Low free T3 levels are related to early mortality in patients with decompensated cirrhosis and acute-on chronic liver failure
Authors: Danai Agiasotelli, Alexandra Alexopoulou, Larisa Vasilieva, Spyros P. Dourakis
Journal: Journal of Hepatology (2014)

Serum ferritin predicts early mortality in patients with decompensated cirrhosisJournal of HepatologyVol. 61Issue 1PreviewSerum 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. Full-Text PDF Reply to: "Low free T3 levels are related to early mortality in patients with decompensated cirrhosis and acute-on chronic liver failure"Journal of HepatologyVol. 61Issue 6PreviewWe would like to thank Agiasotelli et al. for taking a keen interest in our recently published manuscript where we showed that serum ferritin is a predictor of early mortality in patients with decompensated cirrhosis [1]. Agiasotelli and colleagues demonstrate that low T3 levels in patients with ACLF are associated with an increased mortality. We would like to clarify that our patient population was comprised of decompensated cirrhosis and not ACLF patients. Further, we did not use the CLIF definition for the diagnosis of ACLF [2,3]. Full-Text PDF Open Access We read with interest the article by Maiwall et al. in which serum ferritin along with hepatic encephalopathy, leukocyte count, acute-on-chronic liver failure (ACLF) grades and CTP score predict early mortality in patients with decompensated cirrhosis (DC) [[1]Maiwall R. Kumar S. Chaudhary A.K. Maras J. Wani Z. Kumar C. et al.Serum ferritin predicts early mortality in patients with decompensated cirrhosis.J Hepatol. 2014; 61: 43-50Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. ACLF has recently been recognized as a specific clinical form of liver failure with short term mortality [2Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar, 3Cordoba J. Ventura-Cots M. Simón-Talero M. Amorós À. Pavesi M. Vilstrup H. et al.CANONIC Study Investigators of EASL–CLIF Consortium. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).J Hepatol. 2014; 60: 275-281Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Thyroid test abnormalities in ACLF and their association with survival have not been determined so far.The plasma thyroid hormone profile in patients with cirrhosis resembles the low T3 or "sick euthyroid" syndrome, common in many sick patients and normal subjects with caloric deprivation [4Hepner G.W. Chopra I.J. Serum thyroid hormone levels in patients with liver disease.Arch Intern Med. 1979; 139: 1117-1120Crossref PubMed Scopus (70) Google Scholar, 5Güven K. Kelestimur F. Yücesoy M. Thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy.Eur J Med. 1993; 2: 83-85PubMed Google Scholar]. Thus, a low T3 state in cirrhosis may reflect impairment of hepatic uptake and conversion of T4 to T3 due to diminished hepatocellular function or to reduced caloric intake. It may be considered as an adaptive hypothyroid state, which is important for preserving body protein stores [[6]Faber J. Thomsen H.F. Lumholtz I.B. Kirkegaard C. Siersbaek-Nielsen K. Friis T. Kinetic studies of thyroxine, 3,5,3′-triiodothyronine, 3,3,5′-triiodothyronine, 3′,5′-diiodothyronine, 3,3′-diiodothyronine, and 3′-monoiodothyronine in patients with liver cirrhosis.J Clin Endocrinol Metab. 1981; 53: 978-984Crossref PubMed Scopus (59) Google Scholar]. We aimed to better understand the thyroid test abnormalities in patients with (DC) and ACLF compared to those without ACLF.128 patients (91 [71.1%] males, median age of 61 [interquartile range 53–69] years) with DC were followed for a median of 91 (44–110) days. ACLF was diagnosed in 65 (50.8%) patients according to the CLIFF consortium criteria [[2]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar]. No patient had signs or symptoms of thyroid disease. Levels of free T3 (FT3) and free T4 (FT4) correlated inversely with the severity of liver disease as expressed by the MELD-Na score (r = −0.482 and −0.346, respectively, p <0.001). On the contrary, there was no correlation of the thyroid-stimulating hormone (TSH) with the MELD-Na score.Patients with ACLF compared to those without had significantly lower FT3 (1.54 [1.18–1.88] vs. 2.00 [1.55–2.46], p <0.001) and FT4 levels (1.00 [0.83–1.19] vs. 1.14 [1.00–1.24], respectively, [p = 0.005]). TSH did not differ between the two groups. 42 (65%) and 18 (29%) patients had low FT3 levels in the ACLF and non-ACLF group, respectively (p <0.001). Patients with low FT3 compared to those with normal FT3 had significantly higher sequential-organ-failure-assessment (SOFA) (six [5–8] vs. five [4–7.25], p = 0.023). Patients with low FT3 had a worse outcome as it is shown by the Kaplan Mayer survival curve (log rank p <0.042) (Fig. 1). On the contrary, only nine patients, seven in the ACLF and two in the non-ACLF group, had low FT4 levels (p = 0.09). Low FT4 levels were not related to outcome.It is not the first time that the sick euthyroid syndrome has been related to the prognosis of liver cirrhosis. In the past, low levels of the T4 variant in the sick euthyroid syndrome were demonstrated to be a good predictor of decreased survival in liver cirrhosis and T4 levels were inversely correlated with the CTP score [[6]Faber J. Thomsen H.F. Lumholtz I.B. Kirkegaard C. Siersbaek-Nielsen K. Friis T. Kinetic studies of thyroxine, 3,5,3′-triiodothyronine, 3,3,5′-triiodothyronine, 3′,5′-diiodothyronine, 3,3′-diiodothyronine, and 3′-monoiodothyronine in patients with liver cirrhosis.J Clin Endocrinol Metab. 