Daily Intramuscular Levothyroxine in Refractory Hypothyroidism and Malabsorption

Abstract

Background/Objective

In patients with hypothyroidism, levothyroxine (LT4) monotherapy is the standard treatment; however, when standard therapy is ineffective, alternative approaches including liquid LT4, desiccated thyroid extract, LT4/liothyronine combinations, or injectable LT4 can be considered.

Case Report

A 55-year-old Caucasian woman with a history of Hashimoto thyroiditis, diagnosed during her first pregnancy in 1989, was controlled on 125 mcg of Synthroid daily until undergoing Roux-en-Y gastric bypass in 2004. Several years following gastric bypass surgery, she developed persistent hypothyroidism with increased serum thyroid-stimulating hormone (TSH) levels, low free thyroxine levels, and symptoms including fatigue, brain fog, constipation, cold intolerance, hair loss, dry skin, and delayed wound healing. Despite trials of various high-dose oral thyroid hormone regimens—including Tirosint (750 mcg daily), Synthroid (200 mcg daily), a combination of LT4 (175 mcg) and triiodothyronine (10 mcg), and Armour (150 mg daily)—her TSH level remained elevated. Thyroid hormone absorption tests revealed significant reduction in absorption: (1) 9% for Tirosint (1050 mcg), (2) 50% for Synthroid (1000 mcg), (3) 47% for Armour thyroid (600 mcg), and (4) 69% for sublingual LT4. Given her refractory hypothyroidism, intramuscular (IM) LT4 100 mcg daily was started, leading to normalization of TSH level and resolution of symptoms.

Conclusion

Our manuscript highlights the importance of considering alternative therapies for hypothyroidism, including IM LT4 either daily or weekly, when the oral routes are not adequately bioavailable to normalize TSH levels and resolve symptoms. This is the first case report of successful treatment of uncontrolled hypothyroidism with daily IM LT4 in an outpatient setting. Further studies are needed.

Highlights

• •Levothyroxine (LT4) monotherapy is currently the recommended standard treatment, with most patients achieving stable hormone levels through oral formulations
• •When standard therapy is ineffective, alternative approaches including liquid LT4 preparation, desiccated thyroid extract, LT4/liothyronine combinations, or injectable LT4 can be considered

Clinical Relevance

This report describes a 55-year-old woman with refractory hypothyroidism secondary to malabsorption, who was unresponsive to all conventional treatment modalities, thereby requiring intramuscular LT4 for effective disease management.

Introduction

Hypothyroidism is a common endocrine disorder generally characterized by insufficient thyroid hormone production. Levothyroxine (LT4) monotherapy is currently the recommended standard treatment, with most patients achieving stable hormone levels through oral formulations.^1,2 However, in cases of malabsorption, standard therapy may be ineffective, and alternative approaches including liquid LT4 preparation (Tirosint), desiccated thyroid extract, LT4/liothyronine combinations, or injectable LT4 can be considered. We present a case of a 55-year-old woman with refractory hypothyroidism due to malabsorption who failed all the available conventional treatment options, necessitating intramuscular (IM) LT4 for effective disease management.

