The obtained results show that chronic follicular thyroiditis induces anatomical and functional alterations in the gland, independently from the presence of circulating autoantibodies. Furthermore, seronegative thyroiditis and thyroiditis with circulating autoantibodies are completely comparable from the histological and clinical-functional points of view. This is the first paper demonstrating the existence of serum negative thyroiditis thanks to histological evaluation.

Chronic autoimmune thyroiditis is the leading cause of primary acquired non-surgical hypothyroidism and it may cause goiter in the absence of iodine deficiency [1,2,3,4,5,6,7,8,9]. Ab-TPO and Ab-hTg are the circulating hallmark of this autoimmune thyroid disease. However, despite the high sensitivity of modern assay methods for Ab-TPO and Ab- hTg, a percentage of hypothyroid patients present with negative thyroid autoantibodies. As most of these patients display a hypoechoic pattern of their thyroid at neck ultrasound examination, the diagnosis of ‘serum negative thyroiditis’ is commonly used to define the underlying thyroid disorder [26,27,28,29]. Nowadays, no currently published study evaluated a large series of patients with serum negative thyroiditis. Gland chronic inflammation with the consequent destruction of the follicles causes a progressive reduction in hormone synthesis with consequent hypothyroidism. In addition, chronic thyroiditis leads to a surgical condition that causes difficult thyroidectomy and correlates with an increased risk of complications [1, 10,11,12,13,14]. Macroscopically, chronic thyroiditis may be characterized by an increase of gland volume. The organ can be lobulated and have a compact and brownish-red appearance and whitish nodular formations may occur [3]. Microscopically, a polymorphic lymphocyte population made up of B and T lymphocytes with the formation of GCs is present. Hurthle cell metaplasia, which often is associated with these lesions, can be focal or extensive and results in partially encapsulated nodules or smaller aggregates [3]. However, in TF patients, it is possible that mutations in thyroglobulin gene or in transacting proteins/elements of the signaling pathways controlling growth and function of thyrocytes may be associated with goiter and hypothyroidism [1, 2, 7].

The recently speculated hypothesis of the existence of an antibody-negative chronic thyroiditis was strengthened and supported by our data, that confirm the existence of this disorder. Indeed, in the absence of autoantibody positivity, the only certain diagnostic element of chronic follicular thyroiditis is represented by the histological examination [2,3,4].

The collected data allow us to observe a statistically significant correlation between hypothyroidism and thyroiditis, independently from the correlation with high levels of circulating specific autoantibodies. Therefore, the presence of thyroiditis, Ab positive or negative, can cause hypothyroidism and goiter [1, 2, 7]. Furthermore, SNT exhibited slightly lower TSH levels compared with SPT group, aligning with the findings reported by other authors [13, 30, 31]. These findings suggest that seronegative thyroiditis causes less thyroid damage, which may be a characteristic feature of the condition.

Chronic thyroiditis also represents a cause of difficult thyroidectomy [21,22,23,24,25,26,27,28,29,30,31,32,33]. Indeed, chronic inflammation determines periglandular fibrotic adherential modifications with relative hypervascularization, which increase the risk of complications because the dissection is technically more complex [1, 10,11,12,13,14]. Despite the relatively small sample, justified by the rarity of total thyroidectomy complications, the most frequent of them, the transient hypoparathyroidism, occurred more frequently in the groups of patients with thyroiditis chronic follicular disease, compared to patients without thyroiditis [1, 10,11,12,13,14, 28,29,30,31,32,33] Also in this case, it emerged that SNT represents an independent risk factor for the occurrence of complications during total thyroidectomy, similarly to SNP. If SNT is diagnosed preoperatively, it may help clinicians to assess the postoperative complication risks and to make the optimal decision regarding the surgical approach and the extent of surgery.

Practically, the observed difference between TF and SNP/SNT groups regarding transient hypoparathyroidism would help clinicians to perform sufficient preoperative/postoperative assessments and to optimize surgical planning. Knowing patients at risk of hypoparathyroidism may optimize postoperative care to minimize the incidence and impact of hypoparathyroidism in thyroidectomy patients. For instance, in SPT and SNT, clinicians may start perioperative oral calcium and vitamin D supplementation, decreasing the risks of symptomatic and biochemical hypocalcemia compared to postoperative supplementation alone. Perioperative supplementation may also shorten the recovery period of symptomatic hypocalcemia to within 24 h.

Croce et al. reported that thyroid-volume significantly decreased in serum-positive thyroiditis, but not in those with serum-negative thyroiditis, needing lower maximum daily substitution dose of levothyroxine [30]. Differently, our research did not find any difference regarding thyroid volume and preoperative daily dose of LT4 among TF, SPT and SNT patients.

Finally, the age at presentation and the female sex prevalence were similar in patients with serum negative thyroiditis and antibody-positive thyroiditis, confirming what reported in the paper of Rotondi et al. [31] This finding would contrast with the common belief that a hypoechoic pattern of the thyroid at US anticipates the appearance of circulating thyroid Abs [30,31,32,33]. However, the duration of diagnosis in SNT group is slightly higher than that of SPT patients, indicating that the course of SNT may be more insidious, with milder symptoms and slower progression. This finding underlines the importance of early diagnosis and screening older age groups.