Pseudohypoparathyroidism Type II in a Woman with a History of Thyroid Surgery

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1 CASE REPORT Pseudohypoparathyroidism Type II in a Woman with a History of Thyroid Surgery Takaaki Murakami, Takuo Nambu, Yuki Morimoto, Yuki Matsuda, Koji Matsuo, Shin Yonemitsu, Seiji Muro and Shogo Oki Abstract We herein describe the case of a woman with pseudohypoparathyroidism (PHP) type II. She had a history of subtotal thyroidectomy against Graves disease without levothyroxine supplementation and presented with stiffness, numbness and muscle cramps. Her surgical history suggested the possibility of secondary hypoparathyroidism; however, the serum intact parathyroid hormone level and results of a Ellsworth-Howard test led to the diagnosis of PHP type II. In the present case, making the differential diagnosis was challenging because two distinct disorders, such as PHP and secondary hypoparathyroidism, may exist simultaneously. This case demonstrates the need to consider the possibility of PHP type II in patients exhibiting hypocalcemia. Key words: Ellsworth-Howard test, Graves disease, hypocalcemia, pseudohypoparathyroidism, pseudohypoparathyroidism type II, thyroidectomy () () Introduction Extracellular calcium is the principal substrate for the mineralization of cartilage and bone and serves as a signaling molecule for a number of intracellular processes (1). Parathyroid hormone (PTH) is a peptide hormone that controls the level of ionized calcium in the blood within a narrow range. An impairment of the PTH function induces changes in calcium homeostasis that lead to clinical problems associated with symptoms resulting from hypocalcemia (2). Hypocalcemic disorders can be divided into two categories: hypocalcemia with a low serum phosphate level and hypocalcemia with a normal to elevated serum phosphate level. The latter can be subdivided into PTH-deficient hypoparathyroidism and pseudohypoparathyroidism (PHP) without chronic renal failure (1, 2). PTH-deficient hypoparathyroidism primarily develops in patients undergoing total thyroidectomy (1, 2). The risk of permanent hypocalcemia following thyroidectomy is related to the number of preserved parathyroid glands and the PTH level, and patients with PTH deficiency usually develop profound hypocalcemia if appropriate therapy with oral supplementation of calcium and activated vitamin D is not administered. Hypocalcemia with a low serum PTH level following thyroidectomy is common in the early postoperative period; however, the serum calcium and PTH levels usually return to and remain normal thereafter without calcium supplementation. Therefore, permanent hypoparathyroidism following thyroid surgery is a relatively rare complication that has been reported to occur in only 1-2% of postthyroidectomy patients (3). PHP constitutes a rare group of disorders characterized by hypocalcemia, normal or increased PTH secretion and target tissue resistance to the actions of PTH. PHP is classified as type Ia, Ib, Ic or II. Although patients with PHP type I fail to show increases in the urinary excretion of either camp or phosphate, those with PHP type II exhibit normal urinary excretion of camp with an impaired phosphaturic response (1, 2, 4). Both PTH-deficient hypoparathyroidism and PHP manifest as hypocalcemia; however, the pathophysiology of these disorders is very different. Moreover, making the differential diagnosis can be challenging, considering the possibility that these two distinct disorders may exist simultaneously. We herein report the case of a 72-year-old woman who suffered Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan Received for publication August 22, 2013; Accepted for publication October 16, 2013 Correspondence to Dr. Takaaki Murakami, t.murakami@osaka-med.jrc.or.jp 743

