Intramuscular and subcutaneous levothyroxine: success in treating refractory hypothyroidism

Abstract

Introduction

Refractory hypothyroidism often poses a clinical problem, as treatment regimens are difficult to individualise to the patient and the feasibility of its delivery is difficult to organise within a healthcare system. We present a patient who became intolerant of intramuscular (IM) levothyroxine (LT₄) after 18 years of treatment; thus, subcutaneous (SC) LT₄ was initiated.

Case presentation

A 13-year-old female with newly diagnosed hypothyroidism remained hypothyroid despite escalating doses of oral LT₄ and LT₃. Thyroxine malabsorption was further suggested by nasogastric administration of LT_4, whereby high-dose thyroxine administration resulted in only a 2.8 pmol/L increase in free T₄ level (normal >5.14 pmol/L). She eventually achieved long-term euthyroid status at the age of 18 with fortnightly IM LT₄ alongside oral LT₄ and LT₃. This was maintained for 18 years. Unfortunately, scar tissue developed around injection sites, resulting in increased pain and difficulty in administration. SC LT₄ was trialled with success, and she has remained euthyroid for the last 6 years with self-administration and minimal side effects.

Conclusion

Refractory hypothyroidism often presents a challenge for clinicians, both for diagnosis and management. We discuss a patient with the longest follow-up to date within the published literature for both IM and SC LT₄ for patient-administered treatment of refractory hypothyroidism and review the literature on alternative formulations available.

Established facts

• Treatment-refractory hypothyroidism is a diagnostic and clinical dilemma with no formal treatment guidelines.

• Diagnosis and management of treatment-refractory hypothyroidism are challenging.

Novel insights

• This is the first case report demonstrating efficacy and safety of both subcutaneous and intramuscular levothyroxine injections, administered by the patient, for long-term treatment of refractory hypothyroidism.

• Many alternative thyroxine formulations are present for traditional tablets, including soft-gel capsules, liquid solutions, rectal suppositories, intravenous, subcutaneous and intramuscular injections. We propose the wider use of self-administered SC LT₄ for its convenience, reduction in pain associated with IM injections and for cost-efficiency.

Introduction

Hypothyroidism is a common endocrinological condition, with a prevalence of 2% in the UK (1). The first-line treatment for hypothyroidism is oral levothyroxine (LT₄) tablets. The recommended treatment dose of oral LT₄ is usually between 1.6 and 1.8 μg/kg/day (2). The majority of LT₄ is absorbed in the small intestine (especially the jejunum and ileum), with an average bioavailability of ∼80% (3).

It is estimated that 24.8% of patients taking LT₄ are on insufficient doses (4). The diagnosis of refractory hypothyroidism is made both on determination of biochemical and clinical evidence. Biochemical evidence involves serum thyroid-stimulating hormone (TSH) levels >4.5 mU/L, 6 weeks after the last dose increase, with an LT₄ dose >1.9 μg/kg/day. Clinical evidence involves the presence of hypothyroid symptoms with an LT₄ dose ≥1.9 μg/kg/day (5). Diagnosis can be challenging, and if supratherapeutic doses of LT₄ are needed to achieve biochemical or clinical euthyroidism, treatment-refractory hypothyroidism should be considered.

There are many causes of treatment-refractory hypothyroidism, the main cause of which includes poor compliance to drug therapy (Table 1). Thyroxine pseudomalabsorption is a diagnosis of exclusion, and a thyroxine absorption test can distinguish this from true thyroxine malabsorption. There are no standard protocols for performing this test, but it usually consists of the administration of a high dose of thyroxine (500–2,000 μg), followed by serial measurements of T₄ and TSH every 1–2 h for 6 h (6, 7, 8, 9). Thyroxine malabsorption is thus diagnosed if the increase of fT4 is less than 0.40 ng/dL (5.14 pmol/L) three hours post high-dose thyroxine administration. This test has high sensitivity (97%) and specificity (80%) (10).

Table 1.

Causes of thyroxine malabsorption^*.

