The Gastrointestinal Tract and Liver in Hypothyroidism
Sanjeev M. Wasan
Joseph H. Sellin
The sluggish and slow response characteristic of the patient with hypothyroidism in general marks the major gastrointestinal (GI) manifestations of hypothyroidism: sluggish intestinal motility ranging from mild obstipation to paralytic ileus and intestinal pseudo-obstruction. Hypothyroidism most often afflicts elderly persons, who frequently discount the significance of an insidious decrease in bowel movements. Severe constipation unresponsive to laxatives, therefore, may be a prominent finding at diagnosis. Younger patients with hypothyroidism secondary to treatment for thyrotoxicosis or thyroid cancer frequently gain weight because of decreased physical activity coupled with unchanged food intake. In infants, the observation of infrequent hard stools should serve as a clue to the diagnosis.
Hypothyroidism affects the GI tract in several additional ways. As with thyrotoxicosis, atrophic gastritis and pernicious anemia may be associated findings. Therefore, prompt investigation of gastric histology and vitamin B12 metabolism should follow the discovery of megaloblastic anemia in the hypothyroid patient. Although there may be a specific hepatic lesion of hypothyroidism, associated autoimmune liver disease is probably more common. In the hypothyroid patient with liver function abnormalities, particular diagnostic efforts should be directed toward the possibility of primary biliary cirrhosis or autoimmune hepatitis.
INTESTINAL MOTILITY IN HYPOTHYROIDISM
Although most patients with hypothyroidism average one bowel movement daily, about one eighth have fewer than three movements weekly; also, laxative use increases significantly (1). Insidious symptoms of vague abdominal pain and distention may be present and often are diagnosed as functional bowel disease. Unusual GI manifestations, such as a gastric phytobezoar (2) or a lesion mimicking carcinoma of the sigmoid colon (3), have been reported. Rectal prolapse, sigmoid volvulus, and intestinal pseudo-obstruction (4) occasionally are seen. Severe cases may present with intestinal atony and ileus (5), often misinterpreted as intestinal obstruction. In recent years, earlier diagnosis of hypothyroidism resulted in fewer cases progressing to pseudo-obstruction. Radiologic studies reveal generalized dilatation of the GI tract, especially the colon. Pathologic examination of the intestine demonstrated a thickened, pale, leathery colon that is generally lengthened; microscopically, myxedema and round cell infiltration of the submucosal and muscle layers is evident. A decrease in colonic crypts suggests mucosal atrophy.
The motility of the GI tract may be assessed using several different methods (see Chapter 34). Studies of hypothyroid humans and dogs demonstrated a decrease in the electric and motor activity of the esophagus, stomach, small intestine, and colon (6,7,8). Dysphagia is not uncommon in hypothyroidism and may be related to esophageal motility abnormalities, including decreases in the amplitude and velocity of peristalsis and a decrease in lower esophageal sphincter pressure. These abnormalities correct with thyroid replacement (6). Gastric emptying as measured with a liquid meal of glucose is prolonged in hypothyroidism and returns to normal with therapy (9). The neuropeptide thyrotropin-releasing hormone (TRH) has a central effect on gastric emptying; injected into the cerebrospinal fluid (CSF), TRH increases phasic motor activity of the stomach, mediated by TRH receptors on postsynaptic vagal neurons (10). Orocecal (intestinal) transit time, as measured by a lactulose-hydrogen breath test, decreased significantly in one study when hypothyroid patients were given thyroid hormone replacement (11), but was normal in another study in the hypothyroid state and was not altered significantly by thyroid hormone replacement (12). In the sigmoid colon and rectum, the number and amplitude of muscular contractions are decreased. The relative importance of the small bowel and colon in the “sluggish gut” of hypothyroidism remains to be determined. Several theories have been proposed to explain the changes of the intestine in hypothyroidism, including autonomic neuropathy, altered impulse transmission at the myoneural junction, intestinal ischemia, and intestinal myopathy.
