Noncompliance With Medical Treatment: Pseudomalabsorption of Levothyroxine.

ABSTRACT: Euthyroidism could not be achieved in a 41-year-old woman with primary hypothyroidism despite escalating doses of oral levothyroxine as high as 600 [micro]g and 100 [micro]g of triiodothyronine daily. Clinical and biochemical evidence of hypothyroidism persisted even with the administration of intramuscular levothyroxine. There was no history compatible with drug-induced malabsorption of levothyroxine. Evaluation of serum showed no thyroid hormone autoantibodies. After hospitalization, intravenous levothyroxine therapy returned thyroid hormone to normal concentrations. Moreover, thyroid hormone loading tests revealed normal oral absorption of both levothyroxine and triiodothyronine. Noncompliance with medical treatment leading to pseudomalabsorption of levothyroxine should be considered in patients who have persistent hypothyroidism with high-dose replacement therapy.

HYPOTHYROIDISM is a common endocrine disorder that is readily treatable with appropriate doses of thyroid hormone replacement therapy. Some patients may be seen with clinical or biochemical evidence of hypothyroidism despite concurrent therapy with a high dose of levothyroxine. If the free thyroxine ([FT.sub.4]) level is elevated in association with an inappropriately elevated thyrotropin (thyroid-stimulating hormone [TSH]) level, the diagnosis of thyroid hormone resistance should be considered. [1] More often, the [FT.sub.4] level is low, with an appropriate elevation of TSH level. In this situation, only a few possibilities emerge; the patient is not compliant in taking levothyroxine, there is malabsorption of the medication (caused by a gastrointestinal condition or drug-drug interaction), or autoantibodies blocking the action of thyroid hormones exist. We report the case of a patient who had persistent evidence of hypothyroidism on high doses of replacement therapy with symptoms severe enough to necessita te hospitalization. Clinical and laboratory investigations delineated the cause of this condition.

CASE REPORT

A 41-year-old woman was referred to our institution for persistent hypothyroidism unresponsive to large doses of levothyroxine replacement therapy. She had had thyroid surgery for "goiter" in 1985 and had been prescribed different doses of thyroid replacement treatment with levothyroxine and triiodothyronine since the operation. She had received oral levothyroxine sodium in doses as high as 600 [micro]g along with 100 [micro]g of triiodothyronine daily with no symptomatic improvement; she had a persistently elevated TSH level as high as 607 IU/mL (normal, 0.47 to 5.01 IU/mL) and low thyroxine ([T.sub.4]) and total triiodothyronine ([T.sub.3]) levels. Given the possibility of malabsorption, intramuscular levothyroxine therapy was initiated at 200 [micro]g daily. After 8 weeks, neither clinical nor biochemical improvement was seen.

The patient had been admitted multiple times for abdominal pain, stool impaction, and pericardial effusion. She reported close adherence to the treatment regimen and denied taking other medications, including over-the-counter agents. The intramuscular injection technique was carefully reviewed with her, and she proved competent. She claimed that various physicians concurred on her inability to absorb thyroid hormones. Because she could not afford the high cost of the intramuscular form of levothyroxine, the patient reported the need to collect donations from her coworkers and her church. She had applied for a disability benefit program and was awaiting approval. Other than hypothyroidism, the patient's medical history was unremarkable. She complained of persistent fatigue, lack of energy, dry skin, constipation, weight gain, depression, and worsening shortness of breath on exertion.

The patient was admitted to our institution for stabilization and further evaluation of her condition. No features of psychotic behavior, delusions, or hallucinations were seen in previous evaluations or during our own observation during this admission. On physical examination, heart rate was regular at 52/min, blood pressure was 116/74 mm Hg, and weight was 88 kg. Periorbital puffiness was seen, with loss of the lateral third of the eyebrows. The thyroid was small, with no palpable nodules. Significant tenderness was elicited at the left lower pole of the thyroid. Heart sounds were distant with no abnormal sounds and no paradoxical pulse. Tendon reflexes were reduced with delay of the relaxation phase. Musculoskeletal examination revealed grade 4/5 muscle power and mild swelling at the knees and elbows with no clinical signs of joint effusion.