Gastrointestinal disease	Helicobacter pylori
	Autoimmune atrophic gastritis
	Coeliac disease
	Intestinal malabsorption
	Small bowel syndrome
	Inflammatory bowel disease
	Giardia infection
Liver disease	Liver cirrhosis
	Obstructive liver disease
Pancreatic disease	Pancreatic insufficiency
Heart disease	Congestive heart failure
Medications	Proton-pump inhibitors
	Iron
	Calcium
	Phenytoin
	Phenobarbital
	Cholestyramine
Diet	Walnuts
	Coffee
	Prunes
	Soy
	Milk
	Food (e.g., breakfast)
Increased body demand	Weight gain
	Pregnancy
Other	Poor medication adherence

^*As modified from (7, 10).

The treatment of refractory hypothyroidism is still relatively uncommon, with no formal guidelines. Cases in the literature report a variety of formulations used, including intravenous, soft-gel capsules, liquid, intramuscular, subcutaneous or rectal thyroxine (summarised in Supplementary Table 1 (see section on Supplementary materials given at the end of the article)).

We report a case of thyroxine malabsorption in a woman with polyglandular syndrome of autoimmune aetiology (hypothyroidism, hypoparathyroidism and Addison’s disease), initially presenting nearly 30 years ago at the age of 13. Other autoimmune causes of malabsorption, including coeliac disease and atrophic gastritis were excluded. Her thyroxine malabsorption was successfully managed with fortnightly IM preparation for 18 years and then with SC LT₄. We discuss the challenges posed and the learning points raised and include an updated summary of the evidence base for alternate formulations available. Furthermore, we provide a literature review of all refractory hypothyroid cases treated with IM and SC LT₄ to date to highlight the rarity of our patient’s case, as well as acknowledging successes and drawbacks learnt from other cases.

Patient information

A 13-year-old female presented to her general practitioner with weight gain, menorrhagia, cold intolerance and lethargy. After biochemical confirmation, she was diagnosed with hypothyroidism. She was started on oral LT₄ tablets but unfortunately remained hypothyroid. Of note, she had a strong family history of autoimmune polyendocrinopathy, with her father and first-degree paternal relatives diagnosed with multiple autoimmune disorders, including autoimmune hypothyroidism, vitiligo, rheumatoid arthritis and type 1 diabetes mellitus. She was also diagnosed with Addison’s disease at the age of 14, for which she started hydrocortisone and fludrocortisone, and hypoparathyroidism at 15 years, for which she commenced 1-α-hydroxycholecalciferol. 0.75 μg alfacalcidol was taken once daily and was confirmed to be taken at least four hours post-levothyroxine administration. A clinical diagnosis of autoimmune polyglandular syndrome type 1 was thus made. Regular biochemistry tests revealed normal calcium, sodium and potassium levels, yet persistent hypothyroidism. Levothyroxine doses were escalated and liothyronine (LT₃) was added. However, despite very high doses of both (thyroxine 700 μg once per day (∼10.8 μg/kg/day) and liothyronine 40 μg twice per day (∼1.23 μg/kg/day)), she remained hypothyroid (TSH >100 mU/L, fT4 <5 pmols/L, fT3 <1 pmols/L). Furthermore, she displayed signs of severe hypothyroidism with significant periorbital, extremity oedema and delayed relaxation of tendon reflexes. Biochemistry and clinical findings were thus all suggestive of selective thyroxine and T3 malabsorption.

Timeline

The timeline of the patient’s hypothyroidism management is shown in Fig. 1.

Figure 1.

Patient timeline of hypothyroidism management.

