Risk factors of hepatic dysfunction in patients with Graves’ hyperthyroidism and the efficacy of 131iodine treatment

Abstract Hepatic dysfunction is often observed in patients with Graves’ hyperthyroidism. The aims of this study were to investigate the risk factors for hepatic dysfunction and to analyze the efficacy of 131I (radioactive iodine-131) treatment. In total, 2385 patients with Graves’ hyperthyroidism (478 males, 1907 females; age 42.8 ± 13.5 years) were involved in our study. Of these, 1552 cases with hepatic dysfunction received 131I treatment. All clinical data were retrospectively reviewed to explore the risk factors associated with hepatic dysfunction using logistic regression analysis. Furthermore, we observed thyroid and liver function indices for the 1552 subjects at 3, 6 and 12 months after 131I treatment, in order to evaluate efficacy. Overall, 65% patients were affected by hepatic dysfunction. The most common abnormality was elevated alkaline phosphatase (ALP), of which the prevalence was 52.3%. The percentages of hepatocellular injury type, bile stasis, and mixed type were 45.8%, 32.4%, and 21.8%, respectively. Both univariate and multivariate analyses demonstrated that age, duration of Graves hyperthyroidism, free triiodothyronine (FT3)level, and thyrotrophin receptor antibody (TRAb) concentration were the most significant risk factors predicting hepatic dysfunction. Additionally, the patients with mild hepatic dysfunction, or hepatocellular injury type were more likely to attain normal liver function after 131I treatment. Furthermore, after 131I treatment, liver function was more likely to return to normal in the cured group of patients compared with the uncured group. Older patients and cases with a longer history of Graves’ hyperthyroidism, higher FT3 or TRAb concentration were more likely to be associated with hepatic dysfunction, and the prognosis of hepatic dysfunction was closely associated with the outcomes of Graves’ hyperthyroidism after 131I treatment.


Introduction
Graves hyperthyroidism is an autoimmune thyroid disease which can affect multiple organ systems, including the cardiovascular, gastrointestinal, and hepatic systems. In clinical practice, hepatic dysfunction in patients with Graves hyperthyroidism is common. [1,2] Although most patients have no obvious clinical symptoms, except for abnormal liver function indices, serious liver injury, and even liver failure can occur in a few patients. [3][4][5] There are 3 main factors that contribute to hepatic dysfunction in the context of hyperthyroidism, including the independent effects of excessive thyroid hormones, antithyroid drug (ATD)related liver injury, and the presence of concomitant liver disease. Historically, the control of hyperthyroidism has required 3 options including ATD, surgery, and radioiodine-131 therapy (RIT). In China, the current treatment guideline for Graves hyperthyroidism states that RIT should be the first choice of treatment in patients with hepatic dysfunction. [6] This has proven to be a relatively safe procedure with a high cost-effective ratio in retrospective studies. The normal interaction between the thyroid and liver is critical for maintaining homeostasis. However, to date, reports demonstrating predictive factors related to hepatic dysfunction in Graves' hyperthyroidism are both scarce and controversial, and studies exploring RIT and liver function are rare. Therefore, identification of the factors resulting in hepatic dysfunction is crucial.
In the present study, we retrospectively collected large-scale clinical data on 2385 patients with Graves hyperthyroidism to investigate the risk factors for hepatic dysfunction in patients with Graves hyperthyroidism and further analyzed the therapeutic effect of 131 I treatment.

Ethics statement
This study is a retrospective clinical study. It is the summary and analysis of a large number of clinical data. The ethics committee of Tianjin Medical University General Hospital waived the need to obtain written informed consent from all patients. All clinical data used in this study were analyzed anonymously.

Patients
A total of 2385 patients who were diagnosed with Graves hyperthyroidism (478 males, 1907 females; age 42.8 ± 13.5 years) were retrospectively reviewed. Graves hyperthyroidism was diagnosed on the basis of thyrotoxicosis, increased thyroid hormones and decreased thyroid-stimulating hormone (TSH), elevated thyroid radioiodine uptake, and diffuse goiter, or exophthalmos, or pretibial myxedema, or positive TRAb. [7] Of these, 1073 patients had been treated with ATD before, and 1552 cases were associated with hepatic dysfunction and received RIT. We used hepatitis virus markers, abdominal ultrasonography, echocardiography, and determination of auto-antibodies and immunoglobulin subtypes for patients with hepatic dysfunction, in order to exclude other apparent causes of liver damage. Other causes included viral hepatitis, liver cirrhosis or biliary tract disease, chronic cardiac dysfunction or autoimmune liver disease.
According to the different liver function indices, hepatic dysfunction was further classified as hepatocellular injury type, bile stasis type, or a mixed type.

