Hypercalcemia is frequently encountered in clinical practice. Although the differential diagnosis of hypercalcemia is quite broad, primary hyperparathyroidism remains the most common cause of hypercalcemia in the nonhospitalized patient, affecting on average 25–60 individuals per 100,000 [16]. Classic signs and symptoms of severe primary hyperparathyroidism in the developed world are now mainly of historical interest. Osteitis fibrosa cystica, severe bone loss, severe peptic ulcer disease, and nephrocalcinosis are now rarely seen in patients with primary hyperparathyroidism. Rather, hypercalcemia due to primary hyperparathyroidism is typically noted incidentally with patients presenting with asymptomatically or with less dramatic versions of the classically taught “bones, moans, stones, and psychiatric overtones”.

Biochemical diagnosis of primary hyperparathyroidism begins with confirmation of elevated serum calcium and measurement of serum parathyroid hormone (PTH) levels. In malnourished or in patients with advanced liver disease, albumin-corrected levels of calcium should be obtained as 40% of circulating calcium is bound to albumin and levels may be erroneously interpreted in a hypoproteinemic state. Additionally, ionized calcium levels may be tested, particularly in patients with chronic acid–base disorders. Diagnosis of primary hyperparathyroidism is confirmed with the finding or elevated serum calcium or ionized calcium with concomitant elevated or inappropriately normal PTH level.

In the cirrhotic patient, incidental or symptomatic hypercalcemia should also prompt evaluation for malignancy as both cholangiocarcinoma and hepatocellular carcinomas (HCC) have been associated with hypercalcemia [17]. In the case of hepatocellular carcinoma, paraneoplastic syndrome is not an uncommon occurrence, noted in up to 30.9% of patients [18]. Hypercalcemic paraneoplastic syndrome is seen in 4–7% of HCC and is thought to be due to secretion of parathyroid hormone-related peptide (PTH-rP). Such patients have been noted to have poorer prognosis than HCC patients without paraneoplastic syndrome [19]

Vitamin D is a steroid hormone intimately involved in calcium and bone metabolism. Deficiency in vitamin D is more prevalent in patients with primary hyperparathyroidism, occurring in 53–91% of patients compared a prevalence of 36% in the general United States population [20, 21]. In patients with chronic liver disease, vitamin D deficiency has been reported ranging between 64 and 92% [22]. The mechanism of vitamin D deficiency in chronic liver disease is likely multifactorial. Apart from decreased biosynthesis of inactive precursors in cutaneous epithelium and decreased absorption of dietary vitamin D due to malnutrition, production of the active metabolite is impaired due to the liver’s inability to produce necessary binding proteins and catalyze hydroxylation [23]. With end-organ harm from primary hyperparathyroidism accelerated by vitamin D deficiency, recognition and careful correction of vitamin D is recommended to limit ongoing bone loss.

In addition to its role in calcium and bone metabolism, recent studies have demonstrated compelling anti-inflammatory, antifibrotic, and immune-modulating functions of vitamin D [24–27]. Several studies have demonstrated that low levels of vitamin D are associated with poorer response to therapy in the treatment of hepatitis C virus (HCV) [24, 25]. Other studies have suggested an association between initiation and progression of liver fibrosis in chronic HCV infection and vitamin D deficiency [26]. Severe vitamin D deficiency (<12 ng/mL) has also been implicated in organ rejection following liver transplantation [27].

Though any patient with symptomatic primary hyperparathyroidism should be considered for surgery, for most patients exhibiting asymptomatic disease, the decision to proceed with surgery for primary hyperparathyroidism needs an assessment to gauge the degree of end-organ damage. Measurement of phosphate, alkaline phosphatase, blood urea nitrogen, and creatinine should be included with the measurements of calcium, PTH, and 25-hydroxyvitamin D mentioned above. In addition, 24-h urine calcium will help identify patients with hypercalciuria, an indication of surgery, and familial hypercalcemic hypocalciuria, a contraindication. Bone mineral density of the spine, hip, and distal radius is indicated to identify patients with osteoporosis and risk of fragility fracture. The 4th International Workshop for the Management of Asymptomatic Primary Hyperparathyroidism also recommends routine abdominal imaging by means of ultrasound, x-ray or computed tomography (CT) to rule out nephrocalcinosis or nephrolithiasis [28]. Recommendations for surgery by the Workshop are summarized below in Table 22.3.