Diagnostic assessment

Compliance to thyroxine medication was confirmed by the patient’s parents. She was of good psychological status throughout adolescence and reported a strong relationship with her parents; thus we had little reason to suspect non-compliance to LT₄ and LT₃. Furthermore, control of her Addison’s disease and hypoparathyroidism was maintained, suggesting good medication adherence. In addition, given the significant family history of hypothyroidism, thyroid hormone resistance must be considered. However, as all relatives showed well-controlled thyroid function on oral levothyroxine alone, thyroid hormone resistance was not suspected. All causes of thyroxine malabsorption were investigated and excluded, including food interactions, inflammatory bowel disease, atrophic gastritis, coeliac disease and pregnancy. All tests returned normal, including albumin (43 g/L; normal range (NR): 34–52 g/L), iron (19 μmol/L, NR: 13–32), vitamin B12 (390 ng/L; NR: 200–1,100 ng/L), folate (5.0 μg/L; NR: 2.0–14.0 μg/L) and corrected calcium (2.29 mmol/L; NR 2.20–2.60 mmol/L) with negative IgA, intrinsic factor antibodies, Helicobacter pylori testing and anti-endomysial antibodies. These were excluded through a variety of investigations, including upper gastrointestinal endoscopy, small bowel biopsy, barium follow-through and barium enema studies, all of which were normal. Thyroxine absorption testing via a nasogastric tube was subsequently conducted (Fig. 2). A 600 μg dose of levothyroxine was administered via a nasogastric tube, and its absorption was monitored by hourly blood tests measuring free T₄ levels. Ghosh et al. suggest that an increase of fT4 <0.40 ng/dL (5.14 pmol/L) 3 h post-high-dose thyroxine is considered as levothyroxine malabsorption (10). Nevertheless, our patient only showed a 1.3 pmol/L increase in free T₄ at 3 h, with a maximum increase of 2.8 pmol/L 5 h post-thyroxine administration. As a result, as both values were below the proposed threshold of 5.14 pmol/L, we concluded that our patient had treatment-refractory hypothyroidism.

Figure 2.

Thyroxine absorption testing via the nasogastric route.

Therapeutic intervention

She was commenced on weekly IM LT₄ injections at the age of 18; Spanish ‘levothyroid’ 500 μg dry powder injections made by Sanofi Aventis and obtained from IDIS, Surrey, UK, later switched to levothyroxine SERB 200 micrograms/mL solution neat injections due to local pharmacy availability. Initially, her injections were administered by the endocrinology team, after which the patient was taught to self-administer injections at home. The starting dose was a 700 μg 3.5 mL injection weekly (∼1.54 μg/kg/day), alongside oral LT₄ 200 μg once per day (∼3.08 μg/kg/day) and oral LT₃ 40 μg twice per day (∼1.23 μg/kg/day), doses of which were slowly increased until she successfully reached euthyroid status. Oral LT₄ was continued with the aim to limit the IM LT₄ injection volume and thus reduce discomfort at the injection site. Furthermore addition of oral LT₃ initially appeared to stabilise TSH levels; thus, it was speculated whether the patient had better absorption of T₃ as compared to T₄. Euthyroidism was finally achieved with IM LT₄ 2,056 μg split into two 5 mL injections every 14 days (∼2.26 μg/kg/day), alongside daily oral LT₄ 300 μg once per day (∼4.62 μg/kg/day) and LT₃ 40 μg three times per day (∼1.85 μg/kg/day) (TSH 2.07 mU/L, fT₄ 10.2 pmol/L and fT₃ 3.6 pmol/L).

Follow-up and outcomes

She continued on self-administered IM LT₄ injections for 18 years; for the first 15 years, she continued oral LT₄ and LT₃ alongside IM LT₄, and then only oral LT₄ alongside IM LT₄ for the remaining 3 years. These treatments maintained euthyroidism, and she has had two successful pregnancies since, at ages 21 and 23 years. At the age of 34, due to the cost of LT₃ and relatively low T₃ levels despite treatment, oral LT₃ was thus stopped. She remained euthyroid on IM LT₄ 2,056 μg every 14 days (∼2.26 μg/kg/day) with alternating oral LT₄ daily doses of 2,000 μg (∼30.8 μg/kg/day) and 2,500 μg (∼38.5 μg/kg/day). Unfortunately, despite rotating injection sites, increasing scar tissue developed, and injection administration became very painful for the patient. Therefore, alternative formulations of thyroxine were sought.