Available laboratory data before the patient was referred to us showed persistent elevation of TSH level, ranging from 167.0 to 607.0 IU/mL; low [T.sub.4] and [T.sub.3] levels; and low [FT.sub.4] index (Table 1). During a previous hospitalization at another institution for 11 days, the patient was treated with intramuscular levothyroxine 200 [micro]g daily. After 10 days of treatment, the TSH level had normalized for the first time, and (T.sub.4] and [T.sub.3] levels were elevated above the normal reference range (Table 2). Laboratory studies during our evaluation revealed the following values: [FT.sub.4][less than]0.4 ng/dL (normal, 0.71 to 1.85 ng/dL), TSH 327.4 IU/mL (normal, 0.49 to 4.7 IU/mL), [T.sub.3] [less than]50 ng/dL (normal, 80 to 200 ng/dL). An echocardiogram showed mild pericardial effusion with no cardiac compromise.

Intravenous levothyroxine treatment was started with 500 [micro]g as a bolus dose and 100 [micro]g daily thereafter. Autoantibodies to thyroxine and triiodothyronine were not detected. During the patient's hospitalization at our institution, the [FT.sub.4] level increased to 0.8 ng/dL 2 hours after the first dose of levothyroxine and remained in the range of 0.68 to 0.72 ng/dL over the next 3 days. After discharge and with informed consent, two loading tests were done to assess oral absorption of both levothyroxine and triiodothyronine. The tests were done under close observation. In the first test, 100 [micro]g of triiodothyronine was given orally, and serum levels of [T.sub.3] were measured at baseline and after 1 and 2 hours. Serum rose from 56 ng/dL at baseline to 96 ng/dL at 1 hour, and rose to 533 ng/dL at 2 hours (Fig 1). The second test, done on another day, involved administering 1,000 [micro]g of levothyroxine orally and measuring [FT.sub.4] at baseline and after 2 and 4 hours. At baseline, the [FT .sub.4] level was 0.76 ng/dL, at 2 hours it was 2.05 ng/dL, and at 4 hours it was 2.06 ng/dL (Fig 2). Both tests showed normal absorption of both oral levothyroxine and triiodothyronine.

When the patient was confronted with the results, she initially denied noncompliance but finally confessed that she frequently missed doses of the medication. The patient declined psychiatric evaluation. She agreed to have a family member assist her in ensuring daily intake of the medication. The patient was instructed to continue regular follow-up care with her primary care physician. The level of compliance is to be assessed by regular telephone calls and periodic laboratory evaluation.

DISCUSSION

Levothyroxine sodium is the most commonly used thyroid hormone preparation for the treatment of hypothyroidism. Early studies showed the mean dose of thyroid hormone replacement therapy to be 169 [+ or -] 66 [micro]g (2.25 [+ or -] 0.67 [micro]g/kg of body weight) [2] before a reformulation of a major brand in 1982. [3,4] Evaluation of the current levothyroxine formulation revealed a mean daily replacement dose of 112 [+ or -] 19 [micro]g (1.63 [+ or -] 0.42 [micro]g/kg of body weight) and demonstrated absorption from the gastrointestinal tract at approximately 81% of the administered dose. [5]

Levothyroxine is absorbed in the small and large intestines in rats. Absorption is greater in the large intestines in the fasting state and when bacteria are eliminated but is probably greatest in the ileum under normal circumstances. [6] Human studies have shown that the absorption of levothyroxine is greater in the fasting state. [7,8] Malabsorption of levothyroxine has been observed after jejunoileal bypass procedures, [9,10] in short bowel syndrome, [11,12] in association with vitamin [B.sub.12] malabsorption, [13] in severe liver cirrhosis, [14] in congestive heart failure, [15] and possibly in the presence of serum thyroid autoantibodies. [16] Several medications may interfere with the absorption of levothyroxine, such as aluminum hydroxide, [17] sucralfate, [18] ferrous sulfate, [19] cholestyramine, [20] calcium carbonate, [21] and lovastatin. [22]

