Reply to: “Low free T3 levels are related to early mortality in patients with decompensated cirrhosis and acute-on chronic liver failure”
Authors: Rakhi Maiwall, Suman Kumar, S K Sarin
Journal: Journal of Hepatology (2014)

Low free T3 levels are related to early mortality in patients with decompensated cirrhosis and acute-on chronic liver failureJournal of HepatologyVol. 61Issue 6PreviewWe 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]. ACLF has recently been recognized as a specific clinical form of liver failure with short term mortality [2,3]. Thyroid test abnormalities in ACLF and their association with survival have not been determined so far. Full-Text PDF Open AccessSerum 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 We 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]Maiwall R. Kumar S. Chaudhary A. 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 (47) Google Scholar]. 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 [2Sarin S.K. Kedarisetty C.K. Abbas Z. Amarapurkar D. Bihari C. Chan A. et al.Acute-on-chronic liver failure: an update on consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2014; (in press)Google Scholar, 3Moreau R. Jalan R. Gines P. Pawasi M. Angeli P. Cordoba J. et al.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 (1894) Google Scholar]. We have looked into our cohort of patients with decompensated cirrhosis (n = 318, 257 males) and patients with ACLF (n = 148, 109 males), defined according to the APASL criteria [[2]Sarin S.K. Kedarisetty C.K. Abbas Z. Amarapurkar D. Bihari C. Chan A. et al.Acute-on-chronic liver failure: an update on consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2014; (in press)Google Scholar] for abnormalities in thyroid function and their relationship to predictors of mortality [[1]Maiwall R. Kumar S. Chaudhary A. 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 (47) Google Scholar]. Median (IQR) free T3, free T4, and TSH concentration were 2.3 (1.98–2.69) pg/ml, 1.04 (0.9–1.23) ng/L, and 2.47 (1.28–4.27) μIU/ml, respectively in the decompensated cirrhotic group. A significant inverse correlation of T3 was noted with predictors of early mortality i.e. the MELD (p = 0.0004, −0.36) and CTP score (p <0.00001, −0.43), hepatic encephalopathy (p <0.0001, −0.46) and leucocyte counts (p = 0.002, −30). Interestingly, low T3 levels also correlated with an increase in ferritin (p = 0.007, −0.27). Similar to the observation by Agiasotelli et al., low T3 was associated with decreased survival (log rank p = 0.0003), which was not observed for T4 (p = 0.5) and TSH levels (p = 0.6) (Fig. 1 A–C). On multivariate analysis, however, low T3 was not a significant predictor of mortality in our cohort. On the contrary, median (IQR) free T3, free T4, and TSH concentration in patients with ACLF [[2]Sarin S.K. Kedarisetty C.K. Abbas Z. Amarapurkar D. Bihari C. Chan A. et al.Acute-on-chronic liver failure: an update on consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2014; (in press)Google Scholar] were much lower as compared to patients with decompensated cirrhosis i.e. 1.9 (1.6–2.2; p <0.0001) pg/ml, 0.96 (0.73–1.12; p = 0.001) ng/L, and 2.1 (0.65–3.5; p = 0.01) μIU/ml, respectively. Low free T3 was noted in 89% vs. 64% (p <0.0001), low T4 in 16% vs. 4% (p <0.0001) and low TSH was noted in 18% vs. 3.5% (p <0.0001) of patients with ACLF, as compared to patients with decompensated cirrhosis, respectively. Interestingly, serum ferritin showed an inverse correlation with both free T3 (r −0.18, p = 0.012) and TSH (r −0.234, p = 0.03). Also, in these patients, a significantly lower survival was noted with low T3 (log rank p = 0.005), low T4 (p = 0.014) as well as low TSH (p = 0.001) (Fig. 1D–F). This could be possible because within the first few hours of the critical illness, T3 concentrations decrease due to decreased peripheral deiodination, while T4 and TSH concentrations may increase or remain normal. However, if the illness becomes more protracted or severe, a decrease in the concentration of T3, T4, and TSH is caused by a decrease in TRH-release from the hypothalamus [[4]Bello G. Ceaichisciuc I. Silva S. Antonelli M. The role of thyroid dysfunction in the critically ill: a review of the literature.Minerva Anestesiol. 2010; 76: 919-928PubMed Google Scholar]. Our patients with ACLF, diagnosed as per APASL definition, have characteristically an acute liver failure–like presentation (not just acute decompensation) on a background of underlying chronic liver disease with a sudden and massive loss of functional hepatocytes and activation of the systemic inflammatory response syndrome that probably puts extra stress on the thyroid [[2]Sarin S.K. Kedarisetty C.K. Abbas Z. Amarapurkar D. Bihari C. Chan A. et al.Acute-on-chronic liver failure: an update on consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2014; (in press)Google Scholar]. In our cohort, we also found patients with hepatorenal syndrome (HRS) with significantly lower free T3 as compared to those with no HRS (2.19 ± 0.47 vs. 2.42 ± 0.62; p = 0.04). This is because the 5′-monodeiodinases, which produce T3, the biologically active hormone, are also present in the kidney apart from the liver. Thus, our data suggest that low T3 levels are frequent in patients with advanced liver disease and correlate with markers of disease severity and outcome, but these abnormalities are more severe in patients with ACLF [[2]Sarin S.K. Kedarisetty C.K. Abbas Z. Amarapurkar D. Bihari C. Chan A. et al.Acute-on-chronic liver failure: an update on consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).Hepatol Int. 2014; (in press)Google Scholar]. However, it remains elusive whether these abnormalities occur as a protective adaptation or as a maladaptive response to the systemic stress. Also, many confounders like starvation, catecholamines, drugs like corticosteroids, furosemide, beta-blockers and others can also contribute to low free T3 concentration, which will need careful evaluation in future studies. It is also not known whether restoration of these alterations with thyroid hormones could contribute to the recovery of any physiological or metabolic parameters of such critically ill patients with liver disease. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.