ABSORPTION IN HYPOTHYROIDISM
In most patients, intestinal absorption is normal. The malabsorption occasionally reported in severely hypothyroid patients remains poorly understood but has been attributed to myxedematous infiltration of the mucosa, decreased intestinal motility, or associated autoimmune phenomena. Intestinal handling of D-xylose is normal, although renal clearance after both intravenous and oral administration is lower as a result of a decrease in glomerular filtration rate. In addition, glucose absorption is normal overall, whereas net transmural transport is enhanced, in part because of decreased glucose utilization (13). Hypercalcemia may occur as a result of increased absorption of dietary calcium in conjunction with a decrease in calcium incorporation into bone (14). Pancreatic function is generally normal in hypothyroidism; hypothermia associated with severe hypothyroidism occasionally may result in hyperamylasemia, probably secondary to pancreatitis (15). The intestinal epithelium may be less responsive to secretory stimuli, such as vasoactive intestinal peptide, suggesting a possible pathophysiologic mechanism for some of the intestinal alterations of hypothyroidism (16). Although rare in hypothyroidism, diarrhea can occur and may be due to bacterial overgrowth from small bowel hypomotility, corrected with antibiotic therapy (17). In hypothyroid patients who receive thyroid hormone replacement, the addition of other pharmacologic agents (e.g., bile acid sequestrants, sucralfate, ferrous sulfate, or aluminum hydroxide) may impair thyroxine T4 absorption and complicate management (18,19). Thyroid function may be altered in inflammatory and immune-mediated diseases of the intestine (see Chapter 34).
THYROID FUNCTION IN MALABSORPTION AND INTESTINAL DISEASE
An enterohepatic circulation of thyroid hormone has been described (20) in which thyroid hormone secreted into bile is delivered into the intestinal lumen, reabsorbed, and delivered back to the liver (see Chapter 34). This system is similar to that described for other hormones, such as vitamin D and estrogens. Interactions of the gut with thyroid hormone, the potential role of the intestine both as a reservoir for thyroid hormones and as a regulator of hormone activity (21), and the presence of the enterohepatic circulation raise several interesting questions: Does intraluminal thyroid hormone affect intestinal function? Does thyroid hormone delivered to the liver through the enterohepatic circulation and portal vein in relatively high concentration have an effect on hepatic function? Given the ability of intestinal bacteria to bind and degrade thyroid hormones (22), is there a clinically important, although indirect, effect of intestinal hypomotility on thyroid hormone economy?
Significant adaptation in fecal losses of thyroid takes place in hypothyroidism (23) both through decreased excretion and increased absorption. Nevertheless, intestinal diseases and malabsorption may affect the metabolism of thyroid hormone. Increased fecal T4 losses may occur in pancreatic steatorrhea, celiac sprue (24), and inflammatory bowel disease (25). In addition, autoimmune thyroid disease (hypothyroidism more frequently than thyrotoxicosis) may be more prevalent in patients with celiac disease (26). Given the association between celiac sprue and thyroid disease, this may be a confounding variable to consider when oral thyroid replacement is difficult. Malabsorption of oral thyroid medication is seen after jejunoileal bypass (27,28). In balance, the euthyroid patient is generally capable of compensating for intestinal losses with increased endogenous thyroid secretion, whereas the hypothyroid patient may require an increase in thyroid hormone replacement dosage.
EPITHELIAL TRANSPORT AND GUT FUNCTION
Because Na+,K+-adenosine triphosphatase (ATPase) is pivotal to both thyroid hormone–regulated thermogenesis and epithelial ion transport, the linkage between thyroid hormone and ion transport has been investigated (29). Thyroid hormone stimulates both Na+,K+-ATPase activity and electrogenic Na absorption in the intestine (30,31). The effect may be due to enhanced message of the β subunit of Na+,K+-ATPase (31). Thyroid hormone also induces Na pump activity, enhances bile flow, and increases the messenger RNA (mRNA) for α and β subunits of Na+, K+-ATPase in the liver (32,33).
Thyroid hormone also may stimulate the activity of apical, amiloride-sensitive Na+ channels in the colon (34). These effects may be indirect; thyroid hormone may function by increasing the sensitivity of these transporters to aldosterone, one of the principal regulators of Na+ absorption in the gut (35,36). Aldosterone has effects on both the amiloride-sensitive Na channel and the Na+ pump. T4 also may have a role in regulating anion transport in the intestine by inhibiting an apical Cl:HCO3 exchanger (37). The effects on nutrient transport are complex. Animal studies have demonstrated complex and conflicting effects on active, electrogenic transfer of amino acids and sugars (38, 39).
