Graves ’ disease , celiac disease and liver function abnormalities in a patient — clinical manifestation and diagnostic difficulties

1Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdansk, Gdańsk, Poland; 2Department of Gastroenterology, Hepatology and Eating Disorders Children’s Memorial Hospital in Warsaw, Warsaw, Poland; 3Department of Patology, Children’s Memorial Hospital in Warsaw, Warsaw, Poland; 4Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdansk, Gdańsk, Poland; 5Faculty of Health Sciences with Subfaculty of Nursing Medical University of Gdansk, Gdańsk, Poland


INTRODUCTION
Graves' disease is a common autoimmune disease with a prevalence of 1/1000 in children (Jacobson et al., 1997).Autoimmune diseases such as Graves' disease, celiac disease and autoimmune hepatitis, due to probable common etiopathogenesis tend to coexist in some patients (Meloni et al., 2001;Strassburger et al., 2002).
Complex clinical presentation with diverse timing of occurrence of particular symptoms and treatment with numerous side effects, may cause diagnostic difficulties.Liver function abnormalities are common in this group of patients.Children appear to be a special group of patients with immature immune system, altered pharmacokinetics of some drugs and compliance.
The aim of this paper is to present diagnostic difficulties and pitfalls in a child with Graves' disease, celiac disease and liver function abnormalities.

CASE REPORT
A 12-year-old girl with no evident burden in perinatal and familial medical history is presented.At the age of 8 the diagnosis of Graves' hyperthyroidism was established -with thyroid hormone fT4 50 pmol/l, undetectable thyroid stimulating hormone (TSH), anti-thyroid peroxidase (TPO) antibodies -598 IU/ml, anti-thyroglobulin (TG) antibodies 1837 IU/ml, and no nodules in the ultrasound scan of thyroid gland.Screening for celiac disease was negative by then and decreased IgA level-0, 16 g /l was noted.Initially, the patients was treated with methimazol (no consent for surgical therapy was ob-tained), and next, because of an ophtalmopathy the steroids were introduced in a primary full dose of 40 mg (1 mg/kg/d) for 6 weeks, and then in the reduced doses for 4 months.Although the therapy brought some improvement, full remission was not achieved -every attempt to withdraw from methimazol was unsuccessful.Still, no consent for surgical therapy was obtained.After 3 years propylthiouracyl (PTU) and Levothyroxine sodium were introduced.
In 2 months time the patient was admitted again to the hospital, because of the hyperthyroidism (fT4 35 pmol/l) and elevated transaminases activity (AlAT up to 300 U/l with no cholestasis in laboratory tests).Laboratory tests showed no features of infectious disease.Tests for the autoimmune processes showed the presence of anti-smooth muscle (SMA, 1:640) and anti-nuclear (ANA; 1:320) antibodies as well as the presence of anti-transglutaminase (tTG) and anti-endomysium (IgG-EMA) antybodies.The diagnosis of celiac disease was confirmed by the histopathological changes within the intestinal mucosa -grade III in Marsh scale (Fig. 1) -vilious atrophy, crypt hyperplasia, increased density of intraepithelial γ/δ T-cells (Marsh, 1992).After the initial treatment with thyrostatics (methimazol) and gluten free diet, strumectomy (accompanied with the liver biopsy) was performed.Liver histopathological findings showed inflammatory (grading 2 in the Batts' scale) and fibrotic (staging 2) changes with no evident features of autoimmune process such as portal bridging necrosis and fibrosis with massive inflammatory infiltrates of lymphocytes and plasma cells and interface hepatitis (Fig. 2) (Batts et al., 1995).Consecutive substitutive hormonal therapy and gluten free diet finally resulted in euthyreosis, normal liver function tests.Control liver biopsy performed in 4 months time showed full regression of inflammatory changes and minor fibrous changes (staging S0/S1) (Fig. 3).

DISCUSSION
Liver function abnormalities were noted few times in the course of the Graves' disease in our patient.Laboratory abnormalities ranged from the increase in aminotransferases activity with cholestasis in the time of PTU treatment, euthyrodism and respiratory tract infection treated with antibiotics to high activity of liver enzymes next to hyperthyroidism and tissue antibodies presence strongly suggestive of some other autoimmune diseases.Sophisticated and comprehensive diagnostic approach was warranted along with side effects of some drugs, which had to be taken under consideration.
Thyrotoxicosis stands for one of the potential causes of liver dysfunction in patients with Graves' disease.The combination of increased oxygen consumption and inadequate perfusion leading to hepatocyte hypoxia is regarded as the main pathogenic mechanism of liver damage in these patients (Shimizu, 2008).However, in the presented case the timing of liver function abnormalities was poorly correlated with high levels of thyroxin.

