Lithium-associated primary hyperparathyroidism:: An evaluation of screening and referral patterns in a southeastern veteran population.

BACKGROUND: Long-term lithium therapy has a well-established but under-recognized association with primary hyperparathyroidism. Rates of hypercalcemia, screening for primary hyperparathyroidism, and referral for parathyroidectomy were evaluated among United States veterans on long-term lithium therapy. METHODS: Patients undergoing chronic long-term lithium therapy (>12 months) were identified from 1999 to 2022. Demographics, long-term lithium therapy duration, post-treatment calcium, parathyroid hormone, creatinine, and vitamin D levels were abstracted. Rates of screening for hypercalcemia (calcium ≥10.2 mg/dL), primary hyperparathyroidism (parathyroid hormone ≥30 pg/mL in the setting of hypercalcemia), referral for parathyroidectomy, and outcomes were evaluated. RESULTS: A total of 1,356 patients underwent long-term lithium therapy, 514 of whom received chronic long-term lithium therapy. Baseline characteristics of patients with and without post-treatment hypercalcemia were compared. Of 148 patients with post-treatment hypercalcemia, 112 (74.7%) underwent no further evaluation for primary hyperparathyroidism, while 36 (25.3%) patients had a parathyroid hormone level recorded. Although 33 (91.7%) hypercalcemic patients screened positive for primary hyperparathyroidism, only 5 (13%) were referred for parathyroidectomy. Of the 4 patients who underwent parathyroidectomy, mean calcium was 11.2 mg/dL (range 11.1-11.4), and mean parathyroid hormone was 272 pg/mL (range 108-622). Three patients were localized on preoperative imaging, 2 of whom underwent unilateral exploration with cure, with 1 experiencing recurrence at 31 months. The remaining patient who localized preoperatively underwent bilateral exploration and had 2 ipsilateral glands resected and persistence. The patient who did not localize preoperatively underwent bilateral exploration with 3 gland resection and cure. CONCLUSIONS: Screening for primary hyperparathyroidism and referral for parathyroidectomy are underutilized in United States veterans undergoing chronic long-term lithium therapy. Institutional protocols to standardize screening, surveillance, and referrals to endocrinology/endocrine surgery could benefit this population at increased risk for primary hyperparathyroidism.

Effect of statin treatment on metabolites, lipids and prostanoids in patients with Statin Associated Muscle Symptoms (SAMS).

BACKGROUND: Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. METHODS AND FINDINGS: We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. CONCLUSIONS: The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (ß-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge.

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

Urgent Need to Define Pretreatment Predictors of Immune Check Point Inhibitors Related Endocrinopathies: A Case Report and Review of Literature.

Immune check point inhibitors have revolutionized the treatment of metastatic malignancies. They are a promising area in oncology and more drugs are likely to be available in the coming years. Along with the promise of better response oncologically, there is an increased incidence of endocrinopathies related to autoimmunity. This case report illustrates the dramatic development of hypothyroidism in a patient with underlying subclinical hyperthyroidism. It also suggests the potential pretreatment predictors of endocrinopathies related to these immune check point inhibitors.

Clinical and laboratory phenotype of patients experiencing statin intolerance attributable to myalgia.

BACKGROUND: Muscle pain without elevation of serum creatine phosphokinase (CPK) (myalgia) is the most common medication-related adverse effect of statin therapy; it occurs in up to 10% of patients who are prescribed statin therapy. Although much is known regarding risk factors for overt myositis, very few studies have provided information on this common form of statin intolerance. METHODS: We defined a detailed clinical and laboratory phenotype of a cohort of patients referred to the lipid clinic of a governmental health maintenance organization for statin intolerance attributable to muscle pain without CPK elevation (myalgia) and characterized their response to alternative lipid-lowering therapy. Baseline and follow-up data were analyzed for 104 patients with statin intolerance attributable to myalgia and 211 statin-tolerant control patients identified from the referral population. RESULTS: Among patients with myalgia, more were white and had hypertension. The prevalence of known risk factors for overt myositis, including renal disease, type 2 diabetes mellitus, thyroid disease, and electrolyte abnormalities, did not differ between statin intolerant and statin tolerant patients. Although individual cases were identified in which the addition of interacting medications was temporally associated with development of statin intolerance, overall use of interacting medications was not more frequent among statin-intolerant patients. The majority of patients were intolerant of two or more statins; however, in more than one-half the cases, successful rechallenge with an alternative statin was accomplished. Despite this and extensive use of nonstatin lipid medications after lipid clinic referral, control of plasma lipoproteins remained significantly worse in statin-intolerant patients. CONCLUSIONS: Statin intolerance attributable to myalgia is a significant barrier to effective treatment of hyperlipidemia. Conventional clinical risk factors for myositis do not appear to predictive of statin-associated myalgia. These findings underscore the need to better define the pathophysiology of statin-induced myalgia and develop methodologies to guide treatment of statin-intolerant patients.

Composite pheochromocytoma-ganglioneuroma: a rare experiment of nature.

OBJECTIVE: To present a rare case of composite pheochromocytoma-ganglioneuroma (Pheo-GN) of the adrenal medulla, review the related literature, and discuss the clinical features, pathologic findings, behavior, and management of such tumors. METHODS: A case report of a patient with composite Pheo-GN of the adrenal gland is presented. Using the online database PUBMED, we searched and analyzed all cases of composite pheochromocytoma reported in the English-language literature during the past 70 years. RESULTS: On computed tomography, a 61-year-old man was incidentally found to have a 3.8-cm nonadenomatous right adrenal lesion. Adrenalectomy revealed a 5-cm mass consistent with composite Pheo-GN. To date, 45 cases of composite pheochromocytomas have been reported during the past 70 years, 71% of which coexisted with ganglioneuromas. These tumors occurred with approximately equal frequency in male and female patients, the majority of whom were from 40 to 60 years old. Only 14 cases have been reported in the United States. Bilateral tumors were found in 3 cases. The mean size was 4 to 6 cm. Preoperatively, functional evidence was found in 76.3% of all composite pheochromocytomas (and in 67% of Pheo-GN). Only one Pheo-GN was found to have liver metastatic lesions at the time of autopsy; the rest were not aggressive. CONCLUSION: To our knowledge, this is the first literature review describing the characteristics and behavior of all reported cases of composite pheochromocytomas, with an emphasis on those with ganglioneuromas. Composite pheochromocytoma is a rare variant of a relatively uncommon disease diagnosed by pathologists only. Fortunately, the treatment of such an entity remains the same as for any pheochromocytoma.