Introduction: Liver cirrhosis is often associated with altered thyroid function, which may reflect the severity of liver dysfunction. Understanding this relationship can help in predicting disease progression and prognosis in cirrhotic patients. The aim of this study was to demonstrate the relationship between thyroid function tests and the severity of liver function in cirrhosis of the liver. Method: A total of 73 patients diagnosed with cirrhosis of liver based on clinical, biochemical, and radiological findings were included. Results: Majority of the patients belonged to the age group of 41-59 years (63%) with male predominance (79.4%). Alcoholism (84.9%) emerged as the leading cause of liver cirrhosis. Fatigue (73.9%), body ache (57.5%), and dysphagia (54.7%) were the most common clinical symptoms linked to thyroid dysfunction. Using the Child-Pugh classification system, 15 patients were categorized as Child A, 37 as Child B, and 21 as Child C. Hypothyroidism (65.7%) was more prevalent than hyperthyroidism among the patients. Significant correlations were found between T3, FT3, and TSH levels and the severity of liver dysfunction, as classified by the Child-Pugh score (p<0.05). Hepatic encephalopathy (42.85%) was the main complication causing mortality, and all fatal cases (7) had abnormal thyroid profiles. Conclusion: In conclusion, altered T3, FT3, and TSH levels were associated with disease progression in cirrhosis and can serve as valuable indicators for prognosis. These findings suggest that thyroid function tests should be considered in evaluating the severity of liver disease progression and outcome of cirrhosis in affected patients.
The histological development of regenerating nodules encircled by fibrous bands in response to chronic liver injury a condition that causes portal hypertension and end-stage liver disease is known as cirrhosis. Clinically, cirrhosis is classified as either "compensated" or "decompensated." Having one or more of the following symptoms is known as decompensation: bleeding varices, ascites, hepatic encephalopathy, or jaundice.1 Ascites is often the first sign of decompensation. Without these complications, the patient is said to have compensated cirrhosis.2
The thyroid gland, the body's largest endocrine organ, plays a key role in metabolism by producing hormones that are processed, metabolized, and eliminated by the liver. Therefore, liver disease can significantly influence thyroid function, leading to thyroid metabolic disorders.3 Conversely, thyroid dysfunction can impact liver function. The relationship between the thyroid and liver function has long been recognized, with research showing that thyroid hormone imbalances can affect the severity and prognosis of liver disease.4 However, the thyroid gland produces three key hormones: thyroxine (T4), triiodothyronine (T3), and calcitonin. T3 is primarily formed by the deiodination of T4 in peripheral tissues. While reverse T3 (rT3) is also created, T3 is the active form of the hormone, and rT3 is biologically inactive. T3 and thyroid hormone are essential for the development, growth, and proper function of organs, including the liver. They regulate the metabolic rate of cells, including hepatocytes, which in turn, influence hepatic function. The liver also plays a significant role in metabolizing thyroid hormones and modulating their systemic endocrine effects.5
The relationship between liver and thyroid function is complex. The liver influences the activation, storage, metabolism, and transportation of thyroid hormones. It produces the proteins that attach to thyroxin (T4) to carry it through the bloodstream, including albumin, T4-binding prealbumin, and globulin. Furthermore, the liver is responsible for converting T4 into the more physiologically active T3, a process facilitated by the enzyme iodothyronine-5-deiodinase, which is primarily located in the liver and kidneys. The liver also removes rT3, an inactive form of T4. About 25% of daily secreted T4 is metabolized by the liver or excreted into bile after glucuronidation and sulphation.6
Cirrhosis impairs the liver’s ability to convert T4 into T3, which results in reduced serum T3 levels. This reduction is primarily due to decreased hepatic deiodination and cellular uptake of thyroid hormones. As liver function deteriorates, serum levels of T3, T4, and thyroid-binding proteins decline. Consequently, the reduced conversion of T4 to T3 in the liver, along with poor hepatic absorption of thyroid hormones, may bring the body into a catabolic state, potentially providing a "protective" effect during severe liver dysfunction.7 Several studies have consistently shown low levels of free T3 (FT3) in patients with cirrhosis, despite normal thyroid-stimulating hormone (TSH) levels, indicating a state of clinical euthyroidism. FT3 levels have been strongly correlated with the severity of liver dysfunction, making it a useful indicator of disease progression.8 The aim of this study was to demonstrate the relationship between thyroid function tests and the severity of liver function in cirrhosis of the liver.
