Article

Serum Ferritin Predicts Early Mortality In Patients With Decompensated Cirrhosis.

March 2014
Journal of Hepatology 61(1)

DOI:10.1016/j.jhep.2014.03.027

Source
PubMed

Authors:

Rakhi Maiwall

Institute of Liver and Biliary Sciences

Suman Kumar

Army Hospital (Research & Referral), New Delhi

Jaswinder singh Maras

Institute of Liver and Biliary Sciences

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Serum ferritin is a known marker of hepatic necro-inflammation and has been studied to predict 1 year mortality and post-transplant survival in decompensated cirrhotics. However, there are no studies evaluating ferritin as a predictor of early mortality. We investigated whether serum ferritin levels could predict 15 day and 30 day mortality in patients with decompensated cirrhosis. 318 patients with decompensated cirrhosis were included. Patients of decompensated cirrhosis [257 males, mean age of 51 [±13] years, were followed for a median of 31 days. Serum ferritin levels were significantly different between survivors and non-survivors [p<0.001] and showed significant correlation with MELD score [p<0.001], CTP score [p<0.001], leucocyte counts [TLC] [p<0.001], serum sodium [p<0.001], ACLF grades [p=0.005], spontaneous bacterial peritonitis [SBP] [p=0.02], hepatic encephalopathy [HE] [p<0.001] and hepatorenal syndrome [HRS] [p=0.012]. Serum ferritin, etiology, MELD, HE, CTP score, sodium, TLC and ACLF grades were significant predictors of mortality on univariate analysis. Ferritin [p=0.04, HR 1.66 95% CI (1.02-2.73)] was a significant predictor of early mortality on multivariate analysis along with HE [ p=0.006, HR 3.47 95% CI (2.13-8.41)] (Model 1), TLC [p=0.02, HR 1.81 95% CI (1.06-3.07)] (Model 2), ACLF grades [p=0.018, HR 2.013,95% CI(1.126-3.60)]and CTP score [p<0.0001,HR 1.36 95% CI (1.17-1.59)] (Model 3). Serum ferritin levels correlate with severity of hepatic decompensation and is associated with early liver related death independent of the MELD score in hospitalized patients with decompensated cirrhosis. This could also have a potential therapeutic implication.

Role of Serum ferritin as a marker of decompensated cirrhosis and its correlation with CTP, MELD and MELD-Na scores

Article

Full-text available

Oct 2024

Objectives: Liver cirrhosis, when decompensated; is associated with considerable morbidity and mortality. Scoring systems used to define the severity of cirrhosis and predict mortality include several clinical and biochemical parameters. Serum ferritin is a universally available biomarker, elevated in inflammatory conditions including hepatic necroinflammation. The study aimed to analyze whether serum ferritin has a role as a biomarker of decompensation and correlation with severity in cirrhotic patients. Methods: 131 patients with cirrhosis; both compensated and decompensated admitted at Gastroenterology, BIRDEM General Hospital, Dhaka, Bangladesh from November 2019 to March 2022 were included in this cross-sectional study. To determine severity, Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD) and MELD-sodium (MELD-Na) were estimated. Comparison of ferritin between and among different groups was done and the relationship with severity was assessed. Results: Serum ferritin was significantly higher in decompensated (mean 474.20±769.53 ng/mL) than in compensated (80.85±35.31) cirrhosis patients (P<0.001). Ferritin levels among different CTP grading differed significantly (P<0.001). It was higher in grade C (694.14±975.57) than in grade B (213.02±219.17) and A (80.85±35.31) as per pairwise comparison. Moderate positive correlations were observed between ferritin and MELD along with MELD-Na scores. Receiver operating characteristic (ROC) analysis of serum ferritin for predicting hepatic decompensation gave a significant area under the curve (AUC) value (0.821) and the best cutoff value was 105.5 ng/mL (sensitivity 76.2%, specificity 84.6%). Conclusion: The study suggests serum ferritin can be used as an alternate biomarker for screening hepatic decompensation and stratifying severity.

Role of Serum ferritin as a marker of decompensated cirrhosis and its correlation with CTP, MELD and MELD-Na scores

Article

Full-text available

Oct 2024

Implications of anemia and response to anemia treatment on outcomes of patients with cirrhosis

Article

Full-text available

Apr 2023

Background & Aims: Anaemia is frequently observed in patients with cirrhosis and was identified as a predictor of adverse outcomes, such as increased mortality and occurrence of acute-on-chronic liver failure. To date, the possible effects of iron supplementation on these adverse outcomes are not well described. We therefore aimed to assess the role of iron supplementation in patients with cirrhosis and its capability to improve prognosis. Methods: Laboratory diagnostics were performed in consecutive outpatients with cirrhosis admitted between July 2018 and December 2019 to the University Hospital Essen. Associations with transplant-free survival were assessed in regression models. Results: A total of 317 outpatients with cirrhosis were included, of whom 61 received a liver transplant (n = 19) or died (n = 42). In multivariate Cox regression analysis, male sex (hazard ratio [HR] = 3.33, 95% CI [1.59, 6.99], p = 0.001), model for end-stage liver disease score (HR = 1.19, 95% CI [1.11, 1.27], p

Predictors of early mortality among patients with acute‐on‐chronic liver failure

Article

Full-text available

May 2021

Background and Aim Acute-on-chronic liver failure (ACLF) is a transpiring entity, which possesses high short-term/early mortality (28 days). Several mortality predictors have been studied, but none were proved reliable. Serum ferritin, an acute phase reactant and marker of hepatic necro-inflammation, is found to predict mortality in multiple liver diseases. We aimed to evaluate the role of serum ferritin and other clinical features, biochemical parameters and conventional scoring systems in predicting early mortality among ACLF. Methods A prospective cohort study was done from October 2017 to March 2019 at a tertiary care (non-transplant) center in eastern India. A total of consecutive 50 ACLF patients diagnosed, based on Asia Pacific Association for the Study of liver disease definition, were investigated for ferritin and other laboratory parameters on day-0, day-7, and followed up for 28 days. Results Although the majority did not have organ failure (ACLF grade 0) according to European Association for Study of Liver-chronic liver failure sequential organ failure assessment criteria, early mortality was high (56%). On undergoing univariate analysis, multiple variables (ascites, HE, creatinine, total leucocyte count (TLC), bilirubin, albumin) predicted mortality. However, on multivariate analysis, only total bilirubin independently predicted. None of the scores on day-0 were predictive, while model for end-stage liver disease [area under the receiver operating characteristics (AUROC)-0.703, 95% confidence interval [CI]: 0.535–0.859] and Child–Turcotte–Pugh (AUROC-0.697, 95% CI: 0.550–0.855) on day-7 did. Conclusion ACLF is a dynamic process; day-7 assessment with above predictors, to be considered a milestone for prognostication and opting treatment modalities. Serum ferritin does not predict early mortality in ACLF.

Serum Transferrin Is an Independent Predictor of Mortality in Severe Alcoholic Hepatitis

Article

Jan 2020

Objectives: Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH. Methods: Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628). Results: Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively). Discussion: In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.

Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications

Article

Full-text available

Feb 2019
ALIMENT PHARM THER

Albert J. Czaja

Background Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. Aims To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management Methods English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Results Hyperferritinemia is present in 4%‐65% of patients with non‐alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%‐52%. Heterozygosity for the C282Y mutation is present in 17%‐48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non‐alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. Conclusions Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co‐morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.

High serum ferritin is associated with worse outcome of patients with decompensated cirrhosis

Article

Full-text available

Jan 2016

Theodora Oikonomou

Background Studies in patients with decompensated cirrhosis showed a correlation between serum ferritin levels and patients’ prognosis. Besides, red blood cell distribution width (RDW) and mean platelet volume (MPV) have been associated with the severity of hepatic function. The aim of this study was to evaluate the prognostic impact of serum ferritin and RDW/MPV in the outcome [survival, death, or liver transplantation (LT)] of patients with stable decompensated cirrhosis. Methods Consecutive adult patients with stable decompensated cirrhosis admitted to our department between September 2010 and February 2016 were included. Serum ferritin, RDW and MPV were recorded in every patient. They were followed up and their outcome (alive, death, or LT) was evaluated. Results 192 consecutive patients with stable decompensated cirrhosis (142 men, age 54.2±12 years); at the end of follow up [12 (range: 1-64) months] 62 patients remained alive and 130 died or underwent LT. In multivariate analysis, serum ferritin (HR 1.001, 95%CI 1.00-1.002, P=0.005) and GFR (HR 0.96, 95%CI 0.92-0.99, P=0.035) were the only independent factors significantly associated with the outcome. Ferritin had low discriminative ability (AUC: 0.61) to the outcome yielding a sensitivity and specificity of 85.3% and 44.2%, respectively, at the best cut-off point (>55 ng/mL), while patients with ferritin >55 ng/mL (n=145) had a worse outcome compared to those with ferritin ≤55 ng/mL (n=47) (log rank P=0.001). RDW and MPV were not associated with the outcome. Conclusion High serum ferritin, but not RDW/MPV, is associated with worse outcome in patients with established decompensated cirrhosis. However, further studies are needed to elucidate better this issue.

