IN WESTERN COUNTRIES, 10 12% of adults develop

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1 X/07/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 92(11): Printed in U.S.A. Copyright 2007 by The Endocrine Society doi: /jc Increased Prevalence of Subclinical Hypothyroidism in Common Bile Duct Stone Patients Johanna Laukkarinen, Gediminas Kiudelis, Marko Lempinen, Sari Räty, Hanna Pelli, Juhani Sand, Esko Kemppainen, Caj Haglund, and Isto Nordback Department of Gastroenterology and Alimentary Tract Surgery (J.L., S.R., H.P., J.S., I.N.), Tampere University Hospital, Tampere FIN-33520, Finland; Department of Gastroenterology (G.K.), Kaunas Medical University Hospital, LT-3007 Kaunas, Lithuania; and Department of Surgery (M.L., E.K., C.H.), Helsinki University Hospital, FIN Helsinki, Finland Context: Earlier, we have shown an increased prevalence of previously diagnosed hypothyroidism in common bile duct (CBD) stone patients and a delayed emptying of the biliary tract in hypothyroidism, explained partly by the missing prorelaxing effect of T 4 on the sphincter of Oddi contractility. Objective: In this study, the prevalence of previously undiagnosed subclinical hypothyroidism in CBD stone patients was compared with nongallstone controls. Patients: All patients were clinically euthyreotic and without a history of thyroid function abnormalities. CBD stones were diagnosed at endoscopic retrograde cholangiopancreatography (group 1; n 303) or ruled out by previous medical history, liver function tests, and ultrasonography (control group II; n 142). IN WESTERN COUNTRIES, 10 12% of adults develop gallstones (1 3). The prevalence of common bile duct (CBD) stones in patients with gallbladder stones varies from 8 to 16% (4, 5). The pathogenesis of gallstones is a complex process involving factors affecting bile content and bile flow. A crucial factor in the forming of bile duct stones is biliary stasis (6), which may be caused for example by sphincter of Oddi (SO) stenosis, SO dyskinesia, or bile duct strictures (7 9). Previously it has been shown that CBD stone patients have significantly more often diagnosed hypothyroidism, compared with gallbladder stone patients or controls (10, 11). The higher prevalence of previously diagnosed hypothyroidism in CBD stone patients, compared with gallbladder stone patients, suggests that factors other than merely changes in the cholesterol metabolism or bile excretion rate, particularly changes in the function of the SO, also may be behind the association between CBD stones and hypothyroidism. Ex vivo experiments with both the pig and human SO have First Published Online August 28, 2007 Abbreviations: CBD, Common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; S-Bil, serum bilirubin; S-FT4, serum free T 4 ; SO, sphincter of Oddi; S-TSH, serum TSH. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community Main Outcome Measures: Serum free FT 4 and TSH (S-TSH) were analyzed; S-TSH above the normal range ( 6.0 mu/liter) was considered as subclinical and S-TSH mu/liter as borderlinesubclinical hypothyroidism. Results: A total of 5.3 and 5.0% (total 10.2%; 31 of 303) of the CBD stone patients were diagnosed to have subclinical and borderlinesubclinical hypothyroidism, compared with 1.4% (P 0.05) and 1.4% (total 2.8%, four of 142; P 0.026) in the control group, respectively. In women older than 60 yr, the prevalence of subclinical hypothyroidism was 11.4% in CBD stone and 1.8% in control patients (P 0.032) and subclinical plus borderline-subclinical hypothyroidism 23.8% in CBD stone and 1.8% in control patients (P 0.012). Conclusion: Subclinical hypothyroidism is more common in the CBD stone patients, compared with nongallstone controls, supporting our hypothesis that hypothyroidism might play a role in the forming of CBD stones. At minimum, women older than 60 yr with CBD stones should be screened for borderline or overt subclinical hypothyroidism. (J Clin Endocrinol Metab 92: , 2007) shown that thyroxine has a direct, prorelaxing effect on the SO motility at physiological concentrations, possibly mediated via thyroid hormone receptors- 1 and - 2, and the absence of T 4 may thus result in an increased tension in the SO (12, 13). In the rat the net bile flow to the duodenum is