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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1544
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 2 465-469
Copyright © 2008 by The Endocrine Society

L-Thyroxine Requirement in Patients with Autoimmune Hypothyroidism and Parietal Cell Antibodies

Serenella Checchi, Annalisa Montanaro, Letizia Pasqui, Cristina Ciuoli, Valentina De Palo, Maria Celeste Chiappetta and Furio Pacini

Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, 53100 Siena, Italy

Address all correspondence and requests for reprints to: Furio Pacini M.D., Section of Endocrinology, Viale Bracci 1, 53100 Siena, Italy. E-mail: pacini8{at}unisi.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Hypothyroid patients on L-T4 therapy may require replacement doses exceeding the theoretical needs to normalize serum TSH due to low patient compliance, drugs interference, and malabsorption.

Objective: We examined whether autoimmune gastritis might cause increased L-T4 requirement in patients with autoimmune thyroiditis receiving L-T4 replacement.

Patients: We studied 391 patients with clinical or subclinical hypothyroidism from autoimmune thyroiditis who had achieved normal serum TSH concentration (0.3–3.0 µU/ml) under L-T4 for at least 6 months. Patients were screened for serum parietal cell antibodies (PCA) as a marker of autoimmune gastritis, and the PCA status was correlated with the L-T4 dose. We also studied a group of 60 patients receiving L-T4 replacement after total thyroidectomy.

Results: PCA-positive (155 of 391) and PCA-negative (236 of 391) patients did not differ for pretherapy serum TSH levels and thyroid volume. The L-T4 requirement was significantly (P = 0.002) higher in PCA-positive (1.24 ± 0.40 µg/kg · d) than in PCA-negative patients (1.06 ± 0.36 µg/kg · d), and a significant positive correlation was found between L-T4 requirement and serum PCA levels. Among PCA-positive patients, L-T4 requirement was even higher in those with proven gastritis (1.52 ± 0.40 µg/kg · d) compared with those without gastric damage (1.15 ± 0.33 µg/kg · d) (P < 0.0001). The increased L-T4 requirement was confirmed also in PCA-positive thyroidectomized patients (1.81 ± 0.27 µg/kg · d) compared with PCA-negative thyroidectomized patients (1.52 ± 0.24 µg/kg · d). Independent variables affecting L-T4 requirement were PCA and serum TSH at diagnosis.

Conclusions: Autoimmune gastritis is an additional factor affecting L-T4 requirement in patients with autoimmune thyroiditis. Serum PCA measurement should be considered in patients with an unexplained high requirement of L-T4.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Thyroid hormone replacement therapy is used to correct thyroid hormone deficiency due to autoimmune thyroiditis or to other causes. T4 replacement is best achieved using synthetic levothyroxine sodium (L-T4). The goal of treatment is to achieve a TSH level in the lower half of the reference range (around 1 µU/ml) (1). Both excess and insufficient thyroid hormone replacement may produce adverse effects in various target tissues, and careful monitoring is advisable to establish the optimal dosage of the drug, which is largely dependent on the degree of hypothyroidism, body weight, and patient age (2, 3).

Whenever L-T4 doses exceeding the theoretical daily requirement are needed to achieve the therapeutic goal, the presence of interfering factors must be considered. These include low patient compliance (4, 5) or reduced L-T4 absorption from concomitant medication or chronic illness. Medications that have been reported to decrease absorption of L-T4 include iron supplements, resins, lovastatin, sucralfate, calcium carbonate (6, 7, 8, 9), antacids (10, 11), proton pump inhibitors (12), soy proteins, and high-fiber intake (13, 14, 15, 16, 17). Some medication affects the level of serum thyroid hormone by increasing metabolic clearance of L-T4 like phenytoin and carbamazepine (18, 19). Malabsorption can occur in patients with celiac disease, pancreatic insufficiency, obstructive liver disease, and cirrhosis of the liver (13, 14). Recently Helicobacter pylori infection has been indicated as an additional cause of reduced L-T4 absorption, secondary to atrophic gastritis and impaired gastric secretion (20). Based on the frequent association of parietal cell antibodies (PCA), another cause of atrophic body gastritis, with autoimmune thyroiditis, we aimed to ascertain whether this association may be an additional cause for increased L-T4 needs in hypothyroid patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We studied a cohort of 697 consecutive patients (median age 55.3 ± 15 yr, range 10–90 yr; female-male ratio 9:1) with clinical or subclinical hypothyroidism secondary to autoimmune thyroiditis receiving L-T4 therapy, seen at our center from January 2004 to April 2006. The diagnosis of autoimmune thyroiditis was based on typical thyroid sonographic changes and presence of serum thyroid peroxidase antibodies (TPOAb) and/or anti-thyroglobulin antibodies (TgAb).