Triiodothyronine (T3) down-regulates lactase, stimulates alkaline phosphatase, and does not affect sucrase gene expression (40). T3 causes epithelial hypertrophy and villus hyperplasia with minimal change in the morphometry of the crypts (40). Thyroid-associated changes in colonic epithelial membrane lipid composition and fluidity may exert generalized functional changes on epithelial function (41). In sum, the effects of thyroid hormone on intestinal function are significant and complex; their clinical implications are not so clear.
GUT AND LIVER DEVELOPMENT
Intestinal development is physiologically regulated by thyroid hormone at multiple levels (42,43,44,45,46,47). In developing animals, hypothyroidism results in decreased mucosal thickness and villous height, weight, and protein content of the small intestine (48) and in abnormal peptide content and binding properties (16,49,50). As for the converse, experimental hyperthyroidism in developing animals leads to mucosal hypertrophy and epithelial hyperplasia. In humans, however, fetal hypothyroidism does not appear to affect the gut seriously.
Overall, thyroid hormone alone has only modest effects on intestinal maturation but, when combined with glucocorticoids, may have a synergistic effect on multiple enzymes, including lactose, sucrase, maltase, and alkaline phosphatase. Thyroid hormone has a role in both gene expression and protein abundance (40,45,46,47,51). In the presence of glucocorticoids, thyroid hormone appears to accelerate the maturation process, changing the programmed alterations in specific enzyme levels during the weaning period.
Although diet may have a role in this modulation, thyroid hormone appears to have a direct effect on the intestine (44,52). Changes in hormonal responsiveness of the intestine during development may reflect changes in the forms of T3 receptors found in the intestine, with fairly constant levels of TR-β1 but decreases in c-erbA levels (44).
Most studies have focused on the effect of thyroid hormone on intestinal brush-border enzymes. Recent observations suggest that thyroid hormone may have a similar permissive effect in the developmental changes of electrogenic Na transport in the weanling colon (53). Thus, thyroid hormone is an important developmental modifier of the biologic effects of other hormones, primarily glucocorticoids and mineralocorticoids.
GASTRIC FUNCTION IN HYPOTHYROIDISM
Immune gastritis coexists with hypothyroidism in about 11% of patients. This association is probably due to the propensity of such patients for autoimmune disease (54). As with thyrotoxicosis, abnormalities of vitamin B12 metabolism without overt anemia, antiparietal cell antibodies, and hypochlorhydria or achlorhydria have been reported much more commonly. Similarly, there is a high incidence of thyroid antibodies in patients with pernicious anemia (55). The mechanism of gastric acid secretory dysfunction is also not clear. The observation that thyrotoxicosis is associated with hypergastrinemia (56,57), whereas patients with hypothyroidism have subnormal serum gastrin levels (58), implies that the pathophysiology of achlorhydria differs in the two conditions. The embryologic similarity between thyroid and gastric tissue, their mutual iodine-concentrating ability, and their similar histologic abnormalities led many investigators to consider that thyrogastric autoimmune disorders are linked pathophysiologically; to date, no human lymphocyte antigen (HLA) association has been found. An association between atrophic autoimmune thyroiditis and Helicobacter pylori infection has been observed (59). In fact, recent studies suggest infection by H. pylori strains expressing CagA is prevalent in patients with autoimmune thyroid disease. H. pylori organisms possessing pathogenicity carry a gene encoding for an endogenous peroxidase, which tends to increase the organism’s inflammatory potential (60).
LIVER IN HYPOTHYROIDISM
An association exists between Hashimoto’s thyroiditis and hypothyroidism with autoimmune liver diseases such as chronic active hepatitis (61,62) and primary biliary cirrhosis (63,64). Hypothyroidism is seen in approximately 5% to 20% of patients with primary biliary cirrhosis (65,66). Primary biliary cirrhosis may be associated with other organ-specific autoimmune diseases and thus with autoimmune polyglandular syndrome (67). In addition, 8% to 12% of patients with autoimmune hepatitis have been found to have hypothyroidism, especially chronic thyroiditis (66,68). Liver, gastric, and thyroid dysfunction in autoimmune disease may constitute a constellation of coexisting abnormalities (see Chapter 34 for a discussion of thyroid and liver interactions). Thyroid hormones have a significant impact in the regulation of hepatic mitochondrial metabolism (69,70). Hypothyroid animals have decreased resting metabolic rate with decreased hepatocyte oxygen consumption (71). A specific hypothyroid hepatic lesion of central congestive fibrosis without myxedematous infiltration has been reported (72). Persistent hyperbilirubinemia in the newborn may suggest the diagnosis of congenital hypothyroidism.