reduced in hypothyroidism and enhanced in hyperthyroidism (14), and in human cholescintigraphy the hepatic clearance of 99m Tecnetium diethyliminodiacetic acid is decreased, and the hilum duodenum transit time tends to be increased in hypothyroidism (15). The reduced prorelaxing effect of T 4 on the SO in hypothyroidism shown in the experimental investigations may thus result in delayed emptying of the biliary tract, and, together with the possible cholesterol load in the bile and decreased hepatocytic excretion rate, may compose an important explanation for the increased association of CBD stones and hypothyroidism. The prevalence of previously undiagnosed thyroid function abnormalities has never been studied in CBD stone patients before. If an increased prevalence of subclinical hypothyroidism will be found, it might have an effect on the diagnostic and therapeutic work-up of patients with CBD stones. Subclinical hypothyroidism is a prevalent condition among adult population; however, it is frequently overlooked. The previous studies about the prevalence of subclinical hypothyroidism among health subjects are few in number. There are no reported studies from Finland. In a

2 Laukkarinen et al. Subclinical Hypothyroidism and CBD Stones J Clin Endocrinol Metab, November 2007, 92(11): recent study from the United Kingdom (16), the prevalence of subclinical hypothyroidism among healthy subjects was 2.6% The aim of this study was to investigate the thyroid function, especially the prevalence of previously undiagnosed subclinical hypothyroidism, in CBD stone patients compared with nongallstone controls. Patients and Methods Patients who were diagnosed in endoscopic retrograde cholangiopancreatography (ERCP), performed as clinically indicated, to have CBD stones and who did not have a history of treated or diagnosed thyroid function abnormalities (group I; n 303; median age 68 yr; range 20 98) were recruited into the study from three hospitals involved (Tampere and Helsinki University Hospitals, Finland, and Kaunas Medical University Hospital, Lithuania). The control patients (group II; n 142; median age 65 yr; range 22 93) were recruited at the wards of gastrointestinal surgery, the inclusion criteria being admission to the hospital because of various gastrointestinal symptoms or diseases, with no gallstones detected at ultrasonography or in the medical history, no cholecystectomy performed, and no history of treated or diagnosed thyroid function abnormalities. Patients with phenytoin or carbamazepine therapy as well as pregnant patients were excluded from both groups. From morning blood samples, serum free T 4 (S-FT4; method: immunofluorometric; normal range pmol liter 1 ), TSH (S-TSH; method: immunofluorometric; normal range mu liter 1 ), and total bilirubin (S-Bil; method: diatso reaction, fotometric reading; normal range 5 25 mol liter 1 ) were analyzed in one laboratory (the laboratory center of Tampere University Hospital), and the results were compared between the two study groups. The symptom-free patients with S-TSH concentrations above the upper limit of the normal range ( 6.0 mu liter 1 ) were considered as subclinically hypothyroid (17), and with S-TSH close to the upper limit of the normal range ( mu liter 1 ) as borderline subclinically hypothyroid. To be able to analyze further the thyroid function in these patients, the levels of subclinical and borderline subclinical hypothyroidism were graded according to the S-TSH and S-FT4 concentrations (see Table 1 for definitions). The blood tests were taken in the morning, before the ERCP procedure and thus not after given the patient oral cholecystographic contrast material or after endoscopic manipulation of the gastrointestinal tract. Only the samples from patients included into the study based on ERCP findings were later analyzed. The data are shown as median and range. To calculate the statistical significance of the differences between the groups, Mann-Whitney U test was used for linear nonparametric variables and 2 test for cross-tabulated variables. Differences of P 0.05 were considered significant. The study was conducted in accordance with the Helsinki Declaration. The study protocol was approved by the Ethical Councils of Tampere University Hospital and Helsinki