After obtaining Institutional Ethical Committee approval and written informed consent from all the patients, this prospective observational study was conducted at internal medicine department in a tertiary care medical centre during a period of 18 months. A total of 73 patients aged 12-80 years of both gender with cirrhosis of liver based on clinical, biochemical, and radiological findings were included in the study. Patient with prior history of thyroid disease, who underwent thyroidectomy, receiving drugs that may interfere with thyroid metabolism and function, patient with diabetes mellitus (NAFLD), pregnancy, age less than 12 years of age and those not willing to give written consent were excluded from the study. A detailed history was taken, and physical examination was done, detailed drug history was taken as per predesigned proforma. Severity of liver dysfunction was graded by using Child Pugh Scoring. The following blood investigations were performed on the cases: Complete blood count, Renal function test, Liver function test, Serum electrolyte, HBV, HCV, Prothrombin time, aPTT and INR, FBS, PPBS, HbA1c, Thyroid function test: T3, T4, FT3, FT4, TSH, Serum proteins- serum albumin, serum globulin. Reference range for biochemical parameters in the study was as- TSH -0.25-5.0 IU/ml, T3- 0.4-2.04 ng/ml, T4- 4.5- 12.6 g/dl, FT3- 2.3-4.2pg/ml, FT4- 0.8-2.0pg/ml. Radiological investigation including Chest X-ray and USG abdomen as well as ECG was done.
Statistical analysis
Data was analysed using IBM SPSS Ver. 20.0.0.0. Descriptive statistics was presented in the form of numbers and percentages. Association between the two non-parametric variables was evaluated using Pearson Chi-square test. Proportional comparison was done using t test for two sample proportion. A p value <0.05 was considered as statistically significant.
Among the 73 patients, majority of the patients were aged between 41-59 years (63%), with a male predominance (79.4%), (Table 1). Alcoholism was identified as the primary cause of cirrhosis in 62 (84.9%) patients, followed by alcoholism with HBV infection (6; 8.2%). Alcoholism with HCV related cirrhosis had the least incidence (5; 6.9%).
Table 1: Age and gender distribution
Age group (years) |
Male |
Female |
Total |
12 to 30 |
04 (6.8%) |
00 (0.0%) |
04 (5.4%) |
31 to 40 |
07 (12%) |
00 (0.0%) |
07 (9.5%) |
41 to 60 |
31 (53.4%) |
15 (100.0%) |
46 (63.0%) |
>60 |
16 (27.5%) |
00 (0.0%) |
16 (21.9%) |
Total |
58 (79.45%) |
15 (20.54%) |
73 (100.0%) |
Fatigue (73.9%), Body-ache (57.5%), Dysphagia (54.7%), Weight gain (32.8%), Constipation (21.9%) were the major clinical symptoms related to thyroid dysfunction seen in study cases. Signs of Thyroid dysfunction seen among the cases were either due to hypothyroidism or hyperthyroidism. Signs of hypothyroidism seen in study cases included- Bradycardia (56.16%), Hypothermia (42.46%,), Anasarca (35.61%,), Hoarseness of voice (24.65%), Delayed tendon reflexes (15.06%) and Dry skin (31.5%). Signs of hyperthyroidism seen in study cases included- Hyperthermia (16.43%), Exophthalmos (12.32%), Tremors (10.95%), Tachycardia (9.58%) and Hyperhidrosis (6.84%), (Table 2).
Table 2: Clinical symptoms and clinical signs of thyroid dysfunction
Clinical symptoms |
Frequency (%) |
Clinical signs |
Frequency (%) |
Fatigue |
54 (73.9%) |
Bradycardia |
41 (56.16%) |
Body-ache |
42 (57.5%) |
Tachycardia |
07 (9.58%) |
Dysphagia |
40 (54.7%) |
Hypothermia |
31 (42.46%) |
Weight gain |
24 (32.8%) |
Hyperthermia |
12 (16.43%) |
Constipation |
16 (21.9%) |
Anasarca |
26 (35.61%) |
Sleep apnea |
14 (19.1%) |
Exophthalmus |
09 (12.32%) |
Snoring |
11 (15.0%) |
Hoarseness of voice |
18 (24.66%) |
Weight loss |
05 (6.8%) |
Delayed muscle reflexes |
11 (15.06%) |
Dysarthria |
02 (2.7%) |
Tremors |
08 (10.95%) |
Diarrhoea |
02 (2.7%) |
Hyperhidrosis |
05 (6.84%) |
Menstrual irregularities |
02 (2.7%) |
Dry skin |
23 (31.50%) |
Patients were classified according to Child Pugh scoring, the majority of cases belonged to Child class B (50.6%), followed by 28.7% of cases in Child class C and 20.5% cases in Child class A as depicted in figure 1.
