Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

34.The Gastrointestinal Tract and Liver in Thyrotoxicosis

Sanjeev M. Wasan

Joseph H. Sellin

Rena Vassilopoulou-Sellin

The classic gastrointestinal (GI) manifestations of thyrotoxicosis are rapid intestinal transit, increased frequency of semi-formed stools, and weight loss from increased caloric requirement or malabsorption. This classic scenario is not necessarily common, and a caveat is in order. Although there are definite GI manifestations of thyrotoxicosis, their lack of specificity is such that they cannot serve as reliable diagnostic clues to the diagnosis. One may find, instead, a paradoxic weight gain despite the hypermetabolic state. The absence of constipation in the elderly patient occasionally has pointed the astute clinician to the diagnosis of thyrotoxicosis. Thyrotoxicosis has been associated with a multiplicity of liver-function abnormalities; however, the interpretation of these derangements may be clouded by the coexistence of congestive heart failure, malnutrition, or autoimmune liver disease. The clinical importance of a direct effect of thyrotoxicosis on the liver, through increased metabolic demand and a relative hypoxia, remains controversial. Because the diagnosis of thyrotoxicosis now can be made easily, more accurately, and earlier, and because effective treatment can promptly correct the symptoms and metabolic consequences of this disorder, prominent GI symptoms usually are confined to cases of diagnostic oversight.

The findings of GI dysfunction associated with thyrotoxicosis suggest that an excess of thyroid hormone disrupts the normal homeostatic mechanisms of the gut. Additionally, they point to a possible role for thyroid hormone in the physiology of the GI tract and liver and serve as a basis for further investigation into the peripheral effects of thyroid hormone.


Frequent bowel movements (more than two a day) are significantly more common in patients with thyrotoxicosis than in normal subjects (1). Most thyrotoxic patients, however, have one bowel movement daily. Although constipation is rare, 3% of thyrotoxic patients take laxatives, about the same as in the general population, thus limiting the value of stool frequency as a clue toward the clinical diagnosis of thyrotoxicosis in an individual patient.

The increased stool frequency is generally ascribed to “hypermotility” of the intestine; however, the physiologic correlates of hypermotility are poorly defined, and the interrelationships between myoelectric activity (propulsive events and transit time) (2,3,4) and contractile force (5) need to be delineated more clearly.

Thyrotoxicosis may cause myopathy, leading to altered function of pharyngeal and upper esophageal muscles. As a result, patients may complain of dysphagia, which is reversed with correction of the thyroid excess. The esophagus has an increased rate of peristaltic propagation (6).

Studies of gastric emptying have yielded variable results. Despite expectations that gastric emptying might be accelerated, in clinical studies emptying was either normal or delayed (7,8,9). No specific relationship between dyspepsia and thyrotoxicosis has been demonstrated. Vomiting associated with thyrotoxicosis has been ascribed to either thyroid stimulation of a chemoreceptor trigger zone in the central nervous system (10) or to gastric stasis (11). Recent studies using electrogastrography (EGG) to measure gastric myoelectrical activity, revealed gastric dysrhythmia in both hypothyroid and thyrotoxic patients (12).

In thyrotoxicosis, the mouth-to-cecum transit time is approximately 40% of normal, and small and large intestinal transit is accelerated (13,14). These changes are reversible after correction of the thyrotoxicosis. Christensen and associates (15) demonstrated that the basic electric rhythm of slow-wave activity of the intestine is increased in thyrotoxicosis, indicating that the intestine is capable of more frequent contractions. In a study examining contractile rather than myoelectric activity, thyrotoxicosis induced changes in both the fasted and fed states, including an increase in contraction frequency during phase 2 of the migrating motor complex during digestion (5), and occasional giant migrating complexes were observed. By using a noninvasive measure of orocecal transit time, the lactulose–hydrogen breath test, investigators have demonstrated a shortened transit time in thyrotoxic patients that normalizes with treatment, with disappearance of gastrointestinal symptoms such as diarrhea and steatorrhea (14,16,17). Abnormalities of anal manometry and rectal sensation also exist in patients with altered thyroid function, with lower threshold sensation in thyrotoxic patients (18).

