Study of prevalence of hypothyroidism in biliary stone patients

Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology ISSN: 2454-132X Impact factor: 4.295 (Volume 5, Issue 1) Available online at: www.ijariit.com Study of prevalence of hypothyroidism in biliary stone patients Dr. Nikhil Dureja [email protected] National Institute of Medical Sciences and Research, Jaipur, Rajasthan Dr. Satyendra Pal Singh [email protected] National Institute of Medical Sciences and Research, Jaipur, Rajasthan ABSTRACT Biliary lithiasis is one of the most common biliary pathology with a reported prevalence of approximately 6%-12%. The pathogenesis of biliary lithiasis is complex and a multifactorial process involving factors which affect the bile content and bile flow. hypersaturation of bile with cholesterol and biliary stasis have been shown to be crucial factors in the development of biliary stones. Hypothyroidism has a worldwide population prevalence of 4%-5%. It leads to a decrease in liver cholesterol metabolism causing serum hypercholesterolemia with 90% of hypothyroid patients having elevated cholesterol levels; approximately 50% higher than in euthyroid patients. This hypercholesterolemia may result in supersaturation of bile with cholesterol. Cholesterol hypersaturation of bile results in impaired motility decreased contractility and reduced filling of the gallbladder causing a prolonged stay of bile in the gallbladder contributing to retention of cholesterol crystals which may lead to nucleation and continuous growth into mature gallstones. Biliary stasis is also caused by sphincter of Oddi dyskinesia leading to the formation of gallbladder and bile duct stones. Several hormones have been shown to affect spincter of Oddi activity including thyroid hormones. Thyroid hormones have been shown to have a direct pro-relaxing effect on sphincter of Oddi and lack of this effect in hypothyroidism may result in delayed bile flow which may lead to the formation of biliary stones. An increased prevalence of hypothyroidism (13.3%) among biliary stone disease patients was found in our study, with the prevalence rate being comparatively higher in CBD stone patients. Hypercholesterolemia was found in 91.67% of the patients having hypothyroidism. Keywords— Biliary stones, Cholelithiasis, Choledocholithiasis, Hypothyroidism, Hypercholesterolemia 1. INTRODUCTION Biliary stone disease is the presence of gallstones either in the gallbladder or common bile duct or both. It is a dominant disease burden of the world population, even today, especially in adults. It is a prevalent disease in Asian populations, with a 5% incidence and in Native American population this incidence is as high as 30-70%.1 Gallstones are formed in approximately 10-12% of adult population in the west.2-4 The number of new patients of biliary stones diagnosed each year in U.S.A is about 1 million with twothirds requiring surgical treatment.5 Choledocholithiasis has a prevalence of about 6-12% in patients having gallbladder stones.6,7 Cholesterol stones form the major type of bile duct stones which develop in the gallbladder and then travel through the cystic duct to reach the extra-hepatic biliary system. The incidence of choledocholithiasis increases with an increase in age. The incidence of biliary stones is more for women in all age groups. The association between thyroid disorders, especially hypothyroidism, and biliary stones has been a source of discussion for quite some time. A group of 668 female patients who underwent cholecystectomy for biliary stones were compared with 782 patients of control group retrospectively and it was found that 2.4% of gallstone patients had been treated for hypothyroidism as compared to 0.8% of controls.8 A prevalence of 8% and 6% for previously diagnosed hypothyroidism in choledocholithiasis and cholelithiasis, respectively, as compared to a prevalence of only 1% in controls was found in some other studies.9 Biliary lithiasis has complex and multifactorial pathogenesis involving mechanisms which affect the bile composition and flow of bile. The mechanisms by which hypothyroidism can predispose a patient for the development of biliary stones include the known link between hypothyroidism and dyslipidemia10,11,12 that can cause a change in bile composition. Decreased bile flow has been demonstrated in hypothyroid patients in some recent studies. 