SUBKLINICZNA NIEDOCZYNNOŚĆ TARCZYCY U PACJENTÓW Z NIEALKOHOLOWĄ STŁUSZCZENIOWĄ CHOROBĄ WĄTROBY NA PODŁOŻU ZABURZEŃ METABOLIZMU WĘGLOWODANÓW
Snizhana V. Feisa, Ivan V. Chopei
Therapy and Family Medicine Department, Uzhhorod National University, Uzhhorod, Ukraine
Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) is 25-30% in the general population and more than 75% among patients with carbohydrate metabolism disorders. One in six patients with NAFLD has concomitant subclinical hypothyroidism.
Materials and methods: 215 patients with NAFLD and type 2 diabetes mellitus (T2-DM) or pre–diabetes (PD) were involved in study and devided into 6 groups according to the functional state of the thyroid gland.
Results: In cases of adding subclinical hypothyroidism systolic and diastolic blood pressure are rising. In patients with overt hypothyroidism average HOMA–IR index is 29,98±1,05, which exceeds the corresponding figure in patients with concomitant subclinical hypothyroidism. In patients whose hypothyroidism has been compensated by levothyroxine, HOMA–IR index was reduced to 18,56±1,58, indicating a tendency to restore the sensitivity of peripheral tissues to insulin, on the assumption under the medicated correction of thyroid functional status. Levels of common cholesterol and triglycerides were higher in cases of NAFLD with subclinical or overt hypothyroidism than in patients with NAFLD and normal thyroid function. Replacement therapy by levothyroxine leads to improving of lipid changes in patients with NAFLD and concomitant overt hypothyroidism: the levels of common cholesterol and triglycerides were reducing from 6,04±1,18 mmol/l and 3,96±1,34 mmol/l to 5,97±1,1 mmol/l and 3,45±1,13 mmol/l in accordance.
Conclusions: Concomitant subclinical hypothyroidism in patients with NAFLD at the background of carbohydrate metabolism disorders leads to atherogenic dyslipidemia, increasing of blood atherogenicity. The index of lipid accumulated product (LAP) and the resistance of peripheral tissues to insulin also increases.
Wiad Lek 2018, 71, 2 cz. I, -264
According to the data of liver ultrasound, the prevalence of non-alcoholic fatty liver disease (NAFLD) is 25-30% in the general population, among the men NAFLD is found twice more often than in women population. . In comparison with general population, patients with type 2 diabetes mellitus suffer for NAFLD more often: the prevalence of non-alcoholic fatty liver disease among patients with carbohydrate metabolism disorder is more than 75% . Despite indistinct clinical manifestations, NAFLD is an important disease, because the correlation between NAFLD and markers of subclinical atherosclerosis was detected, that leads to increase of cardiovascular risk level .
Subclinical hypothyroidism (SH) is also an important disease, because its prevalence is from 5-10% in the general population  to 8-18% among people over 65 years old . This pathology occurs more often in areas where there is a shortage of iodine and selenium [3, 5], the Transcarpathia region is also one of the endemic areas in this aspect.
Most of the world scientificist admit that the problem of comorbidity and polymorbidity is one of the difficult in modern medicine . About 90% of patients of family doctor over 45 years old have more than 2 diseases . Severity of fatal cardiovascular prognosis is associated with concomitant pathology .
According the data , the subclinical hypothyroidism is detected in 16,7% of patients with NAFLD. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus (T2-DM) or prediabetes and concomitant hypothyroidism is typical pathology with comorbidity, when symptoms of each disease mutually complicate each other and form an endless circle . Hypothyroidism exacerbates disorders of carbohydrate metabolism and pathological liver changes . On the other hand, hepatologic disorders increase the hypothyroidism clinic and adversely affect lipid and carbohydrate metabolism [9, 10]. Type 2 diabetes mellitus leads to complication both of the hypothyroidism and non-alcoholic liver disease [10, 11].
Significant prevalence of above mentioned diseases in the general population and negative mutual influence on the clinical course each of them predetermine the relevance of the comorbid pathology study.
Aim: to compare lipid and carbohydrate metabolism states in patients with NAFLD depending on the functional state of the thyroid gland.
Materials and methods
This study is a part of common scientific theme of Therapy and Family Medicine Department «Optimization of Prevention and Treatment of Obesity and Diabetes mellitus in cases of Helicobacter pylori associated diseases». The article is also a part of scientific research work for obtaining a Doctor of Medicine degree “Non-alcoholic fatty liver disease and comorbidity”. The study was carried out in accordance with the requirements of the Helsinki Declaration. The Ethical Committee of the Therapy and Family Medicine Department approved the study protocol, and informed consent was obtained from the participants.
