The general background of ultrasonography has been addressed elsewhere in this book and will not be repeated in detail. Briefly, the ultrasound instrument should be set at higher frequency to maximize resolution (>10 mHz). US localization of parathyroid glands should then be approached in a systematic manner. One popular approach is to initiate the scan at the level of the right subclavian between the carotid and larynx with the transducer in the transverse position, proceeding in the cephalic direction to the level of the superior pole of the thyroid gland. This approach not only searches for a parathyroid adenoma but also evaluates the thyroid gland looking for nodules and other abnormalities. This process is repeated in the left central neck again moving the transducer from the left subclavian to the superior pole of the left lobe between the larynx and the carotid. The superior parathyroid glands are located posterior to the mid-thyroid lobes. Inferior parathyroid glands are most commonly caudal to the inferior thyroid pole. Any suspected adenoma should then be evaluated with the transducer in the sagittal plane. Normal parathyroid glands are typically less than 40 mg and are extremely difficult to characterize by ultrasound. Ultrasound characteristics suggestive of an adenoma include hypoechogenicity and increased blood flow to the pole rather than to the central area as seen in lymph nodes. There also may be increased blood flow to the parathyroid capsule or adjacent thyroid tissue [1]. If there is any uncertainty as to whether or not a nodule is a parathyroid adenoma, fine-needle aspiration biopsy with saline washout and measurement for PTH will establish the diagnosis. This is especially helpful in the rare circumstance of an intrathyroidal parathyroid adenoma that occurs approximately 6 % of the time [2]. In a large meta-analysis of 20,000 patients, primary hyperparathyroidism results from a single adenoma in approximately 88.9 % of cases, double adenoma occurs in 4.1 %, and four-gland disease/hypertrophy in 5.8 % [3]. It has recently been shown that the ability to detect a parathyroid adenoma by US and sestamibi may be related to the severity of the disease [4].

US is almost always used in conjunction with other imaging modalities. The optimal combination of preoperative imaging modalities to this point is unknown. The choice of which imaging modality to employ and in what order is highly dependent upon institutional expertise and available instrumentation. US is routinely performed as an initial study because it is noninvasive, relatively inexpensive, and widely available. However, US is extremely operative dependent and the reported sensitivity of US-identified parathyroid adenoma ranges from 72 to 89 % [5–7]. In one study of 77 consecutive patients with a diagnosis of PHPT who had a preoperative US performed, the correct quadrant was identified in 78 % of patients and the correct side identified in 95 % of the patients [5]. In a prospective study of 56 patients with PHPT, of those with a solitary lesion, the sensitivity of MIBI was 97 % and US 74 % [8]. A retrospective study of 61 PHPT patients with preoperative sestamibi scan and US showed correct localization in 88 % and 77 %, respectively [9]. A recent comparison of US and MIBI showed that US and MIBI successfully identified adenoma in 77 % and 88.5 %, respectively. When both were concordant, 100 % of lesions were correctly identified [9].

Ultrasonography is less effective in localizing parathyroid adenomas in secondary hyperparathyroidism from renal failure or MEN syndromes and in reoperation for persistent/recurrent disease. In a study of 166 patients with HPT as a consequence of renal disease, MIBI and US together failed to detect 61.5 % of ectopic glands [10]. In 288 patients that required a reoperation for persistent hyperparathyroidism sestamibi provided the best results with 67 % true-positive and no false-positive results. US only had a 48 % true-positive result and 21 % false-positive [11]. In a similar study of 102 patients who underwent reoperation for persistent disease, sestamibi scans detected 67 % and US 57 % [12]. US also has a very limited role in identifying ectopic parathyroid glands and is rarely successful. The combination of US and sestamibi scan has been shown to increase diagnostic accuracy [13] and the combination of the two has become first-line in parathyroid localization at many institutions [14].

The diagnostic accuracy of ultrasonography to localize an adenoma in some studies has been shown to be reduced in the presence of thyroid nodules [15] and hyperparathyroidism secondary to renal insufficiency [16]. This was not universally true. The sensitivity was similar between US coupled with FNA and PTH washout (90 %) compared with nuclear medicine imaging of patients without (89 %) and with (74.3 %) thyroid pathology [17]. Well-trained surgeons and endocrinologist have been shown to have similar accuracy rates as compared to those achieved by sestamibi scan or when a radiologist performs the US. In a study of 226 patients with primary hyperparathyroidism, surgeon-performed US correctly identified the parathyroid adenoma in 77 % of cases compared with 57 % correctly identified by sestamibi [18]. In a large series of 916 evaluable patients, surgeon-performed US correctly localized parathyroid adenoma in 80 % of cases compared with 74 % with sestamibi. 156 patients with primary hyperparathyroidism from a single adenoma were evaluated by US performed by an endocrinologist and radiologist. US performed by an endocrinologist identified 12 % of the adenomas missed by US performed by a radiologist [19].