The clinical and experimental data on the effects of thyrotoxicosis on gut motility provide some evidence that thyroid excess affects the orderly propulsion of ingested materials through the GI tract. Significant gaps exist, however, in our knowledge of the thyrotoxic effects on intestinal motility.


The association between thyrotoxicosis and pernicious anemia was first described by Neuser (19) in 1899; since then, a strong clinical impression has prevailed that spontaneous thyroid disease and autoimmune gastritis coincide more frequently than expected by statistical probability. Pernicious anemia has been reported in 2% to 5% of thyrotoxic patients (3,20). The frequency of parietal cell or intrinsic factor antibodies as well as low serum vitamin B12 or intrinsic factor levels, however, has been on the order of 20% to 30% of patients (21,22). Atrophic gastritis, decreased acid secretion, and histamine-fast hypochlorhydria or achlorhydria have been found in thyrotoxic patients, even without overt pernicious anemia (23). Approximately one third of patients with autoimmune thyroid disease have atrophic gastritis (24). Hypergastrinemia also is found occasionally. The incidence of peptic ulcer disease is not increased; therefore, the hypergastrinemia is most probably secondary to decreased acid secretion. It is likely that the frequently coexisting abnormalities of thyroid and gastric function reflect the association of autoimmune hyperthyroid disease with other autoimmune diseases.


Steatorrhea can occur in patients with thyrotoxicosis (23,25,26), with daily fecal fat excretion as high as 20 g (normal, < 7 g daily assuming a daily intake of 100 g fat). This cannot be ascribed exclusively to fat hyperphagia; an element of malabsorption appears to exist, although the cause remains obscure. Pancreatic exocrine function, as measured by standard secretion tests, is normal.

Small bowel biopsies in thyrotoxic patients have not demonstrated any alteration in the normal villous architecture, although minor increases in lymphocytic infiltration and edema have been observed. Small bowel radiographs have noted occasional dilatation and thickening of the circular folds (27). Intestinal absorption of D-xylose is normal. Decreased calcium absorption was demonstrated in clinical and animal studies (28,29), perhaps due to deficient parathyroid-mediated synthesis of 1,25(OH)2 vitamin D.

Rapid intestinal transit is the generally accepted explanation for the steatorrhea of thyrotoxicosis. Analogous to postgastrectomy states, inadequate mixing of food and pancreatic secretions occurs as the intestinal chyme precedes the digestive enzymes through the length of the small bowel; maldigestion results because dietary fat, protein, and carbohydrates are not adequately broken down into components that a normal intestinal mucosa can absorb. An alternative explanation may involve thyroid down-regulation of intestinal brush-border enzymes, such as lactase, inducing selective carbohydrate malabsorption or steatorrhea (30). Propranolol therapy decreases both stool frequency and the amount of steatorrhea, suggesting that some of the intestinal findings are mediated by the sympathetic nervous system (31).

A significant association exists between autoimmune thyroid disorders and intestinal diseases with significant immune components. Careful surveys of patients with autoimmune thyroid disease demonstrated an approximate 5% incidence of celiac sprue; as for the converse, surveys in patients with sprue have revealed a 5% to 15% incidence of thyroid disease (32,33,34,35). Subclinical hypothyroidism is a frequent finding in celiac disease that is often normalized with strict gluten withdrawal (36). A study indicated that as many as 43% of patients with Hashimoto's thyroiditis had an increased density of the γδ T-cell receptor–bearing intraepithelial lymphocytes and signs of mucosal T-cell activation, both features of celiac disease (37). Up to 4% of patients with ulcerative colitis have thyroid disorders (38,39). Thyrotoxicosis may exacerbate ulcerative colitis. The thyroid disease often appears before the colitis, but may occur simultaneously and impair the response to therapy. A hypermetabolic state may make the intestine more susceptible to damage from inflammation, related to autoantibodies or circulating immune complexes (40); a similar picture may occur in the liver (41). Treatment of the intestinal disorder is simplified after therapy for thyrotoxicosis. Secretory diarrhea may rarely occur (42).


The association between the liver and thyroid diseases has been a subject of investigation for over 50 years, but the exact nature of the relationship remains elusive. Possible thyroid–liver interactions include (a) liver damage secondary to the systemic effects of thyroid excess, (b) direct toxic effects of thyroid hormone on the liver, (c) association of intrinsic liver disease with intrinsic thyroid disease through autoimmune mechanisms, (d) alterations of thyroid hormone metabolism secondary to intrinsic liver disease, and (e) subclinical physiologic effects of thyroid hormone on liver function.