215 patients with NAFLD and carbohydrate metabolism disorders (type 2 diabetes mellitus, prediabetes) were examined. Diagnosis of T2-DM or pre-diabetes were confirmed according criteria of American Association of Clinical Endocrinologists and American College of Endocrinology (ACE / ACE) (2015 р.)  and criteria of the Expert Committee for the diagnosis and classification of diabetes mellitus (2012). Criteria of pre-diabetes include the following: increasing fasting plasma glucose to 5,6-6,9 mmol/l; impaired glucose tolerance: fasting plasma glucose level ≤ 7,0 mmol/l, 2-hour postprandial glucose level (random plasma glucose) 7,8 – 11,0 mmol/l, HbA1C 5,7 – 6,4 %. Diagnosis of non-alcoholic fatty liver disease was confirmed according to clinical recommendations of European Association for the Study of the liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) . The diagnosis of NAFLD was based on the results of abdominal ultrasonography, after excluding heavy alcohol consumption, and viral, or other liver diseases.
The inclusion criteria included NAFLD and T2-DM or pre-diabetes in men or women aged 18 years or more. The following subjects were excluded: (a) those with renal diseases, type 1 diabetes, Cushing syndrome or disease, other problems with glucocorticoid therapy; (b) those with known thyroid diseases with nodules current or past history of thyroid hormone and antithyroid drug intake, thyroid nodule at ultrasound; (c) those with any laboratory or clinical evidence suggesting an alternate or coexistent other chronic liver disease including hepatic viral infections (Hepatitis A-E), autoimmune hepatitis, metabolic hepatic disease; (d) those with history of alcohol consumption.
NAFLD patients were subjected to a full assessment of medical history, physical examination, abdominal ultrasonography as well as routine laboratory tests. Ultrasonography of hepatobiliary system of all patients was done. Blood was examined for total bilirubin, alanin-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamat-transferase (GGT), prothrombin time (PT). Serum triglycerides (TG), total cholesterol (TC) and high density lipoprotein (HDL cholesterol) were measured photo metrically using commercial kit provided from «COBAS MIRA Plus». LDL was calculated by the equation: LDL=cholesterol – triglycerides / 5 – HDL. Index Lipid Accumulation Products (LAP) was calculated according to the formula: LAP = (waist circumference (cm) – 65) x triglycerides (mmol/l) for men or: LAP = (waist circumference (cm) – 58) x triglycerides (mmol/l) for women  – steatosis of liver was confirmed if LAP more than 4,28. Glycated hemoglobin (HbA1C) was measured using a column chromatography method. Insulin level was estimated using a commercially available ELISA kit which was modified for use in microtiter plates. Insulin resistance (IR) was calculated using the homeostasis model assessment for IR formula: HOMA-IR = fasting glucose (mmol/l) x fasting insulin µU/ml. IR was confirmed if HOMA-IR more than 2,27. Assessment of thyroid function was performed using the following: Thyroid stimulating hormone (TSH), free serum tri-iodothyronin (FT3) and free serum thyroxine (FT4) were measured by method of immuno-chemoluminescence using automatic laboratory system Roche Hitachi Сobas e411 (Switzerland, Japan). The following interpretation of TSH was used: level of TSH from 0,4 to 4,0 mU/l discribes normal thyroid function, i.e. euthyroidism; level of TSH more than 4 mU/l is considered to be a clinical manifestation of hypothyroidism; level of TSH from 4,01 to 10,0 mU/l detects subclinical hypothyroidism; increase of TSH more than 10 mU/l shows manifestative (overt) hypothyroidism. Level of cardiovascular risk was assessed by Risk calculator (ACC/AHA ASCVD Risk calculator) .
