Patients with sickle cell disease have high morbidity and healthcare utilization due to repeated painful crises. Some coexisting conditions which cause pain similar to sickle cell disease may go undiagnosed in these patients. We report two adults with concurrent hyperparathyroidism who experienced significant improvement in sickle cell pain following parathyroidectomy thereby pointing to hyperparathyroidism as the principal causative factor for their pain. Meticulous evaluation for parathyroid disorders can be rewarding in sickle cell disease.
Sickle cell disease (SCD) is a genetic disorder which affects approximately 100,000 Americans [
Baseline characteristics of the two patients at the time of diagnosis of hyperparathyroidism are summarized in Table
Hb: hemoglobin, HPLC: high performance liquid chromatography, HbS: sickle cell hemoglobin, HbF: fetal hemoglobin, HbA and HbA2: adult hemoglobin, and PTH: parathyroid hormone.
Case 1 | Case 2 | |
---|---|---|
Age | 59 | 26 |
Gender | Female | Male |
Sickle cell genotype | Sickle cell-beta+ thalassemia | Homozygous sickle cell (HBSS) |
Hb (range 14–18 mg/dL) | 9.8 | 7.1 |
Reticulocyte (range 0.5–2.9%) | 2 | 5 |
Lactate dehydrogenase (range 135–225 U/L) | 300 | 269 |
Total bilirubin (range 0.0–1.2 mg/dL) | 1.2 | 0.7 |
HPLC | ||
HbS% | 65.4 | 14.5 |
HbF% | 5.2 | <1 |
HbA% | 22.4 | 81.8 |
HbA2% | 7 | 2.7 |
Calcium level (range 8.4–10.3 mg/dL) | 12.7 | 11.8 |
Phosphate level (range 2.7–4.5 mg/dL) | 1.9 | 9.1 |
PTH level (range 14–72 pg/mL) | 147 | 4078 |
Vitamin D level (range 30–100 ng/mL) | 23 | 20 |
Pathologic diagnosis | Parathyroid adenoma | Parathyroid hyperplasia |
Our first case is a 59-year-old female patient who moved to USA from Haiti two years ago with a diagnosis of sickle cell-beta+ thalassemia. She reported having generalized pain almost on a daily basis which she managed at home with pain medications. She had frequent hospital visits for generalized painful crises as many as twice a month of which some required inpatient treatment. We analyzed her case in detail after one such prolonged admission for 15 days especially as the severity of her presentations for painful crises was unusual given her sickle cell genotype.
High Performance Liquid Chromatography (HPLC) showed HbA of 22.4%, HbA2 of 7%, HbS of 65.4%, and HbF of 5.2% consistent with a diagnosis of sickle cell-beta+ thalassemia. Hemogram showed white blood cell (WBC) count of 4.3, Hb of 9.8 grams/deciliter (g/dL), and platelet (Plt) count of 158. Blood chemistry was significant for elevated calcium (Ca) on multiple occasions with a peak of 12.7 milligrams/deciliter (mg/dL). Phosphate was low on multiple occasions with a nadir of 1.9 mg/dL. Parathyroid hormone (PTH) level was elevated on multiple occasions with a peak of 147 picograms/milliliter (range 14–72 pg/mL). Vitamin D levels ranged from 18 to 23 nanograms/milliliter (range 30–100 ng/mL). Based on the above investigations we reached a diagnosis of primary hyperparathyroidism (PHPT).
Patient underwent imaging studies to localize the parathyroid lesion. Radionuclide parathyroid imaging using technetium sestamibi scan revealed slow washout in the right mid thyroid region (Figure
Patient underwent focused parathyroidectomy of the right inferior parathyroid gland which was confirmed on histopathologic examination to be a parathyroid adenoma. Intraoperative PTH monitoring was not used in this case. Patient’s calcium and PTH levels normalized following surgery and are shown in Figures
Perioperative PTH monitoring, POPTH (postoperative PTH), and Pg/mL (picograms/milliliter).
Perioperative calcium monitoring, POCa (postoperative calcium), and Mg/dL (milligrams/deciliter).
Radionuclide parathyroid imaging using technetium Tc-99m sestamibi showingslow washout in the right mid thyroid region (denoted by arrow).
CT scan of the neck without contrast showing a soft tissue mass posterior to mid pole of the right thyroid lobe (denoted by arrow).
Our second case is a 26-year-old male patient with homozygous sickle cell (HBSS) disease. He also had chronic kidney disease which progressed over 3 to 4 years to end stage renal disease (ESRD) requiring hemodialysis. Patient had frequent presentations for painful crises amounting to 16 ER visits and 82 inpatient days in the preceding year at our institution. His painful crises were notably more frequent since he developed ESRD and were localized in his hips and collar bones.
