Intravenous iron-induced hypophosphatemia and kidney stone disease.

Patients with Crohn's disease are at increased risk for symptomatic nephrolithiasis. Stones in these patients are most commonly composed of calcium oxalate monohydrate or mixed calcium-oxalate and calcium-phosphate. Precipitation of both minerals depends on urinary pH, calcium, phosphate and oxalate excretion. The present manuscript reports on two patients with Crohn's disease and bowel resection, in whom the onset of symptomatic urolithiasis occurred after repeated infusions of ferric carboxymaltose - a drug, which is known to cause hyperphosphaturia. The present study shows that ferric carboxymaltose-induced hyperphosphaturia can be associated with kidney stone formation and symptomatic urolithiasis, especially in patients treated with calcitriol. Calcitriol has been shown to mitigate ferric carboxymaltose-induced secondary hyperparathyroidism and hyperphosphaturia, but is known to increase urinary calcium excretion. Chemical analysis of recovered stones revealed that they were mixed calcium oxalate and phosphate stones. Ring-like deposition of iron detected by spatially resolved elemental analysis using laser ablation-inductively coupled plasma mass spectrometry, showed that the stones also contained iron. Based on our findings, we propose that patients with inflammatory bowel disease requiring intravenous iron therapy should be carefully monitored for the development of hypophosphatemia and urolithiasis. If hypophosphatemia occurs in such patients, calcitriol should be used with caution.

Young hearts, early risks: novel cardiovascular biomarkers in former very preterm infants at kindergarten age.

BACKGROUND: Preterm birth is associated with long-term cardiovascular morbidity and mortality. In adults, fibroblast growth factor-23 (FGF-23), α-Klotho, and secretoneurin have all garnered attention as cardiovascular biomarkers, but their utility in pediatric populations has not yet been ascertained. The aim of this pilot study was to evaluate these novel cardiovascular biomarkers and their association with indicators of cardiovascular impairment in the highly vulnerable population of former very preterm infants. METHODS: Five- to seven-year-old children born at < 32 weeks' gestation were eligible for the study. Healthy same-aged children born at term served as controls. Biomarkers were quantified in fasting blood samples, and echocardiographic measurements including assessment of aortic elastic properties were obtained. RESULTS: We included 26 former very preterm infants and 21 term-born children in the study. At kindergarten age, former very preterm infants exhibited significantly higher plasma concentrations of biologically active intact FGF-23 (iFGF-23; mean 43.2 pg/mL vs. 29.1 pg/mL, p = 0.003) and secretoneurin (median 93.8 pmol/L vs. 70.5 pmol/L, p = 0.046). iFGF-23 inversely correlated with distensibility of the descending aorta. CONCLUSION: In preterm-born children, iFGF-23 and secretoneurin both offer prospects as valuable cardiovascular biomarkers, potentially allowing for risk stratification and timely implementation of preventive measures. IMPACT: Former very preterm infants have increased plasma concentrations of the novel cardiovascular biomarkers intact fibroblast growth factor-23 (iFGF-23) and secretoneurin at kindergarten age. Increases in iFGF-23 concentrations are associated with decreased distensibility of the descending aorta even at this early age. Monitoring of cardiovascular risk factors is essential in individuals with a history of preterm birth. Both iFGF-23 and secretoneurin hold promise as clinically valuable biomarkers for risk stratification, enabling the implementation of early preventive measures.

The BAR Score Predicts and Stratifies Outcomes Following Liver Retransplantation: Insights From a Retrospective Cohort Study.

Liver retransplantation (reLT) yields poorer outcomes than primary liver transplantation, necessitating careful patient selection to avoid futile reLT. We conducted a retrospective analysis to assess reLT outcomes and identify associated risk factors. All adult patients who underwent a first reLT at the Medical University of Innsbruck from 2000 to 2021 (N = 111) were included. Graft- and patient survival were assessed via Kaplan-Meier plots and log-rank tests. Uni- and multivariate analyses were performed to identify independent predictors of graft loss. Five-year graft- and patient survival rates were 64.9% and 67.6%, respectively. The balance of risk (BAR) score was found to correlate with and be predictive of graft loss and patient death. The BAR score also predicted sepsis (AUC 0.676) and major complications (AUC 0.720). Multivariate Cox regression analysis identified sepsis [HR 5.179 (95% CI 2.575-10.417), p < 0.001] as the most significant independent risk factor for graft loss. At a cutoff of 18 points, the 5 year graft survival rate fell below 50%. The BAR score, a simple and easy to use score available at the time of organ acceptance, predicts and stratifies clinically relevant outcomes following reLT and may aid in clinical decision-making.