Case Report

A 55-year-old Caucasian woman with a history of Hashimoto thyroiditis, diagnosed during her first pregnancy in 1989, was treated with Synthroid 125 mcg daily. Past medical history was significant for obesity, iron deficiency, vitamin D deficiency, vitamin B12 deficiency after gastric bypass surgery, hyperlipidemia, gastroesophageal reflux disease, and migraine. Past surgical history included Roux-en-Y gastric bypass in 2004, abdominoplasty, breast augmentation, thigh lift, tonsillectomy, cholecystectomy, and tubal ligation. She reported no known drug allergy. Current medications included iron infusion every 6 to 12 months as needed, cyanocobalamin 1000 mcg subcutaneously monthly, vitamin D 50 000 IU orally twice weekly, Tirosint 750 mcg orally daily, and omeprazole 20 mg orally daily. Social history was significant for smoking half a pack per day and rare alcohol use. Family history revealed mother and maternal grandmother with autoimmune hypothyroidism. Vital signs showed a blood pressure of 134/99 mm Hg, heart rate of 77/min , temperature of 97.9 °F, height of 64 inches, weight of 135 lbs, SpO2 of 100%, and body mass index of 23.17 kg/m². Physical examination was significant for awake; alert; oriented to person, place, and time; euthymic mood; mild fatigue; and dry skin. The result of head, eye, ear, nose, and throat examination was normal without macroglossia and periorbital edema. Heart, lung, abdominal, and neurologic examination was unremarkable. Laboratory results showed a thyroid-stimulating hormone (TSH) level of 63.8 (reference, 0.27-4.2) mIU/mL, total triiodothyronine (T3) level of 48.9 ng/dL (reference, 80-200 ng/dL), free thyroxine (FT4) level of 0.32 ng/dL (reference, 0.93-1.7 ng/dL), 25OH vitamin D level of 37.8 ng/mL (reference, 30-100 ng/mL), vitamin B12 level of 272 pg/mL (reference, 232-1245 pg/mL), and ferritin level of 94.0 ng/mL (reference, 13-150 ng/mL) (Table 1). Several years following gastric bypass surgery, she developed persistent hypothyroidism with increased serum TSH levels, low FT4 levels, and symptoms including fatigue, brain fog, constipation, vertigo, cold intolerance, hair loss, dry skin, and delayed wound healing. Despite trials of various high-dose oral thyroid hormone regimens—including Tirosint (750 mcg daily), Synthroid (200 mcg daily), a combination of LT4 (175 mcg) and T3 (10 mcg), and Armour thyroid (150 mg daily)—her thyroid function remained uncontrolled. Thyroid hormone absorption tests revealed significant reduction in absorption as follows: (1) 9% for Tirosint (1050 mcg), (2) 50% for Synthroid (1000 mcg), (3) 47% for Armour thyroid (600 mcg), and (4) 69% for sublingual LT4; all was well below the expected >80% normal threshold (Table 2). She was also screened for celiac disease and human anti-mouse antibody heterophile antibody; both were negative. Given her persistent hypothyroidism and increased TSH level, she was prescribed IM LT4 (100 mcg daily [2 mL], weight-based), leading to normalization of TSH level and resolution of symptoms within weeks (Table 3 and Fig.). The patient reports doing well with IM injections of LT4 and tolerating them well by alternating sites of injection daily. She would like to continue with IM LT4.

Table 1.

Summary of Laboratory Results

Laboratory tests	Patient's lab values	Reference
WBC	10.1 × 103/mcL	4.2-9.4
Hemoglobin	9.0 g/dL	11.9-15.3
Hematocrit	31.1%	36.9-46.8
MCV	84.3	84.3-99.4
Platelets	500 × 103/mcL	170-388
Iron	16 μg/dL	37-145
TIBC	453 μg/dL	182-416
Iron % saturation	3.5%	15.0-50.0
Ferritin	94.0 ng/mL	13.0-150.0
Sodium	134 mmol/L	136-145
Potassium	4.7 mmol/L	3.5-5.1
BUN	20 mg/dL	6-20
Creatinine	0.67 mg/dL	0.50-1.00
Total protein	5.8 g/dL	6.6-8.7
Albumin	3.8 g/dL	3.5-5.2
Vitamin B12	272 pg/mL	232-1245
25OH vitamin D	37.8 ng/mL	30.0-100.0
Total cholesterol	196 mg/dL	0-199
HDL	51 mg/dL	≥40
LDL	121 mg/dL	0-100
Triglycerides	147 mg/dL	0-149
FT4	1.13 ng/dL	0.93-1.70
Total T3	105.0 ng/mL	80.0-200.0
Total T4	9.2 μg/dL	4.5-11.7
TSH	1.140 uIU/mL	0.270-4.20
TPO antibody	12 IU/mL	0-34

Abbreviations: BUN = blood urea nitrogen; FT4 = free thyroxine; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MCV = mean corpuscular volume; TIBC = total iron binding capacity; T4 = thyroxine; TSH = thyroid-stimulating hormone; T3 = triiodothyronine; WBC = white blood cell.

Table 2.

