Hungry bone syndrome--a foreseen complication: theory versus practice.
Hungry bone syndrome (HBS) refers to a severe, rapid and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesaemia that are the consequences of suppressed parathyroid hormone levels at patients with prior high bone turnover [1-6, 9, 11, 12]. Various risk factors have been suggested for the development of this syndrome, including old age, the long term of primary hyperparathyroidism, the dimensions of the parathyroid glands, radiological signs of active bone disease and low vitamin D levels. After parathyroidectomy, rapid decrease of serum calcium levels occurs, as a sign of successfully removing of one or more hyperactive parathyroid adenoma [1, 4, 6, 9, 11, 12, 14].
Based on a systemic review of the literature made by JE Witteveen the term 'hungry bone syndrome' has been linked to the severe (serum calcium < 8 mg/dl) and prolonged (longer than 4 days post-surgery hypocalcemia), in the case of a curative treatment (parathyroidectomy) of severe hyperparathyroidism. This hypocalcemia is the result of the rapid influx of calcium into the bone as the resorption effect of circulating PTH is abolished and the bone formation is pursued and improved. 
Although there are suggestions that preoperative treatment with bisphosphonates may reduce post-operative hypocalcemia and make it more manageable, it is not always indicated in practice [1,4, 5, 9, 10].
We present a case of a foreseen hungry bone syndrome which turned out to be severe and atypical in spite of the administration of IV bisphosphonates prior to the surgery and the important substitution doses of calcium and vitamin D [1,3, 10].
A 66-year-old female with severe osteoporosis, multiple fractures and chronic renal disease was admitted in the Endocrinology Department at the Elias Hospital for the management of a severe hypercalcemia (14.6 mg/dl). From the case history we mention that the patient was diagnosed with severe osteoporosis. A CT scan performed in 2014 found pubis (Figure 1) and ischium fractures, two osteolytic lesions, one on the right acetabulum and one on first sacrum vertebra (Figure 2).
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
The DXA showed a total hip T score of -3DS, a lumbar T score of -1.8DS and -4.4 DS on the forearm bones.
The laboratory investigation showed hypercalcemia associated with high PTH levels (4000 pg/ml), elevated total alkaline phosphatase (636 UI/L), low serum phosphorus level (2.5 mg/dl), creatinine clearance of 57 ml/mn, microcytic hypochromic anemia, proteinuria, high calciuria (638.4 mg/24h). The value of 25(OH)vitamin D was low (10.2 ng/ml), suggesting the prolonged term of primary hyperparathyroidism [1, 9, 16]. The thyroid function was normal with a TSH of 1.86mUI/dl, the anti-thyroglobulin and anti-thyroperoxidase antibodies were negative. The thyroid ultrasonography revealed a multi micronodular goiter and a hypoechoic mass, posterior of the left thyroid lobe with dimensions of 2.4/1.5 cm, compatible with an abnormal parathyroid gland. Considering the dimensions of the parathyroid adenoma, the fact that it was unique and the high serum calcium, the parathyroid scintigraphy was not performed. Subsequently, we established the diagnosis: primary hyperparathyroidism caused by a parathyroid adenoma associated with euthyroid multinodular goiter and surgical treatment was recommended.
Parathyroidectomy (removing a 2.4/1.5 cm adenoma) (Figure 3), and a subtotal thyroidectomy for the multinodular goiter were performed.
[FIGURE 3 OMITTED]
Considering the extremely high PTH values parathyroid carcinoma was suspected, but the histological examination found an encapsulated, cellular, homogenous lesion, composed of chief cells with some oxyphil cells in a delicate capillary network, with minimal mitotic activity. There was no capsular, vascular of adjacent tissue invasion, pleading for a benign adenoma.
Initially, the clinical outcome was favorable under calcium and vitamin D supplements administration, but after 6 days the patient presented in the Emergency Room for severe paresthesia of the limbs and hypocalcemia (6.4 mg/dl) despite the daily treatment with 1.8 g of calcium, 1200 UI of cholecalciferol and 1.5 pg of alphacalcidol (Figure 4).
