Hearing Loss Severity and Progression in Children with Congenital Hypothyroidism

  

    
Diagnosis
    
N first
    
First PTA (mean & SD)
    
Last PTA
      
(mean & SD)
    
Change in PTA
    
Slope of change in PTA per    year
  
  

    
Congenital
    
Congenital hypothyroidism
      
with goiter
    
9
      
(2.0%)
    
50.8 dB (8.9)
    
37.6 (25.5)
      
N=7
    
-0.5 dB (7.9)
    
-0.24 dB
  
  

    
Congenital hypothyroidism
      
without goiter
    
164 (35.7%)
    
34.5 dB (22.0)
    
33.6 (23.3) N=124
    
-0.8 dB (11.8)
    
0.53 dB
  
  

    
Congenital hypothyroidism with mineral deficiency
    
4
      
(0.9%)
    
20.3 dB
      
(3.6)
    
25.0
      
N=1
    
0.02 dB
      
(0)
    
-0.01 dB
  
  

    
Maternal hypothyroidism
    
2 (0.4%)
    
41.9 dB (5.3)
    
22.8 (11.8)
      
N=2
    
No follow-up
    
N/A
  
  

    
All congenital
    
179
      
(39.0%)
    
35.1 dB (22.6)
    
33.5
      
(23.13) N=135
    
-1.01 (11.79) N=135
    
0.36 dB
  
  

    
Acquired
    
Hashimoto thyroiditis
    
218 (47.5%)
    
28.5 dB (14.8)
    
25.2 (17.38) N=178
    
-4.1 dB (11.1)
    
-5.57 dB
  
  

    
Iatrogenic hypothyroidism
    
62 (13.5%)
    
32.5 dB (20.06)
    
32.5 (21.65)
      
N= 49
    
-0.04 dB (11.1)
    
0.08 dB
  
  

    
All acquired
    
280 (61.0%)
    
29.4 dB (16.18)
    
26.8
      
(18.62) N=227
    
-3.2 (11.25) N=227
    
-4.35
  
  

    
All patients
    
459 (100%)
    
31.6 (19.11)
    
29.0 (20.41) N=362
    
-2.4 (11.49) N=362
    
0.64 dB
  

Table 2: PTA4 values and changes with time by diagnosis.

Patients with Hashimoto thyroiditis demonstrated a vastly greater improvement rate in HL than patients with other types of hypothyroidism, depicted in (Figure 1). Of note, the maternal hypothyroidism and iodine hypothyroidism groups did not have any patients with follow-up audiograms performed so these groups were not included in (Figure 1). Slope of PTA4 change per year is also displayed in (Table 2). Slope of PTA4 in dB/year for each cohort was as follows: -0.24 (congenital hypothyroidism without goiter), 0.53 (congenital hypothyroidism with goiter), -0.01 (congenital hypothyroidism with mineral deficiency), -5.57 (Hashimoto thyroiditis), and 0.08 (iatrogenic hypothyroidism).

Patients with congenital hypothyroidism had greater hearing loss progression over time than those with acquired (0.36 vs. -4.35 dB/ year, p=0.034). Patients with goitrous congenital hypothyroidism had less hearing loss progression over time than those with nongoitrous congenital hypothyroidism (-0.24 vs. 0.53 dB/year, p=0.926).

Discussion

Our results indicate that patients with congenital and acquired hypothyroidism demonstrated PTA values in the hearing loss range. However, mean PTA was significantly higher in the group of patients with congenital hypothyroidism. This can likely be explained by differences in the mechanism of the associated hearing losses, and the time of incidence of these conditions in relation to the critical period of audiologic development. Essentially, cases of acquired hypothyroidism-associated hearing loss occur solely as a consequence of lack of thyroid hormone supply, while congenital hypothyroidism includes the same mechanism at a time when T3 and T4 are necessary for permanent developments in middle and inner ear and central nervous system structure [10].

