Levothyroxine liquid oral substitution as an alternative treatment for refractory hypothyroidism due to gastrointestinal malabsorption: A case report

Introduction

Primary hypothyroidism is a common thyroid disease. It is caused by autoimmune thyroiditis, thyroid surgery, radioactive iodine (RAI) therapy, and drugs such as amiodarone, interferon, and lithium. ¹ Biochemically, the diagnosis of overt primary hypothyroidism is established in the presence of an elevated thyroid-stimulating hormone (TSH) concentration and a low free thyroxine (FT4) level. ² Oral levothyroxine (LT4) in solid tablet form represents the conventional treatment for hypothyroidism. Most patients require approximately 1.6–1.8 µg/kg/day. ³ The treatment target is to reverse the clinical signs of hypothyroidism and to normalize TSH levels. In most cases, appropriate doses of LT4 restore euthyroidism. ¹ However, some patients may present with refractory hypothyroidism, which is defined as a persistent elevated TSH level despite a regular daily LT4 dose higher than 1.9 µg/kg.^3,4 Therapeutic failure can be due to poor adherence to treatment or impaired LT4 absorption because of drug interactions or gastrointestinal diseases such as atrophic gastritis, Helicobacter pylori gastritis, celiac disease, inflammatory diseases, and lactose intolerance.^3–6 In such conditions, the management of hypothyroidism is challenging.

Herein, we report the case of a patient with refractory hypothyroidism due to gastrointestinal malabsorption that was improved after switching to LT4 oral liquid form.

Case presentation

A 49-year-old woman was admitted to our department for refractory hypothyroidism. Her past medical history included left adrenalectomy for ganglioneuroma, asthma treated with salbutamol, vitamin D deficiency, and Graves’ disease treated with RAI therapy. The patient was treated with daily 300 μg oral LT4 tablets (3.9 μg/kg/day). Despite regular intake of this high dose of LT4, she had persistent symptoms of hypothyroidism. She presented with general weakness, weight gain, depressive mood, and persistent constipation.

On physical examination, she had myxedema, a body weight of 76 kg, a height of 156 cm, a body mass index of 31.2 kg/m², a blood pressure of 110/80 mmHg, and a heart rate of 68 beats/min. Electrocardiogram showed a normal sinus rhythm of 65 beats/min without obvious repolarization abnormalities.

Biological investigations revealed hypercholesterolemia, elevated muscle enzymes, elevated TSH level, and decreased FT4 level (Table 1). Two LT4 absorption tests were successively performed. On the first day, 300 µg of LT4 was orally administered. On the second day, a concomitant oral administration of 300 µg of LT4 and 1 g of vitamin C was performed. FT4 levels were measured before drug intake (T0), 2 (T2H), 4 (T4H) and 8 (T8H) hours after. The absorption rate was calculated using the following formula: %LT4 absorption = ((peak ΔT4 × volume distribution (dL))/administered dose of LT4(μg)) × 100 (Volume distribution = 4.42 × body mass index (kg/m²)). It was equal to 0% after the two tests. The diagnosis of LT4 malabsorption was established. Etiological workup showed negative anti-transglutaminase and anti-endomysium antibodies and the presence of antral gastritis on endoscopy. Histopathological examination showed non-atrophic pan-gastritis with no signs of intestinal metaplasia. Helicobacter pylori (H. pylori) infection was positive and adequately treated. However, symptoms of hypothyroidism and elevated TSH persisted. The LT4 dose was progressively adjusted from 300 µg to 400 µg per day. Two months later, biological tests showed a TSH level of 92.4 mIU/L and a FT4 level lower than 0.42 ng/dL (normal range: 0.7–1.5). The patient was treated with LT4 liquid form at a dose of 80 drops/day (400 µg). Two weeks later, she presented with a significant clinical improvement of hypothyroidism symptoms with a normal FT4 level of 1.14 ng/dL.

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Table 1.

Serum biological and hormonal parameters.

