Liver Diseases Clinical Trial
Official title:
Influence of Methylprednisolone Pulse Therapy on Liver Function in Patients With Graves' Orbitopathy
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.
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.
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