Transplant oncology - Current indications and strategies to advance the field.

Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.

Impact of familiarity with the format of the exam on performance in the OSCE of undergraduate medical students - an interventional study.

BACKGROUND: Assessments, such as summative structured examinations, aim to verify whether students have acquired the necessary competencies. It is important to familiarize students with the examination format prior to the assessment to ensure that true competency is measured. However, it is unclear whether students can demonstrate their true potential or possibly perform less effectively due to the unfamiliar examination format. Hence, we questioned whether a 10-min active familiarization in the form of simulation improved medical students´ OSCE performance. Next, we wanted to elucidate whether the effect depends on whether the familiarization procedure is active or passive. METHODS: We implemented an intervention consisting of a 10-min active simulation to prepare the students for the OSCE setting. We compared the impact of this intervention on performance to no intervention in 5th-year medical students (n = 1284) from 2018 until 2022. Recently, a passive lecture, in which the OSCE setting is explained without active participation of the students, was introduced as a comparator group. Students who participated in neither the intervention nor the passive lecture group formed the control group. The OSCE performance between the groups and the impact of gender was assessed using X2, nonparametric tests and regression analysis (total n = 362). RESULTS: We found that active familiarization of students (n = 188) yields significantly better performance compared to the passive comparator (Cohen´s d = 0.857, p < 0.001, n = 52) and control group (Cohen´s d = 0.473, p < 0.001, n = 122). In multivariate regression analysis, active intervention remained the only significant variable with a 2.945-fold increase in the probability of passing the exam (p = 0.018). CONCLUSIONS: A short 10-min active intervention to familiarize students with the OSCE setting significantly improved student performance. We suggest that curricula should include simulations on the exam setting in addition to courses that increase knowledge or skills to mitigate the negative effect of nonfamiliarity with the OSCE exam setting on the students.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

What is wrong in doing good?

Hypophosphataemia is a common side-effect in patients with iron deficiency anaemia treated with ferric carboxymaltose, which is not a class effect of all intravenous (IV) iron formulations. The report by Chu et al. shows that moderate and severe hypophosphataemia is common and can even require IV supplementation of phosphate with unknown long-term consequences. Commentary on: Chu et al. Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-a 3-year experience from a single institution in Singapore. Br J Haematol 2023;202:1199-1204.

Could oral hygiene prevent cases of at-home-acquired Legionnaires' disease? - Results of a comprehensive case-control study on infection sources, risk, and protective behaviors.

Introduction: The "LeTriWa study" on community-acquired cases of Legionnaires' disease (LD) found that most cases likely acquired their infection at home (AHALD). However, which sources confer the infection is largely unknown. We therefore analyzed the data set from the LeTriWa study to find out if individual sources were associated with AHALD and if specific behavioral habits may increase or lower the risk for AHALD. Methods: During the study we had used two comparison groups: (i) controls matched for age group and hospital ("controls"), (ii) household members of cases with AHALD ("AHALD-HHM"). We inquired about exposure to water sources, such as showering or wearing dentures, as well as behavioral factors and habits related to oral hygiene. We took standardized household bathroom water and biofilm samples of both cases with AHALD and controls, and in addition from households of cases with AHALD only samples from suspect residential (non-)drinking water sources. We first conducted bivariate analyses for infection sources and behaviors, followed by multivariable analyses. Results: There were 124 cases with AHALD, 217 controls and 59 AHALD-HHM. In bivariate analyses using controls for comparison, wearing dentures was the only variable significantly positively associated (odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.1-2.7, p-value = 0.02). Behavioral factors such as showering, letting water run before use and not being alcohol abstinent were significantly negatively associated, smoking was significantly positively associated. In a multivariable analysis, we identified good oral hygiene as a preventive factor for both denture wearers (OR = 0.33, 95% CI = 0.13-0.83, p-value = 0.02) and non-denture wearers (OR = 0.32, 95% CI = 0.10-1.04, p-value = 0.06). Analyses of comparisons with AHALD-HHM showed similar effects but lacked statistical power. We identified Legionella in 16 residential (non-)drinking water sources, one of which was a PCR-positive scratch sample of dentures. Discussion: Wearing (inadequately cleaned) dentures or poor oral hygiene might confer an increased risk for AHALD, and oral hygiene may prevent AHALD. The hypothesis that Legionella in oral biofilm or dental plaque may be the cause of cases with AHALD should be examined further. If confirmed this may open new and simple avenues for the prevention of LD.