Summary of Thyroid Hormone Absorption Tests (Using a Body Mass Index of 25 kg/m²)

Absorption test	Synthroid (1000 mcg) October 2021	Tirosint (1050 mcg) February 14, 2022	Armour (600 mg) July 10, 2023	Sublingual levothyroxine (1000 mcg) March 26. 2025
Baseline TT4 (mcg/dL)	3.7	5.2	3.3	6.3
Peak TT4 (mcg/dL)	8.3	6.1	5.9	12.6
% absorbed	50%	9%	47%	69%

Abbreviation: TT4 = total thyroxine.

Increment in TT4: peak TT4 − baseline TT4. Volume of distribution (L): Vd = 0.442 × body mass index. % absorbed = 100 × (increment TT4 [mcg/dL] × 10 [dL/L] × Vd [L])/(total administered levothyroxine).

Table 3.

Thyroid-Stimulating Hormone and Free Thyroxine Levels Over Time With Different Thyroid Hormone Regimens

Year	TSH (mU/L) (reference, 0.27-4.2 mU/L)	FT4 (ng/dL)(reference, 0.93-1.7 ng/dL)	Prescription
1999	14.59	0.79	Synthroid 125 mcg/d
2000	8.54	0.76
2004	7.20	0.78	Roux-en-Y gastric bypass
2009	10.24	0.52
2012	24.38	0.7
2014	81.25	0.35	LT4 175 mcg + T3 10 mcg
2016	81.48	0.41
2017	63.58	0.41
2020	68.29	0.20
2022	48.72	0.66
2023, April	153.6	0.34	Tirosint 750 mcg/d
2023, June	50.43	0.46	Armour 150 mg/d
2023, July: intramuscular levothyroxine 100 mcg/d was approved and started.
2023, September	0.70	1.15
2024, January	3.25	1.13
2025, March	1.14	1.10

Abbreviations: FT4 = free thyroxine; LT4 = levothyroxine; TSH = thyroid-stimulating hormone; T3 = triiodothyronine (cytomel).

Fig.

Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels over time with different thyroid hormone formulations. IM = intramuscular; LT4 = levothyroxine; LT3 = liothyronine.

Discussion

According to the American Thyroid Association guidelines for hypothyroidism, the standard treatment is oral LT4.^1,2 In our patient, despite taking high doses of LT4, it was difficult to keep the TSH level in the normal range, and the patient complained of residual hypothyroid symptoms. She was prescribed different available options including Synthroid, LT4 + T3, desiccated thyroid extract, and liquid thyroid hormone Tirosint, all at high doses. However, she did not respond well to these available treatments.

Despite multiple trials of oral thyroid hormone treatment, including synthetic LT4 (Synthroid and Tirosint), desiccated thyroid extract (Armour thyroid), and LT4/liothyronine combinations, she continued to exhibit classic signs and symptoms of hypothyroidism, along with persistently increased serum TSH and low FT4 levels. She reported taking medications correctly and not missing any doses. Her thyroid hormone absorption test results (50% for Synthroid, 9% for Tirosint, 47% for Armour desiccated thyroid extract, and 69% for sublingual LT4) revealed significantly reduced absorption well below the normal expected threshold of >80%,^3,4 confirming absorption issues or malabsorption.

Our patient experienced a rare but clinically significant complication of Roux-en-Y gastric bypass—the severe malabsorption of oral thyroid hormone therapy, leading to persistent hypothyroidism. Although the prevalence of worsening or uncontrolled hypothyroidism after gastric bypass surgery is relatively low,5, 6, 7, 8, 9 a subset—including the patient presented here—may develop worsening hypothyroidism.

A previous study showed that approximately 15% of patients taking standard LT4 do not respond well and still incur poor quality of life despite being on LT4 orally with a normal TSH level.¹⁰ However, some studies confirmed that LT4 requirements in obese patients with hypothyroidism decrease after bariatric surgery,^8,11 whether it is gastric bypass or gastric sleeve surgery. The mean dose decreased by approximately 9 mcg per day although this did not apply for this patient.

