European Journal of Cardiovascular Medicine

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disorder worldwide, encompassing a spectrum ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis in a proportion of affected individuals. [1] Its global prevalence is estimated at around a quarter of the adult population, closely paralleling the epidemics of obesity, type 2 diabetes mellitus, and the metabolic syndrome. [1,2]

In India, community- and hospital-based studies conducted over the past two decades have documented a substantial and rising burden of NAFLD, with reported prevalence figures ranging from as low as 9% in coastal rural populations to nearly 32% in urban cohorts with insulin resistance. [3,8,11] Amarapurkar et al, in one of the earliest Indian population-based surveys, reported hepatic steatosis on ultrasonography in a substantial minority of apparently healthy adults, drawing attention to NAFLD as an emerging public health concern in the country. [3] Subsequently, Mohan et al demonstrated a strong relationship between NAFLD and insulin resistance in an urban South Indian population, while Singh et al documented an appreciable prevalence of fatty liver even among relatively lean individuals in eastern India, suggesting that Asian Indians may develop hepatic steatosis at lower degrees of adiposity than Western populations. [8,11] Das et al further reinforced this observation by describing a high burden of NASH and significant liver disease even in the non-obese Indian population, underscoring the unique metabolic phenotype — sometimes termed the ‘Asian Indian phenotype’ — that predisposes to hepatic fat accumulation. [14]

Thyroid hormones play a pivotal, well-established role in the regulation of hepatic lipid metabolism. Triiodothyronine (T3) enhances mitochondrial fatty acid oxidation, stimulates lipolysis in adipose tissue, up-regulates hepatic LDL-receptor expression, and promotes conversion of cholesterol to bile acids. A deficiency of thyroid hormone, as occurs in hypothyroidism, is therefore expected to reduce hepatic beta-oxidation and lipoprotein clearance while simultaneously promoting lipogenesis, culminating in hepatic triglyceride accumulation and, ultimately, steatosis.

Hypothyroidism itself is highly prevalent in India. Community screening studies conducted in the pre-2012 period estimated that a substantial fraction of otherwise asymptomatic adults harbour subclinical or overt hypothyroidism, particularly women in the fourth and fifth decades of life. [17,18] Kalra et al, screening patients at a secondary care centre in North India, and Deshmukh et al, in a cross-sectional survey from Mumbai, both reported a considerable prevalence of subclinical hypothyroidism in the general population, often accompanied by dyslipidaemia even before overt clinical manifestations became apparent. [17,18] Given the high background prevalence of both hypothyroidism and NAFLD in India, and the shared metabolic pathways linking the two, several Indian workers explored this association directly. Solanki et al reported a significant relationship between subclinical hypothyroidism and NAFLD in adults above 30 years of age, while Chakraborty et al specifically documented a high prevalence of NAFLD among Indian patients with subclinical hypothyroidism, suggesting that even mild, biochemical thyroid dysfunction — not merely overt disease — may be sufficient to promote hepatic steatosis. [20,24] Duseja et al, in a comprehensive review of NAFLD in the Indian context, similarly emphasised that endocrine disorders including hypothyroidism warranted systematic evaluation as contributory risk factors, given the disproportionately high burden of metabolic liver disease already present in the Indian population. [5]

Despite this growing body of evidence, NAFLD often remains clinically silent and under-recognised in patients with hypothyroidism, as routine screening for hepatic steatosis is not uniformly practised in endocrine or general medicine outpatient settings. Early identification is clinically important because both conditions are amenable to intervention — thyroid hormone replacement in the case of hypothyroidism, and lifestyle modification, weight reduction, and metabolic risk-factor control in the case of NAFLD — and untreated combined disease may accelerate progression to steatohepatitis and fibrosis.

Against this background, the present study was undertaken with the objective of assessing the prevalence of NAFLD in patients with hypothyroidism attending a tertiary care hospital, comparing this prevalence with an age- and sex-matched euthyroid control group, and evaluating the correlation between the degree of thyroid dysfunction (as reflected by serum TSH) and the ultrasonographic grade of hepatic steatosis.