Causes of acquired hypothyroidism in children include autoimmune thyroiditis, postviral thyroiditis, suppurative thyroiditis secondary to bacterial infection, acquired iodine deficiency, medication side effects, and iatrogenic causes including radioactive ablation and thyroidectomy [11]. Thyroid hormones serve as transcription factors in the regulation of expression of prestin, a motor protein in cochlear hair cells5. Additionally, thyroid hormone deficiency in patients with acquired hypothyroidism results in a decrease in cell energy, and subsequent decreases in rates of inner ear organ oxygenation and protein production for myelin in the central nervous system [3]. Low serum thyroid hormone levels cause low expression of KCNQ4 potassium channels in the cochlea, resulting in decreased endolymphatic potential and low cochlear amplification [10]. Another cause of sensorineural hearing loss is cochlear damage caused by mucopolysaccharide accumulation in the cochlea and tectorial membrane [2]. Conductive hearing loss in patients with acquired hypothyroidism is a result of edema and hypertrophy of both the eustachian tube and middle ear, leading to decreased compliance in these structures and in the formation of myxedematous middle ear effusion [2]. Reversibility of hearing loss in patients with acquired hypothyroidism is unclear, but is less likely to be reversible with increased duration from incidence to initiation of treatment [12].

Primary congenital hypothyroidism refers to any condition with low levels of serum thyroid hormone and increased Serum Thyrotropin (TSH) that present at birth [13]. This is in contrast to central hypothyroidism, which refers to hypothyroidism occurring as a result of decreased serum TSH due to failure of either the hypothalamus or anterior pituitary [12]. The incidence of congenital hypothyroidism approximates 1:2000 births [11], with hearing disorders occurring 100 times more frequently in pediatric patients with congenital hypothyroidism than in euthyroid patients [10]. The most common causes of congenital hypothyroidism include thyroid gland dysgenesis and dyshormonogenesis [11]. Dysgenic or embryogenic causes, including agenesis, hypoplasia, and ectopy [14], account for approximately 80% of congenital hypothyroidism cases [11,13,15], while 15-20% of cases of congenital hypothyroidism are caused by hormone synthesis defects. Common dyshormonogenic mutations include those in TPO, NIS, TG, DUOX2, and SLC26A4 genes [14]. SLC26A4 mutations fall under the domain of Pendred syndrome, which produces a triad of sensorineural hearing loss, goiter formation, and either hypothyroidism or euthyroidism [5]. Most patients with Pendred syndrome also exhibit enlarged vestibular aqueductal structures on imaging in addition to sensorineural hearing loss, encompassing a condition called Mondini syndrome [6]. This is hypothesized to occur as a result of insult from low serum thyroid hormone levels early in development that causes cochlear dysplasia [6].

In addition to dysgenesis and dyshormonogenesis, other known causes of antenatal hypothyroidism include maternal ingestion of antithyroid drugs, maternal antibodies blocking the fetal TSH receptors, and either iodine deficiency or excess [11], in which case too much iodine causes suspension of thyroid hormone synthesis per the Wolff-Chaikoff effect [16,17].

It is generally understood that congenital hypothyroidism results in bilateral symmetrical hearing loss that is more frequently sensorineural than conductive [4]. Thyroid hormone, especially T3, is important for inner ear development. A deficiency in this hormone causes impaired epithelial maturation in the cochlea [4] and permanent repression of cochlear potassium channels necessary for propagating an auditory signal [18]. The outer hair cells in the tectorial membrane, along with the central nervous system axonal myelination and maturation process are also underdeveloped if not exposed to adequate thyroid hormone during the critical development period [10]. Any conductive hearing loss is thought to result from hypothyroidism-induced middle ear defects [4], specifically permanent alterations in the ossicular structures [5]. The best predictor of permanent hearing damage in rats undergoing fetal development in a hypothyroidism simulation has been found to be postnatal serum T4 [19]. The prognosis for reversibility of congenital hypothyroidism-induced hearing loss is not certain, and it has been estimated that hearing loss persists in approximately 25% of pediatric patients who have undergone early treatment with levothyroxine [20]. Later initiation of levothyroxine treatment is associated with an increased risk chance for permanent hearing loss, and it is recommended that treatment should be initiated by the 3rd week of life [5]. Furthermore, later treatment initiation can be associated with reduced scores in language and speech comprehension, which improve with the implementation of a hearing aid [5]. One important consideration for prenatally detectable congenital hypothyroidism is the possibility for intraamniotic treatment with levothyroxine. This has been proven to improve the neuro-auditory effects, specifically, of deprivation of thyroid hormone levels during intrauterine development [17]. Our results indicate that, in patients with congenital causes of pediatric hypothyroidism, change in PTA4 per year is minimal (-1.01 dB/year). This means that the baseline or initial PTA4 value obtained from the patient’s first audiogram has far greater prognostic value on the patient’s future hearing status than does the possibility for improvement over time.

