ORIGINAL ARTICLE
Serum Ferritin in Patients With Cirrhosis is Associated With Markers of Liver Insufficiency and Circulatory Dysfunction, but Not of Portal Hypertension Cristina Ripoll, MD, Felix Keitel, MD, Marcus Hollenbach, MD, Robin Greinert, MD, and Alexander Zipprich, MD
Background/Aims: Iron overload is an increasingly recognized phenomenon in nonhemochromatosis cirrhosis. To evaluate the relationship between iron overload and liver insufficiency and portal hypertension. Patients and Methods: Cirrhotics with hepatic hemodynamic and ferritin measurement (within 30 d) were included. Exclusion criteria were malignancy (except hepatocellular carcinoma Milan-in), severe chronic obstructive pulmonary disease, acute events in the previous 2 weeks, immunosuppression, transjugular intrahepatic portosystemic shunt or portal vein thrombosis, and end-stage renal disease. Patients were followed-up until death or liver transplant. Univariate and multivariate analysis were used. Results: Fifty-one patients were included (male 61%; median age 57 y; interquartile range, 47 to 66 y); Child-Pugh A 11/B 25/C 15). A positive correlation was observed between ferritin and markers of inflammation (C-reactive protein: r = 0.273, P = 0.06 and aspartate aminotransferase: r = 0.302, P = 0.035). No correlation between ferritin and hepatic venous pressure gradient was seen. Negative correlations were observed between ferritin and circulatory dysfunction (mean arterial pressure: r = 0.360, P = 0.014 and serum sodium: r = 0.419, P = 0.002). In contrast, associations to markers of liver failure such as international normalized ratio (r = 0.333, P = 0.005), bilirubin (r = 0.378, P = 0.007), albumin (r = 0.265, P = 0.082), model for end-stage liver disease (r = 0.293, P = 0.041), and Child-Pugh score (r = 0.392, P = 0.009) were observed. No differences in survival according to ferritin was detected. Conclusions: In patients with cirrhosis, serum ferritin levels are associated with markers of liver insufficiency, inflammation, and circulatory dysfunction but not portal hypertension. Key Words: ferritin, cirrhosis, iron overload, portal hypertension, liver insufficiency
(J Clin Gastroenterol 2015;49:784–789)
I
ncreased serum ferritin has been frequently described in nonhemochromatosis cirrhosis,1–4 nevertheless its interpretation is somewhat ambivalent as it is both a marker of iron overload and an acute phase reactant. Iron overload has been reported in patients with end-stage liver disease not associated with hereditary hemochromatosis including alcoholic liver disease and viral hepatitis.1–7 The clinical
Received for publication July 16, 2014; accepted November 29, 2014. From the First Department of Internal Medicine, Martin-LutherUniversity Halle-Wittenberg, Halle (Saale), Germany. The authors declare that they have nothing to disclose. Reprints: Cristina Ripoll, MD, First Department of Internal Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, Halle (Saale) 06120, Germany (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
relevance of this iron overload is largely unknown. Several studies suggest that in patients with cirrhosis, an increase in liver iron content leads to increased fibrosis and oxidative stress.8–10 Indeed, increased ferritin evaluated as a categorical variable, has been associated with model for end-stage liver disease (MELD) score and pretransplant and postransplant mortality.1,11 The discovery of hepcidin, a key player in iron homeostasis, has shed new light on iron overload in cirrhosis.12,13 Hepcidin is constitutively produced by the liver and released into the blood in response to excessive iron stores by inhibiting the main iron transporter in the enterocytes (ferroportin) and; therefore, avoiding dietary iron absorption.14 Hepcidin has also been involved in the innate immunity and its production is also regulated by inflammatory state.14 Little is known regarding the hepatic production of hepcidin in patients with liver cirrhosis without hereditary hemochromatosis or other genetic disorders associated with iron overload. Taking into account that hepcidin is produced in the liver, hypothetically with increasing liver failure there could be a reduced hepcidin production despite adequate or excessive deposits of iron, which would in turn lead to a greater absorption of iron from the intestine and hence iron overload. In contrast, patients with advanced liver disease and ascites have bacterial translocation15 and; therefore, could have greater inflammation, which may affect the production of hepcidin or lead to an increase of ferritin as an acute phase protein. Reciprocally, iron overload could lead to an increase in hepatic inflammation by means of oxidative stress and fibrosis and could, therefore, have an effect on portal pressure. Therefore, the aim of this study was to evaluate the relationship between ferritin, liver insufficiency, and portal hypertension in patients with cirrhosis and secondly to evaluate the impact of serum ferritin on survival in patients with cirrhosis.
