Hypothyroidism and Gallbladder Disease

World J Gastroenterol. 2005 Sep 21;11(35):5530-4.
Association between thyroid function and gallstone disease.
Völzke H, Robinson DM, John U.
To investigate those associations using data of the population-based Study of Health in Pomerania.
A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease was available for analyses. Serum TSH was used to assess thyroid function. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on ultrasound. Logistic regression was performed to analyze independent associations between thyroid function and cholelithiasis.
There were 385 persons (10.3%) with low (<0.3 mIU/L), 3 321 persons (88.6%) with normal and 43 persons (1.2%) with high serum TSH levels (>3 mIU/L). The proportion of cholelithiasis among males and females was 14.4% and 25.3%, respectively. Among males, there was an independent relation between high serum TSH and cholelithiasis (OR 3.77; 95%-CI 1.06-13.41; P<0.05). Also among males, there was a tendency towards an elevated risk of cholelithiasis in persons with low serum TSH (OR 1.40; 95%-CI 0.96-2.02; P = 0.07). In the female population, no such relation was identified.
There is an association between thyroid and gallstone disease with a gender-specific relation between hypothyroidism and cholelithiasis.

Surgery. 2003 Mar;133(3):288-93.
Is bile flow reduced in patients with hypothyroidism?
Laukkarinen J, Sand J, Saaristo R, Salmi J, Turjanmaa V, Vehkalahti P, Nordback I.
Disturbances in the sphincter of Oddi (SO) function may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. We have previously shown increased prevalence of diagnosed hypothyroidism in CBDS patients, thyroxine (T(4)) -induced inhibition of the SO contractility both in animal and in human experiments ex vivo, and reduced bile flow to duodenum in hypothyroid rats. The aim of the present study was to investigate human biliary dynamics in relation to altered thyroid gland function.
Eight female patients, 1 with diagnosed untreated hypothyroidism and 7 with total thyroidectomy performed due to thyroid cancer, were studied in hypothyroid stage and again after thyroxine replacement therapy in euthyroid stage, with quantitative (99m)Tc HIDA cholescintigraphy (QC), biliary ultrasonography, and serum determinations. Each patient served as her own control in the 2 stages of the study.
In QC, maximal uptake of (99m)Tc HIDA was not changed in hypothyroidism compared to euthyroidism. The first appearance of radioactivity to large bile ducts at the hepatic hilum remained unchanged in the 2 stages of the study. Hepatic clearance of (99m)Tc HIDA was decreased at 45 minutes (28% [11-38] vs 50% [33-54]; P =.028; median and range) and at 60 minutes (55% [28-80] vs 69% [61-79]; P =.028; median and range) and hilum-duodenal transit time increased by 31% compared to euthyroid stage. In US no changes were seen in gall bladder or bile ducts in the 2 stages of the study. Serum hypercholesterolemia was observed in the hypothyroid stage.
We conclude that hypothyroidism may result in delayed emptying of the biliary tract, as studied with QC. In addition to the changes in bile composition and excretion rate suggested before to take place in hypothyroidism, according to the present study changes in biliary emptying also may be included in the probable causes for the increased prevalence of CBDS in hypothyroidism. This may be due to the absence of the prorelaxing effect of thyroxine on SO, which we have shown before to exist ex vivo.

Neurogastroenterol Motil. 2002 Apr;14(2):183-8.
Bile flow to the duodenum is reduced in hypothyreosis and enhanced in hyperthyreosis.
Laukkarinen J, Koobi P, Kalliovalkama J, Sand J, Mattila J, Turjanmaa V, Porsti I, Nordback I.
Disturbances in sphincter of Oddi (SO) function may prevent normal bile flow and thus enhance probability of common bile duct stone (CBDS) formation. We have previously shown increased prevalence of diagnosed hypothyroidism in CBDS patients, which may be explained by thyroxine-induced inhibition of SO contractility, in addition to previously suggested changes in bile composition and hepatocytic excretion. The aim of this study was to investigate biliary dynamics in relation to altered thyroid gland function in rat, a rodent without a gallbladder. Euthyroid, hypothyroid or hyperthyroid Spraque-Dawley rats were anaesthetized with i.p. urethane, and exsanguinated at 15, 45, or 60 min after intravenous 99mTc HIDA injection. At these timepoints, the bile flow to intestine was determined by measuring the relative intestine vs. liver radioactivity. At 45 min this was 44% lower in hypothyroid rats and at 60 min 73% higher in hyperthyroid rats compared to euthyroid rats, while hepatic radioactivity at 15 min and blood pressure at injection were similar in the groups. We conclude that the bile flow to duodenum is reduced in hypothyreosis and enhanced in hyperthyreosis.