It is important to note however that there is a wide discrepancy between the resolution of US instrumentation in radiology departments compared with the resolution of less expensive instrumentation often employed in the community. The majority of studies evaluating US localization have been done on high-resolution instruments in well-trained hands.

The procedure for parathyroid ethanol injection (PEI) involves the accurate localization of the parathyroid adenoma, precise placement of the needle tip within the adenoma, and careful injection of ethanol. The amount of ethanol injected varies widely between studies and the optimal volume has not been determined. Up to 2 ml of ETOH was injected in one study [20] and others calculated the volume of the adenoma with administration of 70–100 % of this volume with ethanol [21–23]. This discrepancy may partially explain the wide discrepancy in results from various studies.

Often more than one surgery is required to render tertiary hyperparathyroid and MEN1 patients eucalcemic/hypocalcemic. Reoperation in these patients is considerably longer and the risk of complications is increased. PEI has been used primarily in these patient populations. PEI within a parathyroid adenoma under US guidance was first used to destroy parathyroid parenchyma in secondary hyperparathyroidism and normalize PTH levels in 1985 [24]. The reduction in PTH levels was shown to be rapid, occurring within a median of 24 h in seven patients with PHPT injected on 3 consecutive days [25].

In a large study of 321 hemodialysis patients with secondary hyperparathyroidism, PEI reduced calcium from 10.7 ± 0.8 to 10.1 ± .5 mg/dl in 62 % of patients. Success was primarily dependent upon the number of identified hyperplastic glands [23]. 39 patients with tertiary HPT were prospectively followed after either surgery (17) or PEI (22). In 11 of 22 patients, a greater than 30 % reduction in PTH level was achieved with a mean of 1.8 injections. However, no significant reduction was achieved in 11 patients even after a mean of 2.5 injections and these patients required parathyroidectomy. Importantly, four patients developed recurrent laryngeal nerve palsy, two of which were permanent. The authors felt that the outcome was poor compared with parathyroidectomy and could not recommend the procedure in this patient population [26]. In another study, 27 patients underwent 63 ethanol injections with normal calcium and PTH levels obtained in 15 patients. However 4 of the 15 “cured” patients had recurrence after 1–2 years of follow-up. No major complications were observed [27]. In a recent study, 41 PEI were performed in 22 MEN1 patients and the mean calcium level went from 10.6 to 9.5 mg/dl. All but one patient had a decrease in serum calcium after PEI; however, 50 % of the patients required additional PEI [28]. The experience at Mayo Clinic with PEI in MEN1 patients with recurrent HPT from 2007 to 2013 was recently reported [28]. Thirty-seven patients were studied. 80 PEI were performed with 123 ethanol injections. Calcium levels went from 10.7 mg/dl ± 0.57 before injection to 9.6 mg/dl ± 0.76 post-injection. Normocalcemia was achieved in 73 % of patients and hypocalcemia in 8.1 %. Transient hoarseness occurred in four patients, but there were no lasting complications.

Surgery is most commonly utilized for the treatment of PHPT, but some patients are at a high surgical risk because of previous surgical attempts at resection, and medical comorbidities, or they refuse the procedure. Several investigators have examined the utility of PEI in the treatment of PHPT. Thirteen PHPT patients underwent PEI and were followed for up to 49 months. Seven patients had complete normalization of PTH levels. Four patients had normalization of calcium levels but incomplete PTH response. PEI failed in two patients. No major complications were reported [29]. PEI has also been employed to partially ablate a single remaining adenoma. This was part of a study of 33 patients with PHPT in whom it was felt that reoperative surgery would be technically unsafe, had exclusive medical comorbidities, or had a single remaining adenoma who underwent PEI. There were no long-term complications; however two patients had temporary recurrent laryngeal nerve injury and four had temporary hypocalcemia. 34 % of attempted complete ablations were eucalcemic after 16 months whereas only 2 of 7 partial ablations were successful [30].