After establishing biochemical diagnosis of primary hyperparathyroidism, localizing studies are recommended to identify the abnormal parathyroid gland or glands. A cervical ultrasound and technetium-99 m sestamibi scanning allow for anatomic and functional imaging with sensitivities generally ranging from 70 to 90% for each modality [29, 30]. Cervical sonography provides the additional benefit of identifying concomitant thyroid pathology, present in 24–76% of patients with primary hyperparathyroidism with thyroid cancer noted in 6–17% of patients [31]. The addition of single photon emission computed tomography (SPECT) to sestamibi scanning additionally aids in identifying ectopic parathyroid glands high in the neck or in the mediastinum [32].

The decision to bring a patient with advanced liver disease for parathyroid surgery mirrors that of thyroidectomy. Patients with Childs class A or B cirrhosis, who are medically optimized and with adequate platelet counts, may proceed with parathyroidectomy. There remains considerable debate among parathyroid surgeons with regard to the extent of parathyroid exploration. Proponents of routine four-gland exploration advocate examination of all parathyroid glands by means of a bilateral neck exploration. Surgeons cite lower recurrence rate with bilateral exploration [33] as up to 15% of patients with preoperatively localized disease and appropriate drop in intraoperative parathyroid hormone (normalization of PTH level with 50% drop in value 10–15 min after excision) have an additional enlarged gland [34]. Proponents of focused parathyroidectomy, frequently called minimally invasive parathyroidectomy, argue that as 85% of primary hyperparathyroidism patients have a single adenoma, focused unilateral exploration with intraoperative parathyroid hormone measurement obviates the risk of bilateral recurrent laryngeal nerve injury and permanent hypoparathyroidism [35]. Several studies cite recurrence rates of focused parathyroidectomy between 95 and 98% [36–38]. In August of 2016, the American Association of Endocrine Surgeons published their first set of evidence-based guidelines for the definitive management of primary hyperparathyroidism [39]. In their guidelines, the authors state that both bilateral and focused parathyroidectomy are acceptable options for surgery, except in patients with known or suspected multigland disease.

It is not uncommon to discover incidental adrenal masses during the work-up and surveillance of a patient with advanced liver disease. According to autopsy studies, adrenal incidentalomas occur with a prevalence of approximately 1–8.7% among the general population [40]. The prevalence appears to increase with age [41]. Patients with hepatocellular carcinoma frequently exhibit adrenal metastases, occurring in 11–20% of patients [42]. In light of these findings, proper work-up of an adrenal neoplasm is essential.

The diagnostic work-up of an adrenal neoplasm begins with biochemical evaluation to assess for hormonal excess. We recommend morning fasting adrenocorticotropic hormone and cortisol levels, serum aldosterone and plasma renin activity, and plasma fractionated metanephrines and catecholamines, and a 1-mg overnight dexamethasone suppression test. These tests will provide an effective and sensitive screen for the most common secreting adrenal tumors, namely, cortisol-secreting adenoma, aldosterone-secreting adenoma, and pheochromocytoma. Clinical suspicion for malignancy should also include testing for dihydoepiadrosterone sulfate (DHEA-S), which is frequently elevated in cases of adrenocortical carcinoma [43].

There are several caveats, diagnostic pitfalls, and occasionally necessary confirmatory testing in the biochemical diagnosis of adrenal tumors. Interfering medications, cyclic hormonal secretion, and differing methods of laboratory collection and analysis can make the proper diagnosis of such tumors a challenge [44, 45]. Thus we advocate a multi-disciplinary approach with involvement of an experienced adrenal endocrinologist.