Ain et a1 [23] evaluated four cases of persistent hypothyroidism despite high doses of thyroid replacement therapy. They evaluated thyroid hormone absorption by measuring serum [T.sub.4] after administering a single high dose (1,000 to 2,000 [micro]g) of levothyroxine, and serum [T.sub.3] after one dose (75 to 100 [micro]g) of triiodothyronine. All patients had normal absorption of oral levothyroxine, indicating noncompliance with therapy. The authors described the involvement of psychiatric issues leading to noncompliance with therapy, and suggested the term "pseudomalabsorption of levothyroxine." Ogawa et al [24] reported a case of hypothyroidism in which there was no clinical or biochemical improvement with high doses of levothyroxine. They evaluated the oral absorption of thyroid agents using loading tests similar to those implemented by Am et al. [23 Their patient had abnormal absorption with the use of levothyroxine in the tablet form; however, normal absorption was observed with both liquid form and cru shed tablets through a nasogastric tube. The investigators later discovered that the patient intennonally induced vomiting immediately after taking the tablets.

Results of thyroid function tests had been normal only once in our patient, during a previous hospitalization when intramuscular levothyroxine was administered for 11 days. Hypothyroidism recurred despite reported therapy with intramuscular levothyroxine 200 [micro]g daily for 8 weeks. Nevertheless, serum autoantibodies that may interfere with the action of thyroid hormones were not detected, and the loading tests with oral levothyroxine and triiodothyronine given under direct observation showed normal absorption of both medications. Peak absorption occurs 2 to 4 hours after the administration of levothyroxine and 1 to 2 hours after ingesting triiodothyronine at 82% to 100% of the administered does. [23,25,26]

The behavioral characteristics in our patient's case could be best described as noncompliance with medical treatment. [27,28] One diagnostic alternative is Munchausen's syndrome, [29,30] which features falsified symptoms, lying or using aliases, masochistic tendencies, multiple hospital admissions, and extensive medical knowledge. Since the incidence of pseudomalabsorption of levothyroxine is not known, it is not clear if it represents a clinical manifestation of hypothyroidism or a separate psychiatric entity. Confrontation and psychiatric evaluation, if the patient agrees, are appropriate.

Assurance of compliance could become a challenging issue. Direct observational treatment with intramuscular or intravenous levothyroxine under supervision of a nurse or family member may be considered to ensure compliance. However, cost issues and time constraints for nursing may make this option impractical. In addition, precise dosing and frequency of those forms of levothyroxine treatment are not standardized. Some of the reported patients were lost to follow-up after being informed about their diagnosis, and the possibility of their seeking medical attention from other physicians should be considered. If compliance is ensured, the daily' dose of levothyroxine should be reduced to avoid iatrogenic thyrotoxicosis.

CONCLUSION

When physicians encounter patients with hypothyroidism who require high doses of levothyroxine, [FT.sub.4] level should be measured to rule out thyroid hormone resistance. If the level of [FT.sub.4] is low, drug interactions and systemic diseases leading to malabsorption of levothyroxine are to be evaluated. If these possibilities are excluded, noncompliance with medical treatment leading to pseudomalabsorption of levothyroxine should be considered. In such cases, appropriate studies to assess oral absorption of thyroid agents are warranted before embarking on an extensive evaluation for malabsorption syndromes.

Acknowledgment. We thank L. Maria Belalcazar, MD, for her helpful comments during manuscript preparation.

From the Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Texas Medical Branch, Galveston, and the Department of Emergency Medicine, University of Texas--Houston Health Science center.

Reprint requests to Mohsen S. Eledrisi, MD, University of Texas Medical Branch, Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical Research Building 8.138, 301 University Blvd, Galveston, TX 77555.

References

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(3.) Bantle JP: Replacement therapy with levothyroxine: evolving concepts (Letter). Thyroid Today 1987; 10:17

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(5.) Fish LH, Schwartz HL, Cavanaugh J, et al: Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. N Engl J Med 1987; 316:764-770

(6.) Chung SJ, Van Middlesworth L: Absorption of thyroxine from the intestine of rats. Am J Physiol 1967; 212:97-100

(7.) Wenzel KW, Kirschsieper HE: Aspects of the absorption of oral L-thyroxine in a normal man. Metabolism 1977; 26:1-8

