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.

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.

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.

Apelin and the gut microbiome: Potential interaction in human MASLD.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with increasing numbers worldwide. Adipokines like apelin (APLN) can act as key players in the complex pathophysiology of MASLD. AIMS: Investigating the role of APLN in MASLD. METHODS: Fecal and blood samples were collected in a MASLD cohort and healthy controls (HC). MASLD patients with liver fibrosis and MASLD-associated hepatocellular carcinoma (HCC) were included into the study. Systemic concentration of Apelin, Apelin receptor (APLNR) and circulating cytokines were measured in serum samples. RESULTS: Apelin concentration correlated with the Fib-4 score and was elevated in MASLD patients (mild fibrosis, mF (Fib-4 <3.25) and severe fibrosis, sF (Fib-4 >3.25)) as well as in MASLD-associated HCC patients compared to HC. In accordance APLNR and circulating cytokines were also elevated in mF and sF. In contrast apelin levels were negatively associated with liver survival at three and five years. Changes in taxa composition at phylum level showed an increase of Enterobactericae, Prevotellaceae and Lactobacillaceae in patients with sF compared to mF. We could also observe an association between apelin concentrations and bacterial lineages (phyla). CONCLUSIONS: Circulating apelin is associated with liver fibrosis and HCC. In addition, there might exist an interaction between systemic apelin and the gut microbiome.

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.

Gas6 in chronic liver disease-a novel blood-based biomarker for liver fibrosis.

The expression of the receptor tyrosine kinase Axl and its cleavage product soluble Axl (sAxl) is increased in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this multicenter study, we evaluated the diagnostic value of Gas6, the high-affinity ligand of Axl, in patients with chronic liver disease. Levels of sAxl and Gas6, and their albumin (alb) ratios were analyzed in serum samples of patients with biopsy-proven liver fibrosis, end-stage liver disease, HCC, and healthy controls, and were compared to Fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF™) test, Child-Pugh score (CPS), model of end-stage liver disease (MELD) score, hepatic venous pressure gradient, and α-fetoprotein, respectively. A total of 1111 patients (median age 57.8 y, 67.3% male) was analyzed. Gas6/alb showed high diagnostic accuracy for the detection of significant (≥F2: AUC 0.805) to advanced fibrosis (≥F3: AUC 0.818), and was superior to Fib-4 for the detection of cirrhosis (F4: AUC 0.897 vs. 0.878). In addition, Gas6/alb was highly predictive of liver disease severity (Odds ratios for CPS B/C, MELD ≥ 15, and clinically significant portal hypertension (CSPH) were 16.534, 10.258, and 12.115), and was associated with transplant-free survival (Hazard ratio 1.031). Although Gas6 and Gas6/alb showed high diagnostic accuracy for the detection of HCC in comparison to chronic liver disease patients without cirrhosis (AUC 0.852, 0.868), they failed to discriminate between HCC in cirrhosis versus cirrhosis only. In conclusion, Gas6/alb shows a high accuracy to detect significant to advanced fibrosis and cirrhosis, and predicts severity of liver disease including CSPH.

A gut bacterial signature in blood and liver tissue characterizes cirrhosis and hepatocellular carcinoma.

BACKGROUND: HCC is the leading cause of cancer in chronic liver disease. A growing body of experimental mouse models supports the notion that gut-resident and liver-resident microbes control hepatic immune responses and, thereby, crucially contribute to liver tumorigenesis. However, a comprehensive characterization of the intestinal microbiome in fueling the transition from chronic liver disease to HCC in humans is currently missing. METHODS: Here, we profiled the fecal, blood, and liver tissue microbiome of patients with HCC by 16S rRNA sequencing and compared profiles to nonmalignant cirrhotic and noncirrhotic NAFLD patients. RESULTS: We report a distinct bacterial profile, defined from 16S rRNA gene sequences, with reduced α-and ß-diversity in the feces of patients with HCC and cirrhosis compared to NAFLD. Patients with HCC and cirrhosis exhibited an increased proportion of fecal bacterial gene signatures in the blood and liver compared to NAFLD. Differential analysis of the relative abundance of bacterial genera identified an increased abundance of Ruminococcaceae and Bacteroidaceae in blood and liver tissue from both HCC and cirrhosis patients compared to NAFLD. Fecal samples from cirrhosis and HCC patients both showed a reduced abundance for several taxa, including short-chain fatty acid-producing genera, such as Blautia and Agathobacter. Using paired 16S rRNA and transcriptome sequencing, we identified a direct association between gut bacterial genus abundance and host transcriptome response within the liver tissue. CONCLUSIONS: Our study indicates perturbations of the intestinal and liver-resident microbiome as a critical determinant of patients with cirrhosis and HCC.