13 Also, sphincter of Oddi has been shown to express thyroid receptors and thyroxine has a direct pro-relaxing effect on the sphincter of Oddi.14 Decrease in the flow of bile and dysfunction of the sphincter of Oddi are considered to be key mechanisms that can lead to the formation of biliary stones. © 2019, www.IJARIIT.com All Rights Reserved Page | 530 Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology The present study has been undertaken, to assess the prevalence of hypothyroid status, both clinical and subclinical, in patients of biliary stone disease. Should an increased prevalence of hypothyroidism be found, the present study should provide guidelines for diagnostic and therapeutic workup of biliary stone patients. 2. MATERIAL AND METHODS This study was an observational, cross-sectional study, carried out at the Department of General Surgery at National Institute of Medical Sciences and Research, Jaipur between January 2017 and June 2018. A total of 180 patients between the ages of 18-60 years of age and having biliary lithiasis (cholelithiasis and choledocholithiasis) were included in the study, however, those patients who had already undergone cholecystectomy were excluded from the study. After applying the inclusion and exclusion criteria the outdoor and indoor patients of the Department of General Surgery with a present or past history suggestive of biliary lithiasis were further evaluated. A detailed history including history of presenting illness, past history including any treatment history, family history and personal history was taken. A clinical examination of the patient was done to include a general physical examination and systemic examination. Detailed interrogation of the patient with signs and symptoms suggestive of biliary lithiasis and hypothyroidism was done and following biochemical and radiological investigations were done: 2.1 Thyroid function tests Thyroid function tests were done on morning fasting blood samples of the patients to evaluate the patient’s serum TSH, T3 and T4 levels. The laboratory reference range for normal TSH levels was 0.35-5.60 mcIU/L, for serum T3 it was 0.60-1.81 ng/ml and for serum T4 it was 4.50-10.90 mcg/dl. Subclinical hypothyroidism was diagnosed when serum TSH values were >5.60 mcIU/L but <10 mcIU/L. Clinical hypothyroidism was diagnosed when serum TSH values were found to be above 10 mcIU/L. 2.2 Lipid profile Lipid profile was tested to assess the patient’s total serum cholesterol levels. 2.3 Abdominal Ultrasonography/USG Neck Abdominal ultrasonography evaluation of patients was carried out primarily to confirm the presence or absence of gallstones and/or CBD stones. USG neck was also done for patients with hypothyroidism to detect the presence or absence of a neck swelling. 2.4 MRCP/ERCP It was performed if there was any evidence of CBD stone on abdominal ultrasonography. The composition of gallstones was not considered in the study. Informed consent was taken from the patients. 3. OBSERVATIONS AND RESULTS The study was conducted in the Department of General Surgery, National Institute of Medical Sciences and Research, Jaipur from Jan 2017 to June 2018. Table 1: Age-wise distribution of biliary stone disease Age group Number of cases Percentage ≤ 30 11 6.11 31 to 40 40 22.22 41 to 50 77 42.78 51 to 60 52 28.89 180 100 Total A total of 180 cases of biliary stone patients, between the ages 18-60 years, were included in the study. The maximum number of cases were in the age group of 41-50 years followed by the age-group 51-60 years. There were 77(42.78%) cases in the age group 41-50 years and in the age group 51-60 years, there were 52(28.89%) cases. Table 2: Sex-wise distribution of biliary stone disease Sex Number of cases Percentage Female 101 56.11 Male 79 43.89 Total 180 100 Out of the total 180 cases of the biliary stone disease, 101 (56.1%) of the cases were females and 79 (43.9%) of the cases were males. © 2019, www.IJARIIT.com All Rights Reserved Page | 531 Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology Thyroid Status Euthyroid Hypothyroidism Total Table 3: Thyroid status Number of patients 156 24 180 Percentage 86.7 13.3 100 The patients were evaluated for thyroid function by testing the serum TSH, T3 and T4 levels. Out of the 180 patients, hypothyroidism was found in 24 (13.3%) of the patients. Table 4: Hypothyroidism status Hypohyroidism Status Number of patients Percentage Euthyroid 156 86.67 Subclinical Hypothyroidism 16 8.89 Clinical Hypothyroidism 8 4.44 Total 180 100 Out of the 24 patients with hypothyroidism, subclinical hypothyroidism was found in 16(8.89%) of the patients and clinical hypothyroidism was found in 8(4.44%) of the patients. Table 5: Age-wise distribution of thyroid status Euthyroid Subclinical Hypothyroidism Clinical Hypothyroidism Total Age group Number Percentage Number Percentage Number Percentage Number