Ascites is a rare and poorly understood complication of severe hypothyroidism (73); it consists of a yellow, gelatinous peritoneal exudate. There is a high protein content of the fluid (>2.5 g/dL), a high serum-ascites albumin gradient, a long duration of the ascites, and resolution with thyroid replacement (72). It has been suggested that the ascites is related to congestive heart failure, enhanced capillary permeability, or the inappropriate secretion of antidiuretic hormone associated with hypothyroidism.
Reversible abnormalities of liver function tests are common, although usually mild, in hypothyroidism. In addition, there is abnormal fuel use with significant decrease in gluconeogenesis (74). Hypothyroid patients have specific defects in hepatic handling of amino acids resulting in decreased urea nitrogen generation (75).
Thyroid status clearly affects bile flow and composition. In experimental models of hypothyroidism, a decrease in bile flow is due primarily to a decrease in the bile salt–independent component (32). Additionally, the biliary excretion of bilirubin is diminished in association with some subtle alterations of hepatic bilirubin metabolism (76). Hypothyroidism may alter several critical steps in cholesterol and bile acid synthesis (77). In addition, thyroid hormone modifies lipoprotein metabolism in the liver (78,79,80,81,82,83,84). It is unclear whether this is a direct thyroid effect on liver enzymes or secondary to altered intestinal handling of cholesterol and bile acids (85,86). The changes in enzyme activities, the hypercholesterolemia of myxedema, and the hypotonia of the gallbladder in hypothyroidism suggest the possibility of increased cholesterol saturation of bile (85,86) and a higher incidence of gallstones. Direct measurements of the lithogenicity of hypothyroid bile are not available, however.
HEPATITIS C, INTERFERON, AND THE THYROID
Although autoimmune liver disease has long been associated with thyroid disease, the increasingly frequent diagnosis of hepatitis C and its treatment with interferon-α has suggested novel and different linkages between the thyroid and viral hepatitis. A relationship exists between the low thyroid hormone levels (free T4, T4, T3) and the degree of hepatic dysfunction based on the Child-Pugh classification in chronic viral hepatitis (87). There is an increased incidence of both thyroid antibodies and clinically significant thyroid disease in patients with hepatitis C prior to treatment. The incidence of anti-TPO (thyroid peroxidase) antibodies is about 10% to 15% (88,89,90,91,92), whereas overt thyroid dysfunction occurs in 0% to 4% of patients. Antithyroid antibodies are found more frequently in hepatitis C virus–positive women when compared with men (92).
Thyroid dysfunction and antithyroid antibodies, especially anti-TPO antibodies, both increase with interferon treatment, which generally lasts up to 12 months in treatment of hepatitis C. Anti-TPO antibodies occur in 20% to 30% of patients, although titers may vary considerably during treatment (91). Clinical manifestations of thyroid dysfunction occur in 10% to 15% of patients and may present as either hyperthyroidism or hypothyroidism (90,91,92,93). Thyrotoxicosis usually occurs due to silent thyroiditis, but Graves’ disease during interferon therapy has been reported. Hypothyroidism occurs from 2 months to 2 years after initiating interferon-α therapy and thyrotoxicosis from 6 weeks to 6 months. Thyroid dysfunction is transient in greater than two thirds of cases; however, thyroid function tests may not return to normal until up to as many as 17 months after discontinuation of therapy (94). From studies in a Japanese population, HLA-A2 is highly linked to autoimmune thyroid disease induced by interferon-α therapy in patients with chronic hepatitis C (95).
Whereas some investigators have found a higher incidence of anti-TPO and anti-thyroglobulin antibodies in hepatitis C compared with hepatitis B (88), others have not (89). Interferon therapy in a variety of other diseases also has been associated with thyroid abnormalities; however, the problem appears to be more common with hepatitis C, suggesting that some specific (but as yet undefined) factors that may be involved. The mechanisms for interferon-induced thyroid disease are unknown but may involve increased expression of major histocompatability (MHC) class I antigens, induction of autoantibodies, or a direct effect of interferon on the thyroid. There are some suggestions that interferon may interfere with iodide organification (95,95).
