Low serum total thyroxine and free triiodothyronine in patients with hepatic encephalopathy due to non-alcoholic cirrhosis

The liver plays an important role in the metabolism of thyroid hormones, being involved in their conjugation, excretion and peripheral deiodination, and in synthesising thyroid binding globulin (TBG) [1, 2]. Evidence of an association between chronic diseases of the liver and thyroid alterations have often been reported, but limited information is available on thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy. Most studies have been carried out in patients with cirrhosis of alcoholic origin. Studies have revealed that T4 levels are usually within normal limits, but, as cirrhosis progresses, FT4 levels increase secondary to decreased serum levels of thyroxine-binding protein [3]. T3 and FT3 concentrations are usually decreased in correlation with the severity of the disease, but this is still controverted [4]. To our knowledge, there has been no previous study comparing thyroid hormone levels in patients with non-alcoholic decompensated cirrhosis and those with cirrhosis complicated with hepatic encephalopathy. In this study we investigated thyroid hormone levels in non-alcoholic decompensated cirrhotic patients with and without hepatic encephalopathy. We also attempted to determine whether or not thyroid function tests may be a useful prognostic indicator for the development of hepatic encephalopathy in decompensated cirrhotic patients. Principles: We evaluated serum thyroid hormone levels in non-alcoholic cirrhotic patients with and without hepatic encephalopathy. Methods: 15 consecutive patients with hepatic encephalopathy secondary to non-alcoholic cirrhosis (8 males and 7 females, age 37–75 years) and 33 non-alcoholic cirrhotic patients without encephalopathy (22 males and 11 females, age 36–74 years) were investigated. A control group consisted of 20 healthy subjects (10 men and 10 women aged 26–69 years). The levels of serum triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), free T3 (FT3) and free T4 (FT4) were studied in serum samples drawn in the morning. Thyroid function tests were set in relation to the severity of hepatic dysfunction and to the presence or absence of hepatic encephalopathy. Results: Serum levels of FT3 and total T4 (but not total T3 and FT4) were significantly lower in patients with hepatic encephalopathy compared to decompensated cirrhotic patients without encephalopathy (p = 0.006 for T4, P <0.05 for FT3). Prothrombin-time also differed significantly between decompensated cirrhotic patients (Child C) with and without encephalopathy groups (p = 0.002). Conclusions: These results suggest that patients with hepatic encephalopathy secondary to decompensated non-alcoholic cirrhosis are typified by low FT3 and low total T4, as well as by aprolonged prothrombin time. Low FT3 does not obviously put patients at risk for hepatic encephalopathy, and thyroid parameters are secondary and late events.

The liver plays an important role in the metabolism of thyroid hormones, being involved in their conjugation, excretion and peripheral deiodination, and in synthesising thyroid binding globulin (TBG) [1,2].Evidence of an association between chronic diseases of the liver and thyroid alterations have often been reported, but limited information is available on thyroid function tests in non-alcoholic cirrhotic patients with hepatic encephalopathy.Most studies have been carried out in patients with cirrhosis of alcoholic origin.Studies have revealed that T 4 levels are usually within normal limits, but, as cirrhosis progresses, FT4 levels increase secondary to decreased serum levels of thyroxine-binding protein [3].T 3 and FT 3 con-centrations are usually decreased in correlation with the severity of the disease, but this is still controverted [4].To our knowledge, there has been no previous study comparing thyroid hormone levels in patients with non-alcoholic decompensated cirrhosis and those with cirrhosis complicated with hepatic encephalopathy.
In this study we investigated thyroid hormone levels in non-alcoholic decompensated cirrhotic patients with and without hepatic encephalopathy.We also attempted to determine whether or not thyroid function tests may be a useful prognostic indicator for the development of hepatic encephalopathy in decompensated cirrhotic patients.

Principles:
We evaluated serum thyroid hormone levels in non-alcoholic cirrhotic patients with and without hepatic encephalopathy.
Methods: 15 consecutive patients with hepatic encephalopathy secondary to non-alcoholic cirrhosis (8 males and 7 females, age 37-75 years) and 33 non-alcoholic cirrhotic patients without encephalopathy (22 males and 11 females, age 36-74 years) were investigated.A control group consisted of 20 healthy subjects (10 men and 10 women aged 26-69 years).The levels of serum triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), free T3 (FT3) and free T4 (FT4) were studied in serum samples drawn in the morning.Thyroid function tests were set in relation to the severity of hepatic dysfunction and to the presence or absence of hepatic encephalopathy.
Results: Serum levels of FT 3 and total T 4 (but not total T3 and FT 4 ) were significantly lower in patients with hepatic encephalopathy compared to decompensated cirrhotic patients without encephalopathy (p = 0.006 for T 4, P <0.05 for FT3).Prothrombin-time also differed significantly between decompensated cirrhotic patients (Child C) with and without encephalopathy groups (p = 0.002).
Conclusions: These results suggest that patients with hepatic encephalopathy secondary to decompensated non-alcoholic cirrhosis are typified by low FT3 and low total T4, as well as by a prolonged prothrombin time.Low FT3 does not obviously put patients at risk for hepatic encephalopathy, and thyroid parameters are secondary and late events.