University Hospital, Finland, and Kaunas Medical University Hospital, Lithuania. Results Age and gender of the patients were similarly distributed in groups I (CBD stone) and II (control). There were 109 men (40%) in the CBD stone and 54 (38%) in the control group. Median age was 68 (range 18 98) and 65 (22 93) yr at the time of hospitalization in the CBD stone and control patients, respectively. Differences were nonsignificant between the groups. None of the patients included in the study were septic, and no weight loss was recorded. S-Bil values were significantly higher in the CBD stone patients, compared with control patients ([56.6 ( ) vs. 9.2 ( ) mol liter 1, P 0.001; median and range)]. All control patients had a normal S-Bil level ( mol liter 1 ). None of the patients recruited into the study had symp- TABLE 1. The prevalence of borderline subclinical and subclinical hypothyroidism graded (grades I- IV) according to the S-TSH and S-FT4 levels in the group I (CBD stone) and group II (control) patients in different age groups and in total Age (yr) Borderline subclinical hypothyroidism Subclinical hypothyroidism Total Total Grade I S-TSH 5 6 mu liter S-FT4 10 pmol/liter Grade II S-TSH 5 6 mu liter S-FT pmol/liter Grade III S-TSH 6mU liter, S-FT pmol/liter Grade IV S-TSH 6mU liter S-FT4 9 pmol/liter Grades I-IV n (%) n (%) n (%) n (%) n (%) n (%) Group I Total a a b b c 10.2 Group II Total a a b b c 2.8 a NS (grades borderline I-II subclinical hypothyroidism between groups I and II). b P 0.05 (grades III-IV subclinical hypothyroidism between groups I and II). c P [total (grades I-IV) borderline subclinical plus subclinical hypothyroidism between groups I and II].

3 4262 J Clin Endocrinol Metab, November 2007, 92(11): Laukkarinen et al. Subclinical Hypothyroidism and CBD Stones toms of hypothyroidism. There was no difference in the median values of S-TSH (1.5, range vs. 1.2, range mu liter 1 ) and S-FT4 (14.1, range vs. 14.0, range pmol liter 1 ) between the groups. S-TSH was above the upper normal range ( 6.0 mu liter 1 ; subclinical hypothyroidism) in 16 CBD stone patients (5.3%), compared with two controls (1.4%; P 0.05). Fifteen CBD stone patients (5.0%) had S-TSH close to the upper limit of normal range (5 6 mu liter 1 ; borderline subclinical hypothyroidism), compared with two patients (1.4%) in the control group (P 0.026). Thus, 5.3 and 5.0% (in total 10.2%; 31 of 303) of CBD stone patients had subclinical or borderline subclinical hypothyroidism, compared with 1.4 and 1.4% (in total 2.8%, four of 142; P 0.026) in the control group, respectively. The thyroid function of the 31 CBD stone (10.2%) and four control patients (2.8%) with S-TSH levels above 5.0 mu liter 1 is shown as graded into subgroups of borderline subclinical and subclinical hypothyroidism (grades I-IV) (Table 1), by combining the S-TSH and S-FT4 data. In each grade the prevalence of subclinical or borderline subclinical hypothyroidism was three to four times higher in CBD stone patients than the control patients. The prevalence of subclinical (S-TSH 6.0 mu liter 1 ; grades III-IV) and borderline subclinical (S-TSH mu liter 1 ; grades I-II) hypothyroidism in women was 6.7 and 6.2% (total 12.9%) in CBD stone group and 2.3 and 2.3% (total 4.6%; NS) in the control group and in men 2.8 and 2.8% (total 5.5%) in the CBD stone group and 0 and 0% (total 0%, P NS) in control group, respectively. In the patients older than 50 yr in the CBD stone group, the prevalence of subclinical (S-TSH 6.0 mu liter 1 ; grades III-IV) and borderline subclinical (S-TSH mu liter 1 ; grades I-II) hypothyroidism was 7.4 and 5.9% (total 13.3%), compared with 0.9% (P 0.026) and 1.8% (total 2.6%; P 0.033) in the control group, respectively. In patients older than 60 yr, the prevalences of subclinical and borderline subclinical hypothyroidism were 6.9 and 5.4% (total 12.3%) in the CBD stone group and 1.2% (P 0.048) and 0% (P 0.048) (total 1.2%; P 0.007) in the control group, respectively. Most of the cases (12 of 16; 75%) with S-TSH values over 6.0 mu liter 1 (subclinical hypothyroidism; grades III-IV) in the CBD stone group were found in women older than 60 yr; in this subgroup the prevalence was 11.4% (12 of 105) in the CBD stone and 1.8% (one of 56) in the control group (P 