Bone Marrow Iron Predicts Mortality in Cirrhosis with Normal Liver Iron

Vertebral R2 relaxometry identifies a high-risk subgroup of patients with cirrhosis facing a fourfold increase in five-year mortality.*

Systemic Iron Dysregulation in Chronic Liver Disease

In patients with cirrhosis, the liver serves as the primary reservoir for pathological iron accumulation, a process closely linked to the progression of fibrosis and increased risks of malignancy [1, 2, 3]. While magnetic resonance imaging has become the standard for non-invasive quantification of liver iron concentration, systemic iron distribution in chronic liver disease remains incompletely understood [2, 3]. Beyond the hepatic parenchyma, iatrogenic and metabolic iron overload can affect the myocardium and bone marrow, potentially contributing to cardiovascular complications and impaired hematopoiesis [4, 5, 6]. Current clinical guidelines primarily rely on serum biomarkers like ferritin and transferrin saturation, yet these metrics often fail to reflect true tissue iron stores due to the confounding effects of chronic inflammation [7, 4]. A retrospective study of 190 patients now investigates whether quantifying iron deposition in the vertebral bone marrow using R2 relaxometry (a magnetic resonance technique that measures the rate of signal decay to quantify tissue iron concentration) can refine risk stratification for patients with cirrhosis, particularly those who appear to have stable hepatic iron levels [8]. Among patients without liver iron overload, moderate vertebral bone marrow iron deposition was associated with a nearly fourfold increase in 5-year overall mortality (hazard ratio, 3.981; p = 0.014)* [8].

Quantifying Extrahepatic Iron via R2* Relaxometry

To assess systemic iron distribution beyond the liver, researchers analyzed a cohort of 190 patients with cirrhosis who underwent liver magnetic resonance elastography between January 2018 and October 2024. The investigators utilized R2 relaxometry, a specialized magnetic resonance imaging sequence that measures how quickly a magnetic signal decays, allowing clinicians to accurately quantify iron concentration within specific tissues. This method provided a non-invasive window into extrahepatic iron deposition by precisely evaluating vertebral bone marrow iron content. Alongside these vertebral measurements, the researchers estimated liver iron concentration and recorded liver R2 values to establish a comprehensive profile of iron storage across different physiological compartments.

To facilitate clinical comparison, patients were categorized into normal, mild, or moderate groups for both liver and vertebral bone marrow iron overload. The researchers employed a rigorous statistical framework to evaluate these classifications, using Spearman's rank correlation coefficient to assess the relationships between tissue iron levels and hematologic indices. Furthermore, binary logistic regression was used to identify independent predictors of iron overload, while Cox proportional hazards regression was applied to analyze the impact of these findings on patient survival. By stratifying the 190 patients into these specific iron overload categories, the study aimed to determine if vertebral bone marrow R2* values could serve as a distinct prognostic marker, particularly in cases where hepatic iron levels remain within a normal range.

Prevalence and Predictors of Bone Marrow Deposition

Extrahepatic iron deposition proved highly prevalent across all stages of hepatic iron accumulation, including in patients with clinically normal liver iron levels. Among the 190 patients analyzed, vertebral bone marrow iron overload occurred in 28.7% of patients with normal liver iron, 51.5% of patients with mild liver iron overload, and 85.6% of patients with moderate liver iron overload. These findings suggest that the bone marrow serves as a significant site of iron storage even when the liver, the primary storage organ, does not yet show signs of pathological accumulation. The severity of deposition in the marrow generally mirrored the severity in the liver. However, the presence of marrow iron in nearly 29% of the normal liver iron group highlights a subset of patients with systemic dysregulation that might otherwise go undetected in routine clinical practice.

When examining more advanced stages of deposition, the researchers found that moderate vertebral bone marrow iron overload was present in 23.3% of the normal liver iron group, 35.2% of the mild liver iron overload group, and 50.0% of the moderate liver iron overload group. To identify which clinical factors might signal this advanced marrow deposition, the authors utilized binary logistic regression. The analysis identified two independent predictors of moderate vertebral bone marrow iron overload: liver R2* (odds ratio, 1.010; p = 0.002) and total iron-binding capacity (odds ratio, 0.990; p = 0.035). These metrics, which reflect both direct hepatic iron concentration and the capacity of the blood to transport iron, provide clinicians with specific physiological markers that correlate with the risk of significant iron sequestration within the vertebral column.