Study design and setting

This was a hospital-based, cross-sectional, observational, analytical study conducted in the Department of General Medicine of a tertiary care teaching hospital, over a period of 18 months.

Study population

A total of 150 subjects were enrolled by consecutive sampling and divided into two groups:

•             Group A (Cases): 100 patients aged 18–60 years with a confirmed biochemical diagnosis of hypothyroidism (subclinical or overt), whether newly diagnosed or already on treatment.

•             Group B (Controls): 50 age- and sex-matched euthyroid individuals attending the outpatient department for unrelated, non-hepatic complaints.

Inclusion criteria: Adults aged 18–60 years who consented to participate and underwent the complete study protocol.

Exclusion criteria

•        History of significant alcohol consumption (>21 units/week in men, >14 units/week in women)

•        Chronic viral hepatitis (HBsAg or anti-HCV positive)

•        Known chronic liver disease of other aetiology (autoimmune, Wilson disease, haemochromatosis)

•        Use of steatogenic drugs (corticosteroids, amiodarone, tamoxifen, sodium valproate)

•        Pregnancy

•        Other causes of secondary dyslipidaemia (nephrotic syndrome, uncontrolled diabetes with ketosis).

Data collection

A pre-designed, pre-tested proforma was used to record demographic details, history, and clinical examination findings including body mass index (BMI, kg/m²) and waist circumference. Venous blood samples were collected after a 10–12 hour overnight fast for estimation of serum TSH, free T4 (FT4), fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C), liver function tests (AST, ALT, ALP, serum bilirubin), and fasting blood glucose.

Operational definitions

•        Hypothyroidism: Serum TSH >5.5 mIU/L. Subclinical hypothyroidism was defined as elevated TSH with normal FT4, and overt hypothyroidism as elevated TSH with low FT4.

•        NAFLD: Ultrasonographic evidence of hepatic steatosis (increased hepatic echogenicity relative to the renal cortex, vascular blurring, and posterior beam attenuation) in the absence of significant alcohol intake or other identifiable causes of secondary hepatic fat accumulation.

•        Grading of steatosis (USG): Grade 0 – normal; Grade I – mild (slight diffuse increase in hepatic echogenicity); Grade II – moderate (increased echogenicity with partial obscuration of portal vein walls and diaphragm); Grade III – severe (marked increase in echogenicity with poor visualisation of the diaphragm and posterior right lobe).

Imaging

Abdominal ultrasonography was performed by a single experienced radiologist, blinded to the thyroid status of the participant, using a 3.5 MHz curvilinear probe, to minimise inter-observer variability.

Statistical analysis: Data were entered in Microsoft Excel and analysed using SPSS version 25.0. Continuous variables were expressed as mean ± standard deviation and compared using the unpaired Student’s t-test. Categorical variables were expressed as frequencies and percentages and compared using the Chi-square test or Fisher’s exact test as appropriate. Correlation between TSH level and grade of NAFLD was assessed using the Pearson correlation coefficient. A two-tailed p value <0.05 was considered statistically significant.

Ethical considerations

The study protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from all participants prior to enrolment. Confidentiality of patient data was maintained throughout the study.

A total of 150 subjects completed the study — 100 hypothyroid cases and 50 euthyroid controls. The two groups were comparable with respect to age and sex distribution, but cases had a significantly higher mean BMI and waist circumference than controls, reflecting the known association between hypothyroidism and weight gain (Table 1).

Table 1: Demographic and anthropometric characteristics of study participants

* Statistically significant (p<0.05)

The mean TSH in cases was 12.8 ± 8.4 mIU/L compared with 2.6 ± 0.9 mIU/L in controls (p<0.001). Of the 100 hypothyroid cases, 62 (62.0%) had subclinical hypothyroidism and 38 (38.0%) had overt hypothyroidism (Table 2).