According to the thyroid function all of patients were divided into some clinical group. The first group consisted of 32 patients with NAFLD, T2-DM and concomitant subclinical hypothyroidism (NAFLD+T2-DM+SH), the second group included 40 patients with NAFLD at the background of pre-diabetes and concomitant subclinical hypothyroidism (NAFLD+PD+SH). The 62 patients with NAFLD, T2-DM and normal thyroid function belonged to the third group (NAFLD+T2-DM+Euthyroid), and 55 patients with NAFLD at the background of pre-diabetes and normal thyroid function were included into the forth group (NAFLD+PD+Euthyroid). The fifth group consisted of 15 patients with NAFLD at the background of type 2 diabetes mellitus or pre-diabetes and concomitant overt hypothyroidism (NAFLD+T2-DM/DM+OH). The 11 patients formed the sixth group, with cases of type 2 diabetes mellitus or pre-diabetes compensated by levothyroxine (NAFLD+T2-DM / PD+KH). The control group consisted of 25 almost healthy persons (without NAFLD, T2-DM or PD), there were no statistically significant difference between the patients and the controls regarding age and sex. The statistical analysis was made using «Statistica 10.0» after making of database in tables Excel.
The average age (average ± SD) of patients was 53,4±10,6 years, in controls 55,12±11,4 years. Most of the persons in both groups were men: 170 among 215 (79,07%) in patients group and 20 among 25 in controls (80%).
Ultrasonography of hepatobiliary system to assess the liver echotexture and hepatic steatosis was done and revealed that 87 patients (40,46%) had hepatomegaly and 215 (100%) of patients had both increased liver echogenicity and hepatomegaly. According liver ultrasonography, index LAP, levels of ALT, AST, GGT, in 156 patients (72,56%) was detected steatosis and in 59 (27,44%) was revealed non-alcoholic steatohepatitis (NASH). Type 2 diabetes mellitus was confirmed in 99 patients (46,05%), pre-diabetes – in 116 persons (53,95%). Subclinical hypothyroidism was detected in 72 patients (33,49%).
There were statistically significant difference between patients and controls as regards ALT, GGT, fasting blood sugar, glycated hemoglobin (HbA1C), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, TSH, FT4, FT3, insulin resistance (IR), but there were no statistically significant difference between patients and controls as regards AST, total bilirubin and prothrombin time.
In cases add subclinical hypothyroidism, systolic and diastolic blood pressure increases: in the second group 132,5±3,12 mmHg and 92,61±1,57 mmHg in comparison in the 4th group where systolic blood pressure was 124,30±2,4 mmHg and diastolic 81,1±1,96 mmHg. There was no statistically significant difference between groups 1 and 2 as regards systolic and diastolic blood pressure. This one allows suggest that subclinical hypothyroidism is important factor which form arterial hypertension in patients with NAFLD independent of the type of carbohydrate metabolism disorders, i.e. type 2 DM or prediabetes. The average diastolic blood pressure in patients of the fifth group was 93,86±2,05 mmHg without statistically significant difference between patients of groups 1, 2 and 3. Consequently, hypofunction of thyroid gland (hypothyroidism) leads to an increase of systemic vascular resistance and vasoconstriction, which are important factors of high cardiovascular risk.
Comparative analysis of carbohydrate metabolism showed a statistically significant difference between groups 3 and 4 as regards fasting blood sugar, HbA1C, and IR (HOMA-IR) as well as between groups with subclinical hypothyroidism (1 and 2 groups) as regards these indexes. It was revealed that both overt and subclinical hypothyroidism lead to an increase of insulin resistance which was associated with a violation of the assimilation of glucose in peripheral tissues. There was a statistically significant difference between patients of groups 1 and 3 as regards HOMA-IR: 28,56±2,14 and 24,41±1,97. There also was a statistically significant difference between patients of groups 2 and 4 as regards this index: in the second group HOMA-IR = 17,32±2,08, in the group 4 – 12,87±1,97. In patients with overt hypothyroidism (group 5) the mean HOMA-IR 29,98±1,05 was more than in patients with subclinical hypothyroidism, but there were no statistically significant differences (р>0,05). In cases when patients with overt hypothyroidism intake levothyroxine, HOMA-IR decrease to 18,56±1,58; there was a significant difference between patients of group 5 and group 6 as regards HOMA-IR. This fact allows to suggest that peripheral tissues may recover sensitivity to insulin if patient intakes replacement dose of levothyroxine.
There was a statistically significant negative correlation between HbA1C and ALT, AST (r=-0,386; r=-0,363) in patients with NAFLD at the background of type 2 diabetes mellitus and concomitant subclinical hypothyroidism which showed that increasing of decompensation of T2-DM was associated with decreasing of ALT and AST.