PATIENTS AND METHODS This study is a retrospective, single-center, cross-sectional study including all patients who had a hemodynamic study between January 2008 and May 2012. These measurements are routinely performed in the evaluation of patients with cirrhosis in our center. All consecutive patients who fulfilled the following criteria were considered for inclusion: (a) patients between 18 and 79 years of age, (b) diagnosis of liver cirrhosis (according to clinical, analytical, imaging tests, hemodynamical variables, or biopsy), (c) performance of hepatic venous pressure gradient (HVPG) measurement, and (d) determination of parameters of iron
784 | www.jcge.com J Clin Gastroenterol Volume 49, Number 9, October 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 9, October 2015
Association of Ferritin With Cirrhosis
metabolism, specifically serum ferritin. Exclusion criteria were: (a) active malignancy (actual or in the previous 2 y) except hepatocellular carcinoma inside of Milan criteria (ie, a maximum of 3 lesions r3 cm or 1 lesion with a maximum of 5 cm), (b) severe comorbidity including chronic obstructive pulmonary disease with steroid requirements or oxygen therapy and end-stage renal disease on dialysis, (c) acute events in the previous 2 weeks (infection, bleeding, alcoholic hepatitis, acute flare of autoimmune hepatitis), (d) immunosuppressive medication, (e) previous transjugular intrahepatic portosystemic shunt. Data regarding etiology of liver disease, previous decompensation (defined by previous or actual variceal bleeding, ascites, or hepatic encephalopathy), laboratory measurements of liver function (including variables used for Child score and MELD), and iron metabolism were recorded. A maximum of 30 days between hemodynamic measurement and ferritin was allowed. Increased ferritin was considered if serum ferritin was Z200 mg/L.
hemodynamic measurement and ferritin measurement (n = 8), (b) immunosuppressive medication (n = 3), (c) acute event (n = 5) [herpes simplex virus infection (n = 1), alcoholic hepatitis (n = 1), autoimmune hepatitis flare (n = 2), unknown acute event (n = 1)], and (d) significant comorbidity (n = 3). The study population was composed of 51 patients. The baseline characteristics of the patients, including iron metabolism parameters, are described in Table 1. Median serum ferritin in these patients was 235 (IQR, 85 to 604) mg/L. Thirty patients (59%) had increased serum ferritin and 9 (18%, from the 28 patients with reported values) had increased transferrin saturation. Serum ferritin correlated to serum iron (r = 0.309, P = 0.05) and transferrin saturation (r = 0.560, P = 0.002). Most patients had alcoholic liver disease (53%) although only 22% had active alcohol consumption. Of note is that the whole spectrum of liver disease was represented with patients from each Child-Pugh class. Most patients had CSPH (86%), but only 12% of patients were on b-blockers at the time of the hemodynamic study.