Most recent HPLC showed HbA of 81.8%, HbF < 1%, HbA2 of 2.7%, and HbS of 14.5% indicating that patient had recently received multiple blood transfusions. Hemogram showed WBC count of 12, Hb of 7.1 g/dL, and platelet count of 333. Blood chemistry was significant for elevated Ca on multiple occasions with a peak of 11.8 mg/dL. Phosphate was high on multiple occasions with a peak of 9.1 mg/dL. PTH was elevated on multiple occasions with a peak of 4078 pg/mL. Vitamin D levels ranged from 13 to 20 ng/mL. Predialysis blood urea nitrogen ranged from 60 to 80 mg/dL and creatinine ranged from 8 to 10 mg/dL. Patient was treated with cinacalcet for secondary hyperparathyroidism but became refractory to treatment after a period of time with persistently elevated calcium and PTH levels. Based on the above investigations, we reached a diagnosis of tertiary hyperparathyroidism due to ESRD.
Imaging studies were done to localize the parathyroid lesion. Radionuclide parathyroid imaging using technetium sestamibi scan showed slow washout in the right lower thyroid region (Figure
Four-gland exploration and parathyroidectomy were performed and a portion of one gland was reimplanted in the left sternohyoid region. Histopathology showed parathyroid hyperplasia of all the resected glands. Intraoperative PTH monitoring was used as shown in Figures
Perioperative PTH monitoring, IOPTH (intraoperative PTH), POPTH (postoperative PTH), and Pg/mL (picograms/milliliter).
Perioperative calcium monitoring, IOCa (intraoperative calcium), POCa (postoperative calcium), and Mg/dL (milligrams/deciliter).
Radionuclide parathyroid imaging using technetium Tc-99m sestamibi showingslow washout in the right lower thyroid region (denoted by arrow).
Bony resorption of greater trochanters of both femoral bones typical of untreated hyperparathyroid bone disease at the locations of the patient’s pain (denoted by arrow).
Bone resorption of the lateral ends of both clavicles (denoted by arrow).
Vasoocclusive episodes in SCD involve multiple organs with musculoskeletal system being most commonly affected. Some patients have acute generalized body pain while others have localized bony pain resulting from bone infarcts [
Hyperparathyroidism may be primary, secondary, or tertiary. Primary hyperparathyroidism (PHPT) is due to oversecretion of PTH most commonly from a parathyroid adenoma [
There are variations in clinical presentation among the different sickle cell genotypes with homozygous HBSS disease and heterozygous sickle cell-beta0 thalassemia patients being the more severely affected ones. In HBSS disease fetal hemoglobin (HbF) is a major modulator of polymerization in that the higher the HbF levels, the more benign the clinical and hematologic features of sickle cell anemia [
Some heterozygous sickle cell variants like sickle cell-beta+ thalassemia and HBSC disease generally have a more benign clinical course. In sickle cell-beta+ thalassemia, normal adult hemaoglobin (HbA) accounts for 18 to 25 percent of total hemoglobin which prevents extensive polymerization. Similarly, in HBSC disease, HBC hemoglobin does not participate in polymerization. Therefore, in both these variants painful events occur at less than half the freuency as the HBSS type [
Our second patient with HBSS disease and ESRD received multiple transfusions for symptomatic anemia not responding to erythropoietin. Though his HbA was >80%, he did not have the benign course in terms of painful events which would be expected with low HbS levels of 14.5%. This led us to evaluate for other coexisting pathologies for his musculoskeletal pain. There were radiological features of untreated hyperparathyroid bone disease at the locations of his pain. There was bone resorption of greater trochanters of both femoral bones and lateral ends of the clavicles but there were no bone infarcts or avascular necrosis of the femoral heads as would be anticipated in SCD (Figures
Patients with phenotypic manifestations which are incongruous with their genotype, that is, more severe and frequent pain symptoms in a milder sickle cell variant, should be investigated for concurrent systemic disorders which can contribute to their pain. Similarly frequent or persistent painful episodes despite relatively normal markers of active sickle disease like lactate dehydrogenase (LDH), reticulocyte count, and bilirubin should also prompt further investigations. Notable findings in our first patient include LDH, reticulocyte percentage, and bilirubin levels which stayed at baseline during painful events over a 22-month period which is unlike that seen in sickle cell crises (Figure
Graphs showing lactate dehydrogenase (LDH), reticulocyte percentage, and total bilirubin levels in the first patient.
The improvement in sickle cell pain in our two patients following parathyroidectomy points towards hyperparathyroidism being the predominant cause of their pain. Further studies need to be done to see if there is a potential causal relationship between the two conditions. There are other potential benefits of treatment of hyperparathyroidism in patients with SCD. Patients with SCD have a high rate of vitamin D deficiency and osteoporosis [
Hyperparathyroidism can occur concurrently with sickle cell disease and can cause symptoms which mimic sickle cell painful events. Timely diagnosis and treatment of hyperparathyroidism can have beneficial effects in patients with sickle cell disease.
This case series review was conducted at New York City Health and Hospitals/Kings County, Brooklyn, New York, USA.
The authors declare that there is no conflict of interests regarding the publication of this paper.