Liver Function After Intravenous Methylprednisolone Administration

Sponsor

Medical University of Warsaw (Other)

Overall Status

Completed

CT.gov ID

NCT03667157

Collaborator

(none)

Enrollment

Arms

Actual Duration (Months)

Study Details

Study Description

Brief Summary

Graves' orbitopathy (GO) is a characterized by orbital soft tissue inflammation and oedema associated with glycosaminoglycan deposition and fibrosis. The most frequent cause is Graves' disease. The classification is comprised based on the severity of orbital changes ranging from mild, moderate-to-severe GO and sight-threatening GO, which includes dysthyroid optic neuropathy (DON). Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment in the active-phase of moderate-to-severe GO and DON. This therapy is more effective and better tolerated than oral glucocorticoids (GCs). The current recommendation of the European Group of Graves' Orbitopathy (EUGOGO) is that cumulative doses of IVMP should not exceed 8.0g in each treatment course, and pulses should not be given on consecutive or alternate days, except in the case of DON. According to EUGOGO recommendations patients with moderate-to-severe GO are treated with IVMP cumulative dose 4.5g during a 12-week period (for the first 6 weeks 0.5g IVMP per week, for the next 6 weeks 0.25g IVMP per week). According to EUGOGO recommendations patients with DON should receive 3.0g IVMP (1.0g/day for 3 consecutive days) as the basic treatment. This limitation in doses are due to the necessity of the prevention of severe side effects that are rare but may be fatal. One of the most severe adverse events is acute liver injury (ALI), in some cases irreversible and/or fatal. The estimated morbidity and mortality of ALI was found to be 1-4 % and 0.01-0.3%, respectively. Since 2000, there were 5 reported fatal cases.

Mechanisms causing an IVMP-induced ALI remains incompletely elucidated. There are some possible hypotheses that may explain the occurrence of ALI. Firstly, GCs can lead to reactivation of autoimmune hepatitis: an immune "rebound phenomenon" following GCs withdrawal. The second mechanism of ALI is reactivation of viral hepatitis. Finally, there is well known direct toxic effect of GCs on hepatocytes, probably dose-dependent.

This study was performed to evaluate the influence of two different, routinely used schemes of therapy with IVMP in patients with moderate-to-severe GO (first scheme) and DON (second scheme) on biochemical liver parameters. Patients included into the study were treated according to EUGOGO recommendations with routine doses of IVMP and routine scheme of administration for moderate-to-severe GO and DON. No additional treatment was performed during the study protocol.

Condition or Disease	Intervention/Treatment	Phase
Graves Disease Graves Ophthalmopathy Liver Diseases Liver Failure Liver Injury Liver Dysfunction Liver Insufficiency Acute Liver Failure Acute Liver Injury Acute Liver Injury, Drug Induced Methylprednisolone Adverse Reaction Glucocorticoids Toxicity Dysthyroid Orbitopathy Dysthyroid Ophthalmopathy	Drug: every week IVMP therapy Drug: very high doses IVMP therapy	Phase 4

Detailed Description

Depending on the severity according to EUGOGO recommendations, patients were divided into two groups: the first group with active, moderate-to-severe GO (49 patients) and the second group with DON (19 patients). Moderate-to-severe GO was diagnosed according to EUGOGO recommendations. Diagnosis of DON in patients with GO was based on at least two signs, including (i) deterioration of VA (< 1.0), (ii) loss of colour vision (more than two errors in Ishihara plates), (iii) optic disc swelling, and/or (iv) signs of DON in a magnetic resonance (MR) scan (presence of apical crowding and/or optic nerve stretching).

Laboratory tests were performed before treatment in all patients from both evaluated groups. Serum markers of exposure to hepatitis B (HBV) and hepatitis C (HCV) were checked: hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), hepatitis B core antibody (HBc-Ab), hepatitis C antibody (HCV-Ab). Serum autoantibodies associated with autoimmune hepatitis including anti-nuclear antibodies (ANA1), anti-smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA) and anti-liver kidney-microsomal antibodies (anti-LKM) were also assessed. Thyroid evaluation included measurement of: thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and serum antithyroid autoantibodies including anti-thyroid peroxidase (aTPO), thyroglobulin antibodies (aTG), thyroid-binding inhibitory immunoglobulin (TBII).

According to EUGOGO recommendations: patients with moderate-to-severe GO were treated with IVMP cumulative dose 4.5g during a 12-week period (for the first 6 weeks 0.5g IVMP per week was administrated and for the next 6 weeks 0.25g IVMP per week) and patients with DON received 3.0g IVMP (1.0g/day for 3 consecutive days).

