Iodine-containing ointment–induced hypothyroidism in a patient with anorexia nervosa and sacral decubitus ulcer: a case report with literature review

Abstract

We present a case of a 58-year-old woman with anorexia nervosa and a sacral decubitus ulcer who developed hypothyroidism because of an iodine-containing ointment. Considering the absence of autoimmune thyroid diseases, the development of hypothyroidism after the use of an iodine-containing ointment, and the recovery of thyroid function after the discontinuation of the ointment, we presumed that her hypothyroidism was induced by the iodine-containing ointment. Although the hypothyroidism improved after discontinuing the iodine-containing ointment, she developed aspiration pneumonia and required long-term hospitalization. Many patients with autoimmune thyroid diseases develop hypothyroidism after excessive iodine intake. However, anorexia nervosa may have exacerbated the iodine-induced hypothyroidism in our patient. To the best of our knowledge, no previous study has reported a case of hypothyroidism caused by iodine-containing ointment in a patient with anorexia nervosa. Hence, physicians must pay careful attention to a patient’s background factors to ensure the early diagnosis of hypothyroidism due to iodine-containing ointments.

PATIENTS with autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves’ disease, are at a high risk of developing hypothyroidism from iodine overdose. The use of oral amiodarone or lithium and anorexia nervosa are some of the risk factors for iodine-induced hypothyroidism [1]. Iodine-induced hypothyroidism is commonly caused by the excessive intake of seaweed and the long-term use of an iodine gargle. Several cases of iodine-containing ointment–induced hypothyroidism have been reported [2-7]. However, to our knowledge, no case report has described iodine-containing ointment–induced hypothyroidism in a patient with anorexia nervosa. Herein, we describe a case of a 58-year-old female with anorexia nervosa who developed hypothyroidism because of an iodine-containing ointment prescribed for a sacral decubitus ulcer.

Case Report

A 58-year-old female presented to our department with dizziness on day –11. She had anorexia nervosa for 30 years and had been receiving treatment for a sacral decubitus ulcer for 1 year. On day –30, she was started on topical therapy with an iodine-containing ointment for the ulcer. On day –11, her body weight was extremely low (height, 158 cm; weight, 31.7 kg; body mass index [BMI], 12.7 kg/m²). Her vital signs were as follows: body temperature, 36.9°C; blood pressure, 150/81 mmHg; pulse, 80 beats/min. She had a sacral decubitus ulcer measuring 10 cm × 5 cm (Fig. 1). Routine laboratory tests showed anemia, elevated levels of hepatobiliary enzymes and amylase, and malnutrition. In addition, she had high serum levels of prolactin and cortisol and low serum levels of insulin-like growth factor-1, gonadotropin, and estradiol, all of which are characteristic findings of anorexia nervosa (Table 1). Although she had marked hypothyroidism, tests for serum thyrotropin receptor antibodies, thyroglobulin antibodies, and thyroid peroxidase antibodies yielded negative results. Her serum thyroid hormone levels were within normal ranges on day –137. Thyroid ultrasonography showed a thyroid gland of normal size, configuration, and echotexture. Color Doppler imaging showed rich blood flow signals. No tumors were detected (Fig. 2). She did not take oral medication, including lithium and amiodarone, or show indications of iodine overdose. Thus, we suspected the iodine-containing ointment to be the cause of hypothyroidism.

Fig. 1

Sacral decubitus ulcer.

Table 1 Laboratoy findings at the first visit

WBC	5,000/μL	AST	37 U/L	TSH	120.3 μIU/mL
Hb	9.2 g/dL	ALT	36 U/L	FT4	0.38 ng/dL
MCV	98 fL	LDH	306 U/L	TRAb	1.4 IU/L
Platelet count	38.4 × 104/μL	ALP	548 U/L	TgAb	17 IU/mL
Fe	32 μg/dL	GGTP	55 U/L	TPOAb	13 IU/mL
TIBC	242 μg/dL	ChE	208 U/L	ACTH	22.1 pg/mL
Ferritin	95.8 ng/mL	TP	6.5 g/dL	Cortisol	22.2 μg/dL
Vitamin B1	3 μg/dL	Alb	3 g/dL	PRL	93.5 ng/mL
Vitamin B12	616 pg/mL	T-cho	278 mg/dL	GH	2.57 ng/mL
Folic acid	6.7 ng/mL	BG	156 mg/dL	IGF-1	35 ng/mL
Zinc	69 μg/dL	HbA1c	5.5%	LH	<0.1 mIU/mL
Copper	70 μg/dL	AMY	218 U/L	FSH	0.54 mIU/mL
		UA	2 mg/dL	E2	14 pg/mL
		BUN	17 mg/dL
		Cre	0.84 mg/dL	Urinalysis
		eGFR	54.1 mL/min/1.73m2	USG	1.016
		Cys-C	0.87 mg/L	Protein	(–)
		CPK	152 U/L	Glucose	(–)
		Na	136 mEq/L	Blood	(–)
		K	3.7 mEq/L
		Cl	98 mEq/L
		Ca	8.2 mg/dL
		P	2.9 mg/dL
		Mg	2 mg/dL
		CRP	<0.3 mg/dL