Figure 1: Distribution of patients according to Child Pugh score
In this study, 60.2% (n=44) of the cases had low total T3 levels. Among them, 25 cases were in Child B and 17 in Child C, with a significant correlation between low T3 and the severity of liver dysfunction (p<0.001). Gender analysis showed that 60% of female cases (9 cases) had normal T3, whereas 65.5% of male cases (38) had low T3 levels. Most cases (83.5%) had normal total T4 levels. Hypothyroidism was present in 65.7% of cases, with 48 showing high TSH levels. A significant correlation (p<0.001) was found between elevated TSH and advanced liver disease, with higher TSH in 27 Child B cases and 18 Child C cases. Only 3 Child A cases had high TSH. Among females, 86.6% had normal TSH, while 79.3% of males had elevated TSH levels. Additionally, 73.9% (n=54) of cases had low FT3, with 13 Child C cases, 31 Child B cases, and 10 Child A cases showing low FT3. This demonstrated FT3 as a sensitive marker for liver disease severity (p<0.001). FT3 was low in 79.3% of males and 53.3% of females. FT4 was normal in 61.6% of cases and showed no significant correlation with Child-Pugh scoring. Overall, T3, FT3, and TSH levels significantly correlated with the severity of liver dysfunction, as determined by Child-Pugh classification (p<0.001), (Table 3).
Table 3: Distribution of patients by gender and thyroid hormones levels (T3, T4, TSH), and comparison of thyroid hormones levels with Child-Pugh Score.
T3 levels (nmol. /L) |
Child Pugh score |
Gender |
Total |
|||
A |
B |
C |
Female |
Male |
||
< 0.4 |
02 |
25 |
17 |
06 |
38 |
44 (60.2%) |
0.4 - 2.04 |
13 |
09 |
04 |
09 |
17 |
26 (35.6%) |
> 2.04 |
00 |
03 |
00 |
00 |
03 |
03 (4.1%) |
T4 levels (ug/dl) |
Child Pugh score |
Gender |
Total |
|||
A |
B |
C |
Female |
Male |
||
< 4.5 |
05 |
03 |
03 |
03 |
08 |
11 (15.0%) |
4.5 – 12.6 |
10 |
34 |
17 |
12 |
49 |
61 (83.5%) |
> 12.6 |
00 |
00 |
01 |
00 |
01 |
01 (1.3%) |
TSH levels (IU/M) |
Child Pugh score |
Gender |
Total |
|||
A |
B |
C |
Female |
Male |
||
0.25 – 5.0 |
12 |
10 |
03 |
13 |
12 |
25 (34.2%) |
5.1 – 10.0 |
03 |
27 |
18 |
02 |
46 |
48 (65.7%) |
FT3 levels (pg/ml) |
Child Pugh score |
Gender |
Total |
|||
A |
B |
C |
Female |
Male |
||
<2.3 |
10 |
31 |
13 |
08 |
46 |
54 (73.9%) |
2.3 – 4.2 |
03 |
04 |
07 |
06 |
08 |
14 (19.1%) |
>4.2 |
02 |
02 |
01 |
01 |
04 |
05 (6.8%) |
FT4 levels (ng/dl) |
Child Pugh score |
Gender |
Total |
|||
A |
B |
C |
Female |
Male |
||
<0.8 |
02 |
16 |
09 |
05 |
22 |
27 (36.9%) |
0.8 – 2.0 |
13 |
21 |
11 |
10 |
35 |
45 (61.6%) |
>2.0 |
00 |
00 |
01 |
00 |
01 |
01 (1.3%) |
The significance of T3 versus FT3 in determining the severity of liver dysfunction was determined using Pearson's correlation. It was found both are inversely related to Child-Pugh scoring and patients with child c scoring had low T3 and FT3. Since FT3 had a higher Pearson's coefficient, it may be a more sensitive marker of liver dysfunction, (Table 4).