Exclusion criteria from the study were 1) serum TSH levels on L-T4 outside the normal range (0.3–3 µU/ml) or 2) history of recent intake (within 3 months) of drugs interfering with gastric function (particularly antacids and proton pump inhibitors), previous therapy for H. pylori infection, history of previous gastric surgery, malignancy, and major chronic diseases (psychiatric disorders, pituitary disorders, cirrhosis, chronic renal insufficiency), alcohol abuse, or BMI higher than 30 kg/m2.

According to these exclusion criteria, 391 patients were eligible for the study. These patients composed the study group and were screened for the presence of serum PCA. The PCA status (positive or negative) was correlated with the dose of L-T4 required to achieve the target serum TSH concentration. Possible confounding factors such as serum TSH level and thyroid volume before therapy, age, sex, and BMI were considered in the analysis to avoid methodological bias.

We also analyzed a cohort of 60 patients previously submitted to total thyroidectomy for multinodular goiter or Graves’ disease, who had normal levels of serum TSH and were on replacement therapy. This group was intended to give information on the PCA interference on L-T4 requirement, eliminating the variable of residual thyroid tissue. These patients were screened for PCA and analyzed in the same way as the autoimmune thyroiditis study group.

Informed consent was obtained from all participants.

Hormonal assays

Thyroid hormones and thyroid autoantibodies in serum were detected by commercial kits. Free T3 (FT3) and free T4 (FT4) were detected by chemiluminescent assay (Beckman Coulter, Inc., Fullerton, CA); TSH was determined by chemiluminescent assay (Euro/Diagnostic Products Corp. Ltd., Llanberies, Gwynedd, UK); TgAb and TPOAb were determined by chemiluminescent assay (Euro/Diagnostic Products); serum TgAb levels greater than 45 U/ml and serum TPOAb levels greater than 35 U/ml were considered as positive.

PCA were determined in serum using an immunoenzymatic assay that recognized the {alpha}- and β-subunits of porcine H+/K+-ATPase (Chemactil, Angri, Italy) with a sensitivity of 0.5 U/ml. The intraassay variations are 3.5, 2.8, and 3.2% for PCA concentrations of 12.5, 22.5, and 75 U/ml, respectively. The interassay variations are 4.2, 3.7, and 2.6% for PCA concentrations of 12, 20.5, and 85.9 U/ml, respectively. To establish the normal upper limit in our laboratory, we have selected the mean +2 SD (14 U/µL) measured in a large group of apparently normal subjects, without autoimmune disorders.

As standard policy in our institution, patients are advised to take L-T4 in the morning under fasting conditions, at least half an hour before breakfast.

Blood samples were taken between 0800 and 1000 h after overnight fasting, separated by centrifugation, and than stored in 0.5-ml aliquots at –20 C until assayed.

Thyroid volume was assessed by neck ultrasonography using a color Doppler apparatus (Technos MP; Esaote Biomedica, Firenze, Italy) with a 7.5-MHz linear transducer. To obtain the thyroid volume, the three diameters of both lobes were measured, and the total volume was calculated according to the ellipsoid model (width x length x thickness x 0.52 for each lobe) (21).

Endoscopy and biopsy

A subgroup of 73 of 155 patients with autoimmune thyroiditis and positive PCA agreed to undergo gastric endoscopy. The indication was just the presence of positive PCA with or without dyspeptic symptoms (dysphagia, unexplained loss of weight, anemia, thoracic palpitations, or atypical chest pain). Three gastric biopsies were taken from the lesser curve of the antrum 3 cm proximal to the pylorus, and three biopsies were taken from the midpoint of the greater curvature, taken with a standard biopsy forceps. The biopsy specimens were stained with hematoxylin-eosin, Alcian blue-periodic acid Schiff, and modified Giemsa stains. The specimens were examined in a blinded manner by a pathologist and scored in accordance with the Sidney system (22).

Statistical analysis

Because serum TSH, FT3, FT4, and PCA values do not conform to a normal distribution, statistical analysis was performed using nonparametric tests, Mann-Whitney U test for comparison of group and differences in distribution of categorical data by Fisher’s exact test; Spearman’s rank correlation test was used for the correlation test. Univariate analysis and multivariate analysis were performed with dedicated software package StatView version 2.0 (Butterworth-Heineman, Surrey, UK). The parameters included in the univariate analysis were age, BMI, serum TSH at diagnosis, TgAb, TPOAb, and PCA levels, thyroid volume, and time on L-T4 therapy. Only the parameters significant in the univariate analysis were entered in the multivariate analysis.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Serum PCA were negative (<14 U/ml) in 236 of 391 patients (60.4%) and were elevated (mean ± SD, 84 ± 91 U/ml; range 14.5–489 U/ml) in 155 of 391 patients (39.6%). As shown in Table 1Go, the two groups did not differ for time on L-T4 therapy since diagnosis (mean ± SD, 90.6 ± 67.1 months in PCA-negative and 93.1 ± 82.1 months in PCA-positive patients), mean serum TSH values before start of therapy (21.7 ± 35 µU/ml in PCA-negative and 17.9 ± 22.9 µU/ml in PCA-positive patients), mean basal thyroid volume (8 ± 5 ml in PCA-negative and 10.5 ± 9.3 ml in PCA-positive patients), age, sex, and BMI.