Diyaliz hastalarında sistemik immün inflamasyon indeksi mortaliteyi öngörebilirSystemic immune inflammation index may predict mortality in dialysis patients

Article

Full-text available

May 2023

Amaç: Böbrek yetmezliğinde artmış inflamasyon söz konusudur. Serum ferritini bir akut faz reaktanıdır. Sistemik immün inflamasyon indeksi, kardiyovaskuler hastalıklarda ve kanserlerde prognostic önemi olduğu gösterilen, nötrofil, lenfosit ve trombosit sayılarından hesaplanan yeni bir belirteçtir. Bu çalışma, sistemik immün inflamasyon indeksinin diyaliz hastalarının mortalite riskini belirlemede kullanılabilirliğini ve mortalite ile ferritin düzeyleri arasındaki ilişkiyi belirlemeyi amaçlamaktadır. Gereç ve Yöntemler: Çalışmaya 84 hemodiyaliz ve periton diyaliz hastası alındı. Hastaların bazal demografik, klinik ve laboratuvar verileri, tıbbi kayıtlardan elde edildi. Mutlak nötrofil lenfosit oranının, mutlak platelet ile çarpımı ile sistemik immün inflamasyon indeksi elde edildi. Sonuç: Hastaların ortalama yaşı 51.3 ± 20.1olup, ortalama takip süreleri 60 (6 ~ 85) aydı. Takip süresince hastaların 45(%53) ü öldü. Hastalar medyan ferritin düzeyine göre analiz edildi. Kaplan-Meier analizine göre ferritinin yüksek olduğu grupta mortalitenin daha yüksek olduğu saptandı (log-rank test, P = 0.029). Yine hastalar medyan sistemik immün inflamasyon indeksine göre analiz edildi. Kaplan-Meier analizine göre sitemik immün inflamasyon indeksinin yüksek olduğu grupta daha yüksek mortalite oranları saptandı (log-rank test, P = 0.029). Çok değişkenli regresyon analizinde yaş (HR 1.060, P=0.00), Kt/V (HR 0.161, P=0.014), CRP (HR1.001, P=0.0429) ve Sistemik immün inflamasyon indeksi (HR 1.001, P=0.00) ve ferritin (HR) 1.001, P=0.013) tüm nedenlere bağlı ölümlerin en önemli belirleyicileriydi. Tartışma: Yeni bir inflamatuar belirteç olan Sistemik immün inflamasyon indeks ve ferritin, diyaliz hastalarında tüm nedenlere bağlı ölümlerle ilişkilidir. Diyaliz hastalarında inflamasyonun Sistemik immün inflamasyon indeks ve ferritin düzeyleri ile takip edilebileceğini düşünüyoruz.

Micronutrient Deficiencies in Patients with Decompensated Cirrhosis

Article

Full-text available

Apr 2021

Patients with cirrhosis often develop malnutrition and micronutrient deficiencies, leading to a worse prognosis and increased mortality. Our main goal was to assess the prevalence of micronutrient deficiencies in patients with decompensated cirrhosis. This was a prospective single-center study including 125 consecutive patients hospitalized for acute decompensation of cirrhosis (mostly of alcoholic etiology). A blood test including trace elements and vitamins was performed on admission. The main micronutrient deficiencies observed were vitamin D (in 94.5%), vitamin A (93.5%), vitamin B6 (60.8%) and zinc (85.6%). Patients in Child-Pugh class C had lower levels of vitamin A (p < 0.0001), vitamin E (p = 0.01) and zinc (p < 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.001) than those in Child-Pugh class A and B. Patients with a higher model of end-stage liver disease (MELD) score had lower levels of vitamin A (p < 0.0001), vitamin E (p < 0.001), magnesium (p = 0.01) and zinc (p = 0.001), and higher levels of ferritin (p = 0.002) and vitamin B12 (p < 0.0001). Severe hepatic insufficiency correlated with lower levels of zinc, vitamin E and vitamin A, and higher levels of vitamin B12 and ferritin.

Abnormal ferritin levels predict development of poor outcomes in cirrhotic outpatients: a cohort study

Article

Full-text available

Mar 2021
BMC GASTROENTEROL

Background Both iron overload and iron deficient anemia can associate with cirrhosis. At the same time, inflammation might be continuously present in cirrhotic patients due to bacterial translocation and patients’ susceptibility to infections. Ferritin is a sensitive and widely available marker of iron homeostasis, in addition it acts as an acute phase protein. Therefore, we evaluated the prognostic potential of serum ferritin in the long-term follow-up of cirrhotic outpatients. Methods A cohort of 244 cirrhotic outpatients was recruited and followed for 2 years. We measured their serum ferritin levels in our routine laboratory unit at enrolment and investigated its association with clinical outcomes. Results Ferritin serum level was higher in males and older patients than in females (median: 152.6 vs. 75 μg/L, p < 0.001) or younger individuals (median: 142.9 vs. 67.9 μg/L, p = 0.002). Patients who previously survived variceal bleeding had lower ferritin levels (median: 43.1 vs. 146.6 μg/L, p < 0.001). In multivariate regression models, including laboratory and clinical factors, lower (< 40 μg/L) ferritin concentration was associated with the development of decompensated clinical stage in patients with previously compensated cirrhosis (sHR: 3.762, CI 1.616–8.760, p = 0.002), while higher (> 310 μg/L) circulating ferritin levels were associated with increased risks of bacterial infections in decompensated patients (sHR: 2.335, CI 1.193–4.568, p = 0.013) and mortality in the whole population (HR: 2.143, CI 1.174–3.910, p = 0.013). Conclusion We demonstrated usefulness of serum ferritin as a prognostic biomarker in cirrhosis, pointing out that both low and high concentrations need attention in these patients.

Systemic inflammation modulates the ability of serum ferritin to predict all-cause and cardiovascular mortality in peritoneal dialysis patients

Article

Full-text available

Jun 2020
BMC Nephrol

Background: This study aimed to ascertain whether the correlation of high serum ferritin with mortality is affected by systemic inflammation and to investigate the optimal serum ferritin level for predicting death when inflammation is considered in peritoneal dialysis (PD) patients. Methods: We classified 221 patients into four groups according to serum ferritin concentration (100 μg/L) and high-sensitivity CRP (hs-CRP) level (3 mg/L), and followed them regularly from the date of catheterization to Dec 31, 2016, at Sun Yat-Sen Memorial Hospital, China. Clinical and biochemical data were collected at baseline, and clinical outcomes such as all-cause and cardiovascular mortality were assessed. Results: During a median follow-up of 35 months (3 ~ 109 months), 50 (22.6%) deaths occurred. Cardiovascular disease (46.0%) was the most common cause of death, followed by infection (10.0%). The Kaplan-Meier survival analysis and log-rank test revealed significantly worse survival accumulation among PD patients with higher serum ferritin (≥100 μg/L) under elevated hsCRP levels (> 3 mg/L) (P = 0.022). A multivariate Cox regression analysis revealed that an increased serum ferritin level was independently associated with a higher risk of all-cause and cardiovascular mortality in PD patients (HR = 3.114, P = 0.021; and HR = 9.382, P = 0.032) with hsCRP above 3 mg/L after adjusting for relevant confounding factors. Conclusion: Higher serum ferritin levels were associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing PD only in the presence of elevated hsCRP levels. The correlation of serum ferritin with poor outcome should take into consideration systemic inflammation.

Low Serum Hepcidin Is Associated With Reduced Short-Term Survival in Adults With Acute Liver Failure

Article

Dec 2018

The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)‐induced ALF mouse model A representative subset of 121 ALF adults (including 66 APAP‐related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) vs. death/transplantation (NSS). Mice were assessed prior to (controls), four and 18 hours after injection of 300 mg/kg APAP ALF patients as well as APAP‐treated mice displayed increased ferritin, diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1 vs. 34.5 μmol/l; p<0.05) and transferrin saturation (60.9 vs. 79.1%; p<0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/ml; p<0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; p<0.001) than NSS. In a multivariate analysis, a log transformed hepcidin‐containing model displayed similar prognostic power as the established ALFSG index (C‐statistic 0.87 vs. 0.85) and was better than MELD score (C‐statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury Our findings demonstrate that several serum iron parameters significantly associate with 3‐week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP‐induced ALF, and is an independent predictor and might be a useful component of future prognostic scores. This article is protected by copyright. All rights reserved.

Low transferrin and high ferritin concentrations are associated with worse outcome in acute liver failure

Article

Jan 2017
LIVER INT

Background & aims: Serum ferritin and transferrin have been identified as prognostic markers in patients with chronic diseases. In the present study we investigated if these parameters can predict outcome in patients with acute liver failure. Methods: 102 consecutive patients with acute liver failure were retrospectively analyzed. The patients were grouped by outcome: spontaneous recovery vs. liver transplantation and/or death; or survival vs. death. Routine laboratory parameters, transferrin and ferritin concentrations in serum, and anthropomorphic data collected on admission were analyzed. Results: Non-spontaneously recovering patients had higher ferritin (12252±25791 vs. 4434.4±9027.2 μg/l; p<0.05) and lower transferrin levels (140.4±66.7 vs. 206.9±65.8 mg/dl; p<0.05) than spontaneously recovering patients. Similarly non survivors exhibited higher serum ferritin and lower transferrin than non-transplanted survivors. Patients with severe hepatic inflammation (A3) had higher ferritin levels compared to patients with mild-moderate inflammation (A1-2) (5280±5094 vs. 2361±2737 μg/l; p=0.025). ROC analysis of single parameters was performed in non transplanted patients, resulting in an area under the curve, sensitivity and specificity of 0.812, 83.3%, and 77.1% for age, 0.871, 84.1% and 75% for transferrin and 0.802, 91.7% and 62.9% for ferritin. A model incorporating age, MELD and transferrin had the best predictive value with an area under the curve of 0.947, a sensitivity of 100% and corresponding specificity of 77.8%. Conclusions: High ferritin and low transferrin levels are associated with worse outcome in patients with acute liver failure. A model incorporating age, MELD score and transferrin outperformed MELD score for 90-days overall survival of non-transplanted patients. This article is protected by copyright. All rights reserved.