Biological and hormonal parameters	Values	Normal ranges
Fasting blood glucose level (mmol/L)	4.84	3.88–5.55
Total cholesterol (mmol/L)	9.6	3.2–5.5
Triglycerides (mmol/L)	1.2	0.56–1.92
Natremia (mmol/L)	142	135–145
Kalemia (mmol/L)	4	3.5–5.1
Creatinine level (μmol/L)	109.01	53–97
CPK (IU/L)	2747	30–200
LDH (IU/L)	797	125–245
Calcium (mmol/L)	2.48	2.2–2.6
Phosphorus (mmol/L)	1.22	0.8–1.4
White blood cells (elements/mm3)	4340	4000–10,000
Hemoglobin (g/dL)	12.9	12–16
TSH (mIU/L)	92.4	0.35–4.94
FT4 (ng/dL)	<0.42	0.7–1.5

CPK: creatine phosphokinase; LDH: lactate dehydrogenase; TSH: thyroid-stimulating hormone; FT4: free thyroxine.

Discussion

Conventional treatment of primary hypothyroidism consists of oral LT4 substitution in solid tablet form. Compared to other drugs, oral LT4 substitution requires fasting and abstinence from eating for at least 30 min after its ingestion. ⁷

Orally administrated LT4 is absorbed through the small intestine mucosa with an absorption rate ranging from 60% to 82% during the first 3 h after ingestion.^3,8 However, oral substitution fails to achieve euthyroidism in some patients despite escalating dosages of LT4 beyond 1.9 μg/kg/day. This situation is not uncommon in clinical practice.^4,9 Data regarding treatment-refractory hypothyroidism are increasingly published. However, its prevalence has not been fully determined. ⁴

Establishing the cause of refractory hypothyroidism can be particularly difficult. Assessing compliance with treatment and adequate drug intake should be the first step. Poor adherence to treatment is the most common cause of increased LT4 doses. ¹⁰ Then, other causes should be rigorously screened using appropriate diagnostic tools. Questioning should screen the concomitant use of other drugs that affect LT4 absorption and bioavailability, particularly proton-pump inhibitors, calcium carbonate, iron salts, and laxatives.^3,11

LT4 absorption can also be compromised by several gastrointestinal diseases, including celiac disease, atrophic gastritis, H. pylori infection, gastroparesis, inflammatory bowel disease, short bowel syndrome, and lactose intolerance.^3,4 Identification and adequate treatment of these conditions generally lead to TSH level normalization. However, in our case, TSH levels did not normalize even after appropriate treatment of H. pylori infection. In such cases, LT4 absorption test is needed to distinguish malabsorption syndrome from pseudomalabsorption (noncompliance to treatment). ¹²

The protocol and interpretation of LT4 absorption test results are not standardized.^9,13,14 The protocol involves oral administration of a single dose of LT4, typically ranging from 600 to 1000 μg, followed by hourly FT4 monitoring during 2–5 h.^14,15 This test requires careful hemodynamic monitoring since hypothyroidism decreases cardiac output and increases the risk of coronary artery disease. ¹⁶ Gonzales et al. ¹⁷ established that an LT4 absorption rate higher than 60% should be considered as normal. Our patient had an absorption rate of 0% that did not improve by concomitant administration of vitamin C. Several studies have shown improvement in hypothyroidism control by adding vitamin C alongside with LT4 dose.^18,19 Patients with gastrointestinal diseases could have an elevated gastric pH, which may decrease LT4 dissolution and thus absorption. Adding vitamin C temporarily decreases gastric pH, which improves the dissolution of LT4 tablets. ¹⁸

Some authors suggested that alternative formulations of LT4, including soft gel, liquid, intravenous, subcutaneous and intrarectal formulations are more effective than LT4 solid tablets in controlling refractory hypothyroidism.^20–25 Naman et al. ²⁵ demonstrated the efficacy of subcutaneous injection of LT4 three times weekly in restoring euthyroidism in a patient with refractory hypothyroidism due to malabsorption. Santaguida et al. ²¹ showed that switching from LT4 tablets to soft gel capsules led to the reduction of the required dose of LT4 and improved hypothyroidism symptoms in most patients with impaired gastric acid secretion. In fact, many authors showed that changes in gastric pH have a negligible effect on liquid and soft gel capsule LT4 absorption compared to LT4 tablets.^23–25 As in previously reported cases, our patient’s FT4 level normalized 2 weeks after switching to a liquid formulation. ⁵

Conclusion

LT4 oral substitution may fail to restore euthyroidism in patients with gastrointestinal disorders. The present case serves as a reminder that refractory hypothyroidism warrants rigorous investigations to identify the underlying cause of malabsorption. In case of gastrointestinal malabsorption, switching to a liquid formulation may resolve this issue.