ACTH: adrenocorticotropic hormone, Alb: albumin, ALP: alkaline phosphatase, ALT: alanine aminotransferase, AMY: amylase, AST: aspartate aminotransferase, BG: blood glucose, BUN: blood urea nitrogen, Ca: calcium, ChE: cholinesterase, Cl: chloride, CPK: creatine phosphokinase, Cre: creatinin, CRP: C-reactive protein, Cys-C: cystatin C, E2: estradiol, eGFR: estimated glomerular filtration rate, Fe: iron, FSH: follicle stimulating hormone, FT4: free thyroxine, GGTP: γ-glutamyl transpeptidase, GH: growth hormone, Hb: hemoglobin, HbA1c: Hemoglobin A1c, IGF-1: insulin-like growth factor 1, K: potassium, LDH: lactate dehydrogenase, LH: luteinizing hormone, MCV: mean corpuscular volume, Mg: magnesium, Na: natrium, P: phosphorus, PRL: prolactin, T-cho: total cholesterol, TgAb: thyroglobulin antibodies, TIBC: total iron binding capacity, TPOAb: thyroid peroxidase antibodies, TRAb: thyroid receptor antibodies, TSH: thyroid stimulating hormone, UA: uric acid, USG: urine specific gravity, WBC: white blood cell

Fig. 2

Thyroid ultrasonography. The thyroid gland appears normal in size, configuration, and echotexture

Color Doppler shows rich blood flow signals.

Treatment with oral levothyroxine (LT4) was started at an initial dose of 12.5 μg/day on day –11 and was increased to 25 μg/day on day –5. Although the iodine-containing ointment was discontinued on day –2, she needed to be hospitalized because of general weakness, dyspnea, and inability to walk or eat. On admission, she was alert, but her responses were slow. Moreover, she was unable to stand up from a sitting position and also reported experiencing chills and cold extremities. Whole-body computed tomography showed no abnormal findings. The clinical course is shown in Fig. 3. LT4 was continued after admission. On day 2, she developed aspiration pneumonia and was started on antibiotics along with total parenteral nutrition. LT4 was continued using a nasogastric feeding tube. On day 32, her thyroid hormone levels were normalized (thyroid-stimulating hormone [TSH], 2.93 μIU/mL; free thyroxine [FT4], 1.34 ng/dL). On day 57, she was transferred to another hospital for the treatment of swallowing disorders and physical rehabilitation. The required LT4 dose was gradually decreased after discharge. Normal thyroid function was maintained without LT4 replacement. Subsequently, the sacral decubitus ulcer almost disappeared. On follow-up, we confirmed that she was mentally stable and had no complaints of dizziness.

Fig. 3

The clinical course of the patient.

ABPC/SBT, ampicillin/sulbactam; CRP, C-reactive protein; FT4, free thyroxine; GM, gentamicin; LT4, levothyroxine; TPN, total parenteral nutrition; TSH, thyroid-stimulating hormone; WBC, white blood cells

Discussion

This case shows that an iodine-containing ointment can cause iodine-induced hypothyroidism. Hypothyroidism caused by excessive iodine intake is known as the Wolff–Chaikoff effect [8]. Long-term iodine intake in healthy individuals seldom leads to hypothyroidism because of the escape phenomenon [9]. The tolerable upper intake level of iodine for Japanese individuals is 3 mg/day [10]. However, in a study of healthy Japanese individuals, a slight increase in serum TSH levels and a slight decrease in serum FT4 levels occurred after the ingestion of 15–30 g of seaweed, namely, Kombu (iodine content: 35–70 mg), daily for 7–10 days [11]. A reversible increase in thyroid gland volume may occur after an oral dose of licorice lecithin-bound iodine tablets (iodine content: 27 mg) daily for 4 weeks [12]. These results suggest that an iodine load that is 10–20 times higher than the tolerable upper intake level can cause mild and reversible hypothyroidism in healthy Japanese individuals. On the other hand, patients with autoimmune thyroid diseases can easily develop hypothyroidism because of increased sensitivity to iodine [13]. However, our patient showed negative results for autoantibodies indicative of Hashimoto’s thyroiditis and Graves’ disease; thyroid ultrasonography findings also did not suggest the possibility of these diseases.