Early autopsy reports emphasized the severity of liver disease in patients dying of thyrotoxicosis (43) and described marked hepatic inflammation, steatosis, necrosis, and cirrhosis. It is not clear whether these were a direct effect of thyrotoxicosis or were caused by associated conditions (congestive heart failure, infection, or malnutrition) that can, in themselves, lead to hepatic dysfunction. Hepatic changes seen on light microscopy include vacuolization of hepatocytes, balloon degeneration, nuclear glycogen, and mild portal infiltration of mononuclear cells; electron microscopy reveals subtle ultrastructural changes, including hyperplasia of the smooth endoplasmic reticulum, a paucity of glycogen, and mitochondrial abnormalities (44). These are all nonspecific signs of liver injury. Abnormal liver function tests can often occur in thyrotoxic patients, especially with mild elevations of serum alkaline phosphatase or aminotransferases, with prevalence varying from 15% to 76%; these abnormalities are reversible with correction of the thyrotoxicosis (45,46,47). In patients receiving antithyroid drug therapy, it is important to consider that liver function abnormalities may be drug induced. Propylthiouracil therapy can result in mild elevation in liver enzymes, which is often transient and subclinical (48). Therapy is continued unless fulminant hepatotoxicity develops, which has been reported in a few cases (49). Methimazole therapy may rarely cause cholestasis and fulminant hepatic failure if the drug is continued (49a). Liver test abnormalities and hepatotoxicity occur more frequently in women, and tend to occur 3 to 4 months after therapy is begun. Baseline hepatic function tests are usually not performed before the initiation of propylthiouracil, so the true incidence of hepatotoxicity is not known (50).

Within the context of the generalized hypermetabolic state of thyrotoxicosis, resting metabolic rate and hepatic oxygen consumption increase (51), probably secondary to increased Na+,K+-ATPase activity. Increased hepatic oxygen uptake also has been described, despite normal fructose-6-phosphate and pentose cycling (52). The metabolic impact of thyroid hormone on the liver appears multifactorial, mediated by alterations of insulin-like growth factor homeostasis (53), cytochrome P450 regulation (54), and changes in fatty acid and lipid synthesis (55). Although mitochondrial metabolism is stimulated by thyroid hormone, it has been difficult to establish a clear-cut relationship between mitochondrial metabolism and thyroid function (56,57). Because hepatic blood flow is not increased (58), a combination of relative anoxia and increased metabolic demands develops that may lead to the centrizonal necrosis occasionally seen in severe thyrotoxicosis. A hypermetabolic state may make the liver more susceptible to injury. This has been observed in several experimental and clinical conditions, including ischemia-reperfusion and cold storage (59), drug-induced liver failure (60), and alcoholic hepatitis (61,62,63). Although propylthiouracil has been used clinically in the treatment of alcoholic hepatitis with possible benefit, it has not achieved widespread acceptance as standard therapy among hepatologists.

No firm evidence has been found that thyroid hormone is directly toxic to the liver. Therefore, the thyrotoxic patients who present with liver dysfunction require careful investigation for nonthyroidal illness; this investigation frequently results in the detection of an autoimmune disorder because multisystem autoimmune diseases may affect both the liver and the thyroid (64). Perhaps the strongest association exists between lymphocytic thyroiditis and primary biliary cirrhosis (65,66). In a survey of 95 patients with primary biliary cirrhosis, Crowe and colleagues (67) found that 26% had thyroid microsomal antibodies, 16% had thyroglobulin antibodies, and 16% had either clinical or biochemical evidence of hypothyroidism.


The interpretation of concomitant thyroid and liver function abnormalities must take into account the fact that thyroid hormone metabolism is abnormal in severe liver disease. Both the production of thyroxine (T4)-binding globulin (TBG) and the peripheral conversion of T4 to triiodothyronine (T3) may be decreased in patients with chronic liver disease. Conversely, serum TBG concentrations increase in patients with hepatitis, probably due to decreased clearance of TBG secondary to its increased sialic acid content (68). Despite the increased energy expenditure found in cirrhosis (69), most patients with cirrhosis are clinically euthyroid. In patients with chronic hepatitis C, therapeutic administration of interferon-α may precipitate clinical thyroid dysfunction, especially if antithyroid antibodies were present before treatment (70).

