carcinoma (HALTHCC), in an international cohort. From 2002 to 2014, 4,089 patients (both MC in and out [25.2%]) across 16 centers in North America, Europe, and Asia were included. A continuous risk score using pre-LT levels of alpha-fetoprotein, Model for End-Stage Liver Disease Sodium score, and tumor burden score was recalibrated among a randomly selected cohort (n = 1,021) and validated in the remainder (n = 3,068). This study demonstrated significant heterogeneity by site and year, reflecting practice trends over the last decade. On explant pathology, both vascular invasion (VI) and poorly differentiated component (PDC) increased with increasing HALTHCC score. The lowest-risk patients (HALTHCC 0-5) had lower rates of VI and PDC than the highest-risk patients (HALTHCC > 35) (VI, 7.7%[ 1.2-14.2] vs. 70.6% [48.3-92.9] and PDC:4.6% [0.1%-9.8%] vs. 47.1% [22.6-71.5]; P < 0.0001 for both). This trend was robust to MC status. This international study was used to adjust the coefficients in the HALTHCC score. Before recalibration, HALTHCC had the greatest discriminatory ability for overall survival (OS; C-index = 0.61) compared to all previously reported scores. Following recalibration, the prognostic utility increased for both recurrence (C-index = 0.71) and OS (C-index = 0.63). Conclusion: This large international trial validated and refined the role for the continuous risk metric, HALTHCC, in establishing pre-LT risk among candidates with HCC worldwide. Prospective trials introducing HALTHCC into clinical practice are warranted.

Performance of different Dixon-based methods for MR liver iron assessment in comparison to a biopsy-validated R2* relaxometry method.

OBJECTIVES: To prospectively evaluate a 3D-multiecho-Dixon sequence with inline calculation of proton density fat fraction (PDFF) and R2* (qDixon), and an improved version of it (qDixon-WIP), for the MR-quantification of hepatic iron in a clinical setting. METHODS: Patients with increased serum ferritin underwent 1.5-T MRI of the liver for the evaluation of hepatic iron overload. The imaging protocol for R2* quantification included as follows: (1) a validated, 2D multigradient-echo sequence (initial TE 0.99 ms, R2*-ME-GRE), (2) a 3D-multiecho-Dixon sequence with inline calculation of PDFF and R2* (initial TE 2.38 ms, R2*-qDixon), and optionally (3) a prototype (works-in-progress, WIP) version of the latter (initial TE 1.04 ms, R2*-qDixon-WIP) with improved water/fat separation and noise-corrected parameter fitting. For all sequences, three manually co-registered regions of interest (ROIs) were placed in the liver. R2* values were compared and linear regression analysis and Bland-Altman plots calculated. RESULTS: Forty-six out of 415 patients showed fat-water (F/W) swap with qDixon and were excluded. A total of 369 patients (mean age 52 years) were included; in 203/369, the optional qDixon-WIP was acquired, which showed no F/W swaps. A strong correlation was found between R2*-ME-GRE and R2*-qDixon (r2 = 0.92, p < 0.001) with Bland-Altman revealing a mean difference of - 3.82 1/s (SD = 21.26 1/s). Correlation between R2*-GRE-ME and R2*-qDixon-WIP was r2 = 0.95 (p < 0.001) with Bland-Altman showing a mean difference of - 0.125 1/s (SD = 30.667 1/s). CONCLUSIONS: The 3D-multiecho-Dixon sequence is a reliable tool to quantify hepatic iron. Results are comparable with established relaxometry methods. Improvements to the original implementation eliminate occasional F/W swaps and limitations regarding maximum R2* values. KEY POINTS: • The 3D-multiecho-Dixon sequence for 1.5 T is a reliable tool to quantify hepatic iron. • Results of the 3D-multiecho-Dixon sequence are comparable with established relaxometry methods. • An improved version of the 3D-multiecho-Dixon sequence eliminates minor drawbacks.

Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis.

AIMS: Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. The aim of this study was to determine frequency, severity, duration and risk factors of incident hypophosphataemia after treatment with FCM and IIM. METHODS: A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005-2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphataemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphataemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphataemia. RESULTS: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphataemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 vs. 0.06 mmol/L). Hypophosphataemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphataemia. CONCLUSION: FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphataemia.

Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease.

Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.

Reduced iron export associated with hepcidin resistance can explain the iron overload spectrum in ferroportin disease.