Predictors of survival in autoimmune liver disease overlap syndromes

Article

Sep 2024

BACKGROUND Survival in patients with autoimmune liver disease overlap syndromes (AILDOS) compared to those with single autoimmune liver disease is unclear. AIM To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death. METHODS Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap (AIH-PBC) or autoimmune hepatitis and primary sclerosing cholangitis overlap (AIH-PSC) and were identified from three tertiary centres for this cohort study. Liver-related death or transplantation (liver-related mortality) was determined using a population-based data linkage system. Prognostic scores for liver-related death were compared for accuracy [including liver outcome score (LOS), Hepascore, Mayo Score, model for end-stage liver disease (MELD) score and MELD incorporated with serum sodium (MELD-Na) score]. RESULTS Twenty-two AILDOS patients were followed for a median of 3.1 years (range, 0.35-7.7). Fourteen were female, the median age was 46.7 years (range, 17.8 to 82.1) and median Hepascore was 1 (range, 0.07-1). At five years post enrolment, 57% of patients remained free from liver-related mortality (74% AIH-PBC, 27% AIH-PSC). There was no significant difference in survival between AIH-PBC and AIH-PSC. LOS was a significant predictor of liver-related mortality (P < 0.05) in patients with AIH-PBC (n = 14) but not AIH-PSC (n = 8). A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients (P = 0.012, log-rank test, 100% sensitivity, 77.8% specificity) (Harrell's C-statistic 0.867). The MELD score, MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group. CONCLUSION Survival in the rare, AILDOS is unclear. The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients. Further trials investigating predictors of survival in AILDOS are required.

Iron Metabolism in the Recovery Phase of Critical Illness with a Focus on Sepsis

Article

Full-text available

Jun 2024
INT J MOL SCI

Iron is an essential nutrient for humans and microbes, such as bacteria. Iron deficiency commonly occurs in critically ill patients, but supplementary iron therapy is not considered during the acute phase of critical illness since it increases iron availability for invading microbes and oxidative stress. However, persistent iron deficiency in the recovery phase is harmful and has potential adverse outcomes such as cognitive dysfunction, fatigue, and cardiopulmonary dysfunction. Therefore, it is important to treat iron deficiency quickly and efficiently. This article reviews current knowledge about iron-related biomarkers in critical illness with a focus on patients with sepsis, and provides possible criteria to guide decision-making for iron supplementation in the recovery phase of those patients.

Extracellular vesicles-derived ferritin from lipid-induced hepatocytes regulates activation of hepatic stellate cells

Article

Full-text available

Jun 2024

Introduction and objectives: Extracellular vesicles (EVs) have emerged as key players in intercellular communication within the context of non-alcoholic fatty liver disease (NAFLD). This study aims to explore the intricate crosstalk between hepatocytes and hepatic stellate cells (HSCs) mediated by EVs in NAFLD. Materials and methods EVs ferritin was detected in hepatocytes stimulated with free fatty acids (FFA) as well as in NAFLD mice. Deferoxamine (DFO) was employed to reduce ferritin levels, while GW4869 was utilized to inhibit EVs. The impact of EVs ferritin on the HSCs activation was evaluated both in vitro and in vivo. Additionally, serum EVs ferritin levels were compared between NAFLD patients and controls. Results FFA treatment induces the formation and secretion of EVs and facilitates the release of ferritin from hepatocytes via EVs. Subsequently, EVs ferritin is hijacked by HSCs, prompting accelerated HSCs activation. Silencing ferritin with DFO and inhibiting EVs formation and secretion with GW4869 can reverse the effects of FFA treatment and disrupt the communication between hepatocytes and HSCs. Accumulation of ferritin leads to excessive reactive oxygen species (ROS) production, promoting HSCs fibrogenesis. Conversely, depleting EVs ferritin cargo restores liver function, concurrently mitigating NAFLD-associated fibrosis. Notably, NAFLD patients exhibit significantly elevated levels of serum EVs ferritin. Conclusions This study unveils a previously underestimated role of ferritin in HSCs upon its release from hepatocytes, emphasizing DFO as a promising compound to impede NAFLD advancement.

Iron Metabolism in the Recovery Phase of Critical Illness

Preprint

Full-text available

May 2024

Iron is an essential nutrient for humans and microbes, such as bacteria. Iron deficiency occurs commonly in critically ill patients, but iron replacement therapy is not considered during the acute phase of critical illness, since it increases iron availability for invading microbes and oxidative stress. However, persistent iron deficiency in the recovery phase is harmful with potential adverse outcomes such as cognitive dysfunction, fatigue and cardiopulmonary dysfunction. Therefore, it is important to treat iron deficiency timely and efficiently. This article reviews current knowledge about iron-related biomarkers in critically ill patients and provides possible criteria to guide decision-making for iron supplementation in the recovery phase of critical illness.

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease

Article

Full-text available

Jan 2024

Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell’s C-index and its improvement by including ferritin as a covariate. Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

Iron as an emerging therapeutic target in critically ill patients

Article

Full-text available

Dec 2023

The multiple roles of iron in the body have been known for decades, particularly its involvement in iron overload diseases such as hemochromatosis. More recently, compelling evidence has emerged regarding the critical role of non-transferrin bound iron (NTBI), also known as catalytic iron, in the care of critically ill patients in intensive care units (ICUs). These trace amounts of iron constitute a small percentage of the serum iron, yet they are heavily implicated in the exacerbation of diseases, primarily by catalyzing the formation of reactive oxygen species, which promote oxidative stress. Additionally, catalytic iron activates macrophages and facilitates the growth of pathogens. This review aims to shed light on this underappreciated phenomenon and explore the various common sources of NTBI in ICU patients, which lead to transient iron dysregulation during acute phases of disease. Iron serves as the linchpin of a vicious cycle in many ICU pathologies that are often multifactorial. The clinical evidence showing its detrimental impact on patient outcomes will be outlined in the major ICU pathologies. Finally, different therapeutic strategies will be reviewed, including the targeting of proteins involved in iron metabolism, conventional chelation therapy, and the combination of renal replacement therapy with chelation therapy.

Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

Article

Full-text available

Feb 2023

Background and aim: Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways. Methods: We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men. Results: The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%, p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18-9.82, p=0.023). Conclusions: In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.

Serum Ferritin Has Limited Prognostic Value on Mortality Risk in Patients with Decompensated Cirrhosis: A Propensity Score Matching Analysis

Article

Full-text available

Aug 2022

Objective The prognostic value of serum ferritin remains elusive in the literature. We aimed to examine the association between serum ferritin and mortality risk in cirrhosis. Methods A total of 257 cirrhotic patients were recruited. The cut-off of serum ferritin was determined by X-tile. The Cox regression and Kaplan-Meier method were used. A 1:1 propensity score matching (PSM) was performed to diminish the impacts of selection bias and possible confounders. Results The difference regarding mortality was mostly significant for serum ferritin >158 ng/mL. Before PSM, serum ferritin >158 ng/mL was an independent predictor of mortality. However, the clinical relevance of high ferritin level for prognostication was blunted after PSM (survival rate: 86.8% vs 96.3%, P = .078). Cox regression indicated that model for end-stage liver disease remains only independent risk factor of 180-day mortality after PSM. Conclusion Serum ferritin may not serve as an independent prognostic indicator of mortality risk in decompensated cirrhotic patients.

Proton Pump Inhibitor Therapy Does Not Affect Prognosis of Cirrhosis Patients With Acute Decompensation and Acute-on-Chronic Liver Failure: A Single-Center Prospective Study

Article

Full-text available

Nov 2021

Background: The aim of this study was to investigate the impact of proton pump inhibitor (PPI) therapy on complications and prognosis in cirrhosis patients with and without acute-on-chronic liver failure (ACLF). Materials and Methods: Cirrhosis patients with acute decompensation (AD) ( n = 489) admitted in our center were enrolled in this prospective observational cohort study. According to treatment received, patients were identified as users or nonusers of PPI. Clinical and laboratory data, complications during hospitalization, and overall survival were recorded in all the patients. Results: Of the 489 patients, 299 (61.1%) patients received PPI therapy. The logistic regression analysis showed that age, albumin, history of previous hepatic encephalopathy (HE), and the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score were independent risk factors for HE in patients with decompensated cirrhosis [odds ratio (OR) = 1.07, 95% CI: 1.03–1.12, p = 0.001; OR = 1.13, 95% CI: 1.04–1.24, p = 0.006; OR = 242.52, 95% CI: 40.17–1464.11, p < 0.001; and OR = 2.89, 95% CI: 2.11–3.96, p < 0.001, respectively]. Previous severe liver injury and previous bacterial infections were independent risk factors for spontaneous bacterial peritonitis (SBP) in patients with decompensated cirrhosis (OR = 3.43, 95% CI: 1.16–10.17, p = 0.026 and OR = 6.47, 95% CI: 2.29–18.29, p < 0.001, respectively). The multivariate Cox proportional hazards regression model showed that the type and dose of the PPI used were not related to 28-day and 90-day mortality in cirrhosis patients with AD or ACLF. Conclusion: PPI use does not appear to increase mortality or the risk of HE and SBP in the hospitalized cirrhosis patients with and without ACLF.

DOUTOR, EU PRECISO FAZER FLEBOTOMIA?

Article

Jan 2016

Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases

Article

Full-text available

Jul 2020

Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.

The prevalence and associated mortality of non‐anaemic iron deficiency in older adults: a 14 years observational cohort study

Article

Full-text available

Feb 2020
BRIT J HAEMATOL

Iron is central to multiple biological pathways, and treatment of non‐anaemic absolute iron deficiency (NAID) is beneficial in certain conditions. However, it is unknown if NAID is associated with increased mortality in older adults. A nationally representative sample of 4451 older adults from the English Longitudinal Study of Ageing was used. NAID was defined as serum ferritin < 30 μg/l and haemoglobin ≥ 120 g/l (women) or ≥ 130 g/l (men). Cumulative mortality was estimated by Kaplan–Meier method. Unadjusted and adjusted hazard ratios (HRs) of mortality were calculated using Cox proportional hazards regression models. Baseline NAID prevalence was 8·8% (95% confidence interval [CI] 8·0–9·7%); 10·9% (95% CI 9·7–12·3%) for women and 6·35% for men (95% CI 5·3–7·5%). The HR for mortality for individuals with NAID compared with non‐anaemic individuals without iron deficiency over the 14‐year follow‐up was 1·58 (95% CI 1·29–1·93). This association was independent of all identified demographic, health‐related and biological covariates, and robust in multiple sensitivity analyses. In older adults in England, NAID is common and associated with an increased mortality rate compared to non‐anaemic individuals with normal serum ferritin. The association is principally driven by an excess mortality in women.