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.

Interleukin-11 drives human and mouse alcohol-related liver disease.

OBJECTIVE: Alcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD. DESIGN: IL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort (n=186). Primary human hepatocytes exposed to ethanol were studied in vitro. Ethanol-fed wildtype mice were treated with a neutralising murine IL-11 receptor-antibody (anti-IL11RA) and examined for severity signs and markers of ALD. RESULTS: IL-11 serum concentration and hepatic expression increased with severity of liver disease, mostly pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 pg/mL was a model of end-stage liver disease independent risk factor for transplant-free survival in patients with compensated and decompensated cirrhosis. In mice, severity of alcohol-induced liver inflammation correlated with enhanced hepatic IL-11 and IL11RA expression. In vitro and in vivo, anti-IL11RA reduced pathogenic signalling pathways (extracellular signal-regulated kinases, c-Jun N-terminal kinase, NADPH oxidase 4) and protected hepatocytes and murine livers from ethanol-induced inflammation and injury. CONCLUSION: Pathogenic IL-11 signalling in hepatocytes plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signalling might be a therapeutic option in human ALD, particularly AH.

Impact of preoperative anemia, iron-deficiency and inflammation on survival after colorectal surgery-A retrospective cohort study.

BACKGROUND: Anemia is present in up to two-thirds of patients undergoing colorectal surgery mainly caused by iron deficiency and inflammation. As anemia is associated with increased risk of perioperative death, diagnosis and treatment of preoperative anemia according to etiology have been recommended. OBJECTIVE: The aim of the present study was to assess if the association between anemia and survival in patients undergoing colorectal surgery was determined by the severity of anemia alone or also by anemia etiology. METHODS: To determine the prevalence of anemia and etiology, preoperative hematological parameters, C-reactive protein, ferritin and transferrin saturation were retrospectively assessed and correlated with outcome in a cohort of patients undergoing colorectal surgery between 2005 and 2019 at the University Hospital of Innsbruck. Anemia was defined as hemoglobin <120 g/L in females and <130 g/L in males. The etiology of anemia was classified on the basis of serum iron parameters, as iron deficiency anemia, anemia of inflammation or other anemia etiologies. RESULTS: Preoperative anemia was present in 54% (1316/2458) of all patients. Anemia was associated with iron deficiency in 45% (134/299) and classified as anemia of inflammation in 32% (97/299) of patients with available serum iron parameters. The etiology of anemia was a strong and independent predictor of survival, where iron deficiency and anemia of inflammation were associated with better postoperative survival than other anemia etiologies. One year survival rates were 84.3%, 77.3% and 69.1% for patients with iron deficiency anemia, anemia of inflammation and other anemia types. Inflammation indicated by high C-reactive protein is a strong negative predictor of overall survival. CONCLUSIONS: Anemia has a high prevalence among patients undergoing colorectal surgery and rational treatment requires early assessment of serum iron parameters and C-reactive protein.

Prognostic Factors for 10-Year Survival in Patients With Hepatocellular Cancer Receiving Liver Transplantation.