Hemodynamic Measurement
Association of Ferritin With Markers of Portal Hypertension
After an overnight fast, a vascular introducer sheath (Medikit Co. Ltd, Tokyo, Japan) was placed into the right internal jugular or femoral vein according to Seldinger technique. Afterwards, a 7-Fr balloon catheter (Cordis SA, Miami, FL) was placed into the right hepatic vein for the assessment of free and wedged hepatic venous pressures (FHVP and WHVP) as previously described.16 The wedged position was confirmed by the absence of reflux after injection of 2 mL of contrast medium, and FHVP was measured with the tip of the catheter 365 had higher MELD score than patients with ferritin under this threshold.11 A recently published study including 318 patients with decompensated cirrhosis divided patients in 3 groups according to ferritin and observed greater MELD and Child-Pugh score with increasing ferritin.20 To our knowledge, only 1 study has evaluated the association between ferritin as a continuous variable and markers of liver insufficiency, in this case Child-Pugh class.2 Similar to our observations, patients with greater Child-Pugh class had greater serum ferritin. Several pathophysiological mechanisms could account for increased iron overload in patients with cirrhosis. Firstly, it could be that patients with cirrhosis and ascites have bacterial translocation, increased inflammation that could lead to the increased ferritin. In this sense, in the present study significantly greater values of ferritin were observed in patients with ascites compared with patients without ascites. Secondly, liver insufficiency could also lead to a reduction in the hepatic production of hepcidin and; therefore, an uninhibited absorption of iron from the gut. In turn, iron overload itself, a well-known source of oxidative stress could have an impact on the liver disease, mainly portal hypertension. It is well established that portal hypertension has both a dynamic and a structural component and the former is influenced by different mediators including mediators involved in inflammation that could be accentuated by iron overload. Nevertheless, we were not able to confirm this hypothesis with the results of our study, as no association between HVPG, an estimation of portal pressure, and ferritin was observed. Our results suggest that iron overload is associated mainly to circulatory dysfunction and liver insufficiency. Previous studies have emphasized the predominance of portal hypertension in earlier phases of liver disease, where HVPG has been identified as an important predictive factor in the development of clinically relevant events, namely decompensation, but even mortality. Liver insufficiency is a later event in the natural history of liver disease. Indeed, markers of liver insufficiency in this stage of the disease are the main predictors of death. Circulatory dysfunction is also a later event in the course of natural history of liver disease, occurring typically in patients with refractory ascites. In the present study, ferritin was associated with markers of more advanced disease, suggesting that this event would take place later on in the natural history of the disease. The greatest limitation of the study is its retrospective design. Because of its retrospective nature, a thorough evaluation of alcohol consumption was not possible. It is possible that some patients that were classified as not having active alcohol consumption, did actually actively consume alcohol. Indeed the association between ferritin values and markers of systemic and hepatic inflammation could be due to ongoing alcohol consumption that could explain both the inflammation and the ferritin values. Unfortunately, systematic magnetic resonance imaging which could allow an estimation of iron overload was not performed in these patients, nor were liver biopsies performed in all patients. Finally the transversal design of the study does not allow establishing causality, as the temporal relationship between the cause and effect could not be evaluated.
788 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 9, October 2015
Association of Ferritin With Cirrhosis
TABLE 2. Linear and Logistic Multivariate Analysis to Evaluate the Independent Predictors of Serum Ferritin (Linear) or Increased Ferritin (Logistic)
Variables Included
B
Final Model
Linear regression MELD, CRP, ASAT, MAP Creatinine, serum sodium, sex Variables Included Logistic regression MELD, CRP, ASAT, MAP Creatinine, serum sodium, sex
Serum sodium Sex
301.170 36.697
Final Model
OR
MELD Serum sodium
1.282 0.728
95% CI 589.024, 61.651,
13.307 11.742
P 0.022 0.005
95% CI
P
1.002, 1.639 0.554, 0.957
0.030 0.003
ASAT indicates aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; MAP, mean arterial pressure; MELD, model for end-stage liver disease; OR, odds ratio.
This study concludes that serum ferritin is not only associated with systemic and hepatic inflammation but also to liver failure and circulatory dysfunction. Nevertheless, increased ferritin does not have an impact on portal hypertension as estimated by the HVPG. REFERENCES 1. Walker NM, Stuart KA, Ryan RJ, et al. Serum ferritin concentration predicts mortality in patients awaiting liver transplantation. Hepatology. 2010;51:1683–1691. 2. Buyukasik NS, Nadir I, Akin FE, et al. Serum iron parameters in cirrhosis and chronic hepatitis: detailed description. Turk J Gastroenterol. 2011;22:606–611. 3. Jurczyk K, Wawrzynowicz-Syczewska M, Boron-Kaczmarska A, et al. Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis. Med Sci Monit. 2001;7:962–965. 4. Guyader D, Thirouard AS, Erdtmann L, et al. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol. 2007;46:587–595. 5. Stuart KA, Fletcher LM, Clouston AD, et al. Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation. Hepatology. 2000;32:1200–1207. 6. Adams PC. Iron overload in viral and alcoholic liver disease. J Hepatol. 1998;28(suppl 1):19–20. 7. Eng SC, Taylor SL, Reyes V, et al. Hepatic iron overload in alcoholic end-stage liver disease is associated with iron deposition in other organs in the absence of HFE-1 hemochromatosis. Liver Int. 2005;25:513–517. 8. Pietrangelo A. Mechanism of iron toxicity. Adv Exp Med Biol. 2002;509:19–43. 9. Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:77–85.