Anorexia nervosa has been reported to be a risk factor for iodine-induced hypothyroidism; however, the underlying mechanism is still unclear [1]. Increased sensitivity to iodine, as seen in Hashimoto’s thyroiditis and Graves’ disease, may be a potential mechanism. Haraguchi et al. reported a case of iodide-induced hypothyroidism with anorexia nervosa in whom the uptake of I¹²³ was elevated despite high serum iodine levels [14, 15]. Patients with persistent starvation, such as in anorexia nervosa, may experience a decrease in serum thyroid hormone levels; this is known as low T3 syndrome, which is thought to be a biological response to reduce energy expenditure by lowering metabolism. The increased sensitivity to iodine of patients with anorexia nervosa might be an adaptation to maintain thyroid function suppression and a low metabolic state. The local chronic inflammation of the decubitus ulcer might have also caused low T3 syndrome in our patient.

We believe that enhanced transcutaneous iodine absorption via the decubitus ulcer into the systemic circulation was an important factor in the development of hypothyroidism in our patient. The development of severe hypothyroidism due to enhanced transcutaneous iodine absorption has also been observed in patients with diabetic gangrene [2] and burns [16]. A similar mechanism may occur in neonates with immature skin [6]. The iodine-containing ointment used in the present case contained 300 mg of active iodine in 100 g of ointment. Although details of the use of the iodine-containing ointment by our patient could not be confirmed, medical records showed that 30 g of ointment (90 mg of active iodine) was applied to the ulcer every other day. A previous case report of a patient with Hashimoto’s thyroiditis noted that the patient developed hypothyroidism after initiating treatment with 10–20 g/day of iodine-containing ointment for diabetic foot gangrene [2]. These previous findings support the possibility of percutaneous iodine hyperabsorption from the decubitus ulcer and iodine-induced hypothyroidism at the iodine dose used by our patient.

We searched “Igakuchuozasshi” (Japan Medical Abstracts Society) and PubMed for case reports that are similar to the present case. We found five case reports of iodine-induced hypothyroidism associated with anorexia nervosa [14, 15, 17-20] and six case reports of hypothyroidism caused by iodine-containing ointments (Table 2) [2-7]. However, to the best of our knowledge, no previous paper has reported a case of hypothyroidism caused by an iodine-containing ointment in a patient with anorexia nervosa. Therefore, this is the first case report to highlight this specific combination of characteristics.

Table 2 Previous case reports

No.	References	Age/sex	Pathology				Chief complaints	Pre-treatment data
			Anorexia nervosa (BMI)	Iodine ointment	Excessive intake of seaweed	Underlying thyroid disease		FT4 (ng/dL)	TSH (μIU/mL)
1	Haraguchi et al. [14, 15]	39 F	+ (12.1)	–	+	–	Weight loss and frailty	0.50	162.1
2	Matsubayashi et al. [17]	20 F	+ (14.9)	–	+	Unknown	Weight loss and edema	0.48	60.4
3	Ikema et al. [18]	17 F	+ (Unknown)	–	+	Unknown	General fatigue	<0.20	93.0
4	Hiwa et al. [19]	42 F	+ (16.6)	–	+	–	Edema	0.07	156.0
5	Kita et al. [20]	13 F	+ (12.5)	–	+	–	General fatigue	0.51	27.8
6	Hayashi et al. [2]	82 M	–	+	–	+	Disturbance of consciousness	0.20	76.7
7	Minakata et al. [3]	34 M	–	+	–	Unknown	Unknown	Unknown
8	Takeuchi et al. [4]	64 F	–	+	–	Unknown	Unknown	0.95	10.3
9	Uchinuma et al. [5]	79 M	–	+	–	–	General fatigue	0.21	73.6
10	Nakagawa et al. [6]	0 F	–	+	–	Unknown	–	0.63	72.4
11	Higaki [7]	71 F	–	+	–	Unknown	Tachycardia	0.70	52.0
12	Present case	58 F	+ (12.7)	+	–	–	Dizziness	0.21	123.1

BMI: body mass index, FT4: free thyroxine, TSH: thyroid stimulating hormone

The aging of patients with anorexia nervosa in Japan could be a possible reason why such a case was reported for the first time. Although there are no large-scale domestic surveys on the aging of patients with anorexia nervosa, a single-center study reported that the average age of patients with anorexia nervosa has been increasing [21]. Patients with thyroid autoantibody-negative status and iodine-induced hypothyroidism were reported to be older than those with thyroid autoantibody-positive status [22]. In addition, patients with iodine-induced hypothyroidism without anorexia nervosa or Hashimoto’s thyroiditis were relatively older (usually aged ≥55 years) [23]. Hence, old age can increase the risk of iodine-induced hypothyroidism in patients with anorexia nervosa.