The major risk factor implicated in the development of thyroid disease during interferon treatment has been the presence of a high titer anti-TPO antibodies (88,90); however, it is clear that patients with preexisting thyroid disease do not necessarily worsen on interferon, and most patients who develop thyroid disease do not have preexisting antibodies. Cessation of interferon treatment usually leads to resolution of thyroid dysfunction.
Hypothyroidism appears to affect the GI tract more profoundly than thyrotoxicosis. Hypomotility with constipation is a fairly frequent, although usually mild, manifestation of hypothyroidism. Associated gastric, liver, and thyroid dysfunctions are often due to systemic autoimmune diseases. Although the clinical picture of hypothyroidism has been well characterized, the mechanisms of thyroid action on the gut and liver remain poorly understood.
1. Baker JT, Harvey RF. Bowel habits in thyrotoxicosis and hypothyroidism. BMJ 1971;1:322.
2. Kaplan LR. Hypothyroidism presenting as a gastric phytobezoar. Am J Gastroenterol 1980;74:168.
3. Duks S, Pitlik S, Rosenfeld JB. Hypothyroidism mimicking a tumor of the sigmoid colon. Mayo Clin Proc 1979;54:623.
4. Bassotti G, et al. Intestinal pseudoobstruction secondary to hypothyroidism. Importance of small bowel manometry. J Clin Gastroenterol 1992;14(1):56.
5. Abbasi AA, Douglass RC, Bissel GW, et al. Myxedema ileus. JAMA 1975;234:181.
6. Eastwood GL, Braverman LG, White EM, et al. Reversal of lower esophageal sphincter hypotension and esophageal aperistalsis after treatment for hypothyroidism. J Clin Gastroenterol 1982;4:307.
7. Karaus M, Wienbeck M, Grussendorf M, et al. Intestinal motor activity in experimental hyperthyroidism in conscious dogs. Gastroenterology 1989;97:911.
8. Kowalewski K, Kolodej A. Myoelectrical and mechanical activity of stomach and intestine in hypothyroid dogs. Am J Dig Dis 1977;22;235.
9. Kahraman H, Kaya N, Demircali A, et al. Gastric emptying time in patients with primary hypothyroidism. Eur J Gastroenterol Hepatol 1997;9:901.
10. Raybould HE, Jacobsen LJ, Tache J. TRH stimulation and L-glutamic acid inhibition of proximal gastric motor activity in the rat dorsal vagal complex. Brain Res 1989;49:319.
11. Shafer RB, Prentiss RA, Bond JH. Gastrointestinal transit in thyroid disease. Gastroenterology 1994;86:852.
12. Tobin MV, Fisken RA, Diggory RT, et al. Orocecal transit time in health and disease. Gut 1989;30:26.
13. Khoja SM, Kellett GL. Effects of hypothyroidism on glucose transport and metabolism in rat small intestine. Bioch Biophys Acta 1993;1179:76.
14. Lekkerkerker JF, Van Woudenberg F, Beekhuis H, et al. Enhancement of calcium absorption in hypothyroidism. Isr J Med Sci 1971;7:399.
15. Maclean D, Murison J, Griffiths PD. Acute pancreatitis and diabetic ketoacidosis in accidental hypothermia and hypothermic myxoedema. BMJ 1973;4:757.
16. Molinero P, Calvo JR, Jimenez J, et al. Decreased binding of vasoactive intestinal peptide to intestinal epithelial cells from hypothyroid rats. Biochem Biophys Res Commun 1989;162: 701.
17. Goldin E, et al. Diarrhea in hypothyroidism: Bacterial overgrowth as a possible etiology. J Clin Gastroenterol 1990;12:98.
18. Shakir KM, Michaels RD, Hays JH, et al. The use of bile acid sequestrants to lower serum thyroid hormones in introgenic hyperthyroidism. Ann Intern Med 1993;118:112.
19. Sherman SI, Tielens ET, Ladenson RW. Sucralfate causes malabsorption of L-thyroxine. Am J Med 1994;96:531.
20. Miller JL, Gorman CA, Go VLM. Thyroid-gut interrelationships. Gastroenterology 1978;75:901.
21. Hays MT. Thyroid hormone and the gut. Endocr Res 1988; 14:203.
22. Distefano JJ III, De Luze A, Nguyen TT. Binding and degradation of 3,5,38-triiodothyronine and thyroxine by rat intestinal bacteria. Am J Physiol 1993;264:E966.