Copyright
r
10. Metwally MA, Zein CO, Zein NN. Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection. Am J Gastroenterol. 2004;99: 286–291. 11. Weismuller TJ, Kirchner GI, Scherer MN, et al. Serum ferritin concentration and transferrin saturation before liver transplantation predict decreased long-term recipient survival. Hepatology. 2011;54:2114–2124. 12. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liverspecific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811–7819. 13. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA. 2001;98:8780–8785. 14. Pietrangelo A. Hepcidin in human iron disorders: therapeutic implications. J Hepatol. 2011;54:173–181. 15. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology. 2010;52:2044–2052. 16. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology. 2004;39:280–282. 17. Valla D, Bercoff E, Menu Y, et al. Discrepancy between wedged hepatic venous pressure and portal venous pressure after acute propranolol administration in patients with alcoholic cirrhosis. Gastroenterology. 1984;86:1400–1403. 18. Perello A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virusrelated cirrhosis. Hepatology. 1999;30:1393–1397. 19. Barry M. Iron and the liver. Gut. 1974;15:324–334. 20. Maiwall R, Kumar S, Chaudhary AK, et al. Serum ferritin predicts early mortality in patients with decompensated cirrhosis. J Hepatol. 2014;61:43–50.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
789
Serum Ferritin in Patients With Cirrhosis is Associated With Markers of Liver Insufficiency and Circulatory Dysfunction, but Not of Portal Hypertension Cristina Ripoll, MD, Felix Keitel, MD, Marcus Hollenbach, MD, Robin Greinert, MD, and Alexander Zipprich, MD
Background/Aims: Iron overload is an increasingly recognized phenomenon in nonhemochromatosis cirrhosis. To evaluate the relationship between iron overload and liver insufficiency and portal hypertension. Patients and Methods: Cirrhotics with hepatic hemodynamic and ferritin measurement (within 30 d) were included. Exclusion criteria were malignancy (except hepatocellular carcinoma Milan-in), severe chronic obstructive pulmonary disease, acute events in the previous 2 weeks, immunosuppression, transjugular intrahepatic portosystemic shunt or portal vein thrombosis, and end-stage renal disease. Patients were followed-up until death or liver transplant. Univariate and multivariate analysis were used. Results: Fifty-one patients were included (male 61%; median age 57 y; interquartile range, 47 to 66 y); Child-Pugh A 11/B 25/C 15). A positive correlation was observed between ferritin and markers of inflammation (C-reactive protein: r = 0.273, P = 0.06 and aspartate aminotransferase: r = 0.302, P = 0.035). No correlation between ferritin and hepatic venous pressure gradient was seen. Negative correlations were observed between ferritin and circulatory dysfunction (mean arterial pressure: r = 0.360, P = 0.014 and serum sodium: r = 0.419, P = 0.002). In contrast, associations to markers of liver failure such as international normalized ratio (r = 0.333, P = 0.005), bilirubin (r = 0.378, P = 0.007), albumin (r = 0.265, P = 0.082), model for end-stage liver disease (r = 0.293, P = 0.041), and Child-Pugh score (r = 0.392, P = 0.009) were observed. No differences in survival according to ferritin was detected. Conclusions: In patients with cirrhosis, serum ferritin levels are associated with markers of liver insufficiency, inflammation, and circulatory dysfunction but not portal hypertension. Key Words: ferritin, cirrhosis, iron overload, portal hypertension, liver insufficiency
(J Clin Gastroenterol 2015;49:784–789)
I
ncreased serum ferritin has been frequently described in nonhemochromatosis cirrhosis,1–4 nevertheless its interpretation is somewhat ambivalent as it is both a marker of iron overload and an acute phase reactant. Iron overload has been reported in patients with end-stage liver disease not associated with hereditary hemochromatosis including alcoholic liver disease and viral hepatitis.1–7 The clinical