Correlation between Serum Ferritin Levels and Liver Stiffness measured by Fibroscan in patients with Chronic Hepatitis C

Article

Full-text available

Feb 2020

Objective: To determine correlation between transient elastography values with serum ferritin and duration of infection in patients of hepatitis C. Methods: A cross-sectional study was conducted at medical units of Civil Hospital, Karachi. The study protocol was approved by the Research Evaluation Unit of College of Physician and Surgeon Pakistan (CPSP). Patients fulfilling inclusion criteria were included after taking informed consent. Serum ferritin levels were tested by standard laboratory procedures and transient elastography by fibroscan. Regression analysis was done to see correlation of ferritin with transient elastography and duration of HCV. Results: Over all 120 patients fulfilling the selection criteria were selected after informed consent. These included 68 (56.7%) male & 52 (43.3%) female. Significant differences in ferritin levels by Fibrosis stages were observed by ANOVA (df = 3; F =12.768; p = <0.001). Serum ferritin showed linear pattern across Fibrosis stages (F = 33.948; p = <0.001). Regression analysis of ferritin and duration of HCV showed significant impact on TE scores (r2 = 0.317). Conclusions: There is significant correlation between serum ferritin and duration of HCV with TE scores.

Lack of Correlation Between Serum Ferritin Levels and Patient Outcome in Israeli Adults with Hepatitis A Infection

Article

Full-text available

Oct 2019
ISR MED ASSOC J

Background: In developed countries, hepatitis A virus (HAV) infection occurs mainly in adults. It is usually symptomatic and may cause acute liver failure (ALF). In patients with chronic liver disease, serum ferritin levels (SFL) can predict short-term prognosis. Objectives: To determine whether admission SFL can serve as a prognostic marker in patients with HAV infection. Methods: A retrospective analysis of 33 adults with HAV infection was conducted. Because none of our patients presented with ALF, the parameter "length of hospital stay," was used as a surrogate marker of disease severity. Results: The mean (± SD) at admission SFL was 2529 ± 4336 ng/ml. SFL correlated with the levels of international normalized ratio (INR), liver enzymes, and degree of hemolysis that occurred during the disease course. SFL did not correlate with the levels of either albumin or bilirubin or with the length of the hospital stay. The mean length of hospital stay was 5.1 ± 2.0 days, which correlated with the levels of INR, albumin, and bilirubin as well as the degree of hemolysis. However, in multivariate analysis only albumin and bilirubin predicted the length of the hospital stay. Follow-up SFL, which were available only in eight patients, decreased during the hospital stay. Conclusions: In adults with acute HAV infection, SFL may be increased. SFL correlated with the degree of liver injury and hemolysis that occur during the disease. However, in our cohort of HAV patients, who had a relatively benign disease course, SFL were of no prognostic value.

Iron and liver fibrosis: Mechanistic and clinical aspects

Article

Full-text available

Feb 2019
WORLD J GASTROENTERO

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis. ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Serum levels of ferritin do not affect the prognosis of patients with hepatocellular carcinoma undergoing radiofrequency ablation

Article

Full-text available

Jul 2018
PLOS ONE

Background & aims Hepatic iron accumulation can accelerate liver injury in patients with various chronic liver diseases and lead to hepatocarcinogenesis. We elucidated the impact of serum levels of ferritin on the prognosis of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) in a large cohort. Methods We retrospectively analyzed 578 treatment-naïve HCC patients who underwent RFA. We divided our cohort into four groups by the quartile points of serum ferritin level: G1 (≤55 ng/mL, n = 148), G2 (56–130 ng/mL, n = 142), G3 (131–243 ng/mL, n = 144) and G4 (≥244 ng/mL, n = 144). We analyzed the recurrence and survival of patients using the Kaplan–Meier method. We also evaluated pathological iron deposition among patients with a solitary tumor smaller than 2 cm. Results The cumulative rates of overall recurrence and survival at 5 years were 81.6% and 66.3%, respectively. The serum levels of ferritin were correlated with pathological iron deposition. There were no significant differences in recurrence and survival rates according to serum levels of ferritin and pathological hepatic iron deposition. Conclusions Serum levels of ferritin do not affect the prognosis of HCC patients undergoing RFA.

Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis

Article

Full-text available

Oct 2016
HEPATOB PANCREAT DIS

Background: The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. Data sources: PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. Results: Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. Conclusion: Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.

Minimally invasive clinical biomarkers for use in acetaminophen hepatotoxicity

Chapter

Jan 2025

Serum Ferritin Levels and Liver‐Related Events in Individuals With Steatotic Liver Disease: A Longitudinal Cohort Study

Article

Full-text available

Nov 2024
ALIMENT PHARM THER

Background Serum ferritin has been suggested as a potential biomarker associated with disease progression in metabolic dysfunction–associated steatotic liver disease (MASLD). Aims We investigated the association between serum ferritin levels and liver‐related events (LREs) in individuals with steatotic liver disease (SLD). Methods This cohort study included 17,560 adults with SLD (MASLD [n = 15,744], MASLD with increased alcohol intake (MetALD) [n = 1103] and cryptogenic SLD [n = 713]) without LRE at baseline. A steatotic liver was diagnosed using ultrasound, and LRE was defined as the development of decompensation (ascites, variceal bleeding and hepatic encephalopathy) or hepatocellular carcinoma. Participants were categorised into high (≥ 300 μg/L for males, ≥ 200 μg/L for females) or normal to low (< 300 μg/L for males, < 200 μg/L for females) ferritin levels. Results During 211,425 person‐years of follow‐up (median: 12.3 years), 74 incident LRE cases were identified, with 63 cases in MASLD, 10 in MetALD and 1 in cryptogenic SLD. The multivariable‐adjusted hazard ratio (aHR) for LRE comparing individuals with high and normal‐to‐low ferritin level was 3.13 (95% confidence interval [CI] 1.89–5.18). Increased risk of LRE in individuals with high serum ferritin level compared to those with normal to low serum ferritin level was consistent across SLD subtypes (aHR 2.69, 95% CI 1.55–4.67 for MASLD; aHR 5.73, 95% CI 1.31–25.0 for MetALD), and SLD severity assessed by Fibrosis‐4 (FIB‐4) index (aHR 2.38, 95% CI 1.34–4.21 for FIB‐4 ≥ 1.3; aHR 3.13, 95% CI 1.18–8.29 for FIB‐4 < 1.3). Conclusions Serum ferritin levels correlated with the risk of LRE in patients with SLD.

Anti-PD-1 Autoantibody Predicts Survival of Patients With Hepatocellular Carcinoma Receiving Atezolizumab/Bevacizumab

Article

Aug 2024

Background and Aims Methods for predicting therapeutic response to immune checkpoint inhibitors in cancer therapy are in high demand. In patients with advanced hepatocellular carcinoma (HCC), atezolizumab (anti-programmed cell death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor) combination therapy (Atezo/Bev therapy) is a first-line treatment. However, no reliable biomarkers are currently available to predict its efficacy. Here, we examined serum anti-PD-1 autoantibody levels as candidate biomarkers. Methods We prospectively enrolled 63 patients with advanced HCC who received Atezo/Bev therapy. Serum anti-PD-1 autoantibody levels were measured before treatment using an indirect enzyme-linked immunosorbent assay. The correlation between the titers and response to therapy was statistically examined. Results Serum anti-PD-1 autoantibody levels were not significantly associated with the treatment response in any patient. However, when examining only patients who received the Atezo/Bev as their first-line therapy, higher anti-PD-1 autoantibody levels were significantly associated with worse overall survival rates. The titer was an independent risk factor for poor prognosis (odds ratio [OR] = 7.8, P = .013), in addition to a higher neutrophil-to-lymphocyte ratio (OR = 7.1, P = .009) and lower albumin levels (OR = 14.2, P = .003). Conclusion Serum anti-PD-1 autoantibody levels correlated with the overall survival rate in patients who received Atezo/Bev as first-line therapy. Serum anti-PD-1 autoantibody levels may serve as new biomarkers for predicting the efficacy of immune checkpoint inhibitors in patients with HCC.

Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population

Article

Feb 2024
SCAND J GASTROENTERO

Background & aims: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. Methods: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. Results: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. Conclusion: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Advances in Iron Metabolism in Echinococcosis

Article

Full-text available

Jan 2023

碧昕姚

Correlation of serum ferritin with severity of liver disease

Article

Jul 2023

Background and Aim Serum ferritin is a marker of hepatic inflammation and has been studied to predict mortality in decompensated cirrhotics. No study has been done to evaluate ferritin as an independent marker of liver disease severity. We investigated whether serum ferritin levels can be correlated with Child–Pugh and Model for End-stage Liver Disease (MELD) scores. Materials and Methods Seventy-five patients fulfilling the criteria were included and a cross-sectional observational study was done. Results Seventy-five patients (68 males and 7 females) were evaluated. Serum ferritin levels were found to be significantly elevated in patients having higher Child–Pugh and MELD scores and showed a significant correlation with Child–Pugh score (P = 0.001) and MELD score (P = 0.027). On univariate analysis, serum ferritin, bilirubin, international normalized ratio, ascites, and sodium were found to be significantly associated with severity of liver disease. On multivariate analysis, however, serum ferritin was not found to have a significant association with severity of liver disease. AUROC was also determined which showed that serum ferritin had relatively poor discriminative ability. Conclusion Elevation of serum ferritin is prevalent in chronic liver disease (CLD). In patients of CLD, severity is associated with a higher serum ferritin level. In future, a study may be designed, to obtain a prognostic model in incorporating serum ferritin into MELD similar to MELD-Na scoring system.