Parameter assessments
Thyroid function tests were measured by chemiluminescence immunoassays (ADVIA CENTAUR XP SIEMENS AG). TPOAb and TgAb were detected by immulite (Immulite 2000 SIEMENS AG), and TRAb was detected by ELISA (enzyme-linked immunosorbent assay) (MEDIPAN Germany). Liver function indexes were measured by colorimetry (Hitachi C7600 Japan).

Patient follow-up and efficacy after 131 I treatment
We measured serum levels of thyroid and liver function indices on the 1552 patients at 1, 3, 6, and 12 months after 131 I therapy to evaluate the treatment efficacy. We defined complete remission (euthyroid) and hypothyroidism as "cure" (cured group), and partial remission, inefficacy, or recurrence as "uncure" (uncured group).

Statistical analysis
A chi square test was used to analyze the difference between the ratios. To identify the risk factors for hepatic dysfunction, we used a bivariate logistic regression model (univariate analysis) and stepwise logistic regression (multivariate analysis) with a variable entrance criterion of 0.05 or less. Missing values for TgAb and TPOAb were assigned to the mean level. All P values presented were 2-tailed, and values < 0.05 were considered to be statistically significant. Statistical analysis was performed using SPSS (Statistical Package for Social Sciences) for windows, version 12.0 (SPSS, Chicago, IL).

Clinical features of hepatic dysfunction
Overall, 65% (1552/2385) of patients with Graves hyperthyroidism were affected by hepatic dysfunction. Moreover, we found the prevalence of hepatic dysfunction was 68.1% (731/1073) in ATD-treated patients, and prevalence was 62.6% (821/1312) in patients without ATD treatment. The patients who received ATD treatment had a significantly higher prevalence of hepatic dysfunction compared with those who did not receive ATD treatment (P = 0.005).

Outcome of hepatic dysfunction after 131 I treatment
The outcome of hepatic dysfunction after 131 I treatment is displayed in Table 3. In total, the liver function tests returned to normal in 77.3% (1200/1552) of patients with hepatic dysfunction 6 months after 131 I treatment. Moreover, we found that the remission rates in patients with mild, moderate, and severe hepatic dysfunction were 86.8%, 65.5% and 55.9%, respectively. Additionally, the remission rate of mild hepatic dysfunction was higher than that of moderate (P < 0.001) or severe dysfunction (P < 0.001). Similarly, we found the remission rates with hepatocellular injury type, bile stasis, and mixed type were 91.7%, 59.2%, and 74.0%, respectively, and the remission rate of hepatocellular injury type was also higher than that of bile stasis (P < 0.001) or the mixed type (P < 0.001).

Efficacy of Graves' hyperthyroidism and outcome of hepatic dysfunction after 131 I treatment
We measured serum levels of thyroid and liver function indices on the 1552 patients with Graves' hyperthyroidism at 3, 6, and 12 months after 131 I treatment to evaluate the therapeutic effect. In Table 1 Bivariate logistic regression analysis of the factors for Graves' hyperthyroidism accompanied by hepatic dysfunction.  the present study, we defined complete remission (euthyroid) and hypothyroidism as cure (cured group), and partial remission, inefficacy or recurrence as uncure (uncured group). The relationship between efficacy of Graves' hyperthyroidism and outcomes of hepatic dysfunction after 131 I treatment are displayed in Table 4. The cure rate of Graves' hyperthyroidism (including euthyroid and hypothyroidism) was 72.6% (1126/1552) after initial 131 I therapy. Hypothyroidism occurred in about 34.1% of (530/ 1552) patients. The liver function tests in 90.8% (1022/1126) of the cured group patients returned to normal, although the remission rate of hepatic dysfunction was only 41.8% (178/426) in the uncured group of patients. The remission rate of hepatic dysfunction in the cured group was higher than that of the uncured group (P < 0.001). Thus, the prognosis for hepatic dysfunction was significantly associated with the outcomes of Graves' hyperthyroidism.