Long-term follow-up of patients discontinuing bulevirtide treatment upon long-term HDV-RNA suppression.

Background & Aims: Bulevirtide (BLV) is a novel antiviral drug licensed for the treatment of chronic hepatitis D. Data on the safety and efficacy of stopping BLV therapy upon long-term HDV-RNA suppression are scarce. Methods: A total of seven patients (age, 31-68 years, four with cirrhosis) included in a prospective Austrian HDV registry discontinued BLV treatment (duration, 46-141 weeks) upon long-term HDV suppression (HDV-RNA negativity, 12-69 weeks). Pegylated interferon-ɑ2a was used in combination with BLV in two patients. HDV-RNA, alanine aminotransferase, and quantitative HBsAg levels were closely monitored during treatment-free follow-up. Results: The seven patients were followed up for 14 to 112 weeks. Six patients completed ≥24 weeks of follow-up. HDV-RNA became detectable again in three patients within 24 weeks, whereas one additional patient showed an HDV-RNA relapse after almost 1 year. All patients who relapsed at any point had undergone BLV monotherapy. Meanwhile, HDV-RNA remained undetectable in two patients who were treated with BLV + pegylated interferon-ɑ2a. Only one patient showed significant alanine aminotransferase increases within 24 weeks of follow-up. BLV was reintroduced in three patients after 13-62 BLV-free weeks and was well tolerated, and all patients achieved virologic response again. Conclusions: BLV discontinuation upon long-term HDV-RNA suppression seems safe. Retreatment with BLV was effective in case of virologic relapse. These findings are within a limited number of patients, and future studies are needed to define stopping rules and further investigate the safety of stopping BLV. Impact and Implications: Limited data exist on stopping bulevirtide (BLV) treatment in patients who achieve long-term HDV-RNA suppression. In a small cohort of seven Austrian patients discontinuing BLV therapy, HDV-RNA relapses were observed in four patients during long-term follow-up, whereas significant alanine aminotransferase increases were recorded in only one. Retreatment with BLV was effective in relapsers. The safety and efficacy of stopping BLV needs to be further studied in larger cohorts.

Austrian consensus on the diagnosis and management of portal hypertension in advanced chronic liver disease (Billroth IV).

The Billroth IV consensus was developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on the 26th of November 2022 in Vienna.Based on international recommendations and considering recent landmark studies, the Billroth IV consensus provides guidance regarding the diagnosis and management of portal hypertension in advanced chronic liver disease.

Transmission of oral microbiota to the biliary tract during endoscopic retrograde cholangiography.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) possesses a translocation risk of microbes to the biliary system. We studied bile contamination during ERC and its impact on patients' outcome in a real-life-situation. METHODS: Ninety-nine ERCs were analyzed and microbial samples were taken from the throat before and from bile during ERC and from irrigation fluid of the duodenoscope before and after ERC. RESULTS: 91.2% of cholangitis patients had detectable microbes in the bile (sensitivity 91%), but the same was true for 86.2% in the non-cholangitis group. Bacteroides fragilis (p=0.015) was significantly associated with cholangitis. In 41.7% of ERCs with contaminated endoscopes these microbes were found in the bile after the procedure. Analysis of duodenoscopes' irrigation liquid after ERC matched the microbial bile analysis of these patients in 78.8%. Identical microbial species were in throat and in bile samples of the same ERC in 33% of all cases and in 45% in the non-cholangitis group. Transmission of microbes to the biliary tract did not result in more frequent cholangitis, longer hospital stays, or worse outcome. CONCLUSIONS: During ERC bile samples are regularly contaminated with microbes of the oral cavity but it did not affect clinical outcome.

Tissue iron distribution in patients with anemia of inflammation: Results of a pilot study.