Research of lipid metabolism shows that level of total cholesterol in cases of concomitant hypothyroidism was higher than when functional thyroid states was normal: 6,32±1,34 mmol/l (group 1), 6,21±1,76 mmol/l (group 2) – concomitant subclinical hypothyroidism) and 6,04±1,18 mmol/l (group 5 – overt hypothyroidism). The levels of triglycerides in these groups were also different from the groups of patients with euthyroid state. Therefore, presence of hypofunction of thyroid gland in patients with T2-DM and NAFLD, even at the stage of subclinical hypothyroidism, is associated with significant atherogenic dyslipidemia. There was revealed that replacement therapy by levothyroxine can improve lipid metabolism in patients with NAFLD and overt hypothyroidism. This is evidenced by significantly lower levels of total cholesterol and low density lipid (LDL-C) in group 6 (5,97±1,1 mmol/l and 3,45±1,13 mmol/l) in comparison with the corresponding levels in group 5 (6,04±1,18 mmol/l and 3,96±1,34 mmol/l).
The average LAP index (lipid accumulation product) in patients of the first (51,14±5,67) and second (28,04±4,21) groups were higher than corresponding levels in groups 3 (40,03±3,98) and 4 (18,7±5,28). This fact demonstrates an increase of lipid accumulation in liver in case hypofunction of thyroid gland. So, thyroid hormones influence on the lipid metabolism and leads to decrease lipid include in liver, because the level of LAP in patients of group 6 was significantly lower than this one in group 5.
Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of histological abnormalities, from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH). The base of NAFLD is the accumulation of triglycerides as fat droplets within the cytoplasm of hepatocytes, which is a prerequisite for subsequent events of NASH, as more than 5-10% of hepatocytes have fat droplets, as evident on liver biopsy. Patients with NAFLD may have hypertension, beside obesity, type 2 diabetes mellitus, and hypertriglyceridemia. Many patients have no symptoms, but the most frequent symptoms are right upon quadrant pain. As a risk factor of NASH related cirrhosis and hepatocellular carcinoma, hypertriglyceridemia is also associated with insulin resistance and NAFLD.
Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormones or from their impaired activity at tissue level. The patient’s presentation may vary from asymptomatic to, rarely, multisystem organ failure. Persons with subclinical hypothyroidism are often asymptomatic, but clinical manifestations can include non-specific complaints or symptoms similar overt hypothyroidism such as fatigue, weakness, weight gain, cold intolerance, constipations. Hypothyroidism is closely associated with NAFLD independently of known metabolic factors, confirming a revealed clinical relationship between these two diseases . Subclinical hypothyroidism is defined as serum TSH level over 4mIU/l with normal FT4 (0,93-1,71 ng/ml) or FT3 (2,57-4,43 pg/ml) concentrations. The most common cause of subclinical hypothyroidism is autoimmune thyroiditis especially Hashimoto’s thyroiditis.
In our study, there was a significant increase of levels of total cholesterol, LDL-C, triglycerides with significant low levels of HDL-C in our patient with subclinical hypothyroidism as compared with patients without subclinical hypothyroidism. Our results were in agreement with the findings of other studies that suggest a correlation between hypothyroidism and hyperlipidemia  The increase in triglycerides in patients with hypothyroidism may be explained by the reduced hepatic activity of triglyceride lipase and increased fatty acid oxidation . Our results also coordinate with study , according to which hypothyroidism was more prevalent in patients with type 2 diabetes mellitus and was associated with diabetic microangiopathy. Our study has revealed that subclinical hypothyroidism worsens insulin resistance. But the study has some limitations: first of all the diagnosis of NAFLD in our study was based only on ultrasound data and non-invasive index (LAP) and severity of liver diseases was not confirmed histologically.
The results of the present study confirm a correlation between increased TSH concentrations and hepatic steatosis. We found out that in patients with NAFLD at the background of T2-DM or pre-diabetes and concomitant subclinical hypothyroidism the levels of blood pressure, systolic and, more often diastolic, rise as a result of a systemic vascular resistance and vasoconstriction. Therefore, the subclinical hypothyroidism is a significant factor of high cardiovascular risk in patients with NAFLD and carbohydrate metabolism disorders. Comorbidity with hypofunction of thyroid gland associated with increase of lipid metabolism disorders, appear atherogenic dyslipidemia and increase of lipid accumulation in liver. We also found out that subclinical hypothyroidism is a significant predictor of lipid, glucose dysmetabolism and peripheral tissue insulin resistance.
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ADDRESS FOR CORRESPONDENCE
Ivan V. Chopei
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