Several mechanisms likely contributed to the malabsorption seen in this patient. Roux-en-Y gastric bypass surgery significantly reduces the absorptive surface of the small intestine, particularly the duodenum and proximal jejunum, which are key sites for LT4 absorption.¹² LT4 absorption is known to be significantly reduced when taken alongside proton pump inhibitors (PPIs) such as omeprazole, which lower stomach acid levels necessary for LT4 dissolution¹³ and may have played a role in this patient’s impaired absorption. Our patient was concurrently taking ferrous sulfate and omeprazole, both of which can interfere with the absorption of LT4 through distinct mechanisms. Ferrous sulfate can chelate LT4 in the gastrointestinal tract, forming an insoluble complex that reduces its absorption in the small intestine and subsequently lowers its bioavailability.¹⁴ To minimize this interaction, it is advised that LT4 and oral iron supplements be administered at least 4 hours apart. PPIs, such as omeprazole, decrease gastric acid secretion, which is essential for the proper dissolution and absorption of LT4. A less acidic gastric environment can impair the solubilization of LT4,¹³ potentially necessitating higher doses in patients receiving long-term PPI therapy to maintain euthyroidism.

There are few case reports of parenteral LT4 (weekly IM injection of LT4 500-1000 mcg/wk) to treat refractory hypothyroidism with gastrointestinal disorder or surgery or malabsorption in both pediatric and adult patients (Table 4).15, 16, 17, 18, 19 These authors showed that weekly injections of LT4 could be safe and well tolerated for these patients. Our patient tolerates the administration of LT4 IM daily (100 mcg = 2 mL) without any adverse effects. She feels much better with resolution of previous hypothyroid symptoms on this regimen. Our patient was offered a weekly LT4 injection but refused due to the large volume of the injection (700 mcg = 14 mL per week). She preferred to take IM LT4 100 mcg (2 mL) daily with alternate injection sites and wished to continue this current regimen.

Table 4.

Case Reports of Intramuscular Levothyroxine in the Treatment of Refractory Hypothyroidism

Reference	Patient age (y)	Sex	Possible cause of refractory hypothyroidism	TSH before IM LT4 (reference, 0.35-5.5 mIU/L)	Oral dose of LT4 (mcg/d)	Intramuscular dose of LT4 (mcg/wk)
Kalathil et al15	47	Female	Malabsorption	82.4	1000	500
Taylor et al16	82	Female	Myxedema coma	>100	75	500
Alba et al17	16	Female	Unknown	345	LT4 250 mcg + T3 75 mcg twice a day	500
Alba et al17	12	Female	Malabsorption	186	200	500
Alba et al17	6	Female	Malabsorption	480	100	300
Anderson et al18	18	Female	Unknown	>100	200	1000
Garayalde et al19	55	Male	Gastrectomy, enterectomy, malabsorption	>100	175	400 mcg on Mondays and 200 mcg on Thursday
Hoang et al (present case)	55	Female	Roux-en-Y gastric bypass, malabsorption	153	750 mcg Tirosint daily	100 mcg daily

Abbreviations: IM = intramuscular; LT4 = levothyroxine; TSH = thyroid-stimulating hormone; T3 = triiodothyronine.

This case highlights that hypothyroidism management should be individualized and emphasizes the importance of trying all available treatment options,¹ given that severe, uncontrolled hypothyroidism can lead to myxedema coma with a mortality rate up to 20% to 25% or, in some cases, as high as 60%. Clinicians may consider outpatient injectable (IM) LT4, although painful due to its alkaline pH, when it is not feasible to have patients come into the clinic for intravenous administration. Our patient was not interested in taking LT4 sublingually due to adverse effects (nausea). Although not commonly used, the initiation of outpatient IM LT4 led to the normalization of TSH level and resolution of symptoms in this patient, which calls attention to the need of additional studies and long-term data to better understand its safety and efficacy.

From a cost perspective, IM LT4 is significantly more expensive than its oral counterpart, with a single IM dose costing 10 to 100 times more than a month’s supply of oral LT4. When administered weekly, IM LT4 therapy may range from $400 to $1200 per month, compared with $4 to $100 per month for oral formulations.²⁰ This difference is further compounded by additional administration fees, particularly when injections are performed in clinical or hospital settings.

In conclusion, it is important to consider other alternative therapies for hypothyroidism, including IM LT4 either daily or weekly, when the oral routes are not adequately bioavailable to normalize TSH levels and resolve symptoms. This is the first case report of successful treatment of uncontrolled hypothyroidism with daily IM LT4 in an outpatient setting. Further studies with longer duration are needed.

Disclosure

The authors have no conflicts of interest to disclose.