Received for publication July 16, 2014; accepted November 29, 2014. From the First Department of Internal Medicine, Martin-LutherUniversity Halle-Wittenberg, Halle (Saale), Germany. The authors declare that they have nothing to disclose. Reprints: Cristina Ripoll, MD, First Department of Internal Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, Halle (Saale) 06120, Germany (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
relevance of this iron overload is largely unknown. Several studies suggest that in patients with cirrhosis, an increase in liver iron content leads to increased fibrosis and oxidative stress.8–10 Indeed, increased ferritin evaluated as a categorical variable, has been associated with model for end-stage liver disease (MELD) score and pretransplant and postransplant mortality.1,11 The discovery of hepcidin, a key player in iron homeostasis, has shed new light on iron overload in cirrhosis.12,13 Hepcidin is constitutively produced by the liver and released into the blood in response to excessive iron stores by inhibiting the main iron transporter in the enterocytes (ferroportin) and; therefore, avoiding dietary iron absorption.14 Hepcidin has also been involved in the innate immunity and its production is also regulated by inflammatory state.14 Little is known regarding the hepatic production of hepcidin in patients with liver cirrhosis without hereditary hemochromatosis or other genetic disorders associated with iron overload. Taking into account that hepcidin is produced in the liver, hypothetically with increasing liver failure there could be a reduced hepcidin production despite adequate or excessive deposits of iron, which would in turn lead to a greater absorption of iron from the intestine and hence iron overload. In contrast, patients with advanced liver disease and ascites have bacterial translocation15 and; therefore, could have greater inflammation, which may affect the production of hepcidin or lead to an increase of ferritin as an acute phase protein. Reciprocally, iron overload could lead to an increase in hepatic inflammation by means of oxidative stress and fibrosis and could, therefore, have an effect on portal pressure. Therefore, the aim of this study was to evaluate the relationship between ferritin, liver insufficiency, and portal hypertension in patients with cirrhosis and secondly to evaluate the impact of serum ferritin on survival in patients with cirrhosis.
PATIENTS AND METHODS This study is a retrospective, single-center, cross-sectional study including all patients who had a hemodynamic study between January 2008 and May 2012. These measurements are routinely performed in the evaluation of patients with cirrhosis in our center. All consecutive patients who fulfilled the following criteria were considered for inclusion: (a) patients between 18 and 79 years of age, (b) diagnosis of liver cirrhosis (according to clinical, analytical, imaging tests, hemodynamical variables, or biopsy), (c) performance of hepatic venous pressure gradient (HVPG) measurement, and (d) determination of parameters of iron
784 | www.jcge.com J Clin Gastroenterol Volume 49, Number 9, October 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 9, October 2015
Association of Ferritin With Cirrhosis
metabolism, specifically serum ferritin. Exclusion criteria were: (a) active malignancy (actual or in the previous 2 y) except hepatocellular carcinoma inside of Milan criteria (ie, a maximum of 3 lesions r3 cm or 1 lesion with a maximum of 5 cm), (b) severe comorbidity including chronic obstructive pulmonary disease with steroid requirements or oxygen therapy and end-stage renal disease on dialysis, (c) acute events in the previous 2 weeks (infection, bleeding, alcoholic hepatitis, acute flare of autoimmune hepatitis), (d) immunosuppressive medication, (e) previous transjugular intrahepatic portosystemic shunt. Data regarding etiology of liver disease, previous decompensation (defined by previous or actual variceal bleeding, ascites, or hepatic encephalopathy), laboratory measurements of liver function (including variables used for Child score and MELD), and iron metabolism were recorded. A maximum of 30 days between hemodynamic measurement and ferritin was allowed. Increased ferritin was considered if serum ferritin was Z200 mg/L.