0.032). In women older than 60 yr in CBD stone patients, the prevalence of grades I-IV (S-TSH 5.0 mu liter 1 ) subclinical plus borderline subclinical hypothyroidism was 25 of 105 (23.8%), compared with one of 56 (1.8%) in the control group (P 0.012). There were two patients (1.4%) in the control group (none in CBD stone group) who were recognized to have S-TSH values below the lower normal limit ( 0.4 mu liter 1 ). Of these two patients, one had S-FT4 above the upper normal limit ( 19.0 pmol liter 1 ), and the other had S-FT4 within the normal range. In addition, one patient in group I with S-TSH within the normal range (0.3%) had S-FT4 above the upper normal range. There was no statistical difference between the two groups. In the general linear model multivariate analysis, patient group, age, and gender were associated with the level (grades I-IV) of thyroid function. Discussion Earlier, an association between CBD stones and diagnosed hypothyroidism and delayed emptying of the biliary tract in experimental and clinical hypothyroidism have been shown, explained at least partly by the lack of the prorelaxing effect of T 4 on the sphincter of Oddi contractility (11 15). In this study we further investigated the prevalence of previously undiagnosed thyroid function abnormalities in CBD stone patients. To our knowledge, this has not been studied before. It was found that in the CBD stone patients, subclinical and borderline subclinical hypothyroidism are significantly more common, compared with the nongallstone controls (10.2 vs. 2.8%; P 0.026), the prevalence in the subgroup of women older than 60 yr being as high as 23.8%, compared with 1.8% in the control patients. The two study groups were well comparable for age and gender distribution. Because of the possible effects on the serum thyroid values, patients with phenytoin or carbamazepine therapy as well as pregnant patients were excluded from both of the groups. The group I patients were diagnosed at ERCP to have CBD stones at the time of the procedure; patients with a suspicion of passed CBD stones but no stones seen at ERCP were not accepted into the study. Base on a normal serum bilirubin level, none of the control patients had signs of biliary stasis. Neither did the control patients have a history of gallstone disease or stones at ultrasonography performed during the study. In general, at ultrasonography about 95% of the gallbladder stones can be diagnosed (17). In addition, contrary to CBD stones, dilatation of bile ducts, suggesting ductal obstruction, may be detected with high sensitivity. In fact, the sensitivity of ultrasound in detecting biliary obstruction is about 85% (17), with a negligible falsepositive rate (5), but a negative result does not exclude CBD stones or obstruction. Because there was no suspicion of CBD stones in the control patients, no imaging techniques except for ultrasonography (e.g. magnetic resonance cholangiopancreatography) were used to confirm the absence of CBD stones. The laboratory hallmark of primary hypothyroidism and the most sensitive test for detecting early thyroid failure is an increased S-TSH concentration. The S-FT4 level is decreased in clinical hypothyroidism (18). In the subclinical form, an increased S-TSH level is accompanied by a normal S-FT4 level, and the patient is asymptomatic (19). In the present study, none of the patients was clinically hypothyroid. It was recognized that in 5.3% of the patients with CBD stones, S-TSH levels were above the upper limit of the normal range (defined as subclinical hypothyroidism), compared with 1.4% in the control patients (P 0.05). Furthermore, as many as 31 patients (10.2%) in the CBD stone group had S-TSH levels above or close to the upper limit of the normal range (defined as subclinical or borderline subclinical hypothyroidism, respectively), compared with four patients (2.4%) in the control group (P 0.026). Thus, subclinical and borderline subclinical forms of hypothyroidism are significantly