Background: Long-term survival after liver transplantation (LT) for hepatocellular cancer (HCC) continues to increase along with the modification of inclusion criteria. This study aimed at identifying risk factors for 5- and 10-year overall and HCC-specific death after LT. Methods: A total of 1,854 HCC transplant recipients from 10 European centers during the period 1987-2015 were analyzed. The population was divided in three eras, defined by landmark changes in HCC transplantability indications. Multivariable logistic regression analyses were used to evaluate the significance of independent risk factors for survival. Results: Five- and 10-year overall survival (OS) rates were 68.1% and 54.4%, respectively. Two-hundred forty-two patients (13.1%) had HCC recurrence. Five- and 10-year recurrence rates were 16.2% and 20.3%. HCC-related deaths peaked at 2 years after LT (51.1% of all HCC-related deaths) and decreased to a high 30.8% in the interval of 6 to 10 years after LT. The risk factors for 10-year OS were macrovascular invasion (OR = 2.71; P = 0.001), poor grading (OR = 1.56; P = 0.001), HCV status (OR = 1.39; P = 0.001), diameter of the target lesion (OR = 1.09; P = 0.001), AFP slope (OR = 1.63; P = 0.006), and patient age (OR = 0.99; P = 0.01). The risk factor for 10-year HCC-related death were AFP slope (OR = 4.95; P < 0.0001), microvascular (OR = 2.13; P < 0.0001) and macrovascular invasion (OR = 2.32; P = 0.01), poor tumor grading (OR = 1.95; P = 0.001), total number of neo-adjuvant therapies (OR = 1.11; P = 0.001), diameter of the target lesion (OR = 1.11; P = 0.002), and patient age (OR = 0.97; P = 0.001). When analyzing survival rates in function of LT era, a progressive improvement of the results was observed, with patients transplanted during the period 2007-2015 showing 5- and 10-year death rates of 26.8% and 38.9% (vs. 1987-1996, P < 0.0001; vs. 1997-2006, P = 0.005). Conclusions: LT generates long-term overall and disease-free survival rates superior to all other oncologic treatments of HCC. The role of LT in the modern treatment of HCC becomes even more valued when the follow-up period reaches at least 10 years. The results of LT continue to improve even when prudently widening the inclusion criteria for transplantation. Despite the incidence of HCC recurrence is highest during the first 5 years post-transplant, one-third of them occur later, indicating the importance of a life-long follow-up of these patients.

Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease.

Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5 ; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.

Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management.

Contemporary intravenous iron formulations allow administration of high doses of elemental iron and enable correction of total iron deficit in one or two infusions. An important but underappreciated complication of certain formulations is hypophosphatemia caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). The pathophysiology of FGF23-induced hypophosphatemia due to certain intravenous iron formulations has been recently investigated in prospective clinical trials. To reach the correct diagnosis, clinicians must recognize the typical clinical manifestations of intravenous iron-induced hypophosphatemia and identify a specific pattern of biochemical changes (hyperphosphaturic hypophosphatemia triggered by high FGF23 that causes low 1,25 (OH)2 vitamin D, hypocalcemia and secondary hyperparathyroidism). Physicians and patients should be aware of hypophosphatemia as a common complication of intravenous iron therapy and monitor serum phosphate concentrations in patients receiving repeated doses of specific intravenous iron formulations. Symptoms of hypophosphatemia are associated with severity and duration. Persistent hypophosphatemia can occur with iron therapy and can cause debilitating diseases including myopathy, osteomalacia and fractures. This review summarizes the current understanding of the iron-phosphate axis as well as complications of intravenous iron-induced hypophosphatemia.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose.

CONTEXT: Hypophosphatemia, osteomalacia, and fractures are complications of certain intravenous iron formulations. OBJECTIVE: This study investigated risk factors for incident, severe, and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment. METHODS: We analyzed data from the PHOSPHARE-IDA randomized clinical trials, comprising 245 patients aged 18 years or older with iron deficiency anemia at 30 outpatient clinics in the United States who received intravenous ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Outcome measures included serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase. RESULTS: FCM was the only consistent risk factor for incident hypophosphatemia (< 2.0 mg/dL; odds ratio vs FDI: 38.37; 95% CI: 16.62, 88.56; P < 0.001). Only FCM-treated patients developed severe hypophosphatemia (< 1.0 mg/dL; 11.3%; 13/115) or persistent hypophosphatemia (< 2.0 mg/dL at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all P < 0.05). Patients with persistent vs resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D, and N-terminal procollagen-1 peptide levels (all P < 0.01), but alkaline phosphatase increased similarly in both groups. CONCLUSION: Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.

A proteomic survival predictor for COVID-19 patients in intensive care.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.