Effect of elevated serum ferritin on the risk of death in patients with decompensated cirrhosis: a meta-analysis

Article

May 2023

It is still debatable whether serum ferritin is a potential prognostic marker in patients with decompensated cirrhosis. In this meta-analysis, we hope to investigate the relationship between elevated serum ferritin and the risk of death in patients with decompensated cirrhosis. We systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, SinoMed, WAN FANG, and ClinicalTrials.gov without language restrictions from inception to 3 October 2022, and finally identified a total of eight eligible studies with 1829 patients. The pooled prevalence of elevated serum ferritin in decompensated cirrhosis was 40.6% [95% confidence interval (CI) 32.1-49.2%], and it was higher in males, patients with alcohol-associated liver disease, those with Child-Pugh grade C, those with hepatic encephalopathy, and nonsurvivors. Nonsurvivors had significantly higher serum ferritin levels than survivors [mean difference 247.90; 95% CI, 130.97-364.84]. With a pooled unadjusted hazard ratio of 2.38 (95% CI, 1.78-3.18), high serum ferritin was associated with an increased risk of death in patients with decompensated cirrhosis, with low heterogeneity among the included studies. In conclusion, high serum ferritin levels were associated with mortality in patients with decompensated cirrhosis. More prospective and homogeneous clinical studies are required to validate our findings.

Iron as a therapeutic target in chronic liver disease

Article

Full-text available

Jan 2023
WORLD J GASTROENTERO

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Plasma human neutrophil peptides as biomarkers of disease severity and mortality in patients with decompensated cirrhosis

Article

Jan 2023
LIVER INT

Background & aims: Human neutrophil peptides (HNP)-1, -2 and -3 are the most abundant proteins in neutrophil azurophilic granules and are rapidly released via neutrophil degranulation upon activation. The aims of our study were to assess the role of HNP1-3 as biomarkers of disease severity in patients with decompensated cirrhosis and their value in predicting short-term mortality. Methods: In this study, 451 patients with acutely decompensated cirrhosis (AD) were enrolled at the two medical centres. Overall, 281 patients were enrolled as the training cohort from October 2015 to April 2019, and 170 patients were enrolled as the validation cohort from June 2020 to February 2021. Plasma HNP1-3 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: Plasma HNP1-3 increased stepwise with disease severity (compensated cirrhosis: 0.3 (0.2-0.4); AD without acute-on-chronic liver failure (ACLF):1.9 (1.3-4.8); ACLF-1: 2.3 (1.8-6.1); ACLF-2: 5.6 (2.9-12.3); ACLF-3: 10.3 (5.7-17.2) ng/mL). From the multivariate Cox regression analysis, HNP1-3 emerged as independent predictors of mortality at 30 days and 90 days. Similar results were observed in the subgroup analysis. On ROC analysis, plasma HNP1-3 showed better predictive accuracy for 30-day and 90-day mortality (area under the receiver operating characteristic (AUROC) of 0.850 and 0.885, respectively) than the neutrophil-to-lymphocyte ratio (NLR) and similar accuracy as end-stage liver disease (MELD, 0.881 and 0.874) and chronic liver failure-sequential organ failure (CLIF-SOFA, 0.887 and 0.878). Conclusions: Plasma HNP1-3 levels were closely associated with disease severity and might be used to identify patients with AD at high risk of short-term mortality.

Serum ferritin diagnosis and prediction of hepatitis B virus‐related acute‐on‐chronic liver failure

Article

Sep 2022

Statements of the problem: Early diagnosis and prediction of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to reduce mortality. This study aimed to assess the diagnostic and predictive value of serum ferritin (SF) in HBV-ACLF patients. Method of study: Clinical data from 1905 hospitalized patients with acute deterioration of HBV-related chronic liver diseases were analysed to explore the association between SF and ACLF. A co-expression network based on transcriptomics data for 20 HBV-ACLF patients was constructed to investigate biological processes related to ferritin. Results: Of 1270 patients in the derivation group, 440 and 830 were diagnosed with and without ACLF, respectively, based on Chinese Group on the Study of Severe Hepatitis B-ACLF criteria. SF levels showed high diagnostic accuracy (area under the receiver operating characteristic (AUROC): 0.820) for ACLF at admission. In patients with ACLF, SF was associated with liver and coagulation failure. In patients without ACLF, SF predicted risk for 28-day progression to ACLF (AUROC: 0.808). A validation group of 635 patients confirmed the above results. Moreover, SF was significantly associated with the immune response based on transcriptomics analysis. Conclusion: SF is a potential diagnostic and predictive marker for HBV-ACLF and might play a crucial role in immune disorders in HBV-ACLF. This article is protected by copyright. All rights reserved.

Prognostic value of von-Willebrand factor in patients with liver cirrhosis and its relation to other prognostic indicators

Article

Full-text available

Apr 2022

Background: Von-Willebrand factor (vWF) disposes certain prognostic value in patients with liver cirrhosis, but its relation to other prognostic indicators has not been fully investigated. Aim: To analyze the relation between vWF and other prognostic indicators in cirrhotic patients and to evaluate its prognostic value for mortality. Methods: This analytic prospective study was carried out in a tertiary center and initially enrolled 71 patients with liver cirrhosis and portal hypertension. It analyzed the relation between vWF and the stage of the disease and several inflammatory and prognostic indicators. The prospective analysis, performed on a sample of 63 patients, evaluated the association between the selected variables [vWF, Model for End-stage Liver Disease (MELD) score, C-reactive protein (CRP), ferritin, vitamin D, activated partial thromboplastin time, thrombin time, D-dimer concentration] and the survival time as well as their predictive value in terms of 3-mo, 6-mo and 1-year mortality. Results: vWF was significantly higher in patients with higher Child-Turcotte-Pugh class (P = 0.0045), MELD group (P = 0.0057), ferritin group (P = 0.0278), and D-dimer concentration (P = 0.0232). vWF significantly correlated with D-dimer concentration, ferritin, CRP, International Normalized Ratio, and MELD, Child-Turcotte-Pugh, Sequential Organ Failure Assessment, and CLIF-consortium organ failure (CLIF-C OF) scores. vWF, MELD score, and CRP were significantly associated with death and were significant predictors of 3-mo, 6-mo, and 1-year mortality. Each vWF unit significantly increased the probability for 3-mo mortality by 1.005 times (P = 0.008), for 6-mo mortality by 1.006 times (P = 0.005), and for 1-year mortality by 1.007 times (P = 0.002). There was no significant difference between the diagnostic performance of vWF and MELD score and also between vWF and CRP regarding the 3-mo, 6-mo, and 1-year mortality. Conclusion: In patients with liver cirrhosis, vWF is significantly related to other prognostic indicators and is a significant predictor of 3-mo, 6-mo, and 1-year mortality similar to MELD score and CRP.

Predicting the Onset of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

Article

Mar 2022
CLIN GASTROENTEROL H

Background & Aims Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with rapid progression. This study aims to develop and validate a prognostic score to predict the onset of ACLF in HBV etiology. Methods The prospective clinical data of 1373 patients with acute deterioration of HBV-related chronic liver disease were used to identify clinical characteristics and develop a prognostic score for onset of ACLF. Results Of the patients assessed using the Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF criteria, 903 patients with non-ACLF at admission (1 received transplantation at 5 days) were stratified: 71 with progression to ACLF and 831 without progression to ACLF at 7 days. Four predictors (total bilirubin (TB), international normalized ratio (INR), alanine aminotransferase (ALT), ferritin) were significantly associated with ACLF onset at 7 days. The COSSH-onset-ACLF score was constituted (=0.101×ln(ALT)+0.819×ln(TB)+2.820×ln(INR)+0.016×ln(ferritin)). The C-indexes of the new score for 7/14/28-day onset (0.928/0.925/0.913) were significantly higher than those of five other scores (CLIF-C ACLF-Ds/MELDs/MELD-Nas/COSSH-ACLFs/CLIF-C ACLFs, all P<.001). The improvement in predictive errors, time-dependent receiver operating characteristic, probability density function evaluation and calibration curves of the new score showed the highest predictive value for ACLF onset at 7/14/28 days. Risk stratification of the new score showed two strata with high and low risk (≥6.3/<6.3) of ACLF onset. The external validation group further confirmed the above results. Conclusions A new prognostic score based on 4 predictors can accurately predict the 7/14/28-day onset of ACLF in patients with acute deterioration of HBV-related chronic liver disease and might be used to guide clinical management.

Association between Serum Ferritin, Incident Primary Liver Cancer, and Chronic Liver Disease Mortality in the Linxian Nutrition Intervention Trials: A Nested Case‐Control Study

Article

Jun 2021

Background Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD). Methods We performed a nested case-control study in the Linxian Nutrition Intervention Trials (NIT). Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1,061 age-, gender- and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios (OR) and 95% confidence interval (CI). Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+) and trial. Results Participants with serum ferritin in highest quartile, as compared to those in lowest quartile, had an increased risk of CLD mortality (OR=1.72, 95% CI=1.12, 2.64, p-trend<0.01). Moreover, the association with higher serum ferritin was stronger among alcohol drinkers and those who were HCV+ (p-interaction<0.05). For incident liver cancer, risk estimates were above one but were not statistically significant. Conclusion In this study, higher levels of serum ferritin at baseline were associated with subsequent mortality from CLD, particularly if combined with alcohol drinking or viral hepatitis. Further work is warranted to confirm our findings.