Table 4: Correlation between T3 and FT3 with Child Score
Thyroid function tests |
Pearson’s Correlation (r-value) |
Strength of correlation |
P value |
T3 |
-0.468 |
Moderate negative correlation |
<0.001** |
FT3 |
-0.571 |
Moderate negative correlation |
<0.001** |
T3 & FT3 |
0.534 |
Moderate positive correlation |
<0.001** |
Patients were screened for liver cirrhosis related complications and these included Ascites (75.34%), Hepatic encephalopathy (71.23%), Coagulopathy (64.38%), Spontaneous bacterial peritonitis (42.46%), Hepatorenal syndrome (28.76%), Hepatopulmonary syndrome (2.73%), and hepatocellular carcinoma (1.36%), (Figure 2).
Figure 2: Distribution of patients according to complications of Liver Cirrhosis
Patients were screened for thyroid associated complications, and these included coronary artery diseases, pericardial effusion, myxoedema coma, infertility, recurrent infections and depression. These complications were seen in 20.54%, 5.47%, 6.84%, 10.95%, 16.43%, 4.10% cases respectively, (Figure 3).
Results of starting on thyroxine supplementation (weight based or as per clinically indicated) in above complications: Of the 15 cases with coronary artery disease, 6 cases (40%) showed improvement after thyroxine supplementation. Pericardial effusion was present in 4 cases, with 2 cases (50%) demonstrating improvement. Additionally, 2 cases of myxedema coma were identified, and 1 case (50%) experienced improvement following thyroxine supplementation.
Figure 3: Distribution of cases according to thyroid- associated complications
Mortality data of the study included four complications which were related to the cause of death as shown in table 5. Hepatic encephalopathy (42.85%) were the most frequent complications, contributing to mortality followed by coagulopathy (28.57%).
Table 5: Distribution of cases according to the complication leading to death of cases.
Complication causing death |
Number of deaths |
Percentage of total deaths |
Hepatic encephalopathy |
03 |
42.85 |
Coagulopathy |
02 |
28.57 |
Hepatorenal syndrome |
01 |
14.28 |
Hepatocellular carcinoma |
01 |
14.28 |
Total |
07 |
100.0 |
In the present study, it was observed that low FT3, FT4, T3 and slightly raised TSH in most of the patients. Patients with chronic liver disease have been observed to exhibit low T3 syndrome on a regular basis9 Out of the 73 patients, 21 (28.7%) belonged to Child-Pugh class C, 37(50.6%) as Child-Pugh class B and remaining 15(20.5%) as Child-Pugh class A. This demonstrates that the majority of individuals with decompensated liver cirrhosis arrived at an advanced stage. Major causes for cirrhosis were alcoholic liver disease followed by alcohol with hepatitis B associated cirrhosis and alcohol with HCV related cirrhosis this is in line with the studies done by Mukarjiee PS et al.10 We found that free T3 levels were inversely correlated with the Child-Pugh class as similar to the previous studies by Kamath PS et al11 whereas on Model for end stage liver disease also suggested similar results in studies by Verma et al12 which showed low free T3 and low total T3 in patients with decompensated liver disease. Patients with liver cirrhosis had considerably lower levels of FT3 in investigations by Kayacetin et al13 When compared to all cirrhotic survivors, FT3 levels were similarly considerably lower in all cirrhotic nonsurvivors.13 However, the negative relationship between the severity of liver injury and the decreased free T3 levels observed in patients with cirrhosis of the liver has been explained by a number of processes. One theory claims that the so-called sick euthyroid syndrome is primarily caused by a lack of peripheral deiodination, which results in lower free T3 levels.13 In patients with liver cirrhosis, a drop in free T3 has been associated with poor nutrition14. It's possible that the release of cytokines like interleukin-6 (IL-6) is what causes ill euthyroid syndrome. Additionally, there is a clear correlation between alcohol consumption and decreased hepatic deiodinase activity.15