At the age of 37, she was trialled on SC LT₄ injections. Just as with IM LT₄, after a period of supervised injections by the endocrinology team, she was able to safely self-administer injections. Euthyroidism has been successfully maintained on SC LT₄ 1,200 μg every 12 days (∼1.54 μg/kg/day) for the last 6 years to the present day, with no additional oral supplementation required. Each 1,200 μg dose is split into two 3 mL injections, minimising pain at the injection site. The patient reports much greater tolerance to these injections, with increased ease of administration and reduced accumulation of scar tissue. Due to the small volume and greater tolerability of subcutaneous injections, alongside stable thyroid function tests, there was no need for additional oral LT₄ and LT₃ supplementation to achieve euthyroidism. Moreover, with erratic absorption of oral LT₄ and LT₃ suspected from previous history, our patient showed much greater stability in thyroid status with subcutaneous thyroxine injections alone, perhaps due to increased absorption availability as compared to previous formulations. Furthermore, our patient has experienced no complications of medication, including no adverse bone or cardiovascular outcomes.

Literature review and discussion

Our case represents the rare diagnosis of selective thyroxine and liothyronine malabsorption, and highlights the difficulty with management. Despite very high doses of oral LT₃ and LT₄, she remained hypothyroid biochemically and clinically. She was successfully treated with IM LT₄, alongside large doses of oral levothyroxine and liothyronine, for 18 years. She unfortunately developed injection intolerance with increasingly high doses (and thus volume) of IM LT₄ necessary to maintain euthyroidism. It is unknown why increasingly high doses of IM LT₄ were needed, but perhaps was due to increasing tissue fibrosis and hence reduced intramuscular absorption. She was then switched to SC LT₄, which has successfully maintained euthyroid status for the last 6 years with minimal side effects reported. Very few cases in the literature report long-term follow-up of parenteral LT₄ administration; thus we wish to highlight the success of both IM and SC LT₄ long-term to treat complex refractory hypothyroid cases.

Many different formulations of LT₄ exist to treat hypothyroidism. Daily oral LT₄ tablets remain the first-line management for patients with hypothyroidism; however, in those with treatment-refractory hypothyroidism, alternative options may be considered. These are summarised in Supplementary Table 1 and are discussed in more detail below.

Due to the relatively long half-life of T₄ (5–7 days), oral LT₄ can be administered once weekly under observation for patients who suffer with non-adherence. However, due to contrasting evidence comparing weekly versus daily LT₄, longer-duration randomised controlled trials are ideally needed to guide clinical practice (11, 12).

Alternative formulations of LT₄ have shown considerable benefit in treating hypothyroidism as compared to standard oral tablets. We did a comprehensive literature review focussing on IM and SC thyroxine use in refractory hypothyroidism. The search was conducted in CINAHL, Ovid Embase and Medline databases using the following key search terms: ‘hypothyroid*’ and ‘intramuscular or IM’ or ‘subcut*’ or ‘SC’ and ‘*thyroxine or LT₄’. For IM LT₄ search, this retrieved 144 papers in Ovid Embase, 183 in Ovid Medline and two in Cinahl. After exclusion of conference abstracts and irrelevant articles, two relevant case reports were identified in Embase, eight in Medline and none in Cinahl. In comparison, for the SC LT₄ search, this retrieved four papers in CINAHL, 364 in Embase and 175 in Ovid Medline. From these, four relevant case reports were identified in Embase, four case reports in Medline and one in CINAHL. Duplications were deleted, leaving five relevant articles. Unfortunately, for both searches, one paper was not translated to English for analysis (13), thus this left nine papers for inclusion in the IM literature review (Supplementary Table 2) and four papers for the SC literature review (Table 2).

Table 2.

Cases in the literature to date reporting treatment with subcutaneous levothyroxine injections. Doses, manufacturers and volumes of levothyroxine injections have been included when mentioned by authors.