Several investigators have systematically examined thyroid function in patients with hepatitis and cirrhosis (usually alcohol-related). Despite considerable variability in serum total T4 concentrations, serum free T4 index values are usually normal or mildly increased, serum T3 concentrations are usually decreased, and thyrotropin reverse T3 concentrations are high (71,72,73). In cirrhosis, basal serum (TSH) concentrations may be high, and the TSH response to thyrotropin-releasing hormone is not different from that of normal subjects (73,74). Overall, this picture is most consistent with the changes that occur in systemic nonthyroidal illness (see section on nonthyroidal illness in Chapter 11).


The liver handles thyroid hormone similarly to the way it handles several organic anions. T4 and T3 are glucuronidated and sulfated, secreted into the biliary canaliccli, and concentrated in bile. The daily biliary excretion of T(20 mmol) is miniscule compared with that of other organic anions (e.g., 600 mol bilirubin). Thyroid hormone has profound effects on hepatic organic anion transport and biliary excretion. Although bilirubin glucuronide formation is not changed in vitro, extrahepatic factors result in abnormal bilirubin metabolism in vivo (75,76). In experimental animals, thyrotoxicosis is associated with an increased bilirubin output in bile, which may result from increased degradation of hepatic heme (77). Thyroid-induced alterations in hepatic metabolism of bilirubin, specifically a decrease in glucuronyl transferase, may be responsible for the clinical occurrence of unconjugated hyperbilirubinemia, possibly by unmasking previously unrecognized Gilbert's syndrome (77).

Thyroid hormone decreases bile acid production and total bile acid pool size (78). Clinically, duodenal bile salt concentration in thyrotoxic patients appears to be normal (79). The clinical import of thyroid-induced alterations in organic anion excretion, bile flow, and microsomal enzyme activity requires further investigation but points to the important effects of thyroid hormone in normal liver function.


Medullary carcinoma of the thyroid (MCT) is a calcitonin-producing tumor of the thyroid gland. Calcitonin and calcitonin gene–related peptide (CGRP) are primary markers of MCT (80). One third of patients with this carcinoma develop a watery diarrhea, which is thought to be due to the high serum concentrations of calcitonin or CGRP. Initial studies suggested that calcitonin induces small intestinal fluid secretion; however, decreased colonic water absorption secondary to a motor disturbance may be the main mechanism of diarrhea in these patients (81,82).

Many patients with gastric cancer have been found to have antithyroid antibodies, as many as 25% in one study, but the presence of these antibodies did not necessarily indicate thyroid dysfunction (83).

Thyroid carcinomas can invade the aerodigestive tract, including the larynx, pharynx, and esophagus. A retrospective study found that papillary thyroid carcinoma, when invasive, involved the esophagus in 21% of cases (84). When thyroid carcinoma does invade the aerodigestive tract, complete resection offers prolonged palliation and best opportunity for cure (85). An association also appears to exist between carcinomas of the esophagus and the thyroid, albeit infrequent. Metachronous or synchronous esophageal cancer has been identified in patients with head and neck cancer and in other locations of the gastrointestinal tract, but cases also include the thyroid (86). Other primary gastrointestinal carcinomas also rarely metastasize to the thyroid gland.

Patients with familial adenomatous polyposis (FAP) have an increased incidence of extracolonic cancer, including thyroid cancer (87). Papillary thyroid cancer is the most common type and tends to occur in women with FAP more than in men. It is usually solitary and unilateral. Thyroid cancer tends to cluster in specific families with FAP. It may be that the mutation of the Adenomatous Polyposis Coli (APC) tumor-suppressor gene responsible for FAP is involved in the pathogenesis of thyroid cancer, but this is speculative (88).


Thyroid hormones play an important role in the normal physiology of GI function; when present in excess, they may result most notably in hypermotility and malabsorption. Patients with thyrotoxicosis may have associated hepatic or gastric dysfunction because of underlying autoimmune disease. Overall, early detection and effective treatment have changed the clinical presentation of thyrotoxicosis so that GI symptoms have become clinically subtle in most patients.


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