Furthermore, renal dysfunction could also be a factor for iodine-induced hypothyroidism because of delayed iodine excretion. In our patient’s case, the serum creatinine levels were relatively high (0.84 mg/dL) for the patient’s body size (BMI, 12.7 kg/m²), and the serum cystatin C level was 0.87 mg/dL, which is the upper limit of the reference range (0.53–0.95 mg/dL). Therefore, the patient may have been prone to renal dysfunction, and this may have exacerbated the iodine-induced hypothyroidism.

Such cases have been reported only in Japan even though iodine-containing ointments are used worldwide. This might be related to the fact that Japan is one of the main countries in the world with excessive iodine intake. A worldwide survey of urinary iodine levels, which are excellent indicators of daily iodine intake, in school-age children as a proxy for the general population showed that Japan did not have outstandingly high levels (265 μg/L, median), and the highest levels were reported in Equatorial Guinea (564 μg/L, median) [24]. Zava et al. reported an iodine intake of 1,000–3,000 μg/day in Japan on the basis of a literature review of dietary records, food surveys, urine iodine analysis (both spot and 24-hour samples), and seaweed iodine content published since 1965 [25]. Although there is no national survey of iodine intake in Japan, in view of the previous evidence, iodine intake levels in Japanese can be presumed to be among the highest levels in the world. Hence, we believe that factors such as iodine ointments may promote iodine overdose in Japanese patients and cause severe hypothyroidism in those who are highly sensitive to iodine. The Japanese population might have a unique iodine metabolic mechanism owing to genetic factors; however, to the best of our knowledge, no study has proven this.

In conclusion, anorexia nervosa can aggravate hypothyroidism caused by iodine-containing ointments. The number of such cases may increase in the future given the eventual increase in the number of older patients with anorexia nervosa in Japan. Iodine-containing ointment-induced hypothyroidism in older patients with anorexia nervosa and decubitus ulcers could potentially be left undiagnosed and untreated. Hence, careful attention to the patient’s background factors, such as malnutrition, age, and renal dysfunction status, can lead to the early diagnose of iodine-containing ointment–induced hypothyroidism.

Disclosure

None of the authors have any potential conflicts of interest associated with this case report.