Dig Dis Sci. 2001 Jan;46(1):182-6.
Direct effect of thyroxine on pig sphincter of Oddi contractility.
Inkinen J, Sand J, Arvola P, Pörsti I, Nordback I.
Sphincter of Oddi (SO) motility has an important role in the regulation of bile flow. SO function disturbances (stenosis or dyskinesia) may prevent normal bile flow and thus enhance the probability of common bile duct (CBD) stone formation. Previously we have shown that there is an increased prevalence of diagnosed hypothyroidism in CBD stone patients, compared with gallbladder stone patients or age-, sex-, and hospital-admission-adjusted controls. The present study was done to test the hypothesis that thyroxine directly effects the SO. The specificity of the effects of thyroxine were studied by comparing with triiodothyronine (T3), progesterone, cortisone, estrogen, and testosterone. For ex vivo studies three or four successive 1 to 1.5-mm SO rings were prepared from each pig and placed between two hooks in oxygenated physiologic salt solution at 37 degrees C. SO contraction was measured with isometric force displacement transducers and registered on a polygraph. Each SO ring was stimulated with KCl (125 mM), acetylcholine (ACh; 10 or 100 microM) and histamine (Hist; 10 or 100 microM) with and without thyroxine (10(-10) or 10(-8) M), T3 (10(-9) or 10(-7) M), progesterone (1 microM), cortisone (1 microM), estrogen (1 microM), or testosterone (1 nM) in the medium. KCI, ACh, and Hist induced strong contractions in the SO rings. The addition of thyroxine did not influence significantly the KCl-induced contractions, but the ACh- and Hist-induced contractions decreased by a mean of 37-44% (P < 0.001) and 54-56% (P < 0.001), respectively, as compared to the contractions without thyroxine. Triiodothyronine had a similar inhibitory effect to thyroxine, whereas cortisone, estrogen, and testosterone had no effect. Progesterone decreased the KCl-, ACh-, and Hist-induced SO contractions. In conclusion, physiological concentrations of thyroxine have an inhibitory effect on receptor-mediated ACh and Hist, but not on the nonspecific KCl-induced SO contraction ex vivo. The inhibitory effect is similar in thyroxine and triiodothyronine. Of the steroid hormones, only progesterone nonspecifically ameliorates SO contractions ex vivo. Because the effect of thyroxine on the SO is prorelaxing, the lack of thyroxine may result in an increased tension of the SO.

Gut. 2001 Mar;48(3):414-7.
Increased sphincter of Oddi basal pressure in patients affected by gall stone disease: a role for biliary stasis and colicky pain?
Cicala M, Habib FI, Fiocca F, Pallotta N, Corazziari E.
Even if the motor activity of the gall bladder and sphincter of Oddi (SO) are integrated, it is not known if the presence of stones in the gall bladder affects SO function. The aim of the study was to compare SO motor activity in patients with and without gall stones.
In a series of 155 patients consecutively submitted to endoscopic retrograde cholangiopancreatography and SO manometry for suspected biliary or pancreatic disease, 23 gall stone patients had recurrent episodes of biliary or pancreatic pain (colicky group); 52 patients had non-biliary/pancreatic-type abdominal pain/discomfort, and of these, 15 had gall stones (non-colicky group), 25 were free of stones (controls), and 12 had undergone cholecystectomy.
SO basal pressure in gall stone patients in the colicky or non-colicky group was significantly higher than in controls (p<0.001). SO basal pressure recorded in postcholecystectomy patients did not differ from controls. SO phasic activity did not differ between the patient groups. SO dysfunction was detected in more than 40% of gall stone patients irrespective of associated biliary/pancreatic pain but in none of the control subjects (p<0.001).
Gall stones are frequently associated with increased SO tone which may obstruct bile flow thus acting to facilitate gall bladder stasis, and may play a role as a cofactor in biliary/pancreatic pain.

The Journal of Clinical Endocrinology & Metabolism November 1, 2007 vol. 92 no. 11 4260-4264
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
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).
Main Outcome Measures: Serum free FT4 and TSH (S-TSH) were analyzed; S-TSH above the normal range (>6.0 mU/liter) was considered as subclinical and S-TSH 5.0–6.0 mU/liter as borderline-subclinical 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 borderline-subclinical 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.