Anemia of inflammation (AI) is frequently present in subjects with inflammatory disorders, primarily caused by inflammation-driven iron retention in macrophages. So far, only limited data on qualitative and quantitative estimates of tissue iron retention in AI patients exist. We performed a prospective cohort study analyzing splenic, hepatic, pancreatic, and cardiac iron content with MRI-based R2*-relaxometry in AI patients, including subjects with concomitant true iron deficiency (AI+IDA) hospitalized between 05/2020-01/2022. Control groups were individuals without inflammation. Spleen R2* values in AI patients with ferritin ≤200 µg/L (AI+IDA) were comparable with those found in controls. In AI patients with ferritin >200 µg/L, spleen (47.6 s-1 vs. 19.3 s-1 , p < .001) and pancreatic R2* values (32.5 s-1 vs. 24.9 s-1 , p = .011) were significantly higher compared with controls, while liver and heart R2*-values did not differ. Higher spleen R2* values were associated with higher ferritin, hepcidin, CRP, and IL-6 concentrations. Spleen R2* values normalized in AI patients after recovery (23.6 s-1 vs. 47.6 s-1 , p = .008), while no changes were found in patients with baseline AI+IDA. This is the first study investigating tissue iron distribution in patients with inflammatory anemia and AI with concomitant true iron deficiency. The results support the findings in animal models demonstrating iron retention in macrophages, which are primarily accumulating in the spleen under inflammatory conditions. MRI-related iron measurement may help to better characterize actual iron needs and to define better biomarker thresholds in the diagnosis of true ID in patients with AI. It may qualify as a useful diagnostic method to estimate the need for iron supplementation and to guide therapy.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Liver Transplantation after Successful Downstaging of a Locally Advanced Hepatocellular Carcinoma with Systemic Therapy.

INTRODUCTION: Liver transplantation (LT) is potentially curative for patients with cirrhosis and hepatocellular carcinoma (HCC). However, this procedure is usually reserved for patients with early tumor stages or after successful downstaging with local regional therapies. In patients with locally advanced HCC, current guidelines recommend locoregional and palliative systemic therapies for tumor stages Barcelona Clinic Liver Cancer (BCLC) B and C, respectively. CASE REPORT: In this article, we describe a 63-year-old male patient with locally advanced HCC (BCLC C) and hepatitis C-associated cirrhosis. Following systemic treatment with the immune checkpoint inhibitor atezolizumab and the anti-VEGF antibody bevacizumab, significant downstaging to a tumor stage within the Milan criteria was achieved after which LT was successfully performed. CONCLUSION: As more effective systemic therapies become available, LT and potential curative treatment could become feasible for selected patients with locally advanced HCC.

Identification and characterization of patients being exposed to computed-tomography associated radiation-doses above 100 mSv in a real-life setting.

Rationale and objectives: Patients receiving high cumulative effective doses (CED) from recurrent computed tomography (CT) in a real-life setting are not well identified. Evaluation of causes and patient characteristics may help to define individuals potentially at risk of radiation-induced secondary malignancies. Materials and methods: Patients who received a CED > 100 mSv from CT scans during October 2012 and April 2020 at a tertiary university center were identified with the help of a radiological radiation dose monitoring system. The primary disease and referral diagnosis, number of CT exams, time period, age, BMI and gender distribution of the 1000 patients with the highest CED were analysed. Results: 3431 patients had a CED of more than 100 mSv, which corresponded to 2.75% of all patients who received a CT exam. From the 1000 patients with the highest CED, mean number of CT exams per patient was 14.6, mean CED was 257 mSv (SD 98, range 177-1339). Mean age of patients was 63.9 years (SD 10.6), male to female ratio 3:2, and mean BMI 28.7 kg/m2 (SD 5.5). 728 (72.9%) patients had cancer. The leading primary diagnosis was liver cirrhosis in 197 patients and 103 patients had a liver transplantation. In patients with liver cirrhosis, 750 exams were indicated for the follow-up of the disease, 662 for the clarification of an acute clinical condition, and 202 for CT-guided stereotactic radiofrequency ablation. Conclusion: Recurrent CT scans of patients with cancer, liver cirrhosis and liver transplantation may lead to critically high CED.