hemodynamic measurement and ferritin measurement (n = 8), (b) immunosuppressive medication (n = 3), (c) acute event (n = 5) [herpes simplex virus infection (n = 1), alcoholic hepatitis (n = 1), autoimmune hepatitis flare (n = 2), unknown acute event (n = 1)], and (d) significant comorbidity (n = 3). The study population was composed of 51 patients. The baseline characteristics of the patients, including iron metabolism parameters, are described in Table 1. Median serum ferritin in these patients was 235 (IQR, 85 to 604) mg/L. Thirty patients (59%) had increased serum ferritin and 9 (18%, from the 28 patients with reported values) had increased transferrin saturation. Serum ferritin correlated to serum iron (r = 0.309, P = 0.05) and transferrin saturation (r = 0.560, P = 0.002). Most patients had alcoholic liver disease (53%) although only 22% had active alcohol consumption. Of note is that the whole spectrum of liver disease was represented with patients from each Child-Pugh class. Most patients had CSPH (86%), but only 12% of patients were on b-blockers at the time of the hemodynamic study.
Hemodynamic Measurement
Association of Ferritin With Markers of Portal Hypertension
After an overnight fast, a vascular introducer sheath (Medikit Co. Ltd, Tokyo, Japan) was placed into the right internal jugular or femoral vein according to Seldinger technique. Afterwards, a 7-Fr balloon catheter (Cordis SA, Miami, FL) was placed into the right hepatic vein for the assessment of free and wedged hepatic venous pressures (FHVP and WHVP) as previously described.16 The wedged position was confirmed by the absence of reflux after injection of 2 mL of contrast medium, and FHVP was measured with the tip of the catheter 365 had higher MELD score than patients with ferritin under this threshold.11 A recently published study including 318 patients with decompensated cirrhosis divided patients in 3 groups according to ferritin and observed greater MELD and Child-Pugh score with increasing ferritin.20 To our knowledge, only 1 study has evaluated the association between ferritin as a continuous variable and markers of liver insufficiency, in this case Child-Pugh class.2 Similar to our observations, patients with greater Child-Pugh class had greater serum ferritin. Several pathophysiological mechanisms could account for increased iron overload in patients with cirrhosis. Firstly, it could be that patients with cirrhosis and ascites have bacterial translocation, increased inflammation that could lead to the increased ferritin. In this sense, in the present study significantly greater values of ferritin were observed in patients with ascites compared with patients without ascites. Secondly, liver insufficiency could also lead to a reduction in the hepatic production of hepcidin and; therefore, an uninhibited absorption of iron from the gut. In turn, iron overload itself, a well-known source of oxidative stress could have an impact on the liver disease, mainly portal hypertension. It is well established that portal hypertension has both a dynamic and a structural component and the former is influenced by different mediators including mediators involved in inflammation that could be accentuated by iron overload. Nevertheless, we were not able to confirm this hypothesis with the results of our study, as no association between HVPG, an estimation of portal pressure, and ferritin was observed. Our results suggest that iron overload is associated mainly to circulatory dysfunction and liver insufficiency. Previous studies have emphasized the predominance of portal hypertension in earlier phases of liver disease, where HVPG has been identified as an important predictive factor in the development of clinically relevant events, namely decompensation, but even mortality. Liver insufficiency is a later event in the natural history of liver disease. Indeed, markers of liver insufficiency in this stage of the disease are the main predictors of death. Circulatory dysfunction is also a later event in the course of natural history of liver disease, occurring typically in patients with refractory ascites. In the present study, ferritin was associated with markers of more advanced disease, suggesting that this event would take place later on in the natural history of the disease. The greatest limitation of the study is its retrospective design. Because of its retrospective nature, a thorough evaluation of alcohol consumption was not possible. It is possible that some patients that were classified as not having active alcohol consumption, did actually actively consume alcohol. Indeed the association between ferritin values and markers of systemic and hepatic inflammation could be due to ongoing alcohol consumption that could explain both the inflammation and the ferritin values. Unfortunately, systematic magnetic resonance imaging which could allow an estimation of iron overload was not performed in these patients, nor were liver biopsies performed in all patients. Finally the transversal design of the study does not allow establishing causality, as the temporal relationship between the cause and effect could not be evaluated.