(8.) Wenzel KW: Improved treatment with levothroxine. Dtsch Med Wochenschr 1986; 111:1356-1362

(9.) Azizi F, Belur R, Albano J: Malabsorption of levothyroxine after jejunoileal bypass for obesity. Ann Intern Med 1979; 90:941-942

(10.) Bevan JS, Munro JF: Thyroxine malabsorpotion following intestinal bypass surgery. Int J Obes 1986; 10:245-246

(11.) Stone E, Leiter LA, Lambert JR, et al: L-Thyroxine absorption in patients with short bowel. J Clin Endocrinol Metab 1984; 59:139-141

(12.) Smaliridge RC, Burman KD: Malabsorption of thyroxine, calcium, vitamin D in a thyroparathyroidectomized woman: efficacy of therapy with medium-chain triglyceride oil. Milit Med 1990; 155:156-158

(13.) Mani LS, Desai KB, Joseph LJ, et al: Intestinal absorption of labeled triiodothyronine in man. Indian J Gastrointerol 1985; 4:239-241

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(15.) Surks MI, Schadlow AR, stock JM, et al: Determination of iodothyronine absorption and conversion of L-thyroxine ([T.sub.4]) to L-triiodothyronine ([T.sub.3]) using turnover rate technique. J Clin Invest 1973; 52:805-811

(16.) Suzuki Y, Takeshita E, Kano S, et al: Impaired absorption of thyroid hormone in a case of Hashimoto's disease with anti[T.sub.3] and [T.sub.4] antibodies. Folia Enocrinol Jpn 1982; 58:1487-1497

(17.) Sperber AD, Liel Y: Evidence for interference with the absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med 1992; 152:183-184

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TABLE 1.
Available Laboratory Values
                   Date (mo/yr)
                   7/94          11/94           11/96   8/97
TSH (UI/mL)           311.6      565.2           607.0  324.5
[T.sub.4] (ng/dL)       1.8        1.0  [less than]1.0    4.6
[T.sub.3] (ng/dL)       -         57.5           105.0    -
FTI                     -          -               -      1.3
[T.sub.3]U (%)          -          -              27.5   28.7
                                                         Reference
                            10/99            1/00  6/00    Range
TSH (UI/mL)                 167.0           191.5  66.2  0.47-5.01
[T.sub.4] (ng/dL)  [less than]0.5  [less than]0.5   -     4.9-11.7
[T.sub.3] (ng/dL)            33.0             -     -    60.0-180.0
FTI                           0.1             0.1   -     1.2-4.5
[T.sub.3]U (%)               27.0            29.0   -    25.0-35.0
TSH = Thyrotropin (thyroid-stimulating hormone); [T.sub.4] = total
thyroxine; [T.sub.3] = total triiodothyronine; FTI = free thyroxine
index; [T.sub.3]U = triiodothyronine uptake.
TABLE 2.
Laboratory Values During Previous Hospitalization While
Receiving Intramuscular Levothyroxine Therapy
                    Date (mo/yr)
                      3/24/00          3/28/00  4/2/00
TSH (UI/mL)            206.5            99.8     1.35
[T.sub.4] (ng/dL)      [less than]0.5   9.3      37.5
[T.sub.3] (ng/dL)      42               86       415
FTI                    0.0              3.5      -
[T.sub.3]U (%)         27.0             36.0     57.0
TSH = Thyrotropin (thyroid-stimulating hormone);
([T.sub.4]) = total thyroxine; ([T.sub.3]) = total
triiodothyronine; FTI = free thyroxine index; T,U =
triiodothyronine uptake.

[Graph omitted]

[Graph omitted]

KEY POINTS

* Clinical and laboratory evidence of primary hypothyroidism persisted in a patient despite reported compliance with high doses of oral and intramuscular thyroid replacement therapy.

* The patient was admitted to the hospital for stabilization of her severe symptoms attributable to hypothyroidism.

* The patient's thyroid laboratory values normalized for the first time during her hospital stay.

* Oral absorption of levothyroxine, using thyroid loading tests, was demonstrated to be normal, indicating noncompliance with treatment.

* Noncompliance with medical treatment should be considered in such cases before proceeding to extensive evaluations for malabsorption syndromes.