BACKGROUND & AIMS: Ferroportin disease (FD) and hemochromatosis type 4 (HH4) are associated with variants in the ferroportin-encoding gene SLC40A1. Both phenotypes are characterized by iron overload despite being caused by distinct variants that either mediate reduced cellular iron export in FD or resistance against hepcidin-induced inactivation of ferroportin in HH4. The aim of this study was to assess if reduced iron export also confers hepcidin resistance and causes iron overload in FD associated with the R178Q variant. METHODS: The ferroportin disease variants R178Q andA77D and the HH4-variant C326Y were overexpressed in HEK-293T cells and subcellular localization was characterized by confocal microscopy and flow cytometry. Iron export and cytosolic ferritin were measured as markers of iron transport and radioligand binding studies were performed. The hepcidin-ferroportin axis was assessed by ferritin/hepcidin correlation in patients with different iron storage diseases. RESULTS: In the absence of hepcidin, the R178Q and A77D variants exported less iron when compared to normal and C326Y ferroportin. In the presence of hepcidin, the R178Q and C326Y, but not the A77D-variant, exported more iron than cells expressing normal ferroportin. Regression analysis of serum hepcidin and ferritin in patients with iron overload are compatible with hepcidin deficiency in HFE hemochromatosis and hepcidin resistance in R178Q FD. CONCLUSIONS: These results support a novel concept that in certain FD variants reduced iron export and hepcidin resistance could be interlinked. Evasion of mutant ferroportin from hepcidin-mediated regulation could result in uncontrolled iron absorption and iron overload despite reduced transport function.

Anemia and iron deficiency in compensated and decompensated cirrhosis: Prevalence and impact on clinical outcomes.

BACKGROUND AND AIM: Iron deficiency anemia (IDA)is the leading cause of anemia worldwide. Data on prevalence and clinical impact of anemia in cirrhosis are scarce. Aim was to report on the following:(i) prevalence of anemia and IDA in cirrhosis and (ii) its possible impact on clinical outcomes. METHODS: Consecutive cirrhotic patients from a prospective registry study were included. Anemia was defined as hemoglobin concentration ≤ 12 g/dL. IDA was defined as Hb ≤ 12 g/dL + transferrin-saturation < 20%. Follow up for hepatic decompensation and mortality started with study inclusion and terminated in December 2017. A retrospective validation cohort of 1244 patients was used to validate our findings. RESULTS: Two hundred forty-two patients with compensated (n = 53 [21.9%]) and decompensated (n = 189 [78.1%]) cirrhosis were included. Anemia was present in 128 patients (52.9%); of those, 63 (49.2%) had IDA. Prevalence of anemia increased with Child-Pugh Score (CPS; A: 26.5%, B: 59.2%, C: 69%; P < 0.001) and with decompensated cirrhosis(62.4% vs 18.8%, P < 0.001). Within anemic patients, a higher proportion of patients in CPS A/B vs C (73% vs 35%; P = 0.025) and in compensated cirrhosis (80% vs 46.6%; P = 0.043) were found with IDA. Model for End-Stage Liver Disease (MELD) scores were significantly lower in patients with IDA (14.4 vs 17.9 non-ID-anemia; P = 0.005). Similar results were found in the validation cohort: median MELD (16[8-28]non-IDA vs 12 [7-23] IDA; P < 0.001) and within anemic patients IDA was more common in patients with MELD <15 (58%) versus >15 (24%, P < 0.001). Anemia was associated with a significant risk for hepatic decompensation and/or mortality both in the validation (aSHR: 1.65, P = 0.008) and in the derivation cohort (aSHR: 2.11, P < 0.001) and an independent risk factor for hepatic decompensation and/or mortality in compensated patients (aHR: 4.91, P = 0.004). CONCLUSION: Anemia is highly prevalent in cirrhosis. In compensated cirrhosis, CPS A/B, and low MELD, IDA seems to be the most likely reason for anemia. Furthermore, anemia is associated with a significant risk for hepatic decompensation or mortality during long-term follow up.

[Magnetic resonance elastography of the liver : Worth knowing for clinical routine]. / Magnetresonanzelastographie der Leber : Wissenswertes zur klinischen Routine.

BACKGROUND: Magnetic resonance elastography (MRE) is a noninvasive, quantitative, MRI-based method to evaluate liver stiffness. Beside biopsy and ultrasound elastography, this imaging method plays in many places a significant role in the detection and additive characterization of chronic liver disease. OBJECTIVES, MATERIALS AND METHODS: Based on the literature, a brief review of the underlying method and the commercially available products is given. Furthermore, the practical procedure, the analysis, and the interpretation of clinically relevant questions are illustrated and a comparison with ultrasound elastography is provided. RESULTS: This relative "young" MRI method allows extensive evaluation of mechanical properties of the liver and is an important diagnostic tool especially in follow-up examinations. The MRE of the liver is with a maximum technical failure rate of 5.8% a robust technique with high accuracy and an excellent re-test reliability as well as intra- and interobserver reproducibility. There is a high diagnostic certainty within the framework of most important clinical indications, the quantification of fibrosis, and with a very good correlation with the "gold standard" biopsy. CONCLUSION: Based on its rising clinical relevance and the broad usage, MRE of the liver is increasingly used in many centers and in routine liver protocols. Therefore, basic knowledge of this method is essential for every radiologist.