Analyzing Efficiency and Slack of Tertiary Hospitals of Punjab: A Case of Data Envelopment Analysis

Article

Full-text available

Jan 2021

Introduction: Data envelopment analysis is an operational research-based method for estimating the efficiency of the general execution of hierarchical units of hospital considering the availability of various data sources in form of inputs and outputs. Objective: This research focuses on analyzing operational efficiency and finding slack in the input of tertiary hospitals of Punjab. Demand for health services is increasing but the availability of health services are still a big issue. In the present circumstance, it has turned out to be difficult for hospitals in Punjab to guarantee increasingly productive methods for administrations. Under the current conditions, it is fundamental to discover the fitting asset blend and its use. Methods: VRS-DEA model of data envelopment analysis is applied on data collected from 1st January 2018to 31st December 2018 for hospitals inputs and outputs to analyze efficiency and find slack of 48 tertiary hospitals of Punjab of three different sizes toward to output. Results: This research indicates that smaller hospitals have an efficiency more than large size and mid-size hospitals as smaller size hospitals average efficiency is .80. The mean efficiency of medium size hospitals is .75and large hospital is .71. Only 4hospitals are working at the constant return to scale and working efficiently and 44 are inefficient as these 44 hospitals are suffering huge slack in Inputs. Mean Slack of 27.31%, 18.5%, 9.5%observed in large size, Medium size and small size hospitals in the number of patients attended. Conclusion: Hospital authorities must benchmark efficiency with the best performing hospitals in that area. Data envelopment analysis must be used to distinguish the hospitals on basis of efficiency and policymakers can use this as a tool to evaluate the performance of public hospitals and set key performance indicators for allocating fund to these hospitals. Key Words: Data envelopment analysis, Input slack, Efficiency, Return to scale, Performance indicators, Operational research

Prospective Evaluation of Factors Affecting the Outcome in Cirrhotic Patients Requiring Intensive Care

Article

Jan 2021

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

Article

Jan 2020

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.

Towards a more comprehensive evaluation of liver fibrosis in patients with chronic hepatitis C

Article

Aug 2019

Chien-Wei Su

Elevated serum ferritin level associated with hepatic steatosis and fibrosis in hepatitis C virus-infected patients

Article

Feb 2019

Background: Serum ferritin is an indicator of iron accumulation in a human body, and it is frequently elevated in patients with systemic inflammatory state in chronic hepatitis C (CHC). Iron accumulation is associated with hepatic fibrosis, steatosis, and unfavorable outcome in CHC patients. We studied the status of elevated serum ferritin level and its association with the liver fibrosis or steatosis in Taiwanese CHC patients. Methods: Seven hundred and thirty-eight Taiwanese CHC patients were consecutively included in this study. Laboratory analysis, four indexes of fibrosis (FIB4), histological assessment of fibrosis, and steatosis were assessed by appropriate elevation of serum ferritin level. Results: Three hundred and one patients (40.8%) had elevated serum ferritin level (sex-specific threshold >1.5 × upper limit of normal). Serum iron level (odds ratio [OR], 1.02; 95% CI, 1.01%-1.03%, p < 0.001), female gender (OR, 1.49; 95% CI, 1.07%-2.08%, p = 0.018), serum gamma-glutamyl transferase level (OR, 1.007; 95% CI, 1.003%-1.01%, p < 0.001), steatosis grade (OR, 1.56; 95% CI, 1.13%-2.16%, p = 0.006), and FIB4 ≥3.25 (OR, 1.63; 95% CI, 1.18%-2.27%, p = 0.003) indexes were associated with high serum ferritin level by multivariate logistic regression analysis. Patients with steatosis (>5%) were associated with older age (OR, 1.01; 95% CI, 1.00%-1.03%, p = 0.015), body mass index (OR, 1.10; 95% CI, 1.05%-1.15%, p < 0.001), and elevated serum ferritin level (OR, 1.001; 95% CI, 1.00%-1.001%, p = 0.024) by multivariate logistic regression analysis. Serum ferritin level also associated with high FIB4 (≥3.25) (OR, 1.001; 95% CI, 1.001%-1.002%, p = 0.010) when multivariate model adjusted together with advanced liver fibrosis by biopsy. Conclusion: Elevated serum ferritin level was noted in 40.8% of Taiwanese CHC patients, and the serum ferritin level was associated with liver steatosis and high FIB4.

SERUM FERRITIN AS A PREDICTOR OF EARLY MORTALITY IN CHRONIC LIVER DISEASE AND ITS RELATION TO MELD SCORE

Article

Jul 2018

The Impact of Iron Overload in Acute Leukemia: Chronic Inflammation, But Not the Presence of Nontransferrin Bound Iron is a Determinant of Oxidative Stress

Article

Jul 2017
J PEDIAT HEMATOL ONC

In the literature, studies on the oxidant effects of nontransferrin bound iron [NTBI (eLPI assay)] during chemotherapy of acute lymphoblastic leukemia and acute myeloblastic leukemia are lacking. We established NTBI and oxidative stress determinants (OSD), iron parameters, high-sensitive C-reactive protein (hs-CRP) levels, liver tests, cumulative chemotherapeutic doses, and transfused blood in 36 children with acute leukemia throughout chemotherapy. These parameters were determined at the beginning and end of chemotherapy blocks (11 time points) and in 20 healthy children using enzyme-linked immunosorbent assay, and colorimetric and fluorometric enzymatic methods. In acute lymphoblastic leukemia, NTBI, OSD, and hs-CRP were higher than controls at 4/11, 7/11, and 9/11 time points (P<0.05). At 3 time points, NTBI and OSD concurrently increased. Ferritin, soluble transferrin receptor, serum iron, and transferrin saturation were higher than in controls at 5 to 11/11 time points (P<0.05). Those with NTBI had higher iron parameters than those without NTBI (P<0.05), but showed similar OSD, hs-CRP, liver enzymes, cumulative chemotherapeutics, and transfused blood (P>0.05). OSD did not correlate with NTBI, but correlated with hs-CRP. In conclusion, NTBI is a poor predictor of OSD in acute leukemia possibly because of the heterogeneity of NTBI and chronic inflammation. Further studies are needed to delineate the pathophysiology of these diseases.

Treatment of hyperferritinemia

Article

Full-text available

May 2012
ANN HEPATOL

Elevated serum ferritin, or hyperferritinemia, is a common finding on routine bloodwork and often prompts referral for further evaluation. In the following review, we outline the various causes of hyperferritinemia and point out that, in the majority of cases, this does not represent true iron overload. Despite much research interest in this area, the precise mechanism of hyperferritinemia and its impact on disease severity in various clinical conditions continues to be debated. While some research suggests that iron reduction in cases of hyperferritinemia is of benefit, the decision to treat such patients should be individualized, and may be influenced by the presence of other features of iron overload.

Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target

Article

Full-text available

Jun 2011

The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage. Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS.

Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL)

Article

Full-text available

Apr 2009

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia-Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22-23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

Child-Pugh-Turcott versus Meld score for predicting survival in a retrospective cohort of black African cirrhotic patients

Article

Full-text available

Jan 2008
WORLD J GASTROENTERO

To compare the performance of the Child-Pugh-Turcott (CPT) score to that of the model for end-stage liver disease (MELD) score in predicting survival of a retrospective cohort of 172 Black African patients with cirrhosis on a short and mid-term basis. Univariate and multivariate (Cox model) analyses were used to identify factors related to mortality. Relationship between the two scores was appreciated by calculating the correlation coefficient. The Kaplan Meier method and the log rank test were used to elaborate and compare survival respectively. The Areas Under the Curves were used to compare the performance between scores at 3, 6 and 12 mo. The study population comprised 172 patients, of which 68.9% were male. The mean age of the patient was 47.5 +/- 13 years. Hepatitis B virus infection was the cause of cirrhosis in 70% of the cases. The overall mortality was 31.4% over 11 years of follow up. Independent factors significantly associated with mortality were: CPT score (HR = 3.3, 95% CI [1.7-6.2]) (P < 0.001) (stage C vs stage A-B); Serum creatine (HR = 2.5, 95% CI [1.4-4.3]) (P = 0.001) (Serum creatine > 1.5 mg/dL versus serum creatine < 1.5 mg/dL); MELD score (HR = 2.9, 95% CI [1.63-5.21]) (P < 0.001) (MELD > 21 vs MELD < 21). The area under the curves (AUC) that predict survival was 0.72 and 0.75 at 3 mo (P = 0.68), 0.64 and 0.62 at 6 mo (P = 0.67), 0.69 and 0.64 at 12 mo (P = 0.38) respectively for the CPT score and the MELD score. The CPT score displays the same prognostic significance as does the MELD score in black African patients with cirrhosis. Moreover, its handling appears less cumbersome in clinical practice as compared to the latter.

Practice Guidelines Committee, American Association for the Study of Liver Diseases

Article

Jan 2011

A model to predict survival in patients with end-stage liver disease

Article

Apr 2001
GASTROENTEROLOGY

A recent mandate emphasizes severity of liver disease to determine priorities in allocating organs for liver transplantation and necessitates a disease severity index based on generalizable, verifiable, and easily obtained variables. The aim of the study was to examine the generalizability of a model previously created to estimate survival of patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure in patient groups with a broader range of disease severity and etiology. The Model for End-Stage Liver Disease (MELD) consists of serum bilirubin and creatinine levels, International Normalized Ratio (INR) for prothrombin time, and etiology of liver disease. The model's validity was tested in 4 independent data sets, including (1) patients hospitalized for hepatic decompensation (referred to as "hospitalized" patients), (2) ambulatory patients with noncholestatic cirrhosis, (3) patients with primary biliary cirrhosis (PBC), and (4) unselected patients from the 1980s with cirrhosis (referred to as "historical" patients). In these patients, the model's ability to classify patients according to their risk of death was examined using the concordance (c)-statistic. The MELD scale performed well in predicting death within 3 months with a c-statistic of (1) 0.87 for hospitalized patients, (2) 0.80 for noncholestatic ambulatory patients, (3) 0.87 for PBC patients, and (4) 0.78 for historical cirrhotic patients. Individual complications of portal hypertension had minimal impact on the model's prediction (range of improvement in c-statistic: <.01 for spontaneous bacterial peritonitis and variceal hemorrhage to ascites: 0.01-0.03). The MELD scale is a reliable measure of mortality risk in patients with end-stage liver disease and suitable for use as a disease severity index to determine organ allocation priorities.

Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis

Article

Jan 1996

V Arroyo

Challenges and Advances in the Treatment of AKI

Article

Jan 2014
J AM SOC NEPHROL

Treating or preventing AKI requires treating or preventing a rise in serum creatinine as well as the immediate and remote clinical consequences associated with AKI. Because a substantial number of patients with AKI progress to ESRD, identifying patients likely to progress and halting progression are important goals for treating AKI. Many therapies for AKI are being developed, including RenalGuard Therapy, which aims to maintain high urine output; α-melanocyte-stimulating hormone, with anti-inflammatory and antiapoptotic activities; alkaline phosphatase, which detoxifies proinflammatory substances; novel, small interfering RNA, directed at p53 activation; THR-184, a peptide agonist of bone morphogenetic proteins; removal of catalytic iron, important in free-radical formation; and cell-based therapies, including mesenchymal stem cells in vivo and renal cell therapy in situ. In this review, we explore what treatment of AKI really means, discuss the emerging therapies, and examine the windows of opportunity for treating AKI. Finally, we provide suggestions for accelerating the pathways toward preventing and treating AKI, such as establishing an AKI network, implementing models of catalytic philanthropy, and directing a small percentage of the Medicare ESRD budget for developing therapies to prevent and treat AKI and halt progression of CKD.

Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

Article

Mar 2013

Background & aims: Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. Methods: We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). Results: Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. Conclusions: We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.

Serum Ferritin Concentration and Transferrin Saturation Before Liver Transplantation Predict Decreased Long-Term Recipient Survival

Article

Dec 2011
HEPATOLOGY

Unlabelled: Serum ferritin (SF) concentration is a widely available parameter used to assess iron homeostasis. It has been described as a marker to identify high-risk patients awaiting liver transplantation (LT) but is also elevated in systemic immune-mediated diseases, metabolic syndrome, and in hemodialysis where it is associated with an inferior prognosis. This study analyzed whether SF is not only a predictor of liver-related mortality prior to LT but also an independent marker of survival following LT. In a dual-center, retrospective study, a cohort of 328 consecutive first-LT patients from Hannover Medical School, Germany (2003-2008, follow-up 1260 days), and 82 consecutive LT patients from Regensburg University Hospital, Germany (2003-2007, follow-up 1355 days) as validation cohort were analyzed. In patients exhibiting SF ≥365 μg/L versus <365 μg/L prior to LT, 1-, 3-, and 5-year post-LT survival was 73.3% versus 81.1%, 64.4% versus 77.3%, and 61.1% versus 74.4%, respectively (overall survival P = 0.0097), which was confirmed in the validation cohort (overall survival of 55% versus 83.3%, P = 0.005). Multivariate analyses identified SF ≥365 μg/L combined with transferrin saturation (TFS) <55%, hepatocellular carcinoma, and the survival after LT (SALT) score as independent risk factors for death. In patients with SF concentrations ≥365 μg/L and TFS <55%, overall survival was 54% versus 74.8% in the remaining group (P = 0.003). In the validation cohort, it was 28.6% versus 72% (P = 0.017), respectively. Conclusion: SF concentration ≥365 μg/L in combination with TFS <55% before LT is an independent risk factor for mortality following LT. Lower TFS combined with elevated SF concentrations indicate that acute phase mechanisms beyond iron overload may play a prognostic role. SF concentration therefore not only predicts pre-LT mortality but also death following LT.

A Model to Predict Survival in Patients With End–Stage Liver Disease

Article

Feb 2001
HEPATOLOGY

A recent mandate emphasizes severity of liver disease to determine priorities in allocating organs for liver transplantation and necessitates a disease severity index based on generalizable, verifiable, and easily obtained variables. The aim of the study was to examine the generalizability of a model previously created to estimate survival of patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure in patient groups with a broader range of disease severity and etiology. The Model for End-Stage Liver Disease (MELD) consists of serum bilirubin and creatinine levels, International Normalized Ratio (INR) for prothrombin time, and etiology of liver disease. The model's validity was tested in 4 independent data sets, including (1) patients hospitalized for hepatic decompensation (referred to as “hospitalized” patients), (2) ambulatory patients with noncholestatic cirrhosis, (3) patients with primary biliary cirrhosis (PBC), and (4) unselected patients from the 1980s with cirrhosis (referred to as “historical” patients). In these patients, the model's ability to classify patients according to their risk of death was examined using the concordance (c)-statistic. The MELD scale performed well in predicting death within 3 months with a c-statistic of (1) 0.87 for hospitalized patients, (2) 0.80 for noncholestatic ambulatory patients, (3) 0.87 for PBC patients, and (4) 0.78 for historical cirrhotic patients. Individual complications of portal hypertension had minimal impact on the model's prediction (range of improvement in c-statistic: <.01 for spontaneous bacterial peritonitis and variceal hemorrhage to ascites: 0.01-0.03). The MELD scale is a reliable measure of mortality risk in patients with end-stage liver disease and suitable for use as a disease severity index to determine organ allocation priorities.

Serum Ferritin Concentration Predicts Mortality in Patients Awaiting Liver Transplantation

Article

May 2010
HEPATOLOGY

Unlabelled: Additional markers are required to identify patients on the orthotopic liver transplant (OLT) waiting list at increased risk of death and adverse clinical events. Serum ferritin concentration is a marker of varied pathophysiological events and is elevated with increased liver iron concentration, hepatic necroinflammation, and systemic illness, all of which may cause a deterioration in liver function and clinical status. The aim of this study was to determine whether serum ferritin concentration is an independent prognostic factor in subjects awaiting OLT. This is a dual-center retrospective study. The study cohort consisted of 191 consecutive adults with cirrhosis accepted by the Queensland (Australia) Liver Transplant Service between January 2000 and June 2006 and a validation cohort of 131 patients from University of California Los Angeles (UCLA) Transplant Center. In the study cohort, baseline serum ferritin greater than 200 microg/L was an independent factor predicting increased 180-day and 1-year waiting list mortality. This effect was independent of model for end-stage liver disease (MELD), hepatocellular carcinoma, age, and sex. Subjects with higher serum ferritin had increased frequency of liver-related clinical events. The relationship between serum ferritin and waiting list mortality was confirmed in the UCLA cohort; all deceased patients had serum ferritin greater than 400 microg/L. Serum ferritin greater than 500 microg/L and MELD were independent risk factors for death. Conclusion: Serum ferritin concentration is an independent predictor of mortality-related and liver-related clinical events. Baseline serum ferritin identifies a group of "higher-risk" patients awaiting OLT and should be investigated as an adjunct to MELD in organ allocation.

Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club

Article

Feb 1996

During the last decade great advances have been made concerning the pathogenesis and treatment of ascites, A new hypothesis on the mechanism of renal dysfunction and ascites formation in cirrhosis has been proposed and this has greatly stimulated research in this area, The discovery of the important role played by the vascular endothelium in the homeostasis of systemic hemodynamics and renal function has also opened an important field of research into pathophysiology, and evidence has been presented implicating endothelial factors in the pathogenesis of systemic circulatory dysfunction in cirrhosis and hepatorenal syndrome (HRS). The reintroduction of therapeutic paracentesis has greatly modified the treatment of cirrhotic patients with tense or refractory ascites. The transjugular intrahepatic portosystemic shunt is another therapeutic tool of potential interest in the management of refractory ascites. The synthesis of orally-active specific antagonists of the tubular effect of antidiuretic hormone and inhibitors of antidiuretic hormone release will probably add new drugs to the pharmacological armamentarium for patients with cirrhosis and ascites, These ''aquaretic drugs,'' which normalize renal water metabolism in experimental cirrhosis and ascites, are of potential interest for the treatment of water retention and dilutional hyponatremia in human cirrhosis. Finally, the field of spontaneous infection of ascitic fluid (spontaneous bacterial peritonitis) is also experiencing major changes. The demonstration of intestinal bacterial translocation in experimental models of cirrhosis, the potential role of cytokines in some complications associated with this infection, the identification of subgroups of cirrhotic patients predisposed to develop spontaneous bacterial peritonitis, and the effectiveness of selective intestinal decontamination in the primary and secondary prophylaxis of spontaneous bacterial peritonitis are the most relevant developments. In clear contrast to these advances, little attention has been paid to the standardization of the nomenclature and diagnostic criteria of different syndromes associated with ascites in cirrhosis, The existence of a uniform language, however, is essential in modern medicine, It facilitates communication among clinicians and researchers and ensures unambiguous diagnoses and more confident prognoses, Moreover, it improves pathophysiological and therapeutic investigations, simplifies the analysis of therapeutic trials, and stimulates multicenter studies.

Plasma Ferritin in Acute Hepatocellular Damage

Article

Jul 2000

The new liver allocation system: Moving toward evidence-based transplantation policy

Article

Oct 2002

In 1999, the Institute of Medicine suggested that instituting a continuous disease severity score that de-emphasizes waiting time could improve the allocation of cadaveric livers for transplantation. This report describes the development and initial implementation of this new plan. The goal was to develop a continuous disease severity scale that uses objective, readily available variables to predict mortality risk in patients with end-stage liver disease and reduce the emphasis on waiting time. Mechanisms were also developed for inclusion of good transplant candidates who do not have high risk of death but for whom transplantation may be urgent. The Model for End-Stage Liver Disease (MELD) and Pediatric End-Stage Liver Disease (PELD) scores were selected as the basis for the new allocation policy because of their high degree of accuracy for predicting death in patients having a variety of liver disease etiologies and across a broad spectrum of liver disease severity. Except for the most urgent patients, all patients will be ranked continuously under the new policy by their MELD/PELD score. Waiting time is used only to prioritize patients with identical MELD/PELD scores. Patients who are not well served by the MELD/PELD scores can be prioritized through a regionalized peer review system. This new liver allocation plan is based on more objective, verifiable measures of disease severity with minimal emphasis on waiting time. Application of such risk models provides an evidenced-based approach on which to base further refinements and improve the model.