Clinical Correlations and Survival Implications

Vertebral bone marrow R2 relaxometry serves as a reliable indicator of systemic iron status in patients with cirrhosis, correlating closely with established hepatic and hematologic metrics. Statistical analysis demonstrated that vertebral bone marrow R2 values significantly correlated with liver R2 and liver iron concentration (r = 0.347; p < 0.001). Furthermore, these marrow measurements showed significant associations with traditional hematologic markers, including a positive correlation with serum ferritin (r = 0.210; p = 0.004) and a negative correlation with total iron-binding capacity (r = -0.186; p = 0.019)*. These findings suggest that iron deposition in the axial skeleton mirrors the broader iron dysregulation often seen in chronic liver disease, providing a secondary site for assessing total body iron burden.

Despite its relationship with systemic iron markers, vertebral bone marrow iron deposition appears to be independent of the severity of hepatic synthetic dysfunction. The study found that vertebral bone marrow R2* showed no correlation with liver function markers or the Child-Pugh score, a standard clinical tool used to categorize the prognosis of cirrhosis based on bilirubin, albumin, prothrombin time, and the presence of ascites or encephalopathy. This independence suggests that marrow iron accumulation is not merely a byproduct of end-stage liver failure but rather a distinct physiological process. Clinically, this distinction is vital because it identifies a risk factor that traditional staging systems may overlook.

The most significant clinical implication of the study emerged from the survival analysis. Among the subgroup of patients who presented with normal liver iron levels, the presence of extrahepatic iron was a potent predictor of poor outcomes. Specifically, moderate vertebral bone marrow iron overload was associated with a nearly fourfold increase in 5-year overall mortality (hazard ratio, 3.981; p = 0.014). This finding indicates that even when the liver is not yet sequestering pathological levels of iron, significant accumulation within the bone marrow serves as a marker for high-risk patients. For the practicing physician, these data suggest that quantifying vertebral iron may provide essential prognostic information, allowing for earlier targeted interventions in patients with cirrhosis who otherwise appear to have a normal hepatic iron profile.

References

1. Feng Q, Yi J, Li T, Liang B, Xu F, Peng P. Narrative review of magnetic resonance imaging in quantifying liver iron load. Frontiers in Medicine. 2024. doi:10.3389/fmed.2024.1321513

2. Alibiev DE, Zavadovskaya V, Saprina T, et al. Iron overload syndrome. Ethiopatogenesis. magnetic resonance imaging techniques for quantitative assessment of iron overload status: a review. Diagnostic radiology and radiotherapy. 2024. doi:10.22328/2079-5343-2024-15-1-7-14

3. Luo J, Liu Z, Wang Q, Tan S. Liver iron overload and fat content analyzed by magnetic resonance contribute to evaluating the progression of chronic hepatitis B. Biomedical Reports. 2023. doi:10.3892/br.2023.1711

4. Nunes LLA, Reis LMD, Osorio RC, et al. High ferritin is associated with liver and bone marrow iron accumulation: Effects of 1-year deferoxamine treatment in hemodialysis-associated iron overload. PLoS ONE. 2024. doi:10.1371/journal.pone.0306255

5. Dorniak K, Daniłowicz‐Szymanowicz L, Sikorska K, et al. Left Ventricular Function and Iron Loading Status in a Tertiary Center Hemochromatosis Cohort—A Cardiac Magnetic Resonance Study. Diagnostics. 2022. doi:10.3390/diagnostics12112620

6. Rostoker G, Vaziri ND, Fishbane S. Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century. Drugs. 2016. doi:10.1007/s40265-016-0569-0

7. Majoni SW, Nelson J, Germaine D, et al. INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis—a protocol for a prospective open-label blinded endpoint randomised controlled trial. Trials. 2021. doi:10.1186/s13063-021-05854-w

8. Cho SW, Kim Y, Park J, Park JH. Bone marrow R2* correlates with liver iron load and is associated with decreased survival in patients with cirrhosis without liver iron overload.. European radiology. 2026. doi:10.1007/s00330-026-12614-4