4 Laukkarinen et al. Subclinical Hypothyroidism and CBD Stones J Clin Endocrinol Metab, November 2007, 92(11): more common in patients with diagnosed CBD stones, compared with nongallstone control patients. In this study setting, the thyroid function serum determinations were done only once in each individual, and the findings are thus not based on a recording of a persistent abnormality. However, the measuring of the thyroid values was done similarly in both of the groups, and presumably remeasurements would not have changed the greatly significant difference in the prevalence of subclinical and borderline subclinical hypothyroidism between the two groups. However, in clinical practice, recording of a persistent abnormality should be preferred. Subclinical hypothyroidism is a prevalent condition among adult population; however, it is frequently overlooked. The previous studies about the prevalence of subclinical hypothyroidism among health subjects are few in number. There are no reported studies from Finland. Thus, in the Finnish population, at the moment we can compare the results of the study population only with the control population of the current study. In a recent study from the United Kingdom (16), the prevalence of subclinical hypothyroidism among healthy subjects was 2.6%, which is somewhat higher compared with the prevalence of hypothyroidism among the control patients in the present study (1.8%). The prevalence of hypothyroidism (clinical plus subclinical) among women older than 60 yr may be as high as 20% (20). In the present study, the prevalence of subclinical hypothyroidism in women older than 60 yr was 11.4% in the CBD stone patients, compared with 1.8% in the control patients (P 0.032). The currently diagnosed 23.8% prevalence of subclinical plus borderline subclinical hypothyroidism and the previously diagnosed 11% prevalence of hypothyroidism (11) in female CBD stone patients older than 60 yr support the findings of Dickey and Feld (20) and suggest that at least this subgroup of patients might need to be screened for current thyroid dysfunction. It is uncertain whether treatment will improve quality of life in healthy, symptom-free patients who have abnormal TSH levels and normal FT4 levels (21, 22). Treatment of subclinical hypothyroidism is recommended if it is associated with changes in the cholesterol level, cardiovascular effects, or neuromuscular symptoms. Short-term studies have demonstrated that a positive effect on these symptoms may be achieved with early replacement treatment with l-thyroxine (23, 24). Thus, also patients with subclinical hypothyroidism and CBD stones might benefit form the T 4 replacement therapy in general. The role of such therapy in preventing recurrent stone formation has not yet been studied. The pathogenesis of gallstones is a complex process involving factors affecting bile content and bile flow. Brown pigment stones are formed secondary to biliary stasis (6), which is the major factor leading to anaerobic bacterial degradation and precipitation of biliary lipids (25, 26). Mechanical obstruction of the biliary tract leading to biliary stasis may be caused by bile duct strictures, SO stenosis, or SO dyskinesia (6, 8, 9). Brown pigment stones may also occur around a nidus of black or cholesterol stones or foreign material, which partially obstruct the CBD. Once initiated, the pathogenetic mechanism of stasis and bacterial overgrowth is difficult to reverse. The incidence of brown stones increases with age, the phenomenon of which may be associated with deterioration of the SO function (6). In the current study, we did not analyze the composition of the diagnosed CBD stones, which is why the association of hypothyroidism with certain type of gallstones remains unverified. Thyroid hormones are known to have a number of effects on cholesterol metabolism (27). When serum cholesterol values rise in hypothyroidism, bile may also become supersaturated with cholesterol, leading to gallbladder hypomotility (26), depressed contractility (28), and impaired filling (29), giving rise to a prolonged residence of bile in the gallbladder. This may contribute to the retention of cholesterol crystals, thereby allowing sufficient time for nucleation and continual growth into mature gallstones (26). In addition, the rate of bile secretion may be decreased (30), physically impairing clearance of precipitates from the bile ducts and gallbladder. In the present study, we did not study the thyroid values in gallbladder stone patients without CBD stones. If the effect of