Relative Contribution of Iron Burden, HFE Mutations, and Insulin Resistance to Fibrosis in Nonalcoholic Fatty Liver

Article

Jan 2004

The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] = 1.77; 95% CI = 1.21- 2.58; P =.0032) and the oral glucose insulin sensitivity (OR = 0.53; CI = 0.33-0.87; P =.0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD.

CD163: A regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response

Article

Feb 2004

CD163 is a hemoglobin scavenger receptor exclusively expressed in the monocyte-macrophage system. A particularly high expression is seen in macrophages of the 'alternative activation' phenotype playing a major role in dampening the inflammatory response and in scavenging components of damaged cells. CD163-mediated endocytosis of haptoglobin-hemoglobin complexes formed upon red blood cell hemolysis leads to lysosomal degradation of the ligand protein and metabolism of heme by cytosolic heme oxygenase. In accordance with a stimulated expression of haptoglobin, CD163 and heme oxygenase-1 during the acute phase response, there is evidence that this metabolic pathway regulates inflammation by at least two ways. First, CD163 is reported to directly induce intracellular signaling leading to secretion of anti-inflammatory cytokines. Second and perhaps even more important, the CD163-mediated delivery of hemoglobin to the macrophage may fuel an anti-inflammatory response because heme metabolites have potent anti-inflammatory effects. In addition to being present on the macrophage surface, continuous shedding of the extracellular domain of CD163 leads to substantial amounts of soluble receptor in plasma. An increased shedding is due to inflammatory stimuli, and a role for soluble CD163 in immune suppression has been proposed. Furthermore, recent data indicate that soluble CD163 may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions.

Soluble CD163 in patients with liver diseases: Very high levels of soluble CD163 in patients with fulminant hepatic failure

Article

Jan 2005

The levels of several cytokines and chemokines are elevated in various liver diseases, especially in fulminant hepatic failure (FHF). Activated macrophages may have a role in the production of these immune modulators. CD163 is a member of a scavenger receptor family and is expressed mainly on activated macrophages, and a soluble form of CD163 (sCD163) is released from activated macrophages. The aim of this study was to assess sCD163 levels in patients with FHF and to evaluate their clinical significance. The levels of sCD163 in the sera were measured in 21 patients with FHF, 17 patients with acute hepatitis (AH), 22 patients with chronic hepatitis (CH), and 14 normal healthy controls (NC), by an enzyme-linked immunosorbent assay. The levels of sCD163 were observed serially in patients with FHF and AH. The levels of sCD163 in the sera from patients with FHF were significantly higher than those in patients with AH and CH and the NC group (P < 0.0001). There was a good correlation between serum levels of sCD163 and prothrombin time (r = -0.677; P < 0.0001). A kinetic study revealed that the levels of sCD163 decreased in patients with AH and in survivors of FHF, whereas the levels of sCD163 progressively increased in nonsurvivors of FHF. This study shows that the products of activated macrophages may be involved in the pathogenesis of FHF. This study also inspires optimism that sCD163 may possess prognostic importance in FHF.

Management of Hepatocellular Carcinoma

Article

Nov 2005

NAFLD and hyperinsulinemia are major determinants of serum ferritin levels

Article

Apr 2007
J HEPATOL

There is an increasing body of evidence that serum ferritin is associated with the metabolic syndrome. However, no study has tested for NAFLD. The aim was to test the assumption that the association between serum ferritin and the metabolic syndrome is mediated by NAFLD. A cross-sectional study of a sub-sample of the first Israeli national health survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound (US), biochemical tests, and dietary and anthropometric evaluations. Three hundred and forty-nine subjects were included in the analysis. Serum ferritin was higher in the NAFLD group (92.4+/-63.1 vs. 65.1+/-58.0, P<0.001). After adjusting for age and gender, the following variables were significantly associated with increased ferritin levels: abdominal obesity, hyperglycemia, hyperinsulinemia, HOMA, hypertriglyceridemia and the metabolic syndrome itself. After further adjusting for NAFLD, only abdominal obesity [2.1 (1.1-3.9)] and hyperinsulinemia [2.3 (1.3-4.2)] were still significantly associated with ferritin. In a multivariate analysis the interaction between NAFLD and hyperinsulinemia was the second strongest predictor of serum ferritin (P=0.005). The association between serum ferritin and the metabolic syndrome is mediated by undiagnosed NAFLD. The interaction between NAFLD and hyperinsulinemia is a major determinant of serum ferritin levels at the population level.

Soluble CD163 from activated macrophages predicts mortality in acute liver failure

Article

Dec 2007
J HEPATOL

Soluble CD163 (sCD163) is a scavenger receptor shed in serum during inflammatory activation of macrophages. We investigated if sCD163 was increased and predicted outcome in acute liver failure (ALF). Samples from 100 consecutive patients enrolled in the U.S. ALF Study Group for whom sera were available were collected on days 1 and 3, and clinical data were obtained prospectively. sCD163 levels were determined by ELISA. The median level of sCD163 was significantly increased in ALF (21.1mg/l (range 3.6-74.9)) as compared to healthy controls (2.3mg/l (0.65-5.6), p<0.0001) and patients with stable liver cirrhosis (9.8mg/l (3.6-16.9), p=0.0002). sCD163 on day 1 correlated significantly with ALT, AST, bilirubin, and creatinine. sCD163 concentrations on day 3 were elevated in patients with fatal outcome of disease compared to spontaneous survivors, 29.0mg/l (7.2-54.0) vs. 14.6mg/l (3.5-67.2), respectively (p=0.0025). Patients that were transplanted had intermediate levels. Sensitivity and specificity at a cut-off level of 26mg/l was 62% and 81%, respectively. Activated macrophages are involved in ALF resulting in a 10-fold increase in sCD163. A high level (>26mg/l) of sCD163 was significantly correlated with fatal outcome and might be used with other parameters to determine prognosis.

Management of Adult Patients with Ascites due to Cirrhosis

Article

Mar 2004

Bruce A. Runyon

TIPS is a side-to-side portacaval shunt that is placed by an interventional radiologist usually under local anesthesia52, 53, 64–66; in some European centers, TIPS is placed by hepatologists. General anesthesia is used in some centers. One randomized trial demonstrated higher mortality in the TIPS group compared to the medically treated group, but this study was very small and took place very early in our experience with this relatively new technique.64 Four large-scale, multicenter randomized controlled trials comparing TIPS to sequential large-volume paracentesis have been undertaken52, 53, 65, 66 (Table 3). Three of these are completed and published.52, 53, 65 The remaining study is ongoing and has been published only in abstract form.66 All of these report better control of ascites in the TIPS group. One reports no survival advantage by univariate analysis but a statistically significant survival advantage for the TIPS group by multivariate analysis.52 Another reports prevention of hepatorenal syndrome but with higher costs in the TIPS group: there were similar rates of encephalopathy overall but more severe hepatic encephalopathy in the TIPS group.53 Another shows no survival advantage, with a trend (P = .58) toward more moderate or severe encephalopathy in the TIPS group and no effect on quality of life.65 This study is the first to provide a specific cutoff of cardiac ejection fraction (>50%) for eligibility for enrollment.65 The ejection fraction of the patient with cirrhosis is usually greater than 60%.67 An ejection fraction of greater than 60% may be more appropriate as an inclusion criterion for entry into a TIPS study, since patients with an ejection fraction between 50% and 60% may have a higher risk of post-TIPS heart failure.68 The abstract of the ongoing study reports a survival advantage in the TIPS group with similar hospitalization and encephalopathy rates.66 Meanwhile, a polytetrafluoroethylene-covered stent has been developed that has more than twice the patency of the uncoated stent at 1 year in a randomized trial.69 Also, there is a new scoring system, Model for End-Stage Liver Disease, to predict 3-month mortality after TIPS.70 All of these trials were initiated before this scoring system was popularized. Furthermore, some investigators and some trials have withheld diuretics after TIPS. This further limits its efficacy. TIPS usually converts diuretic-resistant patients into diuretic-sensitive patients. Giving diuretics after TIPS and titrating the doses to achieve natriuresis is appropriate.

Iron storage disease

Jan 1994
219-241

Searle
Sj
Kerr Kjr
Halliday
Powell Jw
Lw

Searle SJ, Kerr KJR, Halliday JW and Powell LW, et al. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portman BC, eds. Pathology of the liver. Edinburgh: Churchill Livingstone; 1994;219-241

Laboratory determination of iron status. Iron metabolism in health and disease. London: WB Saunders

Jan 1994
449-476

M Worwood

Worwood M. Laboratory determination of iron status. Iron metabolism in health and disease. London: WB Saunders; 1994, p. 449-476.

Cellular iron processing and storage: the role of ferritin in Iron metabolism in health and disease

Halliday Jw
Ga
Powell
Lw
Brock
Mj

Halliday JW, Ramm GA, Powell LW, Brock JH and Pippard MJ, et al. Cellular iron processing and storage: the role of ferritin in Iron metabolism in health and disease.

Cellular iron processing and storage: the role of ferritin. Iron metabolism in health and disease

Jan 1994
97-121

J W Halliday
G A Ramm
L W Powell
J H Brock
M J Pippard

Halliday JW, Ramm GA, Powell LW, Brock JH, Pippard MJ, et al. Cellular iron processing and storage: the role of ferritin. Iron metabolism in health and disease. London: WB Saunders; 1994, p. 97-121.

Iron storage disease

Jan 1994
219-241

S J Searle
Kjr Kerr
J W Halliday
L W Powell

Searle SJ, Kerr KJR, Halliday JW, Powell LW, et al. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portman BC, editors. Pathology of the liver. Edinburgh: Churchill Livingstone; 1994. p. 219-241.

Serum Ferritin Predicts Early Mortality In Patients With Decompensated Cirrhosis.

Abstract

No full-text available

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