title: Age and Dose Are Major Risk Factors for Liver Damage Associated with Intravenous Glucocorticoid Pulse Therapy for Graves' Orbitopathy.
abstract: BACKGROUND
  High-dose intravenous glucocorticoid (ivGC) pulse therapy, which is commonly used for Graves' orbitopathy (GO), has been associated with acute liver damage (ALD), resulting in a fatal outcome in a few cases. No certain risk factors for ALD have been established. Consequently, a large retrospective cohort study was performed.
  
  
  METHODS
  The relationship between ALD and several potential risk factors was assessed in 1076 consecutive patients with GO given ivGC. ALD was defined as an increase of alanine aminotransferase ≥300 IU/L.
  
  
  RESULTS
  Fourteen cases of ALD were recorded, resulting in a morbidity of 1.3%. Thirteen patients recovered and one died, resulting in a mortality of 0.09%. There was a significant, positive correlation of ALD with age and methylprednisolone acetate (MPA) cumulative dose, and ALD was more common (relative risk [RR]=2.8; p=0.05) in patients aged ≥53 years (9/420; 2.14%) than in those aged <53 years (5/656; 0.76%). In patients aged ≥53 years, there was a significant positive correlation of ALD with MPA cumulative dose, and with MPA dose per infusion. Thus, the frequency of ALD in this age group was greater (RR=3.48; p=0.04) in patients with a MPA dose per infusion ≥0.7 g (5/111, 4.5% vs. 4/308, 1.29%). Regardless of age, no cases of ALD were observed for MPA doses per infusion <0.57 g.
  
  
  CONCLUSIONS
  Age and MPA dose are significant risk factors for ALD, with the following practical implications. First, the total MPA cumulative dose should not exceed 8.5 g (the average dose in patients without ALD). Second, in patients aged ≥53 years, selection and observation should be quite strict. However, being aged ≥53 years should not be seen as an absolute contraindication to ivGC, especially in patients with severe GO, considering that the risk of ALD, although statistically significant, was relatively low. Third, the MPA dose should not exceed 0.57 g per infusion, a measure to be applied regardless of age.
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sisti
authors.affiliation: 2 Hepatology Unit, University Hospital of Pisa , Pisa, Italy .
authors.forename: Barbara
authors.initials: B
authors.lastname: Coco
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Francesca
authors.initials: F
authors.lastname: Menconi
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Marenza
authors.initials: M
authors.lastname: Leo
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Roberto
authors.initials: R
authors.lastname: Rocchi
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Francesco
authors.initials: F
authors.lastname: Latrofa
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Profilo
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Barbara
authors.initials: B
authors.lastname: Mazzi
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Paolo
authors.initials: P
authors.lastname: Vitti
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Claudio
authors.initials: C
authors.lastname: Marcocci
authors.affiliation: 2 Hepatology Unit, University Hospital of Pisa , Pisa, Italy .
authors.forename: Maurizia
authors.initials: M
authors.lastname: Brunetto
authors.affiliation: 1 Department of Clinical and Experimental Medicine, Endocrinology Units, University of Pisa and University Hospital of Pisa , Pisa, Italy .
authors.forename: Michele
authors.initials: M
authors.lastname: Marinò
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000453:epidemiology* / Q000209:etiology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D049970:Graves Ophthalmopathy / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077555:Methylprednisolone Acetate; D008875:Middle Aged; D015999:Multivariate Analysis; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D005938:Glucocorticoids; D000077555:Methylprednisolone Acetate; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D008775:Methylprednisolone