Percentage ≤30 9 5.77 2 12.5 0 0 11 6.11 31 to 40 33 21.15 4 25 3 37.5 40 22.22 41 to 50 68 43.59 6 37.50 3 37.50 77 42.78 51 to 60 46 29.49 4 25.00 2 25.00 52 28.89 Total 156 100.00 16 100.00 8 100.00 180 100.00 Out of the 24 patients with hypothyroidism, the 41-50 years age group had the maximum percentage of patients. There were 9 (37.50%) patients in the 41-50 years age group, out of which, 6 patients had subclinical hypothyroidism and 3 patients had clinical hypothyroidism. The 31-40 years age group had 7 (29.17%) patients with hypothyroidism, out of which, 4 patients had subclinical hypothyroidism and 3 patients had clinical hypothyroidism. The 51-60 years age group had 6 patients with hypothyroidism, out of which, 4 patients had subclinical hypothyroidism and 2 patients had clinical hypothyroidism. Sex Female Male Total Sex Female Male Total Table 6: Sex-wise distribution of thyroid status Euthyroid Hypothyroidism Number Percentage Number Percentage 80 51.28 21 87.50 76 48.72 3 12.50 156 100 24 100 Number 101 79 180 Total Percentage 56.11 43.89 100 Table 7: Sex-wise distribution of hypothyroid status Subclinical Hypothyroid Clinical Hypothyroid Number Percentage Number Percentage 14 87.5 7 87.5 2 12.5 1 12.5 16 100.00 8 100.00 Number 21 3 24 Total Percentage 87.5 12.5 100.00 Out of the total 24 patients with hypothyroidism, 21(87.50%) patients were females and 3(12.50%) patients were males. Out of the 21 female patients with hypothyroidism, 14 patients had subclinical hypothyroidism while 7 patients had clinical hypothyroidism. Out of the 3 male patients with hypothyroidism, 2 patients had subclinical hypothyroidism while 1 patient had clinical hypothyroidism. Table 8: Pattern of hypothyroid status in biliary stone patients Hypothyroidism Number Percentage 18 12.08 Cholelithiasis 6 19.3 Cholelithiasis + Choledocholithiasis Table 9: Distribution of clinical and subclinical hypothyroidism in biliary stone patients Euthyroid Subclinical Hypothyroidism Clinical Hypothyroidism Gallstones Total=131 Total=12 Total=6 Total=149 F 63 10 5 78 M 68 2 1 71 Gallstones + CBD stones Total=25 Total=4 Total=2 Total=31 F 17 4 2 23 M 8 0 0 8 © 2019, www.IJARIIT.com All Rights Reserved Page | 532 Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology Out of the total 149 patients who had only gallbladder stones, 18(12.08%) patients had hypothyroidism, of which 12 patients had subclinical hypothyroidism and 6 patients had clinical hypothyroidism. Of the 12 patients with subclinical hypothyroidism, 10 patients were females and 2 patients were males. Out of the 6 patients with clinical hypothyroidism, 5 patients were females and 1 patient was male. Out of the total 31 patients who had CBD stones associated with gallbladder stones, 6(19.3%) patients had hypothyroidism, of which 4 patients had subclinical hypothyroidism and 2 patients had clinical hypothyroidism. All 6 patients with hypothyroidism were females. Table 10: Cholesterol status in biliary stone and hypothyroid patients Euthyroid Subclinical Hypothyroid Clinical Hypothyroid Total Total serum cholesterol (mg/dl) Number %age Number %age Number %age Number %age High (>200) 15 9.62 16 100 6 75 37 20.56 Normal(125-200) 141 90.38 0 0 2 25 143 79.44 Grand Total (Biliary stone patients) 156 100.00 16 100.00 8 100.00 180 100.00 The patients were also evaluated for serum cholesterol levels. Out of 180 biliary stone patients, elevated serum cholesterol levels were found in 37(20.56%) of the patients. Out of the 37 patients with hypercholesterolemia, 22 patients were also found to be hypothyroid, of which 16 had subclinical hypothyroidism and 6 had clinical hypothyroidism. The percentage of hypothyroid patients having associated hypercholesterolemia was 91.67% (22 patients out of 24 hypothyroid patients). 4. DISCUSSION Biliary stone disease is a dominant disease burden of the world population and it has been observed by various studies that hypothyroidism, which is another common condition, may have an association with it. 8,9,13,15 Hypothyroidism can either be clinical or subclinical. In the present study, we have made an effort to study the association between hypothyroidism and biliary stone disease and establish if there is any link between the formation of gallbladder stone/CBD stone and clinical or subclinical hypothyroidism. The prevalence of biliary stone disease has been found to be 6%-12% in the adult population in North India.16,17,18 The incidence of biliary stones increases with age, and is markedly more frequent after the age of 40 years, becoming 4 to 10 times more likely in older individuals.19,20,21 In our study, a total