A B
Methimazol and propylthiouracyl with some side effects, like increase in liver enzymes, are the antithyroid drugs commonly used in Graves' disease.Most cases of PTU-induced hepatic injury occur in the first few months of PTU therapy (Lazar et al., 2000;Kim et al., 2001).The PTU-induced hepatic injury is manifested histologically as acute cholestatic, hepatocellular or mixed forms.In pediatric patients adverse reactions related to PTU therapy, including moderate increase of liver function tests, are noted in 71% of pre-pubertal vs. 25% of post-pubertal children (Lazar et al., 2000;Kim et al., 2001).Among children receiving transplants due to drug-induced acute liver failure, PTU appears to be the third cause following acetaminophenon and isoniasid (Russo et al., 2004).Clinical manifestation, the results of laboratory tests, the histology of the liver tissue, and the effect of PTU withdrawal are strongly suggestive of this mechanism of liver injury, which was noted at the time of euthyrodism in our patient.
There is a high frequency of anti-neutrophil cytoplasmatic (ANCA) antibodies in patients with Graves' disease treated with PTU.However, in few cases only, a classical ANCA associated vasculitis with kidney or liver manifestation (type 1 autoimmune hepatitis) is observed (Targan et al., 1995;Cui et al., 2003;Sato et al., 2004).Little is still known about some other antibodies in this clinical entity, which may or may not have clinical significance.No ANCA was detected in our patient who also presented with normal kidney function.The presence of SMA and ANA was noted in our patient and appeared to be suggestive of the autoimmune process like autoimmune hepatitis type 1. Autoimmune hepatitis type 2, with the presence of LKM antibodies is reported to appear more often in either children with AIH or patients with Graves' disease (Targan et al., 1995;Cui et al., 2003;Sato et al., 2004).According to the autoimmune hepatitis score system, our patient did not fulfilled the score criteria for the definite diagnosis of AIH.The liver histopathological findings showed no evident features of autoimmune process like portal bridging necrosis and fibrosis with per-portal inflammatory infiltrate of lymphocytes, plasma cells and neutrophils.No glucocorticoids was administered prior to the liver biopsy, which could have abolished the characteristic lymphoplasmacytic infiltrate typical for AIH.
Three types of liver disease are described in celiac disease: mild, transient liver dysfunction, chronic liver disease (with severe fibrosis especially in patients with CD and HCV infection) and autoimmune liver disease (AILD) (Davidson, 2002;Freeman, 2006).They may be within the spectrum of the clinical manifestation of the same disease, where congenital factors and gluten exposure may influence the pattern of liver dysfunction, or may reflect liver abnormalities of different pathogenesis.Non-specific hepatitis with moderate increase in aminotransferases activity is a quite common clinical entity in celiac disease (CD) (Lindberg et al., 1978;Maggiore et al., 1994).
In most cases, aminotransferase normalize with 12 months of gluten-free diet (Novacek et al., 1999;Bardella et al., 1999).Histological changes are mild and include Kupffer cell hyperplasia, mononuclear cell infiltration, steatosis and mild fibrosis (Novacek et al., 1999;Bardella et al., 1999).The latter finding was probably the one, which was noted in the control biopsy in our patient.
In the course of disease and treatment our patient presented with liver injury with the presence of SMA and ANA, but also with the features of cholestasis, which may be suggestive of either autoimmune hepatitis, primary slerosing cholangitis (PSC) and autoimmune slerosing cholangitis (AISC).LKM appear to be the most frequently noted autoantibodies in AIH in the course of either CD or Graves' disease (Volta et al., 1998;Davidson et al., 2002;Cui et al., 2003).However, in some recent studies AIH type 1 is reported to coexist more often with CD even in pediatric group of patients (Rubio-Tapaia et al., 2007;Diamanti et al., 2008).Although according to the autoimmune hepatitis score system, we should have been suspicious of AIH in our patient, the liver histopathological findings showed no typical features of AIH, like portal bridging necrosis and fibrosis with peri-portal inflammatory infiltrate of lymphocytes, plasma cells and neutrophils.Some studies report the prevalence of PSC in CD patients to be increased 4-fold to 8-fold than in individuals without CD (Rubio-Tapaia et al., 2007;Ludvigsson et al., 2007).In other, the prevalence of CD is 1.6% in the group of PSC patients (Volta et al., 1997;Rubio-Tapaia et al., 2007).Liver histology showed no typical features of cholestasis and lymphocytic portal inflammatory process with increased intra-epithelial lymphocytes in biliary ductal epithelium (Frejman et al., 1994;Freeman, 2006).
In summary we highlight the wide range of probable mechanisms involved in the liver injury in the course of Graves' disease and CD.The diagnosis of autoimmune liver disease may cause some difficulties and some other pathogenetic mechanisms should be taken under consideration.
Conflicts of interest and source of funding: none declared.