Out of 73 cases, 65.7% of cases had high TSH and 34.2% cases had normal TSH, the prevalence of hypothyroidism was found to be 65.7%. Out of 15 cases of Child A, 12(80%) had normal TSH and 3 (20%) had high TSH. Out of 37 cases of Child B 27(72.9%) had a high TSH and 10 (27%) had normal TSH and out of 21 cases of Child C, 18(85.7%) had high TSH and 3 (14.2%) had normal TSH. Study demonstrated that as the severity of cirrhosis increased from Child- Pugh as the TSH serum level rose from A to C over the normal range, the p value was statistically significant at 0.001. These results were in line with research conducted by Punker et al1. T3 levels were observed to be low in children B and C who had decompensated liver illness. Apart from all other body cells, thyroid and triiodothyronine regulate baseline metabolic rate in hepatocytes, which in turn modulates hepatic function. By metabolizing hormones, the liver also controls the amount of T3 and T4 in the blood, producing a controlled endocrine action. Type 1 and type 3 deiodinases are the two primary enzymes that function in the liver as part of the iodothyronine seleno-deiodinase enzyme system. They are in charge of the inactivation of thyroid hormones and the extra thyroidal synthesis of T3.16 The results were in line with research conducted by Trivedi PJ et al17 and suggest that the decline in total T3 is likely due to a decrease in deiodinase 1 activity in the liver of cirrhotic individuals. Regardless of the Child Pugh score, T4 was within the normal range for all instances. These results were in contrast to research conducted by Kayacetin E et al13 where 10% of patients had elevated T4 levels and 33% had low T4 levels; in this study, however, 57% of patients had normal T4 levels.13
The majority of the cases involving Child B and C had FT4 levels within the normal range. These results contrasted with research conducted by Verma SK et al12, which discovered a statistically significant correlation between low free T4 and other indicators of liver dysfunction.12 Thyroid function test abnormalities are frequently observed in liver disease patients. The kind and degree of the liver illness affect these anomalies. Decreases in T3 generation may indicate a direct influence of liver disease on the deiodinative process rather than an indirect consequence of systemic sickness, as the liver is most likely the location of greatest importance for the conversion of T4 to T3.
Thyroid hormone transport in blood is greatly impacted by liver disease since the liver is where all three of the binding proteins—albumin, TBPA, and TBG—are synthesized. Because they affect peripheral enzyme pathways, hepatic and renal disease, as well as catabolic states like those brought on by severe injury, illness, or trauma, consistently cause changes in the thyroid hormone profile. The quantity of remnant functional liver tissue determines the abnormal thyroid function test levels in cirrhosis. Overall T4 is typically lower or unchanged, and FT3 is either lower or unchanged.18 In the present study Pearson’s coefficient was used and it was found that both FT3 and T3 were reliable indicators for prognostication of liver disease and FT3 was a more sensitive indicator than total T3.
The limitations of this study include the need for a larger sample size to generalize the findings to the broader population. Additionally, other potential contributory factors, such as autoimmune thyroid disorders, were not explored in the study, which may have influenced the results. Furthermore, the possibility of a sick-euthyroid state, commonly seen in other infectious and inflammatory conditions, could explain the altered thyroid function in some cases, potentially confounding the interpretation of thyroid dysfunction specifically related to cirrhosis. These factors should be considered when interpreting the study's outcomes.
This study found a male predominance in liver cirrhosis cases, with the majority of patients aged 41-59 years and alcoholism as the leading cause. Hypothyroidism was more common than hyperthyroidism in these patients. Thyroid function tests, particularly T3, FT3, and TSH levels, significantly correlated with liver disease severity, as assessed by the Child-Pugh classification. The data suggest that lower levels of T3 and FT3 and higher TSH levels are predictive of advanced liver disease, underscoring their value in determining prognosis. Hepatic encephalopathy was the main complication causing mortality, and all fatal cases had abnormal thyroid profiles. This highlights the potential role of thyroid function as an important marker in predicting disease severity and prognosis in cirrhotic patients. The study emphasizes the importance of regular assessment of thyroid function in patients with liver cirrhosis, as these tests could provide critical insights into the progression and outcomes of the disease. Thus, we recommend incorporating T3, FT3, and TSH evaluations into the routine clinical management of cirrhosis to better predict prognosis and guide treatment decisions.