The Intention-to-Treat Effect of Bridging Treatments in the Setting of Milan Criteria-In Patients Waiting for Liver Transplantation.

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC-dependent LT failure, defined as pretransplant tumor-related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC-in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End-Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha-fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo-population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT-treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC-dependent failure (subhazard ratio [SHR], 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait-list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2-3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC-in patients, up to 3 LRTs are beneficial for success in intention-to-treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC-dependent transplant failure.

Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease.

Alpha-1-antitrypsin deficiency (A1ATD) due to homozygosity for the Z allele (ZZ) is an established risk factor for cirrhosis, but the liver disease risk in heterozygous Z allele carriers (MZ) is controversial. The aim of the present study was to determine the prevalence of the MZ genotype among patients with cirrhosis and the associated risk of decompensation and liver transplantation/mortality. An unselected cohort of 561 patients with cirrhosis and 248 deceased liver donors were genotyped for the A1ATD risk alleles Z and S using a validated allelic discrimination assay. Clinical and biochemical parameters were assessed in 488 genotype MM and 52 MZ patients at baseline when cirrhosis was diagnosed and at the last contact, before liver transplantation or death, as study endpoints. MZ prevalence was 2.8% among liver donors, 5.8%, 9.1%, 10.9%, and 19.0% in patients with cirrhosis and Model for End-Stage Liver Disease-sodium (MELD-Na) ≤10, 11-20, 21-30, and >30, respectively. Among liver transplant recipients, MZ prevalence was 9.7%. MS prevalence was not different between donors, patients with cirrhosis, or transplant recipients. At the end of follow-up, MELD-Na scores were higher among heterozygous Z risk allele carriers (16 versus 19; P = 0.03). Decompensation of cirrhosis with ascites or encephalopathy was significantly more frequent in patients with MZ than in MM patients. In the subgroup with transferrin (Tf) saturation >50% or Tf <180 mg/dL, MZ patients had a significantly higher risk of liver transplantation or death than MM patients. In conclusion, the genotype MZ is a genetic risk factor for more advanced cirrhosis and decompensation. MZ patients with cirrhosis and hypotransferrinemia or increased Tf saturation are at higher risk of death and liver transplantation. Liver Transplantation 24 744-751 2018 AASLD.

Transferrin as a predictor of survival in cirrhosis.

Patients with cirrhosis frequently present with high serum ferritin and low transferrin concentrations, reflecting impaired liver function and inflammation. Recent studies have shown that transferrin and its saturation with iron are Model for End-Stage Liver Disease-independent predictors of mortality in patients with acute-on-chronic liver failure or decompensated cirrhosis. The aim of this study was to evaluate the prognostic utility of serum iron parameters in relation to markers of liver function and immune activation. Clinical, demographic, and biochemical data were retrospectively analyzed from a cohort of 1255 consecutive patients with cirrhosis (age ≥ 18 years) who presented from August 1, 2004 until December 31, 2014 at the University Hospital of Innsbruck. Patients with malignancies at diagnosis including hepatocellular carcinoma were excluded. Survival analysis was carried out by Cox regression by using baseline laboratory parameters, and findings were validated in an independent patient cohort. During a median follow-up of 2.4 years, 193 deaths occurred and 254 patients underwent liver transplantation. In patients with transferrin < 180 mg/dL, 3-month, 1-year, and 5-year transplant-free survival estimates were significantly lower (91.7%, 79.0%, and 30.5%) when compared with the group of patients with transferrin ≥ 180 mg/dL (98.9%, 95.5%, and 68.0%, P < 0.001). Transferrin predicted transplant-free survival independently of Model for End-Stage Liver Disease-sodium (MELD-Na) and C-reactive protein (CRP) in multivariate regression analysis including all patients. When patients with alcoholic or nonalcoholic fatty liver disease were excluded, transferrin was in addition an albumin-independent predictor of transplant-free survival. In conclusion, the association of transferrin with transplant-free survival is independent of MELD-Na score and CRP. In patients without fatty liver disease, transferrin also predicts survival independently of albumin. Liver Transplantation 24 343-351 2018 AASLD.

CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome.

A 52-year old patient presented with lymphedema, protein loosing enteropathy, and sclerosing cholangitis and was diagnosed with lymphedema cholestasis syndrome (LCS). Cholangioscopy revealed dilated lymphatic vessels obstructing the bile duct and compound heterozygosity for collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1) mutations was identified defining a novel type of LCS. (Hepatology 2017;66:286-288).

Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease.

BACKGROUND & AIMS: Chronic alcohol consumption and alcoholic liver disease (ALD) afflicts individuals with substantial morbidity and mortality with limited treatment options available. Hepatic inflammation, triggered by activated Kupffer cells, is a driving force in alcoholic liver disease. Interleukin 37 (IL-37) exerts anti-inflammatory effects in hepatic diseases, however, the impact of Interleukin 37 on alcoholic liver disease is unknown. In this study, we addressed the role of Interleukin 37 in alcoholic liver disease. METHODS: We utilized Interleukin 37 expressing transgenic mice and human recombinant Interleukin 37 in models of alcoholic liver disease. Interleukin 37 expression was measured in liver samples of 20 alcoholic steatohepatitis and 36 non-alcoholic fatty liver disease patients. RESULTS: Interleukin 37 transgenic mice are not protected against hepatic injury and inflammation in alcoholic liver disease. Ethanol suppressed Interleukin 37 expression in transgenic mice. Alcoholic steatohepatitis (ASH) patients similarly exhibited reduced Interleukin 37 expression when compared to non-alcoholic fatty liver disease (NAFLD) patients. Human recombinant Interleukin 37 ameliorated hepatic inflammation in a binge drinking model of alcoholic liver disease. CONCLUSION: We provide evidence for an exogenous noxae that suppresses Interleukin 37 expression which limits its anti-inflammatory effects in alcoholic liver disease.

Quantification of liver iron overload disease with laser ablation inductively coupled plasma mass spectrometry.

BACKGROUND: Hereditary hemochromatosis is the most frequent, identified, genetic disorder in Caucasians affecting about 1 in 1000 people of Northern European ancestry, where the associated genetic defect (homozygosity for the p.Cys282Tyr polymorphism in the HFE gene) has a prevalence of approximately 1:200. The disorder is characterized by excess iron stores in the body. Due to the incomplete disease penetrance of disease-associated genotype, genetic testing and accurate quantification of hepatic iron content by histological grading of stainable iron, quantitative chemical determination of iron, or imaging procedures are important in the evaluation and staging of hereditary hemochromatosis. METHODS: We here established novel laser ablation inductively coupled plasma mass spectrometry protocols for hepatic metal bio-imaging for diagnosis of iron overload. RESULTS: We demonstrate that these protocols are a significant asset in the diagnosis of iron overload allowing iron measurements and simultaneous determination of various other metals and metalloids with high sensitivity, spatial resolution, and quantification ability. CONCLUSIONS: The simultaneous measurement of various metals and metalloids offers unique opportunities for deeper understanding of metal imbalances. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a highly powerful and sensitive technique for the analysis of a variety of solid samples with high spatial resolution. We conclude that this method is an important add-on to routine diagnosis of iron overload and associated hepatic metal dysbalances resulting thereof.

Prognostic significance of hepatic arterial collaterals in liver transplant recipients with biliary strictures.

BACKGROUND: The aim of this study was to determine the prevalence of hepatic artery stenosis (HAS) and the prognostic implications of hepatic arterial collaterals in liver transplant (LT) recipients with biliary strictures. METHODS: The 105 LT recipients transplanted between 2004 and 2015 at our center had documented biliary strictures. HAS and collaterals were assessed in high-quality imaging of the hepatic artery available from 66 recipients. Clinical, demographic, and biochemical recipient and donor data were retrospectively analyzed and tested for their association with biliary or arterial complications after LT. RESULTS: The prevalence of HAS was 68% (45 of 66) in LT recipients with biliary strictures. Seventy-six percent (37 of 49) of patients with nonanastomotic biliary strictures had HAS. This was significantly higher than in patients with anastomotic stricture, where 47% (8 of 17) of patients had a pathological hepatic arteriogram (P=.039). The location of bile duct strictures was not predictive for outcome. In contrast, arterial collaterals were associated with significantly better patient and graft survival. CONCLUSION: Impaired hepatic arterial perfusion is frequently associated with nonanastomotic strictures, but less closely correlated with anastomotic strictures. On survival analysis, hepatic arterial collaterals have a protective effect.