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  		TABLE 1. Clinical features of hypothyroid patients with autoimmune thyroiditis according to PCA status

 
At the time of the study, all patients had serum TSH in the target range (0.3–3 µU/ml) as required by inclusion criterion, and the mean serum TSH (± SD) was similar in the two groups (1.5 ± 0.7 µU/ml in PCA-negative and 1.5 ± 0.7 µU/ml in PCA-positive patients).

As shown in Fig. 1Go, the daily requirement of L-T4/kg · /d was significantly (P = 0.002) higher in PCA-positive patients (1.24 ± 0.4 µg/kg · d) with respect to PCA-negative patients (1.06 ± 0.36 µg/kg · d). The significant increase in the daily dose of L-T4 found in our PCA-positive patients was maintained also when the confounding factor of H. pylori infection was excluded (data not shown).


Figure 1
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  		FIG. 1. L-T4 requirement (µg/kg · d) in hypothyroid patients on L-T4 replacement therapy according to the PCA status (positive or negative). In each column, the horizontal bar represents the mean of the group.

 
When we performed gastric endoscopy in 73 PCA-positive patients, we found that the daily requirement of L-T4 was even higher (P < 0.0001) in the 47 patients with histologically proven gastric atrophy (1.52 ± 0.4 µg/kg · d) compared with the 26 patients with normal gastric mucosa (1.15 ± 0.3 µg/kg · d) (Fig. 2Go). In addition, serum PCA levels were significantly higher (P = 0.008) in patients with gastric atrophy (136 ± 98 U/ml) compared with those with normal mucosa (103 ± 49 U/ml). In the latter, the L-T4 requirement was not different from the mean value found in the whole group of PCA-negative patients (right column of Fig. 1Go). This finding suggests that to have a higher demand of L-T4 requires significant damage of the gastric mucosa.


Figure 2
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  		FIG. 2. L-T4 daily requirement in 73 PCA-positive patients submitted to gastric biopsy according to the histological results (normal mucosa or atrophic changes). The right panel indicates the daily L-T4 requirement according to the degree of gastric injury (mild, moderate, or severe) in those patients with gastric damage.

 
The L-T4 requirement was also related to the degree of gastric atrophy (right panel of Fig. 2Go) and was significantly higher in patients with severe atrophy (1.83 ± 0.29 µg/kg · d) with respect to patients with moderate and mild atrophy (1.49 ± 0.29 and 1.18 ± 0.41 µg/kg · d, respectively; P = 0.006 and P = 0.002, respectively).

As shown in Fig. 3Go, in the whole group of PCA-positive patients (n = 155), a significant positive correlation was found between the daily L-T4 requirement and the levels of serum PCA (r = 0.55; P < 0.0001) but not of antithyroid antibody levels (data not shown). The correlation was even more apparent when the analysis was limited to the PCA+ patients with biopsy-proven gastric damage (Fig. 3Go, open circles).


Figure 3
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  		FIG. 3. Correlation between L-T4 daily requirement and serum PCA levels in 155 PCA-positive, hypothyroid patients receiving L-T4 therapy. The open circles represent patients with biopsy-proven gastric damage. The dashed line and the corresponding r and P values refer to all patients (• and {circ} together); the solid line refers only to patients with proven gastric damage.

 
As expected, the daily dose of L-T4 to obtain the TSH target was significantly higher (P < 0.0001) in patients who underwent total thyroidectomy (1.62 ± 0.29 µg/kg · d) compared with patients affected by autoimmune thyroiditis (1.14 ± 0.41 µg/kg · d). Thirty-eight of 60 thyroidectomized patients (63%) were PCA negative, and 22 of 60 (36.6%) were PCA positive. As shown in Fig. 4Go, also in thyroidectomized patients, the daily requirement of L-T4/kg was significantly higher (P = 0.0003) in PCA-positive patients (1.81 ± 0.27 µg/kg · d) compared with PCA-negative patients (1.52 ± 0.24 µg/kg · d).


Figure 4
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  		FIG. 4. L-T4 requirement in 60 patients submitted to total thyroidectomy for benign diseases according to PCA status (positive or negative).