788 | www.jcge.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Clin Gastroenterol
Volume 49, Number 9, October 2015
Association of Ferritin With Cirrhosis
TABLE 2. Linear and Logistic Multivariate Analysis to Evaluate the Independent Predictors of Serum Ferritin (Linear) or Increased Ferritin (Logistic)
Variables Included
B
Final Model
Linear regression MELD, CRP, ASAT, MAP Creatinine, serum sodium, sex Variables Included Logistic regression MELD, CRP, ASAT, MAP Creatinine, serum sodium, sex
Serum sodium Sex
301.170 36.697
Final Model
OR
MELD Serum sodium
1.282 0.728
95% CI 589.024, 61.651,
13.307 11.742
P 0.022 0.005
95% CI
P
1.002, 1.639 0.554, 0.957
0.030 0.003
ASAT indicates aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; MAP, mean arterial pressure; MELD, model for end-stage liver disease; OR, odds ratio.
This study concludes that serum ferritin is not only associated with systemic and hepatic inflammation but also to liver failure and circulatory dysfunction. Nevertheless, increased ferritin does not have an impact on portal hypertension as estimated by the HVPG. REFERENCES 1. Walker NM, Stuart KA, Ryan RJ, et al. Serum ferritin concentration predicts mortality in patients awaiting liver transplantation. Hepatology. 2010;51:1683–1691. 2. Buyukasik NS, Nadir I, Akin FE, et al. Serum iron parameters in cirrhosis and chronic hepatitis: detailed description. Turk J Gastroenterol. 2011;22:606–611. 3. Jurczyk K, Wawrzynowicz-Syczewska M, Boron-Kaczmarska A, et al. Serum iron parameters in patients with alcoholic and chronic cirrhosis and hepatitis. Med Sci Monit. 2001;7:962–965. 4. Guyader D, Thirouard AS, Erdtmann L, et al. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol. 2007;46:587–595. 5. Stuart KA, Fletcher LM, Clouston AD, et al. Increased hepatic iron and cirrhosis: no evidence for an adverse effect on patient outcome following liver transplantation. Hepatology. 2000;32:1200–1207. 6. Adams PC. Iron overload in viral and alcoholic liver disease. J Hepatol. 1998;28(suppl 1):19–20. 7. Eng SC, Taylor SL, Reyes V, et al. Hepatic iron overload in alcoholic end-stage liver disease is associated with iron deposition in other organs in the absence of HFE-1 hemochromatosis. Liver Int. 2005;25:513–517. 8. Pietrangelo A. Mechanism of iron toxicity. Adv Exp Med Biol. 2002;509:19–43. 9. Kowdley KV, Belt P, Wilson LA, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:77–85.
Copyright
r
10. Metwally MA, Zein CO, Zein NN. Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection. Am J Gastroenterol. 2004;99: 286–291. 11. Weismuller TJ, Kirchner GI, Scherer MN, et al. Serum ferritin concentration and transferrin saturation before liver transplantation predict decreased long-term recipient survival. Hepatology. 2011;54:2114–2124. 12. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liverspecific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811–7819. 13. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA. 2001;98:8780–8785. 14. Pietrangelo A. Hepcidin in human iron disorders: therapeutic implications. J Hepatol. 2011;54:173–181. 15. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology. 2010;52:2044–2052. 16. Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology. 2004;39:280–282. 17. Valla D, Bercoff E, Menu Y, et al. Discrepancy between wedged hepatic venous pressure and portal venous pressure after acute propranolol administration in patients with alcoholic cirrhosis. Gastroenterology. 1984;86:1400–1403. 18. Perello A, Escorsell A, Bru C, et al. Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virusrelated cirrhosis. Hepatology. 1999;30:1393–1397. 19. Barry M. Iron and the liver. Gut. 1974;15:324–334. 20. Maiwall R, Kumar S, Chaudhary AK, et al. Serum ferritin predicts early mortality in patients with decompensated cirrhosis. J Hepatol. 2014;61:43–50.
2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
789