[FIGURE 4 OMITTED]
The clinical examination revealed severe paresthesia and muscle aches, slightly dehydrated and pail skin, bilateral and multiple lipoma on the forearms (Figure 5), hip arthralgia with irradiation in the limb, blood pressure of 110/80 mmHg, heart rate of 90bpm, constipation, left cecity.
[FIGURE 5 OMITTED]
Biologically, hypocalcaemia (6.4 mg/dl), high PTH levels (80.1 pg/dl), moderate normocytic normochromic anemia, creatinine clearance of 32ml/min and inflammatory syndrome with an ESR of 77 mm/h (Table 1) were identified.
In order to alleviate the clinical manifestations and reach a normal total calcaemia, continuous intravenous administration of calcium was needed, with a gradual dose increase to a total dose of 14 g per day, for three days, associated with oral vitamin D up to 6 [micro]g/day and magnesium administration.
Afterwards, we replaced the intravenous calcium with oral supplementation. For the aggravated anemia, a hematological consult was required, setting the diagnosis of iron-deficiency anemia and the patient received 1 unit of blood. After blood transfusion, hemoglobin was at the same level, so a medullar aspirate was performed which raised the suspicion of iron-deficiency and megaloblastic anemia. Bone biopsy was performed, showing bone fibrosis and hipocellularity of the bone marrow.
The clinical outcome of the patient was favorable, after 3 months the serum calcium level was normal (9.3 mg/dl) due to daily treatment with 0.5 mcg of alphacalcidol and 2000mg calcium (Table 2).
Also the anemia was improved with hemoglobin level reaching 10.5 mg/dl (Figure 6).
The PTH was normal (20 pg./ml). Another osteodensitometry was scheduled in 6 months.
The association between renal impairment, low 25(OH)-vitamin D, anemia, marrow fibrosis, severe osteoporosis, fibrocystic osteitis, high level of alkaline phosphatase and considerable volume of the parathyroid adenoma suggested a long neglected primary hyperparathyroidism and were considerable risk factors for a postoperative hungry bone syndrome. The stage 3 chronic renal disease associated to nephrocalcinosis might be related to the forearm lipomas, a soft tissue ultrasonography might be useful to assess this condition. There are no current guidelines to manage this severe hypocalcaemia related to hungry bone syndrome, but the treatment is aimed to normalize the serum calcium and restored the physiological bone turnover using high doses of calcium, vitamin D and metabolites of vitamin D, but also magnesium [3-6].
The preferred administration for calcium is iv initially, but it is required to associate oral supplements of calcium and vitamin D with alphacalcidol or calcitriol as soon as possible. Although the level of serum calcium usually responds rapidly to this treatment, this is not always the case [1,4, 5, 15].
Preoperative treatment of vitamin D deficiency with cholecalcipherol does not increase calciuria, the administration of iv bisphosphonates is recommended, preferring zolendronic acid to pamidronate for its effects on the calcium level [5, 10, 13, 15].
The differential diagnosis between primary and secondary hyperparathyroidism was made in our case; we note that secondary hyperparathyroidism was excluded because of the important serum hypercalcaemia (in secondary hyperparathyroidism the calcium level is normal or low), low phosphorus level, very high value of PTH. The low level of vitamin D is often seen in neglected primary hyperparathyroidism because of the use of 1,25-(OH)-vitamin D by PTH to absorb intestinal calcium but also to the high levels of serum calcium that directly inhibit the renal lahydroxylase [1, 4, 16]. The PTH levels in secondary hyperparathyroidism are not as high.