Introduction
No financial support declared.
This study was carried out in 15 patients (mean age 51 ± 8.74 years, range 37-75 years) with hepatic encephalopathy due to non-alcoholic cirrhosis, consecutively admitted to the Division of Gastroenterology, and in 33 non-alcoholic cirrhotic patients (mean age 55 ± 7.71, range 36-74 years) without encephalopathy.20 healthy subjects (10 male, 10 female, aged 49.7 ± 8.45 years, range 26-69 years) matched for age, height and sex served as control group.None of the patients or controls had a history of alcohol consumption.All the subjects were clinically euthyroid, none was known to have a present or past history of thyroid disease and none was taking any drug known to affect thyroid function.The main characteristics of the patients are summarised in table 1.
The diagnosis of cirrhosis was based on case history, clinical examination, biochemical, endoscopic and ultrasound findings, or liver biopsy.Liver biopsies were not performed if coma, reduced coagulability or extensive ascites was present.The functional severity of the liver injury was determined on the basis of the Child-Pugh grading system [5].The size of the groups were as follows: Child A: 9 patients, mean age 51.33 ± 8.81 years (range 37-65 years), Child B: 11 patients, mean age 52.72 ± 7.80 years (range 44-75 years), Child C: 13 patients, mean age 57.21 ± 9.40 years (range 51-72 years).27 patients had positive serological markers for viral hepatitis (19 hepatitis B surface antigen-associated and 8 hepatitis C virus antibody-associated), the remaining 6 having cirrhosis of unknown origin.
The degree of encephalopathy was defined on the basis of previously reported criteria [6] ranked between grade 1 and grade 4. Encephalopathy was related to hepatitis B virus in 10 patients and to hepatitis C virus in 5. Hepatitis B virus infection was assumed if hepatitis B surface antigen was detected in the sera, whereas hepatitis C virus infection was diagnosed when anti-HCV antibodies were found in an enzyme immunosorbent assay (Anti-HCV Enzyme Immunoassay kit, Diasorin S.A., Madrid, Spain).Encephalopathic patients were further divided into two groups, survivors and non-survivors.
On admission, the following parameters for evaluation of the severity of liver dysfunction were recorded: albumin (n: 3.5-5.2g/dl); bilirubin (n: 1.3-3.1 mg/dl); serum aspartate transaminase (AST) (n: 10-30 U/L); serum alkaline phosphatase (ALP) (n: 44-155 U/l) and prothrombin time (n: 1.04-1.5 [INR]).These biochemical tests were performed by standard auto-analyser methods.Plasma prothrombin ratios were measured with human brain thromboplastin tissue (STA-Neoplastine CI Plus kits, France).In all cases, blood samples for hormone determinations were drawn in the morning after overnight fasting.FT3, FT4, T3, and T4 were measured by competitive radioimmunoassay using DPC kit (Diagnostic Products Corporation, United Kingdom).TSH was measured by an immunometric assay method (DPC-UK).On the basis of the patients' and control subjects' thyroid function values we calculated a 95% confidence interval for this parameter.

Statistical analysis
Student's t test was used to compare the continued variables between two groups.The analysis of variance (ANOVA) was used to test the significance of continued variables within groups.All values are reported as mean ± standard deviation.The correlation between serum albumin bilirubin levels, prothrombin time and T3, T4, FT3 levels in both groups was assessed by Pearson's correlation coefficient.P value <0.05 was considered statistically significant.Normal values in our laboratory are as follows: FT3: 1.57-4.71pg/ml; FT4: 0.85-1.78ng/dl: T3: 60-164 mg/dl; T4: 4.5-12.1 µg/dl; TSH: 0.4-4 µIU/ml.