Gastroenterology. 1986 Aug;91(2):297-304.
Effect of dietary cholesterol on biliary cholesterol content and bile flow in the hypothyroid rat.
Field FJ, Albright E, Mathur SN.
The hypothyroid rat model was used to investigate the effect of dietary-induced hypercholesterolemia on biliary cholesterol content and bile flow. Rats were divided into four dietary groups–diet A: Rat Chow; diet B: Rat Chow plus 0.1% propylthiouracil; diet C: Rat Chow plus 0.1% propylthiouracil, 0.3% taurocholate, 5% lard; diet D: Rat Chow plus 0.1% propylthiouracil, 0.3% taurocholate, 5% lard, and 1% cholesterol. After 6 wk, bile was collected and livers were excised for the preparation of membranes. In cholesterol-fed animals, biliary cholesterol content was increased. However, because of a significant decrease in the rate of bile flow that occurred in these animals, biliary cholesterol output was unchanged from the cholesterol output observed in control animals. Dietary cholesterol also caused a threefold increase in liver membrane cholesterol content and a 64% decrease in the activity of sodium-potassium-stimulated adenosine triphosphatase (Na+,K+-ATPase). In a separate group of animals, microsomes prepared from livers of control rats were incubated with phosphatidylserine liposomes, liposomes containing cholesterol, or buffer. The activity of Na+,K+-ATPase was increased in microsomes incubated with phosphatidylserine liposomes. However, when the cholesterol content of the microsomes was increased twofold by incubating the membranes with liposomes containing cholesterol, the stimulation of Na+,K+-ATPase activity was significantly decreased. The data suggest that in the cholesterol-fed hypothyroid rat, biliary cholesterol content is significantly increased; however, because of a decrease in the rate of bile flow, biliary cholesterol output is not changed. The decrease in bile flow is associated with an accumulation of cholesterol and a decrease in the activity of Na+,K+-ATPase in hepatic membranes.

Hepatogastroenterology. 2000 Jul-Aug;47(34):919-21.
Association between common bile duct stones and treated hypothyroidism.
Inkinen J, Sand J, Nordback I.
The purpose of this study was to investigate the frequency of diagnosed hypothyroidism in patients with common bile duct stones.
The common bile duct stone group (Group I) consisted of all the patients who had verified gallstones in the common bile duct in endoscopic retrograde cholangiopancreatography during 1995. The control group (Group II) was matched for age, sex, and hospital admission. These patients did not have diagnosed gallbladder or common duct stones. In both groups there were 86 patients (56 women and 30 men). The median age in these groups was 73 (range: 22-92) years at the time of common bile duct stone diagnosis. Medical records of all patients were reviewed.
In Group I the prevalence of previously diagnosed hypothyroidism was 7/86 (8%) compared with 1/86 (1%) in Group II (P = 0.01). Hypothyroidism was previously diagnosed only in the common bile duct stone patients (Group I) of over 60 years of age, where the prevalence was 7/66 (11%). In addition, we studied 36 consecutive gallbladder stone patients (Group III) of over 60 years, who had no evidence of common bile duct stones. Hypothyroidism had been diagnosed in them less frequently (2/36 = 6%) than in the age and hospital admission matched common bile duct stone patients (P = 0.01). Other diagnosed endocrine disorders did not differ between the study groups.
There is a significant association between the common bile duct stones and previously diagnosed hypothyroidism. There stronger association between the common bile duct stones and hypothyroidism compared to gallbladder stones and hypothyroidism suggests a mechanism other than merely the cholesterol metabolism mediated mechanism. The 11% prevalence of previously diagnosed hypothyroidism in the common bile duct stone patients of over 60 years of age suggests all patients with common bile duct stones be screened for current thyroid dysfunction.

Hepatogastroenterology. 1981 Feb;28(1):60-1.
Dissolution of gallstones following thyroxine administration. A case report.
Vassilakis JS, Nicolopoulos N.
A case of disappearance of five radiolucent gallstones within six months is reported. During this time the patient was taking carbimazole and thyroxine orally for toxic goiter. Three more cases of disappearance of gallstones after iatrogenic alteration in the thyroid status by thyroid hormone administration have been published. It is concluded that thyroid hormone may play a role in the dissolution of gallstones by altering the metabolism of cholesterol.

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