23. Distefano JJ III, Morris WL, Nguyen TT, et al. Enterophepatic regulation and metabolism of 3,5,38-triiodothyronine in hypothyroid rats. Endocrinology 1993;132:1665.
24. Vanderschuren-Lodeweyckx M, Eggermont E, Cornette C, et al. Decreased serum thyroid hormone levels and increased TSH response to TRH in infants with coeliac disease. Clin Endocrinol 1977;6:361.
25. Janerot G, Kagedal B, Von Schenk H, et al. The thyroid in ulcerative colitis and Crohn’s disease. Acta Med Scand 1976;199:229.
26. Counsell CE, Taha A, Rudell WJJ. Coeliac disease and autoimmune thyroid disease. Gut 1994;35:844.
27. Azisi F, Belur R, Albano J. Malabsorption of thyroid hormones after jejunoileal bypass for obesity. Ann Intern Med 1979;90:941.
28. Topliss DJ, Wright JA, Volpe R. Increased requirements for thyroid hormone after a jejuno-ileal bypass operation. Can Med Assoc J 1978;123:765.
29. Edelman IS, Ismail-Beigi F. Thyroid thermogenesis and active sodium transport. Rec Prog Horm Res 1974;30:235.
30. Giannella RA, Orlowski J, Jump ML, et al. Na+-K+-ATPase gene expression in rat intestine Caco-2 cells: response to thyroid hormone. Am J Physiol 1993;265:G775.
31. Wiener H, Nielsen JM, Klaerke DA, et al. Aldosterone and thyroid hormone modulation of alpha 1, beta 1-mRNA and Na, K pump sits in rabbit distal colon epithelium: evidence for a novel mechanism of escape from the effects of hyperaldosteronemia. J Membr Biol 1993;133:203.
32. Layden TJ, Boyer JL. Effect of thyroid hormone on bile-salt-independent bile flow and Na+-K+-ATPase activity in liver plasma membrane enriched bile canaliculi. J Clin Invest 1976; 57:1009.
33. Gick GG, Ismail-Beigi F. Thyroid hormone induction of Na(+)-K(+)-ATPase and its mRNAs in a rat liver cell line. Am J Physiol 1990;258:C544.
34. Pacha J, Pohlova I, Zemanova Z. Hypothyroidism affects the expression of electrogenic amiloride-sensitive sodium transport in rat colon. Gastroenterology 1996;111:1551.
35. Edmonds CJ, Willis CJ. Aldosterone and thyroid hormone interaction on the sodium and potassium transport pathways of rat colonic epithelium. J Endocrinol 1990;124:47.
36. Barlet C, Doucet A. Triiodothyronine enhances renal response to aldosterone in the rabbit collecting tubule. J Clin Invest 1987; 79:629.
37. Tenore A, Fasano A, Gasparini N, et al. Thyroxine effects on intestinal Cl-HCO3-exchange in hypo- and hyperthyroid rats. J Endocrinol 1996:151:431.
38. Levin RJ, Syme G. Differential changes in the “apparent Km” and maximum potential differences of the hexose and amino acid electrogenic transfer mechanisms of the small intestine, induced by fasting and hypothyroidism. J Physiol 1971;213: 46.
39. Syme G, Levin RJ. The effects of hypothyroidism and fasting on electrogenic amino acid transfer. Biochim Biophys Acta 1977; 464:620.
40. Hodin RA, Chamberlain SM, Uptan MP. Thyroid hormone differentially regulates rat intestinal brush border enzyme gene expression. Gastroenterology 1992;103:1529.
41. Brasitus TA, Dudeja PH. Effect of hypothyroidism on the lipid composition and fluidity of rat colonic apical membranes. Biochim Biophys Acta 1988;939:189.
42. Galton VA, McCarthy PT, St. Germain DL. The ontogeny of iodothyronine deiodinase systems in liver and intestine of the rat. Endocrinology 1991;128:1717.
43. Henning JJ. Permissive role of thyroxine in the ontogeny of jejunal sucrase. Endocrinology 1978:102:9.
44. Hodin RA, Meng S, Chamberlain SM. Thyroid hormone responsiveness is developmentally regulated in the rat small intestine: a possible role for the α-2 receptor variant. Endocrinology 1994;135:564.
45. Yeh KY, Yeh M, Holt PR. Differential effects of thyroxine and cortisone on jejunal sucrase expression in suckling rats. Am J Physiol 1989;256:G604.