Discussion
In clinical practice, hepatic dysfunction in Graves' hyperthyroidism patients is common. Most of these patients have no obvious symptoms except for mild nonspecific discomfort. Only a minority of patients suffer from severe liver damage and develop liver failure. The mechanism may be related to the following factors: [11][12][13][14][15] (1) long-term excessive thyroid hormones produnction has direct toxicity on the liver; (2) thyrotoxicosis hastens liver glycogen and protein decomposition, which causes liver cell degeneration; (3) A hypermetabolic state leads to an increasement in organic energy consumption and liver burden. However, the blood supply to the liver does not concomitantly increase. This causes hepatocellular anoxia and free radical damage; (4) autoimmune mechanisms might have a role in the process of hepatocyte injury; (5) hyperthyroid heart disease with cardiac insufficiency might cause hepatic ecchymosis and hepatocyte necrosis; 6. ATD has direct toxicity on the liver. It might be related to the individual's heterogeneous reaction.
Our study demonstrated that 65% of patients with Graves' hyperthyroidism were associated with different degrees of hepatic dysfunction. Most of these patients had mild or moderate liver injury, and severe hepatic dysfunction occurred in only 6.6% of patients. Additionally, an increase in ALP was found to be the most common abnormal indicator, and the prevalence was 52.3%.
To explore the risk factors of hepatic dysfunction for patients with Graves' hyperthyroidism, we analyzed 13 related factors, such as age and gender, and found that hepatic dysfunction is more likely to occur in patients aged ≥45 (OR = 2.386), a history of Graves' hyperthyroidism >3 years (OR = 3.985), heart rate >90 bpm (OR = 1.617), FT 3 level >19.5 pmol/L (OR = 2.116), TRAb concentration >15IU/L (OR = 1.857), and positive TPOAb (OR = 1.453) using univariate analysis (all P < 0.01). Additionally, we found that older subjects, cases with longer duration of Graves' hyperthyroidism, higher FT 3 level or higher TRAb concentrations were more likely to be associated with hepatic dysfunction as patients with Graves' hyperthyroidism using multivariate logistic regression analysis. The findings are different from previous research data of Li's group. [16] Li's research showed that the influential factors for hepatic function injury were age, hyperthyroidism duration, heart rate, thyroid weight, FT 4 , RAIU, TgAb, TPOAb, and TRAb. However, their research subjects were patients with hyperthyroid hepatic injury and those patients who had been treated with ATD were excluded from their analysis.
Older patients are more likely to have chronic cardiac insufficiency, hepatic vein congestion, or even liver centrilobular necrosis. [17] The liver plays an important role in thyroid hormone metabolism. In those patients with long-term duration of Graves' hyperthyroidism, excess thyroid hormones increase liver burden, and have direct toxicity on the liver, so the likelihood of hepatic dysfunction rises. [12,14] Increased TRAb concentration indicates an active autoimmune response, [18] which results in hyperfunction of the thyroid gland, an increased excitability of multiple systems and augmented metabolism. [19,20] Our study showed that patients with hepatic dysfunction had higher TRAb levels, which corroborates recent reports. [21] FT 3 has more tissueactivity than FT 4 , and studies have confirmed excess T 3 induces apoptosis of hepatocytes. [22] Excessive thyroid hormones secretion may cause superfluous oxidative stress, an imbalance between pro-oxidant and antioxidant, which can then lead to hepatocyte damage. [23] In addition, excessive thyroid hormones increase heart rate and cardiac output. However, in the liver, increased tissue oxygen consumption may cause hepatocellular anoxia resulting in liver injury. [24,25] Thus, higher TRAb or FT 3 level can increase the risk of hepatic dysfunction for patients with Graves' hyperthyroidism.
In total, hepatic function indices returned to normal 6 months after 131 I treatment in 77.3% of patients. Moreover, the remission rate of mild hepatic dysfunction (86.8%) was higher than that of moderate (65.5%) or severe dysfunction (55.9%), and the remission rate of hepatic dysfunction for hepatocellular injury type (91.7%) was higher than that for bile stasis (59.2%) or the mixed type (74.0%). Therefore, the remission rate of hepatic dysfunction is closely related to its severity and types. Additionally, our study revealed that progntosis of hepatic dysfunction was associated with the outcomes of Graves' hyperthyroidism. The remission rate of hepatic dysfunction in the cured group of patients (90.8%) was higher than that in the uncured group of patients (41.8%). 131 I treatment should be the  Table 4 The relationship between efficacy of 131 I treatment for Graves' hyperthyroidism and outcomes of hepatic dysfunction after treatment. prior choice for those patients with hepatic dysfunction in order to control hyperthyroidism timely and effectively. The metabolic process of 131 I usually does not cause radiation damage to the liver. [26] In our study, hepatic dysfunction mildly deteriorated in the 2 weeks after 131 I treatment in a small minority of patients with severe liver damage. This may be related to the early release of thyroid hormones and the transient aggravation of hyperthyroidism. We did not observe an obvious exacerbation of hepatic dysfunction through long-term follow-up.

Efficacy of hyperthyroidism
Our study had some inherent limitations associated with the retrospective analysis. The 1552 patients involved in our study had hepatic dysfunction induced by Graves hyperthyroidism and/or ATD. Those patients with liver diseases (such as autoimmune liver disease) or biliary tract diseases were rejected. However, corresponding testing or examination was not universally performed to exclude these patients. Additionally, we selected the cases with complete data to perform our retrospective analysis. The exclusion of a few patients who were lost to follow-up might result in potential bias. Therefore, rigorous prospective studies will need to be performed to confirm these preliminary findings.

Conclusions
Hepatic dysfunction is more likely to occur in older patients, and cases with a longer history of Graves' hyperthyroidism, and higher FT 3 or TRAb concentrations. Additionally, the prognosis of hepatic dysfunction is closely associated with the outcomes of Graves hyperthyroidism after 131 I treatment.