References

• 1   Braverman  LE,  Cooper  DS (eds) (2012) Werner & Ingbar’s the thyroid: a fundamental and clinical text (10th). Lippincott Williams & Wilkins, Philadelphia, USA.
• 2   Hayashi  M,  Onodera  K,  Suzuki  K,  Kataoka  Y,  Tachikawa  K, et al. (2011) A case of consciousness disturbance resulting from severe hypothyroidism due to chronic thyroiditis and excess iodine absorption. Intern Med 50: 2627–2632.
• 3   Minakata  T,  Suzuki  K,  Kuro  A,  Izumino  H,  Nakatani  T, et al. (2012) A case of hypothyroidism suspected to be caused by povidone iodine ointment. Program of 8th Japanese Society of Pressure Ulcers Kinki Block, O3-3 (Abstract in Japanese).
• 4   Takeuchi  M,  Saiba  C,  Tsukiyama  I,  Saito  H,  Wakida  Y, et al. (2015) An example of the severe burn case that resulted in thyroid function abnormality by iodine-containing ointment preparation large doses. Program of 58th Annual Meeting of Japan Thyroid Association, P1-14-6 (Abstract in Japanese).
• 5   Uchinuma  H,  Harima  N,  Harai  N,  Ichijo  M,  Takizawa  S, et al. (2017) A case of squamous cell carcinoma of the gluteal region complicated by hypothyroidism caused by iodine ointment. Program of 18th Annual Meeting of Japan Endocrine Society Kanto-Koshinetsu branch, O2-3 (Abstract in Japanese).
• 6   Nakagawa  T,  Kawaguchi  T,  Shimonishi  N,  Tani  Y,  Tonegawa  H, et al. (2016) A long period of time by using the Isodine Sugar Pasta ointment for the wound treatment of post-operative, 1 newborn example exhibited a decrease in thyroid function. Program of 61st Annual Meeting of Japan Society for Neonatal Health and Development, P242 (Abstract in Japanese).
• 7   Higaki  Y (2019) A case of bedridden elderly with hypothyroidism caused by long-term application of Isodine Sugar as a decubitus ulcer treatment. Program of 30th Chugoku Regional Meeting of Japan Geriatrics Society, 5 (Abstract in Japanese).
• 8   Wolff  J,  Chaikoff  IL (1948) Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem 174: 555–564.
• 9   Wolff  J (1969) Iodide goiter and the pharmacologic effects of excess iodide. Am J Med 47: 101–124.
• 10  (2020) The dietary reference intakes for Japanese. Ministry of Health, Labour and Welfare of Japan. https://www.mhlw.go.jp/stf/newpage_08517.html accessed on April 25, 2022 (In Japanese).
• 11   Miyai  K,  Tokushige  T,  Kondo  M,  Iodine Research  Group (2008) Suppression of thyroid function during ingestion of seaweed “Kombu” (Laminaria japonoca) in normal Japanese adults. Endocr J 55: 1103–1108.
• 12   Namba  H,  Yamashita  S,  Kimura  H,  Yokoyama  N,  Usa  T, et al. (1993) Evidence of thyroid volume increase in normal subjects receiving excess iodide. J Clin Endocrinol Metab 76: 605–608.
• 13   Braverman  LE,  Ingbar  SH,  Vagenakis  AG,  Adams  L,  Maloof  F (1971) Enhanced susceptibility to iodide myxedema in patients with Hashimoto’s disease. J Clin Endocrinol Metab 32: 515–521.
• 14   Aida  K,  Haraguchi  K,  Akasu  F,  Takazawa  K,  Onaya  T (1986) A case of iodide-induced hypothyroidism in the course of anorexia nervosa. Naika 57: 1193–1196 (In Japanese).
• 15   Haraguchi  K,  Aida  K,  Akasu  F,  Takazawa  K,  Onaya  T (1986) Iodide-induced hypothyroidism in a patient with anorexia nervosa. Endocrinol Jpn 33: 61–65.
• 16   Lavelle  KJ,  Doedens  DJ,  Kleit  SA,  Forney  RB (1975) Iodine absorption in burn patients treated topically with povidone-iodine. Clin Pharmacol Ther 17: 355–362.
• 17   Matsubayashi  S,  Mukuta  T,  Watanabe  H,  Fuchigami  H,  Taniguchi  J, et al. (1998) Iodine-induced hypothyroidism as a result of excessive intake of confectionery made with tangle weed, Kombu, used as a low calorie food during a bulimic period in a patient with anorexia nervosa. Eat Weight Disord 3: 50–52.
• 18   Ikema  S,  Michihata  N,  Horikawa  R,  Takahashi  A,  Ikuta  N, et al. (2003) A case of anorexia nervosa with iodine-induced hypothyroidism. Program of 37th Annual Meeting of Japanese Society for Pediatric Endocrinology, 178 (Abstract in English).
• 19   Hiwa  R,  Sada  R,  Azuma  T,  Ishimaru  H,  Hatta  K, et al. (2009) A 42-year-old female with anorexia nervosa complicated by hypothyroidism due to excess iodine ingestion and refeeding syndrome. Tenri Igaku Kiyo (Tenri Med Bull) 12: 61–67.
• 20   Kita  Y,  Mori  J,  Hosoi  H (2019) Iodine-induced hypothyroidism in a girl with anorexia nervosa. Pediatr Int 61: 528–529.
• 21   Ishikawa  T,  Tamura  N (2014) Aging of eating disorders. Shinshin-Igaku (Jpn J Psychosom Med) 54: 935–939 (In Japanese, abstract in English).
• 22   Konno  N,  Makita  H,  Yuri  K,  Iizuka  N,  Kawasaki  K (1994) Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab 78: 393–397.
• 23   Yoshimura  H,  Takeda  R (1996) A case of hypothyroidism induced by seaweed abuse, developed in chronic thyroiditis. Kyosai Iho (Medical Journal of Mutual Aid Association) 45: 243–249 (In Japanese, abstract in English).
• 24  (2021) Global scorecard of iodine nutrition in 2021 in the general population based on school-age children. Iodine Global Network. https://www.ign.org/scorecard.htm accessed on June 20, 2022.
• 25   Zava  TT,  Zava  DT (2011) Assessment of Japanese iodine intake based on seaweed consumption in Japan: a literature-based analysis. Thyroid Res 4: 14.