Table 2: Thyroid profile of the study population

NAFLD, diagnosed on ultrasonography, was present in 46 of the 100 hypothyroid cases (46.0%) compared with only 9 of the 50 controls (18.0%). This difference was statistically highly significant (χ²=11.9, p<0.001), indicating that hypothyroid patients were more than twice as likely to have NAFLD as euthyroid individuals (Table 3).

Table 3: Prevalence of NAFLD in hypothyroid cases versus euthyroid controls

On grading the severity of steatosis, hypothyroid cases showed a higher proportion of moderate and severe disease (Grades II and III) compared with controls, in whom steatosis — when present — was almost invariably mild. Mean TSH values rose progressively with increasing grade of steatosis (Table 4), and this relationship was confirmed to be statistically significant on correlation analysis (Table 5).

Table 4: Grade-wise distribution of hepatic steatosis on ultrasonography

Table 5: Correlation between TSH level and severity of NAFLD

A significant positive correlation was observed between serum TSH and USG grade of NAFLD (r=0.52, p<0.001). Patients with overt hypothyroidism had nearly three-fold higher odds of NAFLD compared with those with subclinical disease (OR 2.74, 95% CI 1.21–6.19).

On comparing the metabolic profile of hypothyroid patients with and without NAFLD, those with NAFLD had significantly higher total cholesterol, triglycerides, LDL-cholesterol, ALT, and AST, and significantly lower HDL-cholesterol, than hypothyroid patients without NAFLD (Table 6), confirming a close relationship between the severity of dyslipidaemia and hepatic fat accumulation in this population.

Table 6: Comparison of lipid profile and liver enzymes between hypothyroid patients with and without NAFLD

The present study demonstrates a significantly higher prevalence of NAFLD among hypothyroid patients (46.0%) compared with euthyroid controls (18.0%), along with a positive correlation between the degree of thyroid dysfunction and the severity of hepatic steatosis. These findings are consistent with, and add to, a substantial both Indian and international supporting a mechanistic link between thyroid hormone deficiency and hepatic fat accumulation.

The overall prevalence of NAFLD observed in our control group (18.0%) is comparable to earlier Indian community-based estimates. Amarapurkar et al, in a population-based ultrasonographic survey, reported hepatic steatosis in a broadly similar proportion of the general adult population, while Singh et al found a somewhat lower prevalence in a rural coastal cohort from eastern India, a difference likely attributable to variation in dietary patterns, physical activity, and background obesity between urban and rural populations. [3,11] Our finding of a markedly higher prevalence in the hypothyroid group is in agreement with Mohan et al, who linked NAFLD closely to insulin resistance and the metabolic syndrome in an urban South Indian population — a milieu that overlaps considerably with the metabolic derangements seen in hypothyroidism, including weight gain, dyslipidaemia, and reduced insulin sensitivity. [8] The particularly high susceptibility of Indians to hepatic steatosis at relatively modest degrees of adiposity, first highlighted by Das et al in their description of a high burden of NASH even in non-obese subjects, may partly explain why our hypothyroid cohort — despite only a modest elevation in mean BMI compared with controls — showed such a marked excess of NAFLD. [14]

Our observation that even subclinical hypothyroidism was associated with NAFLD, albeit to a lesser degree than overt disease, corroborates the work of Solanki et al and Chakraborty et al, both of whom specifically studied Indian patients with subclinical hypothyroidism and reported a significant excess of hepatic steatosis in this group. [20,24] This is clinically important because subclinical hypothyroidism is frequently asymptomatic and may escape attention unless actively screened for, as emphasised by Kalra et al and Deshmukh et al in their respective community and hospital-based surveys of thyroid dysfunction in India. [17,18] Taken together with the review by Duseja et al, which called for systematic evaluation of endocrine contributors to the rising Indian NAFLD burden, our results support the case for including thyroid function testing as part of the metabolic work-up of patients diagnosed with NAFLD, and conversely, for considering hepatic ultrasonography in patients newly diagnosed with hypothyroidism, particularly when accompanied by obesity or dyslipidaemia. [5]

Internationally, our findings mirror those of Chung et al, who described a graded increase in NAFLD prevalence across the spectrum of thyroid function from euthyroid to overtly hypothyroid subjects in a Korean cohort, and Bano et al, who reported in the large population-based Rotterdam Study that lower thyroid function, even within the normal range, was independently associated with a higher risk of NAFLD and its more severe forms.