of 180 cases of biliary stone patients, between the ages 18-60 years, were included. The maximum number of cases were in the age group of 41-50 years followed by the age-group 51-60 years. There were 77(42.78%) cases in the age group 41-50 years and in the age group 51-60 years, there were 52(28.89%) cases. There were 40(22.22%) cases in the age-group of 31 – 40 years and a minimum number of cases were found in the age group of patients less than 30 years. There were 11(6.11%) cases in the age group of fewer than 30 years. Sandeep Sachdeva et al. 201122, Kedar Nath et al. 201723, Volzke H et al. 200515, Ahmad MM et al. 201524, reported similar age distribution in their studies. Women are more likely to develop gallstone disease than males, especially during the fertile years. 16,19 In women, the female sex hormones, use of oral contraceptives, parity, and estrogen replacement therapy are established risk factors for cholesterol gallstone formation.25,26,27 Hepatic biliary secretion and gallbladder function are adversely affected by female sex hormones. The secretion of cholesterol is increased under the influence of estrogens, while, the secretion of bile salts is diminished. Progestins also reduce bile salt secretion and cause impairment of gallbladder emptying which leads to biliary stasis.19 In our study, out of the total 180 cases of biliary stones, 101 (56.1%) of the cases were females and 79 (43.9%) of the cases were males. Krishnasamy Narayanasamy DM et al. 201728, Jayan Stephen et al. 201629, Sandeep Sachdeva et al. 201122, Laura M. Stinton, et al. 201219, E A Shaffer, et al. 200520 have noted the similar pattern of distribution of gallstone disease among genders in their studies. Of the total 180 cases of biliary stones in our study, 149 (82.8%) cases had only gall bladder stones, whereas, 31 (17.2%) cases had CBD stones associated with gall bladder stones. Out of the 149 cases with only gall bladder stones, 71(47.65%) cases were males and 78(52.35%) cases were females. Out of the 31 cases with CBD stones associated with gallbladder stones, 8(25.81%) cases were males and 23(74.19%) cases were females. The male to female ratio for choledocholithiasis, in our study, was 1:2.875. In their study, Rai MK et al. 201730, reported an 18.4% prevalence of choledocholithiasis associated with cholelithiasis and a male to female ratio of 1:2.83. Yuk Tong Lee et al. 200831, reported a similar prevalence for choledocholithiasis. Hypothyroidism has a worldwide prevalence of 4%-5%.32,33 It is more commonly prevalent in women than in men and the incidence increases with increasing age.34,35 Hypothyroidism can either be clinical hypothyroidism or subclinical hypothyroidism. In the U.S. National Health and Nutrition Examination Survey III (NHANES III) prevalence of hypothyroidism was found to be 4.6%, out of which overt/clinical hypothyroidism had a prevalence of 0.3% and subclinical hypothyroidism had a prevalence of 4.3%. 36 Subclinical hypothyroidism is biochemically defined as an increased serum TSH level with a serum free T4 level that lies within the reference range.37 A serum TSH cut-off level of 10mcIU/L is usually used to distinguish between clinical and subclinical © 2019, www.IJARIIT.com All Rights Reserved Page | 533 Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology hypothyroidism.37 Adults with serum TSH levels of >5mcIU/L but <10mcIU/L are diagnosed as having subclinical hypothyroidism and adults with serum TSH levels above 10mcIU/L are diagnosed as having clinical hypothyroidism. 38 In our study, the laboratory reference range for serum TSH was 0.35 - 5.60mcIU/ml. Serum TSH levels >5.60mcIU/L but <10mcIU/L were taken as subclinical hypothyroidism and serum TSH levels above 10mcIU/L were taken as clinical hypothyroidism. Out of the 180 patients with the biliary stone disease, hypothyroidism was found in 24 (13.3%) of the patients. Out of the 24 patients with hypothyroid status, subclinical hypothyroidism was found in 16(8.89%) of the patients and clinical hypothyroidism was found in 8(4.44%) of the patients. These findings were similar to the findings of studies conducted by Singh BR et al. 201839, Debabrata S et al. 201740, Arora BK et al. 201741 and Laukkarinen J et al. 2007.13 Out of the 24 patients of biliary stones with concurrent hypothyroidism, the 41-50 years age group had the most percentage of patients. There were 9 (37.50%) patients in the 41-50 years age group, out of which, 6 patients had subclinical hypothyroidism and 3 patients had clinical hypothyroidism. The 31-40 years age group had 7 (29.17%) patients with hypothyroidism, out of which, 4 