46. Yeh KY, Yeh M, Holt PR. Thyroxine and cortisone cooperate to modulate postnatal intestinal enzyme differential in the rat. Am J Physiol 1991;260:371.
47. Leeper LL, McDonald MC, Heath JP, et al. Sucrase-isomaltase ontogeny: synergism between glucocorticoids and thyroxine reflects increased mRNA and no change in migration. Biochem Biophys Res Commun 1998;246:765.
48. Blanes A, Martinez A, Bujan J, et al. Intestinal mucosal changes following induced hypothryroidism in the developing rat. Virchows Arch A 1977;375:233.
49. Shi YN, Hayes WP. Thyroid hormone-dependent regulation of the intestinal fatty acid-binding protein gene during amphibian metamorphosis. Dev Biol 1994:161:48.
50. Zheng B, Eng J, Yalow RS. Cholecystokinin and vasoactive intestinal peptide in brain and gut of the hypothyroid neonatal rat. Horm Metab Res 1989;21:127.
51. Brewer LM, Betz TW. Thyroxine and duodenal development in chicken embryos. Can J Zool 1979;57:416.
52. Hodin RA, Shei A, Morin M, et al. Thyroid hormone and the gut: selective transcriptional activation of a villus-enterocyte marker. Surgery 1996;120:138.
53. Pacha J. Ontogeny of Na+ transport in rat colon. Comp Biochem Physiol A Physiol 1997;118:209.
54. Irvine WJ. The association of atrophic gastritis with autoimmune thyroid disease. J Clin Endocrinol Metab 1975;4:351.
55. Markson JL, Moore JM. Thyroid auto-antibodies in pernicious anemia. BMJ 1962;2:1352.
56. Muller MK, Pederson R, Olbricht T, et al. Increased release of gastrin in hyperthyroid rats in vitro. Horm Metab Res 1986;18: 675.
57. Noll B, Goke B, Printz H, et al. Influence of experimental hyperthyroidism on the adult rat pancreas, small intestine, and blood gastrin levels. J Gastroenterol 1988;26:331.
58. Seino Y, Matsukura S, Inoue Y, et al. Hypogastrinemia in hypothyroidism. Dig Dis 1978;23:189.
59. deLuis DA, Varela C, de La Calle H, et al. Helicobacter pylori infection is markedly increased in patients with autoimmune atrophic thyroiditis. J Clin Gastroenterol 1998;26:249.
60. Figura N, et al. The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders. J Physiol Pharm 1999:50(5):817.
61. Doniach D, Roitt IM, Walkers JG, et al. Tissue antibodies in primary biliary cirrhosis, active chronic hepatitis, cryptogenic cirrhosis. Clin Exp Immunol 1966;237:262.
62. Tran A, Quaranta HF, Benzaken S, et al. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993; 18:253.
63. Crowe JP, Christensen E, Butler J, et al. Primary biliary cirrhosis: prevalence of hypothyroidism and its relationship to thyroid antibodies. Gastroenterology 1980:78:1437.
64. Culp KS, Fleming CR, Duffy J, et al. Autoimmune association in primary biliary cirrhosis. Mayo Clin Proc 1982;57:365.
65. Elta GH, et al. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983;28:971.
66. Zeniya M. Thyroid disease in autoimmune liver diseases. Nippon Rinsho 1999;57(8):1882.
67. Borgaonkar MR, Morgan DG. Primary biliary cirrhosis and type II autoimmune polyglandular syndrome. Can J Gastroenterol 1999;13(9):767.
68. Cindoruk M, et al. The prevalence of autoimmune hepatitis in Hashimoto’s thyroiditis in a Turkish population. Acta Gastroenterol Belg 2002;65(3):143.
69. Paradies G, Ruggiero FM, Dinoi P. The influence of hypothyroidism on the transport of phosphate and on the lipid composition in rat-liver mitochondria. Biochem Biophys Acta 1991;1070: 180.
70. Sobol S. Long-term and short-term changes in mitochondrial parameters by thyroid hormones. Biochem Soc Trans 1993;21: 799.
71. Liverini G, Iossa S, Barletta A. Relationship between resting metabolism and hepatic metabolism: effect of hypothyroidism and 24 hours fasting. Horm Res 1992;38:154.
72. De Castro F, et al. Myxedema ascites. Report of two cases and review of the literature. J Clin Gastroenterol 1991;13(4):411.