The mechanistic basis for this association is now reasonably well characterised. Thyroid hormone, acting principally through the thyroid hormone receptor-β in hepatocytes, promotes mitochondrial beta-oxidation of fatty acids, stimulates autophagy-mediated lipid clearance, and up-regulates hepatic LDL-receptor expression to enhance clearance of atherogenic lipoproteins. In the hypothyroid state, these protective effects are lost: hepatic lipogenesis proceeds relatively unchecked, very-low-density lipoprotein clearance is impaired, and mitochondrial fatty acid oxidation is reduced, together favouring net accumulation of triglyceride within hepatocytes. Ferrandino et al elegantly demonstrated that hypothyroidism-induced NAFLD is driven substantially by intra-hepatic mitochondrial dysfunction rather than by increased caloric intake alone, providing a direct pathophysiological explanation for the pattern of results observed in our cohort, where NAFLD patients demonstrated significantly deranged lipid profiles and transaminases in parallel with their degree of thyroid dysfunction.

The strong correlation we observed between TSH and both the presence and grade of hepatic steatosis (r=0.52, p<0.001) is consistent with the dose-response relationship reported by Ittermann et al in the Study of Health in Pomerania, where lower free thyroxine levels correlated inversely with the degree of hepatic steatosis even in an unselected, largely euthyroid population, and by Kim et al, who found that both subclinical hypothyroidism and low-normal thyroid function were associated not only with simple steatosis but with more advanced steatohepatitis and fibrosis.

From a clinical standpoint, our results suggest that hypothyroid patients — particularly those with overt disease, obesity, or dyslipidaemia — represent a high-risk group in whom opportunistic screening for NAFLD by abdominal ultrasonography may be worthwhile, given the largely asymptomatic nature of early hepatic steatosis and the potential for disease progression if left unaddressed. Conversely, in patients presenting with NAFLD, particularly in the absence of the conventional risk factors of obesity or diabetes, thyroid function should be evaluated as a potentially reversible contributory factor.

This study has certain limitations. Being a cross-sectional, single-centre study, it establishes association rather than causation, and the temporal relationship between onset of hypothyroidism and development of NAFLD could not be ascertained. Diagnosis of NAFLD was based on ultrasonography, which — while a reasonable and widely used first-line screening modality — is less sensitive than liver biopsy or transient elastography for detecting milder degrees of steatosis or for distinguishing simple steatosis from steatohepatitis and fibrosis. The relatively modest sample size, drawn from a single tertiary care centre, may also limit the generalisability of the findings to the wider population. Larger, prospective, multicentric studies incorporating elastographic or histological assessment of fibrosis are needed to further clarify the natural history of NAFLD in hypothyroid patients and to determine whether thyroid hormone replacement modifies its course

The present study demonstrates that NAFLD is significantly more prevalent among hypothyroid patients than in euthyroid individuals, with the severity of hepatic steatosis correlating positively with the degree of biochemical thyroid dysfunction. Even subclinical hypothyroidism was associated with an appreciable burden of hepatic steatosis. These findings support incorporating thyroid function assessment into the metabolic evaluation of patients with NAFLD, and hepatic ultrasonographic screening into the routine assessment of patients with hypothyroidism, particularly those with coexisting obesity or dyslipidaemia. Early identification and management of this dual metabolic burden may help prevent progression to more advanced liver disease.

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