Study	Age, sex	Cause of HT	LT4 absorption test conducted	Previous daily oral LT4 regime‡	Other LT4 formulations trialled‡	SC dose*	FU, months
Topf et al. (17)	28F	Hashimoto thyroiditis, autoimmune gastritis	Yes – 700 μg oral LT4 resulted in no improvement in fT4 levels	Up to 700 μg/day oral LT4	IV 500 μg LT4 (L-thyroxin Henning inject, 100 μg/mL Sanofi Aventis Gmbh, Germany)	500 μg every week (L-thyroxin Henning® inject, 500 μg/5 mL LT4, Sanofi Aventis Gmbh, Germany, split into 2 × 2.5 mL injections) (1.05 μg/kg/day)	8
Groener et al. (23)	42F	Subtotal thyroidectomy for benign multi-nodular goitre (8 years previous)	Not reported	400 μg/day oral LT4 + 20 μg/day liothyronine	2,200 μg/day oral LT4 and 80 μg/day liothyronine	500 μg every 4 days (L-thyroxin Henning® inject, Henning, Germany) (2 × 250 μg/5 mL injection)	7
Naman et al. (24)	53F	Autoimmune hypothyroidism	Yes – 1,000 μg oral LT4 resulted in insufficient (2.19 pmol/L) increase in fT4 over 6 h	400 μg/day oral LT4 (4.4 μg/kg/day) + 75 μg/day liothyronine	Weekly IV 200 μg LT4 (L-thyroxine serb, 200 μg/mL) injections	3× 200 μg injections per week (0.92 μg/kg/day)	2 years
Ljunggren et al. (25)	50F	Subtotal thyroidectomy for atoxic nodular goitre	Not reported	400 μg/day oral LT4 + 60 μg/day l-triiodothyronine	None	Daily SC 200–300 μg	2
Ljunggren et al. (25)	72F	Hashimoto’s thyroiditis	Not reported	Desiccated thyroid extract †	Trialled other oral tablets with nil success	Daily SC 200–300 μg	2

Text in bold indicate success in achieving euthyroidism. FU, follow-up; HT, hypothyroidism.

^*Euthyroidism achieved with subcutaneous thyroxine injections.

^† Manufacturer stopped production.

^‡ text not in bold are strategies that did not result in euthyroidism.

In the past 16 or so years, soft gel and liquid LT₄ formulations have been introduced into the market (14). LT₄ gel capsules consist of thyroxine dissolved in glycerine and surrounded by an outer gelatine shell, while liquid LT₄ consists of sodium thyroxine dissolved in glycerine and/or ethanol and is sold as drops or ampules. Both gel and liquid formulations do not require pH-sensitive gastric dissolution, thus are minimally affected by interference from high gastric pH and food (6). As a result, soft gel capsules are particularly beneficial in treating hypothyroidism in patients who are unable to take medications fasting or who have gastrointestinal disorders affecting thyroxine absorption, including coeliac disease and lactose intolerance (15). This has been shown in in vivo studies, whereby, while the LT4 tablet dose correlates with gastric pH, the soft gel dose is in fact independent of gastric pH (16). Multiple benefits have been shown in studies comparing liquid and soft gel formulations to oral tablets, some of which are summarised in Supplementary Table 1. Unfortunately, at the time of our patient’s diagnosis, these novel formulations did not exist. However, we are hoping to consider trialling these novel oral formulations due to their numerous advantages, including the avoidance of further injections.

Rectal administration of LT₄ suppositories and enemas has been attempted. Lower bioavailability has been seen for rectal LT₄ compared to oral mode for a variety of reasons: i) low rectal pH may impair suppository dissolution and absorption of LT₄, and ii) variation in expression levels of thyroid hormone transporters between the small intestine and rectum (14), thus, a much higher dose of rectal thyroxine suppositories is needed (3). Very few case reports exist in the literature investigating the effect of rectal LT₄ to treat refractory hypothyroidism, with the maximum treatment regime being 3 weeks, thus further studies are needed to investigate its efficacy and safety long term (17, 18).