Liver function parameters for further analysis included alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin. These parameters were measured the day before treatment in both groups and the day after administration of IVMP in selected pulses: after 0.5g (1st pulse), after 3.0g (6th pulse) and after 4.5g (12th pulse ) in the group with moderate-to-severe GO; after 3.0g IVMP in the group with DON.

Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. However, the investigators also evaluated a 4-fold increase of ALT in comparison to the initial values.

Routine laboratory tests and clinical evaluation were performed before every single pulse. Laboratory tests consisted of: ALT, AST, C reactive protein (CRP). In cases of moderate and severe increase in ALT (more than 100U/L) therapy was stopped.

Follow-up was performed in all of the patients and it included evaluation of AST, ALT and total bilirubin between 1-3 months after completion of IVMP therapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients With Graves' Orbitopathy

Actual Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Oct 30, 2016

Actual Study Completion Date :

Oct 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: moderate-to-severe Graves Orbitopathy active, moderate-to-severe Graves Orbitopathy according to EUGOGO.	Drug: every week IVMP therapy 12 pulses of intravenous methylprednisolone (IVMP) in every week schedule (for the first 6 weeks 0.5g IVMP per week, for the next 6 weeks 0.25g IVMP per week; cumulative dose 4.5g) according to EUGOGO recommendations
Active Comparator: Dysthyroid Orbit Neuropathy Dysthyroid Orbit Neuropathy according to EUGOGO	Drug: very high doses IVMP therapy 3 pulses of intravenous methylprednisolone (IVMP) (1.0g/day for 3 consecutive days; cumulative dose 3.0g) according to EUGOGO recommendations

Arm

Intervention/Treatment

Active Comparator: moderate-to-severe Graves Orbitopathy

active, moderate-to-severe Graves Orbitopathy according to EUGOGO.

Drug: every week IVMP therapy

12 pulses of intravenous methylprednisolone (IVMP) in every week schedule (for the first 6 weeks 0.5g IVMP per week, for the next 6 weeks 0.25g IVMP per week; cumulative dose 4.5g) according to EUGOGO recommendations

Active Comparator: Dysthyroid Orbit Neuropathy

Dysthyroid Orbit Neuropathy according to EUGOGO

Drug: very high doses IVMP therapy

3 pulses of intravenous methylprednisolone (IVMP) (1.0g/day for 3 consecutive days; cumulative dose 3.0g) according to EUGOGO recommendations

Outcome Measures

Primary Outcome Measures

Influence of IVMP pulses in 12 every week schedule on mean ALT [12 weeks]
Administration of IVMP in 12 every week schedule: 6 weeks 0.5g IVMP per week plus 6 weeks 0.25g IVMP per week. Change of mean value of alanine aminotransferase (ALT) between baseline (before administration of IVMP) and the end of the therapy (after the last pulse of IVMP).
Influence of IVMP pulses in 3 consecutive days schedule on mean ALT [3 days]
Administration of 3g IVMP (1g in 3 consecutive days). Change of mean value of ALT between baseline (before IVMP) and the end of the therapy (after the last pulse of IVMP).

Secondary Outcome Measures

Influence of IVMP pulses in 12 every week schedule on prevalence of mild, moderate and severe liver dysfunction. [12 weeks]
Administration of IVMP in 12 every week schedule: 6 weeks 0.5g IVMP per week plus 6 weeks 0.25g IVMP per week. Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. Prevalence of all types of liver dysfunction was count after IVMP treatment.
Influence of IVMP pulses in 3 consecutive days schedule on prevalence of mild, moderate and severe liver dysfunction. [3 days]
Administration of 3g IVMP (1g in 3 consecutive days). Depending on concentrations of ALT, liver dysfunction was divided into: mild (above the upper limit of normal but less than 100 U/L), moderate (100-300 U/L) and severe (>300 U/L). ALI was defined as an ALT concentration >300 U/L. Prevalence of all types of liver dysfunction was count after IVMP treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

active, moderate-to-severe Graves' orbitopathy or dysthyroid orbit neuropathy
euthyroidism

Exclusion Criteria:

alanine aminotransferase and/or aspartate aminotransferase >2x upper limit of normal
active viral hepatitis
cirrhosis
present or past medical history of autoimmune hepatitis
previous glucocorticoids therapy within the last 6 months
alcohol abuse
active inflammation
active neoplastic disease