patients had subclinical hypothyroidism and 3 patients had clinical hypothyroidism. The 51-60 years age group had 6 patients with hypothyroidism, out of which, 4 patients had subclinical hypothyroidism and 2 patients had clinical hypothyroidism. Similar distribution across age-groups was reported by Singh BR et al. 201839, J. Vidhya Priya et al. 201642, Ahmad MM et al. 201524 and Jayan Stephen et al. 201629 in their studies. Out of the total 24 patients with hypothyroidism, 21(87.50%) patients were females and 3(12.50%) patients were males. Out of the 21 female patients with hypothyroidism, 14 patients had subclinical hypothyroidism while 7 patients had clinical hypothyroidism. Out of the 3 male patients with hypothyroidism, 2 patients had subclinical hypothyroidism while 1 patient had clinical hypothyroidism. These findings were similar to the findings reported by Singh BR et al. 201839, J. Vidhya Priya et al. 201642 and Jayan Stephen et al. 201629 in their studies. Out of the total 149 patients who had only gallbladder stones, 18(12.08%) patients had hypothyroidism, of which 12 patients had subclinical hypothyroidism and 6 patients had clinical hypothyroidism. Out of the total 31 patients who had CBD stones associated with gallbladder stones, 6(19.3%) patients had hypothyroidism, of which 4 patients had subclinical hypothyroidism and 2 patients had clinical hypothyroidism. The higher prevalence of hypothyroidism, both subclinical and clinical, in choledocholithiasis patients than cholelithiasis patients is suggestive of a stronger association of hypothyroidism with CBD stones. Inkinen J et al. 2001 9 and Ahmad MM et al. 201524 also reported a similar association of hypothyroidism with CBD stones. Laukkarinen J et al. 201043, in their study also concluded diagnosed hypothyroidism to be a significant risk factor for CBD stones. Hypothyroidism can cause secondary hyperlipidaemia.44 Hypercholesterolemia that occurs in hypothyroidism is a well-recognized and accepted clinical finding.45 Reduced clearance of cholesterol from plasma, decrease in conversion of cholesterol to bile acids in the liver and delayed removal of low-density lipoproteins from the plasma are the mechanisms by which hypercholesterolemia can occur in hypothyroidism.45 In published studies elevated cholesterol levels have been reported in up to 90% of hypothyroid46; which are approximately 50% higher than in euthyroid patients. 47 This hypercholesterolemia may cause hypersaturation of bile with cholesterol.46 Hypersaturated bile can lead to a reduction in motility10, decrease in contractility11 and reduced filling12 of the gallbladder causing stasis of bile in the gallbladder which may contribute to retention of cholesterol crystals leading to nucleation and subsequently the formation of mature gallstones.8,9,48 We evaluated the patients for serum cholesterol levels in our study. Out of 180 biliary stone patients, elevated serum cholesterol levels were found in 37(20.56%) of the patients. Out of the 37 patients with hypercholesterolemia, 22 patients were also found to be hypothyroid, of which 16 had subclinical hypothyroidism and 6 had clinical hypothyroidism. The percentage of hypothyroid patients having associated hypercholesterolemia was 91.67% (22 patients out of 24 hypothyroid patients). These findings are consistent with the findings of Laukkarinen J et al. 201246, Jayan Stephen et al. 201629 and Diehl et al. 198749, who have reported similar findings in their studies. 5. CONCLUSIONS AND RECOMMENDATIONS  There is an increased prevalence of hypothyroidism (subclinical and clinical), associated with the biliary stone disease. If hypothyroidism (subclinical or clinical) is diagnosed and treated timely, can reduce biliary stone disease patients significantly.  All the patients of middle age-group (especially females) of biliary stone disease should be evaluated for the possibility of hypothyroidism.  Hypothyroidism causes hypercholesterolemia, which in turn, is known to be a major factor in the genesis of biliary stones. This vicious circle further proves the correlation between hypothyroidism and biliary lithiasis. Energetic treatment of hypothyroidism, a treatable condition, can normalize serum cholesterol levels and may help to prevent the development of gallstones. © 2019, www.IJARIIT.com All Rights Reserved Page | 534 Dureja Nikhil, Singh Satyendra Pal; International Journal of Advance Research, Ideas and Innovations in Technology 6. REFERENCES [1] M Acalovschi, Cholesterol gallstones: from epidemiology to prevention, Postgrad Med J 2001;77:221-229. 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