73. Clancy RL, MacKay IR. Myxoedematous ascites. Med J Aust 1979;2:415.
74. Comte B, Vidal H, Laville M, et al. Influence of thyroid hormones on gluconeogenesis from glycerol in rat hepatocytes: a dose-response study. Metabolism 1990;39:259.
75. Marchesini G, Fabbri A, Bianchi GP, et al. Hepatic conversion of amino nitrogen to urea nitrogen in hypothyroid patients and upon L-thyroxine therapy. Metabolism 1993:42:1263.
76. Van Steenbergen W, Fevery J, DeVos R, et al. Thyroid hormones and the hepatic handling of bilirubin. Hepatology 1989; 9:314.
77. Balasubramaniam S, Mitropoulous KA, Myant NB. Hormonal control of the activities of cholesterol-7 α-hydroxylase and hydroxy methylglutaryl-CoA reductase in rats. In: Matern S, Hachenschmidt J, Back P, et al., eds. Advances in bile acid research. Stuttgart: Schattauer Verlag, 1975:61.
78. Caro JF, Cecchin F, Folli F, et al. Effect of T3 on insulin action, insulin binding, and insulin receptor kinase activity in primary cultures of rat hepatocytes. Horm Metab Res 1988;20:327.
79. Dang AQ, Fass FH, Carter WJ. Effects of experimental hypo- and hyperthyroidism on hepatic long-chain fatty Acyl-CoA synthetase and hydrolase. Metabol Res 1989;21:359.
80. Davidson NO, Carlos RC, Drewek MJ, et al. Apoliprotein gene expression in the rat is regulated in a tissue-specific manner by thyroid hormone. J Lipid Res 1988;29:1511.
81. Hoogenbrugge van der Linden H, Jansen H, Hulsmann WC, et al. Relationship between insulin-like growth factor-I and low density lipoprotein cholesterol levels in primary hypothyroidism in women. J Endocrinol 1989;123:341.
82. Lin-Lee YC, Strobl W, Soyal S, et al. Role of thyroid hormone in the expression of apolipoprotein A-IV and C-III Genes in rat liver. J Lipid Res 1993;34:249.
83. Staels B, Tol AV, Chan L, et al. Alterations in thyroid status modulate apolipoprotein, hepatic tryglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology 1990:127:1144.
84. Strobl W, Gorder NL, Lin-Lee YC, et al. Role of thyroid hormones in apolipoprotein A-I gene expression in rat liver. J Clin Invest 1990;85:659.
85. Gebhart RL, Stone BG, Andreini JP, et al. Thyroid hormone differentially augments biliary sterol secretion in the rat. I: The isolated-perfused liver model. J Lipid Res 1992;33:1459.
86. Goldfarb S. Regulation of hepatic cholesterogenesis. In: Javitt NB, ed. Liver and biliary tract: physiology I. Baltimore: University Park Press, 1980:317.
87. Novis M, et al. Thyroid function tests in viral chronic hepatitis. Arq Gastroenterol 2001;38(4):254.
88. Fernandez-Soto L, Gonzalez A, Escobar-Jimenez F, et al. Increased risk of autoimmune thyroid disease in hepatitis C vs. hepatitis B before, during, and after discontinuing interferon therapy. Arch Intern Med 1998;158:1445.
89. Deutsch M, Dourakis S, Manesis EK, et al. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alpha therapy. Hepatology 1997;26:206.
90. Watanabe U, Hashimoto E, Hisamitsu T, et al. The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis C. Am J Gastroenterol 1994;89: 399.
91. Kiehne I, Kloehn S, Hinrichesen H, et al. Thyroid autoantibodies and thyroid dysfunction during treatment with interferon-alpha for chronic hepatitis C. Endocrine 1997;6:231.
92. Ploix C, et al. Hepatitis C virus infection is frequently associated with high titers of anti-thyroid antibodies. Int J Immunopharmacol 1999;12(3):121.
93. Roti E, Minelli R, Giuberti T, et al. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha. Am J Med 1996; 101:482.
94. Braga-Basaria M, Basaria S. Interferon-alpha-induced transient severe hypothyroidism in a patient with Graves’ disease. J Endocrinol Invest 2003;26(3):261.
95. Kakizaki S, et al. HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C. J Hepatol 1999;30(5):794.