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. This article is protected by copyright. All rights reserved.

Aims: Hypophosphatemia 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 hypophosphatemia after treatment with FCM and IIM. Methods: A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005 to 2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphatemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphatemia 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 hypophosphatemia. Results: Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphatemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 versus 0.06 mmol/L). Hypophosphatemia 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 hypophosphatemia. Conclusion: FCM is associated with a high risk of hypophosphatemia, 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 hypophosphatemia.

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.

BackgroundFerric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM.AimTo characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort.MethodsElectronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included.ResultsThe prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM—OR = 20.8; 95% CI, 2.6–166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation.ConclusionTreatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

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.

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.

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 http://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.

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.