Results
The thyroid function tests in non-alcoholic cirrhotic patients with encephalopathy, in non-alcoholic cirrhotic patients without encephalopathy and in control patients are shown in table 2. Compared to controls, patients with hepatic encephalopathy and decompensated cirrhotic patients (Child C group) showed a significant decrease in T 3 and FT 3 levels (98.7 ± 17.4 ng/dl vs 40.66 ± 9.6, 51.96 ± 8.21 for T 3 and 2.76 ± 0.45 pg/ml vs 1.61 ± 0.38 and 1.15 ± 0.25 for FT 3 re-spectively; p <0.05), whereas there was no difference in serum T4, TSH and FT4 levels.
Cirrhotic patients with hepatic encephalopathy had significantly reduced serum levels of T 4 , FT 3 and T 3 compared to all cirrhotic patients (p = 0.003 for T 4 , p <0.001 for FT 3 and p = 0.004 for T 3), whereas there was no difference in FT4 and TSH levels.No significant differences in T3, T 4 , TSH, FT 3 and FT 4 levels were observed between survivors and non-survivors with hepatic en- Statistical analysis revealed a significant in-verse correlation between serum FT3 concentrations and the severity of liver dysfunction.An inverse correlation was observed between serum bilirubin and T 3 , T 4 levels (r = -0.65,p = 0.014 for T 3 , r = -0.298,p = 0.047 for T 4 ) as well as between prothrombin time and T 3 , T 4 and FT 3 levels in both groups (r = -0.594,p <0.01 for T 3 , r = 0.476, p = 0.001 for T 4, r = -0.515,p = 0.001 for FT3).On the other hand, a positive correlation was found between serum albumin levels and T3, T4 and FT3 levels (r = 0.634, p <0.001 for T3, r = 0.397, p = 0.007 for T4, r = 0.394, p = 0.011 for FT3.Prothrombin time was significantly longer in patients with hepatic encephalopathy than in Child C patients without encephalopathy (p = 0.002).However, no difference was observed between albumin and bilirubin levels.Thyroid dysfunction has been reported previously in a variety of non-thyroid illnesses including liver, pulmonary and renal neoplastic disease, severe systemic illness, fasting, malnutrition, postoperative state, physical trauma and acute infections.Low total and free T3 with normal total T 4 and thyrotropin concentrations in the absence of clinical hypothyroidism have been frequently reported in patients with non-thyroidal illnesses [7,8,9].Several investigations have been performed to assess the relationship between liver disease and thyroid hormones [1,2,7,10].Hepner and Walfish reported a significant inverse correlation between serum T 3 concentrations and the severity of liver dysfunction.A progressive decrease in T 3 levels in chronic liver diseases has been described as indicative of a poor prognosis [10][11][12].Authors ascribed this finding to diminished conversion of T 4 to T 3 and impaired metabolism of thyroxine-binding proteins.In the present study we demonstrated a fall in FT 3 and T3 parallel to severity of the disease, and a good correlation between T3 concentrations, serum albumin and prothrombin time.These results suggest that serum T3 and FT3 concentrations may be considered a sensitive index of hepatic function in liver disease.We chose non-alcoholic patients because alcohol is considered to have a direct toxic effect on thyroid parenchyma, as previously described in chronic alcoholics [13].
Borzio et al. compared cirrhotics with normal subjects and chronic hepatitis patients.They suggested that T 3 serum levels inversely paralleled severity of liver dysfunction [2].Thyroid function tests have also been performed in acute hepatitis [14].T 4 has been found to be elevated in patients with acute viral hepatitis due to elevation of TBG (possibly secondary to release from injured hepatocytes).
Our study differs from previous investigations in that we determined the alterations of thyroid hormone level in non-alcoholic decompensated cirrhotic patients with and without hepatic encephalopathy.We found a significant reduction in serum FT 3 in non-alcoholic cirrhotic patients compared with a control group, the lowest values being found in patients with hepatic encephalopathy.Low FT 3 levels may be due to reduced extra-thyroidal T 4 -to-T 3 conversion, the mechanism being inversely related to the degree of hepatic dysfunction.
We found no significant difference in functional thyroid parameters between patients surviving and not surviving hepatic encephalopathy (p <0.375), but Guven et al. have reported lower T 3 levels in patients who died than in patients who survived [7,10,15].The reason for this difference is not clear.
In conclusion, patients with decompensated liver disease complicated by hepatic encephalopathy subsequent to non-alcoholic cirrhosis were found to have exceedingly low serum FT 3 and T4 levels.Depressed serum FT3 and T4 levels, together with a prolonged prothrombin-time, therefore appear to be characteristic of a subgroup of decompensated cirrhotic patients prone to develop hepatic encephalopathy.
ˇrul Kayacetin Selcuk Universitesi Meram Tip Fakultesi Ic Hastaliklari AD, Gastroenteroloji BD Meram/Konya Turkey E-Mail: ekayacetin@mynet.com Swiss Medical Weekly: Call for papers Swiss Medical Weekly The many reasons why you should choose SMW to publish your research Official journal of the Swiss Society of Infectious disease the Swiss Society of Internal Medicine the Swiss Respiratory Society Med Wochenschr (1871-2000) Swiss Med Wkly (continues Schweiz Med Wochenschr from 2001) Editores Medicorum Helveticorum