Multiple parenteral formulations have been trialled to treat refractory hypothyroidism. These include intravenous (IV), intramuscular (IM) and subcutaneous (SC) formulations. It is important to consider that parenteral LT₄ is roughly twice as potent as oral replacement; thus, reduced doses are usually needed (19, 20), our case highlighting a rare exception. IV LT₄ has been successfully used to treat medical hypothyroidism emergencies, such as myxoedema. Very few studies report its use in treating refractory hypothyroidism (21, 22). Several case reports (so far n = 12) discuss the use of IM LT₄ for the management of treatment-refractory hypothyroidism, summarised in Supplementary Table 2.

There have been five case reports in the literature that discussed the use of SC LT₄ to treat refractory hypothyroidism. SC injections provide smaller fluctuations in TSH levels and a slower release into circulation as compared to IM injections (14). One of the first cases reported describes a 42-year-old woman who received 500 μg 10 mL SC LT₄ as a single injection regimen. Unfortunately, due to local pain reactions at the injection site, administration via this route was terminated (13). Alternatively, others have treated refractory hypothyroidism with SC LT₄ by splitting the volume from 500 μg 10 mL per injection per week into two 250 μg 5 mL injections once weekly to minimise pain, with injection frequency increasing later to two injections every 4 days to maintain euthyroidism (23). Others have consequently reported success with weekly SC LT4 injections. However, the longest duration of follow-up using SC LT₄ injections while maintaining euthyroidism was 2 years, consisting of three 200 μg 1 mL injections per week (600 μg/week in total) (24). These studies are summarised in Table 2.

Excitingly, Xeris Biopharma have announced in January 2023 their first phase 2 clinical study of once-weekly SC LT₄ in patients with hypothyroidism to assess the safety and tolerability of the medication. Once the results of this study are published, further information on dosing, safety and efficacy will be known.

Conclusion

In conclusion, treatment-refractory hypothyroidism is both a diagnostic and clinical dilemma that may require extensive investigations. Our case is unique and highlights the longest follow-up of both intramuscular and subcutaneous levothyroxine treatment recorded to date; after 18 years of successful therapy with intramuscular thyroxine alongside high-dose oral levothyroxine and liothyronine, worsening pain at injection sites resulted in switching to subcutaneous thyroxine, which has been successful for 6 years to date. Alternative newer thyroxine formulations exist and provide exciting alternative treatment options for treatment-refractory hypothyroidism. Nevertheless, long-term randomised controlled trials demonstrating their efficacy are needed.

Key learning points

i) Multiple causes of refractory hypothyroidism exist, including non-adherence, interference with medications and foods, and gastrointestinal causes, liver and pancreatic causes. ii) Many different treatment options for refractory hypothyroidism exist, including intravenous, subcutaneous and intramuscular injections. iii) Several case reports are noted in the literature for the use of both enteral and parenteral LT4 in treatment of refractory hypothyroidism; however, very few report their long-term efficacy and tolerance. iv) Randomised controlled trials and meta-analyses are needed to investigate the efficacy and safety of different formulations of LT4 as compared to standard oral tablets for use in clinical practice.

Patient perspective

Diagnosis and treatment has been hard for me. Diagnosis was at the same time as puberty and the symptoms I had were quite intense and a lot to deal with. Similarly, the time it took titrating through the medication until we started the IM T4 injections felt never ending. And as I was not responding to the oral T4 medication the symptoms persisted and hampered my life while I tried to complete my education. During this time my consultant faced a series of things he had to prove before he could get the go ahead to order Injections.

I found the IM injection’s fantastic at first. After many years, the administration and the pain felt due to a build-up of scar tissue meant it was almost impossible. The subcut injections are far easier to do, a lot less painful. Although I am now starting to experience areas of scar tissue it’s nothing like the IM caused. I wish for more clinicians to be aware of the need for these medications. And the need for the pharmacy’s stocking these treatments to not discriminate between oral and injectable T4 stock levels.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication was obtained from the patient.

Author contribution statement

NC was the main clinician involved with the writing of the paper, VP was the main clinician in charge of the patient’s care, and WC and PS both contributed to patient care. All authors contributed to the finalised version of the paper.

Ethical review

Ethical review and approval were not required for this publication.