 
To ascertain which parameter affected the daily requirement of L-T4 to obtain the target TSH level, the following variables were included in a univariate analysis: age, BMI, serum TSH at diagnosis, TgAb, TPOAb, and PCA levels, thyroid volume, and time on L-T4 therapy. As shown in Table 2Go, BMI, time on L-T4, basal TSH, thyroid volume, and PCA levels were significant variables. When these variables were entered in the multivariate analysis, PCA levels and basal TSH were the most significant independent variables.


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  		TABLE 2. Univariate and multivariate analysis of factors affecting the daily requirement of L-T4 in hypothyroid patients

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Oral L-T4 is the first choice for replacement therapy in patients with hypothyroidism. The optimal dose of L-T4 is related to body weight and age, with a dose requirement that is higher in infants and adolescents and is lower in elderly subjects (3). The daily dose is also dependent on the severity of hypothyroidism, and it is generally higher in patients with previous thyroidectomy than in those with autoimmune thyroiditis, in whom there may be some residual functioning thyroid tissue (23, 24). Typically, 70–80% of an orally administered dose of L-T4 is absorbed by the gastrointestinal tract, mainly in the ileum, but the mechanism of translocation across the mucosa remains unclear (25, 26). L-T4 malabsorption is observed after jejunoileal bypass operation, in short-bowel syndrome, cirrhosis, obstructive liver disease, or pancreatic insufficiency (13, 14).

Medications that decrease absorption of L-T4 or increase breakdown of L-T4 may be responsible for interference with thyroid hormone replacement therapy (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). In particular, it is demonstrated that L-T4 in an acidic environment adsorbs to calcium carbonate or sucralfate, resulting in a reduction of its adsorption (7, 27). Also, several conditions characterized by impaired gastric acid secretion, such as atrophic gastritis due to H. pylori infection (20), can reduce the absorption of L-T4. The normal acid environment of the stomach becomes altered in patients with gastritis related to H. pylori infection, atrophic gastritis of the body of the stomach, or both (28, 29, 30) as well as in patients who are receiving long-term treatment with proton pump inhibitors (12).

Autoimmune gastritis is an autoimmune disease characterized by the presence of circulating PCA and is frequently associated with autoimmune thyroiditis and other organ-specific diseases (1). The target autoantigen is H+/K+-ATPase, a heterodimeric protein located on the intracellular and apical membranes of gastric parietal cells (31, 32). Chronic gastritis is characterized by a progressive disappearance of oxyntic glands and may lead to atrophic body gastritis (32, 33). Because autoimmune gastritis is frequently associated with autoimmune thyroiditis, our study hypothesis was that PCA-positive patients may require higher doses of replacement L-T4 therapy. We confirmed this hypothesis both in patients with autoimmune thyroiditis and in patients submitted to total thyroidectomy. In both groups, the presence of PCA in the serum together with serum TSH at diagnosis was an independent factor affecting the daily requirement of L-T4. Furthermore, when the gastric damage was enough to determine histologically proven atrophic gastritis, the L-T4 requirement was even higher. These findings and the significant correlation between serum PCA levels and the L-T4 requirement suggest the existence of a correlation between the severity of body gastritis and the daily requirement of L-T4 and suggest that a higher demand of L-T4 requires significant gastric damage.

We are aware that this is a retrospective study with possible bias mainly related to patient selection. We tried to minimize possible bias starting with a very large cohort of patients (n = 697), and although we had to exclude nearly 44% of them because they did not meet the inclusion criteria, the final group was still very large (n = 391). On the contrary, it was more difficult to enrich the group undergoing gastric biopsy, because only 47% of the PCA+ patients accepted this procedure. Thus, the finding in this particular subgroup needs to be confirmed in a larger series, possibly prospective.

The likely mechanism reducing L-T4 absorption in PCA-positive patients may be related to the impaired chlorhydric acid secretion as a result of the chronic damage of the gastric mucosa and particularly of the reduced number and function of the oxyntic glands. Thus, reduction of gastric acidity may be responsible for reduced absorption of L-T4 (12, 20).

In conclusion, our study indicates that autoimmune gastritis is an additional factor influencing the daily requirement of L-T4 in patients with autoimmune hypothyroidism.

Consequently, measurement of serum PCA should be part of the diagnostic work-up of patients with an unexplained high requirement of L-T4 replacement doses.


   Footnotes
 
This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Regional Grant 2005/2006/2007; and Ministero dell’Istruzione, Università e Ricerca (MIUR) Italy, 2005/2006.

Disclosure Information: The authors have nothing to disclose.

First Published Online November 27, 2007

Abbreviations: FT3, Free T3; FT4, free T4; PCA, parietal cell antibodies; TgAb, anti-thyroglobulin antibodies; TPOAb, thyroid peroxidase antibodies.

Received July 11, 2007.

Accepted November 16, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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