Our study also found a significant increase in PTA values in pediatric patients with congenital hypothyroidism and goiter, compared to agoitrous patients with congenital hypothyroidism. In 1988, the Myxedematous Committee of the Clinical Society of London acknowledged that there was a known association between the presence of a goiter and hearing loss [21]. It is possible that there is an association with severity of hearing loss and presence of a goiter due to the fact that etiologies responsible for the formation of a goiter occur at the cell membrane level, and that these same changes are occuring in the cell membrane of the cochlea. This would mean that deficiency of thyroid hormone is only part of the etiology, and that this deficiency synergizes with other etiologies. One important pathology that reflects this possibility is Pendred syndrome, which occur as a result of mutations in the SLC26A4 gene that codes for pendrin. Pendrin is an iodine transporter that exists in both the thyroid follicular cells and the inner ear [5], so mutations in the transporter existing on the inner ear alone would explain hearing loss either independently of or synergistically with a deficiency in thyroid hormone supply. While presence of goiter, hearing loss, and thyroid pathology are the hallmark of Pendred syndrome, the patient can sometimes be euthyroid so it is important to consider that not all patients with Pendred syndrome have been captured by the “congenital hypothyroidism” diagnosis via the ICD-9 code in AugGen. Additionally, Pendred syndrome is only one of many possible causes of neonatal goiter formation. Other common causes include iodine excess or deficiency, the presence of maternal antibodies, excess maternal use of thionamine medication, and other congenital hormonal imbalances [17]. Known consequences of fetal goiter include compression of the trachea with subsequent asphyxia, esophageal compression with subsequent polyhydramnios, arteriovenous shunt with subsequent high output heart failure, preterm delivery risk, and shoulder dystocia due to neck hyperextension during delivery [17]. It is important to consider the fact that these potential consequences can have long term sequelae that could secondarily impact fetal hearing function as well. It is notable that, in this study, the changes in PTA4 per year were not significantly different in the goitrous vs. agoitrous groups of patients with congenital hypothyroidism. This emphasizes the importance of the baseline audiogram as the major indicator of future hearing prognosis for the patient.

Limitations for this study are mostly related to limitations with the use of the AudGen database, which sorts patients by ICD-9 diagnostic code and does not include newborn screening. This limits the amount of diagnostic criteria that can be assessed in the study. For example, iodine deficiency is not its own ICD-9 code, but falls under the code for mineral deficiency. Furthermore, patients with the ICD- 9 code for congenital hypothyroidism can be sorted into categories such as “goiter” or “no goiter,” but the etiology of the congenital hypothyroidism is not always clear. The first PTA’s for each patient used for this study are the first PTA values found on record in the AudGen database, but these PTA values were not all collected at the same age for each subject. Additionally the mean of the PTA values was used which averaged the left and right ears tests when both tests were available. Similarly, treatment status for each of these patients, and severity of the original congenital hypothyroidism is unknown. Since AudGen database reflects a population of patients receiving auditory testing, it is a considerable possibility that hearing loss is overly represented in this population.

Conclusion

Initial hearing loss in patients with pediatric hypothyroidism is significantly greater in severity in patients with congenital as opposed to acquired causes of hypothyroidism. In patients with congenital hypothyroidism, severity of initial hearing loss is significantly greater in patients with a coexisting goiter compared to patients that lack a goiter. Improvements over time do not vary significantly by congenital vs. acquired and goitrous vs. nongoitrous etiologies of pediatric hypothyroidism. Prompt diagnosis and treatment of patients with hypothyroidism-associated hearing loss is vital to support proper social and intellectual learning in the developing pediatric patient.

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