1981; 53: 978-984Crossref PubMed Scopus (59) Google Scholar]. In addition, low FT3 levels were considered as indicators of poor prognosis in cirrhotics with non alcoholic liver disease [[5]Güven K. Kelestimur F. Yücesoy M. Thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy.Eur J Med. 1993; 2: 83-85PubMed Google Scholar]. However, the prognostic significance of low T3 levels in the sick euthyroid syndrome have not been evaluated so far in the ACLF setting.In conclusion, free T3 levels are inversely correlated with the severity of liver disease and are significantly lower in patients with decompensated cirrhosis who developed ACLF. Sick euthyroid syndrome with low FT3 levels was related to early mortality in patients with ACLF.Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We read with interest the article by Maiwall et al. in which serum ferritin along with hepatic encephalopathy, leukocyte count, acute-on-chronic liver failure (ACLF) grades and CTP score predict early mortality in patients with decompensated cirrhosis (DC) [[1]Maiwall R. Kumar S. Chaudhary A.K. Maras J. Wani Z. Kumar C. et al.Serum ferritin predicts early mortality in patients with decompensated cirrhosis.J Hepatol. 2014; 61: 43-50Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. ACLF has recently been recognized as a specific clinical form of liver failure with short term mortality [2Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar, 3Cordoba J. Ventura-Cots M. Simón-Talero M. Amorós À. Pavesi M. Vilstrup H. et al.CANONIC Study Investigators of EASL–CLIF Consortium. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).J Hepatol. 2014; 60: 275-281Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar]. Thyroid test abnormalities in ACLF and their association with survival have not been determined so far. The plasma thyroid hormone profile in patients with cirrhosis resembles the low T3 or "sick euthyroid" syndrome, common in many sick patients and normal subjects with caloric deprivation [4Hepner G.W. Chopra I.J. Serum thyroid hormone levels in patients with liver disease.Arch Intern Med. 1979; 139: 1117-1120Crossref PubMed Scopus (70) Google Scholar, 5Güven K. Kelestimur F. Yücesoy M. Thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy.Eur J Med. 1993; 2: 83-85PubMed Google Scholar]. Thus, a low T3 state in cirrhosis may reflect impairment of hepatic uptake and conversion of T4 to T3 due to diminished hepatocellular function or to reduced caloric intake. It may be considered as an adaptive hypothyroid state, which is important for preserving body protein stores [[6]Faber J. Thomsen H.F. Lumholtz I.B. Kirkegaard C. Siersbaek-Nielsen K. Friis T. Kinetic studies of thyroxine, 3,5,3′-triiodothyronine, 3,3,5′-triiodothyronine, 3′,5′-diiodothyronine, 3,3′-diiodothyronine, and 3′-monoiodothyronine in patients with liver cirrhosis.J Clin Endocrinol Metab. 1981; 53: 978-984Crossref PubMed Scopus (59) Google Scholar]. We aimed to better understand the thyroid test abnormalities in patients with (DC) and ACLF compared to those without ACLF. 128 patients (91 [71.1%] males, median age of 61 [interquartile range 53–69] years) with DC were followed for a median of 91 (44–110) days. ACLF was diagnosed in 65 (50.8%) patients according to the CLIFF consortium criteria [[2]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1689) Google Scholar]. No patient had signs or symptoms of thyroid disease. Levels of free T3 (FT3) and free T4 (FT4) correlated inversely with the severity of liver disease as expressed by the MELD-Na score (r = −0.482 and −0.346, respectively, p <0.001). On the contrary, there was no correlation of the thyroid-stimulating hormone (TSH) with the MELD-Na score. Patients with ACLF compared to those without had significantly lower FT3 (1.54 [1.18–1.88] vs. 2.00 [1.55–2.46], p <0.001) and FT4 levels (1.00 [0.83–1.19] vs. 1.14 [1.00–1.24], respectively, [p = 0.005]). TSH did not differ between the two groups. 42 (65%) and 18 (29%) patients had low FT3 levels in the ACLF and non-ACLF group, respectively (p <0.001). Patients with low FT3 compared to those with normal FT3 had significantly higher sequential-organ-failure-assessment (SOFA) (six [5–8] vs. five [4–7.25], p = 0.023). Patients with low FT3 had a worse outcome as it is shown by the Kaplan Mayer survival curve (log rank p <0.042) (Fig. 1). On the contrary, only nine patients, seven in the ACLF and two in the non-ACLF group, had low FT4 levels (p = 0.09). Low FT4 levels were not related to outcome. It is not the first time that the sick euthyroid syndrome has been related to the prognosis of liver cirrhosis. In the past, low levels of the T4 variant in the sick euthyroid syndrome were demonstrated to be a good predictor of decreased survival in liver cirrhosis and T4 levels were inversely correlated with the CTP score [[6]Faber J. Thomsen H.F. Lumholtz I.B. Kirkegaard C. Siersbaek-Nielsen K. Friis T. Kinetic studies of thyroxine, 3,5,3′-triiodothyronine, 3,3,5′-triiodothyronine, 3′,5′-diiodothyronine, 3,3′-diiodothyronine, and 3′-monoiodothyronine in patients with liver cirrhosis.J Clin Endocrinol Metab. 1981; 53: 978-984Crossref PubMed Scopus (59) Google Scholar]. In addition, low FT3 levels were considered as indicators of poor prognosis in cirrhotics with non alcoholic liver disease [[5]Güven K. Kelestimur F. Yücesoy M. Thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy.Eur J Med. 1993; 2: 83-85PubMed Google Scholar]. However, the prognostic significance of low T3 levels in the sick euthyroid syndrome have not been evaluated so far in the ACLF setting. In conclusion, free T3 levels are inversely correlated with the severity of liver disease and are significantly lower in patients with decompensated cirrhosis who developed ACLF. Sick euthyroid syndrome with low FT3 levels was related to early mortality in patients with ACLF. Conflict of interestThe authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.