Our first guess at the second admission of the patient was noncompliance to the treatment so she was admitted considering the symptomatic hypocalcaemia and the need for the adjustment of treatment. Reviewing the literature, we found that anemia and marrow fibrosis are often found in patients with neglected primary hyperparathyroidism and both improved after successful parathyroidectomy. The possible mechanism of PHPT causing anemia and marrow fibrosis is that PTH has a stimulatory effect on marrow fibroblasts, leading to bone marrow fibrosis, but also to the release of cytokines IL-6 and TNF-[alpha] from the osteoclasts that play an indirect role in the pathogenesis of fibrosis [7, 8, 18].
Hungry bone syndrome is a severe complication of neglected primary hyperparathyroidism, which associated with iron-deficiency, megaloblastic anemia and bone fibrosis, besides the renal failure, suggests that the severity was determined by the term of hyperparathyroidism and the increased number of complications. Hungry bone syndrome appeared as a rare but severe condition triggered by the cure of a long standing primary hyperparathyroidism in spite of the prophylactic treatment.
Conflict of interest--None declared.
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Amalia Ioana Arhire * (1), Cristina Stefan (1,2), Suzana Florea (3), Simona Tau (1), Carmen Gabriela Barbu (1,4)
(1) Endocrinology Department, Elias Hospital, Bucharest, Romania, Ghencea Medical Center, Bucharest, Romania, (3) Internal Medicine Department, Elias Hospital, Bucharest, Romania (4)"Carol Davila" University of Medicine and Pharmacy Bucharest, Romania,
Received: October 2015; Accepted after review: December 2015; Published: December 2015.
* Corresponding author: Amalia loana Arhire, MD, Endocrinology Department, Elias Hospital, 17 Marasti Boulevard, sector 1, 011461, Bucharest, Romania. Tel: 0040 21 316 16 00.
Table 1. Biological investigations (ALKP--alkaline phosphatase, iPTH--intact PTH, MDRD--Modification of Diet in Renal Disease) Blood test Value (normal values) Total serum Ca 6.4 mg/dl (8.5-10.2) Total serum proteins 6.2g/dl(6.6-8.7) HGB 8.5 g/dl(12-15.2) Creatinine 1.35mg/dl (0.5-1.4) Urea 73.5mg/dl (10-20) MDRD 32ml/min/1.73m2 ESR 75mm mm/h (6-13) Phosphorus 3.8mg/dl(2.7-4.5) Magnesium 3.8mg/dl (1.58-2.55) Total ALKP 1928U/L (44-147) iPTH 80 pg/ml (15-65) 25 OH vitamin D 10.2 ng/ml (>30) Table 2. Management of hungry bone syndrome Calcium 6.4 6.9 6.8 7 Magnesium 1.41 1.46 Phosphorus 3.8 3.2 Creatinine 1.35 1.17 ALKP 1928 1749 iPTH 80.1 Dose of orl 1.8g 4g 32g 1.2g calcium Dose of 30mg 80mg 120mg calcium iv Dose of 1200,0.5ug 3520UI,4ug 1500UI, 4ug 300UI,6ug vitaminD Dose of 450mg 450mg magnesium Calcium 7.8 8.9 8.3 10 Magnesium 1.6 1.94 1.87 Phosphorus 2.9 2.4 Creatinine 1.22 1.45 ALKP 1661 iPTH Dose of orl 1.2g 1.2g 3.2g 6.2g calcium Dose of 120mg 120mg calcium iv Dose of 300UI,6ug 300UI,6ug 300UI,6ug 4700UI,3ug vitaminD Dose of 450mg 450mg 450mg 450mg magnesium Fig. 6. Evolution of anemia 1 8.5 2 7.3 3 7.1 4 7.2 5 7.3 6 7 7 6.7 8 7.5 9 7.5 10 9.3 Note: Table made from line graph.
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|Author:||Arhire, Amalia Ioana; Stefan, Cristina; Florea, Suzana; Tau, Simona; Barbu, Carmen Gabriela|
|Publication:||Archive of Clinical Cases|
|Date:||Dec 1, 2015|
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