T 4 or the absence of T 4 affected only the cholesterol metabolism and the hepatic bile secretion, the patients with gallbladder and CBD stones would presumably evince an equally increased prevalence of diagnosed or subclinical hypothyroidism. In a previous study, it was, however, noted the CBD stone patients had two times more previously diagnosed hypothyroidism than the gallbladder stone patients (11). This might be due to the previously shown reduced prorelaxing effect of T 4 on the SO in hypothyroidism (12, 13), resulting in delayed emptying of the bile duct into the duodenum (14, 15), favoring the formation or retention of CBD stones. Thyroid hormones are known to have an enterohepatic circulation (31, 32). Thus, at least theoretically, it might be possible that impaired bile acid secretion in a patient could interfere with the enterohepatic circulation of T 4, increase thyroid hormone clearance, and provoke hypothyroidism in an individual with decreased thyroid reserve, e.g. due to autoimmune thyroiditis. However, this would not explain the phenomena, that hypothyroidism is associated more with CBD stones than gallbladder stones (11), which we assume might be due to the lacking (prorelaxing) effect of T 4 on SO (12, 13). It can also be further speculated whether the diminished biliary T 4 concentration would have a direct effect on the SO contractivity: we have reported that T 4 has a prorelaxing effect on SO in in vitro experiments (12, 13), but it is not known whether, in a patient, in addition to the diminished serum T 4 concentration, a potentially lower biliary T 4 concentration would also play a role in this, having a direct, relaxation-impairing effect on the SO. In a previous study (11), the CBD stone patients with diagnosed hypothyroidism were already receiving T 4 replacement therapy and were already euthyreotic in clinical and laboratory evaluation at the time of the diagnosis of CBD stones. Thus, CBD stone formation may already begin during the period of undiagnosed or subclinical hypothyroidism, later T 4 replacement therapy not having enough effect on clearance of stones already formed. The findings of the present study are not in contrast with this hypothesis. There is only one case report that describes gallstone disappearance after treatment with T 4 (33). There are currently no data to

5 4264 J Clin Endocrinol Metab, November 2007, 92(11): Laukkarinen et al. Subclinical Hypothyroidism and CBD Stones suggest whether therapeutic doses of T 4 could prevent gallstone formation. In conclusion, subclinical hypothyroidism is more common in the CBD stone patients, compared with the nongallstone controls, which supports our previous hypothesis that hypothyroidism might play a role in the forming of CBD stones. Further studies are needed to investigate whether early treatment of subclinical or clinical hypothyroidism could prevent the CBD stones in these patients. At least a subgroup of CBD stone patients, i.e. women older than 60 yr, with the highest prevalence of subclinical hypothyroidism should be screened for thyroid function and offered replacement therapy, a positive effect on the symptoms associated with subclinical hypothyroidism as a possible achievement. Acknowledgments The authors thank Solvay-Pharma for creating the network of investigators in the Pancreas 2000 educational program. Received June 13, Accepted August 21, Address all correspondence and requests for reprints to: Johanna Laukkarinen, M.D., Ph.D., Boston Pancreas Group, Department of Surgery, #37, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts johanna.laukkarinen@fimnet.fi. This work was supported by the Medical Research Fund of Pirkanmaa Hospital District, Finland. Disclosure Statement: The authors have nothing to disclose. References 1. Diehl AK 1991 Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 20: Heaton KW, Braddon FE, Mountford RA, Hughes AO, Emmett PM 1991 Symptomatic and silent gall stones in the community. Gut 32: Kratzer W, Mason RA, Kachele V 1999 Prevalence of gallstones in sonographic surveys worldwide. 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Hepatogastroenterology 28:60 61 JCEM is published monthly by The Endocrine Society ( the foremost professional society serving the endocrine community.