2 Table 1. Laboratory Results of Present Case on Admission Blood Chemistry Hormones Day 9 TP (g/dl) 6.4 TSH (IU/mL) ,25(OH) 2VitD 41.3 ALB (g/dl) 3.7 Free T4 (ng/dl) (OH) VitD (ng/ml) 29 AST (IU/L) 23 Free T3 (pg/ml) 2.90 ALT (IU/L) 14 Estradiol (pg/ml) <15 24-hour urine ALP (IU/L) 238 LH (miu/ml) 35.4 Volume (ml/day) 1,700 Bone ALP (U/L) 16 FSH (miu/ml) 95.1 Cre (mg/day) 670 T-bil (mg/dl) 1.0 IGF-1 (ng/dl) 48 Ca (mg/day) 110 Glucose (mg/dl) 99 GH (ng/ml) 1.08 IP (mg/day) 600 BUN (mg/dl) 12.8 intact-pth (pg/ml) 41 CCr(mL/min) 90.7 Cre (mg/dl) 0.55 Calcitonin (pg/ml) Na (meq/l) 140 Serum NAG (IU/L) 2.1 K (meq/l) 3.9 NTx (nmol BCE) 15 Cl (meq/l) 107 Osteocalcin (ng/ml) 5.5 Urinalysis Ca (mg/dl) 7.7 Anti SS-A Antibody (-) Specific gravity (mg/dl) 2.1 Anti SS-B Antibody (-) ph 5.5 IP (mg/dl) 3.7 ANA 40 Protein (-) UA (mg/dl) 4.9 Speckled 40 Glucose (-) CBC Homogeneous 40 Ketones (-) WBC (/ L) 5,190 Anti CCP Ab (U/mL) <0.6 Blood (-) RBC ( 10 4 / L) 420 Anti TPO Ab (IU/mL) 55 Urobilinogen (EU/dL) 0.1 Hb (g/dl) 13.1 Anti TG Ab (IU/mL) 37 Bilirubin (-) Ht (%) 38.0 Anti TSHR Ab (IU/L) 0.5 WBC (/HPF) <1 Plt ( 10 4 / L) 24.0 RBC (/HPF) <1 TP: total protein, ALB: albumin, AST: aspartate aminotranferase, ALT: alanine aminotranferase, ALP: alkaline phosphatase, Bone-ALP: bone-type alkaline phosphatase, T-bil: total bilirubin, BUN: blood urea nitrogen, Cre; creatinine, Na: sodium, K: potassium, Cl: chloride, g: magnesium, IP: phosphorus, UA: uric acid, CBC: complete blood count, WBC: white blood cell count, RBC: red blood cell count, Hb: hemoglobin, Ht: hematocrit, Plt: platelet count, CCr: creatinine clearance, G: microglobulin, NAG: N-Acetyl- -D-Glucosamidase, free T4: free total thyroxine, free T3: free triiodothyronine, intact PTH: intact parathyroid hormone, serum NTx: serum type I collagen cross-linked N-telopeptide, BCE: Bone Collagen Equivalent, Anti CCP Ab: Anti- cyclic citrullinated peptide antibody, Anti TPO Ab: Anti-thyroid peroxydase antibody, Anti TG Ab: Anti-thyroglobulin antibody, Anti TSHR Ab: Anti-thyroid- stimulating hormone receptor antibody, ANA: Antinuclear antibodies, 1,25(OH) 2 VitD: 1,25-dihydroxyvitamin D: 25(OH) VitD; 25-hydroxyvitamin D, HPF: high-power field Samples were collected on day 9 (day 14 of -hydroxyvitamin D3 therapy withdrawal). from late-onset hypocalcemia following thyroidectomy, with biochemical findings indicative of PHP type II. Case Report A 72-year-old woman was referred to our hospital for an evaluation of hypocalcemia. She presented with stiffness, muscle cramps and numbness in her hands and lower legs, which she had experienced for two years. There was no family history of bone and mineral metabolism disorders or urinary lithiasis. She did not follow any dietary restrictions and reported alcohol consumption, although she denied smoking. Her past history revealed that she had been diagnosed with Graves disease at 26 years of age, which had been treated with bilateral subtotal thyroidectomy. Subsequently, she had been diagnosed with Sjögren s syndrome at 62 years of age. In addition, she had a history of hypertension, atrial fibrillation, osteoporosis, fractures of the lumbar vertebrae and ribs and cervical and lumbar spinal canal stenosis. Her medications included amlodipine besilate (5 mg/day), warfarin (3 mg/day), bazedoxifene acetate (20 mg/ day), cilostazol (100 mg/day), limaprost alfadex (15 μg/day), pregabalin (150 mg/day) and rebamipide (300 mg/day). Levothyroxine sodium had not been previously prescribed. Laboratory tests revealed mild hypocalcemia (corrected serum calcium level, 8.3 mg/dl; normal range, mg/dl) despite the presence of a normal calcium level (8.7 mg/dl) two years earlier. In addition, the patient exhibited normophosphatemia (3.7 mg/dl; normal range, mg/dl) and normomagnesemia (2.0 mg/dl; normal range, mg/dl). The initial diagnosis was secondary hypoparathyroidism due to thyroid surgery, and 1α-hydroxyvitamin D3 (0.5 μg/day) therapy was initiated along with the continuation of bazedoxifene acetate therapy. However, the corrected serum calcium level remained suppressed (7.9 mg/dl) six weeks later, at which time, the 1α-hydroxyvitamin D3 therapy was discontinued, and she was admitted for a further workup. On admission, the patient was alert and oriented. She was cm tall and weighed 63.6 kg. A physical examination revealed an operative scar on the neck, deformities of the proximal interphalangeal and metacarpophalangeal joints and severe xeroderma. No typical findings of Albright s hereditary osteodystrophy were observed. Moreover, Trousseau 744

3 Admission Ellsworth-Howard test Days from admission Intact PTH (pg/ml) Corrected serum calcium (mg/dl) Serum phosphorus (mg/dl) Urine calcium (mg/dl) Urine phosphorus (mg/dl) Urine creatinine (mg/dl) Urine-sampling way spot spot spot 24 hour spot spot spot spot Urine volume (ml/day) FECa (%) FEP (%) Symptoms Day -52~-5 VD Day3 Withdrawal of bazedoxifene acetate Day11~ VD Figure. Clinical course of the symptoms, laboratory data and treatment in the present case. 1α (OH) VD: 1α-hydroxyvitamin D3, FECa: Fractional excretion of calcium, FEP: Fractional excretion of phosphorus Table 2. Results of Ellsworth-Howard Test U1 U2 U3 U4 U5 U-creatinine (mg/h) U-phosphorus (mg/h) U-phosphorus (mg/2h) U-cAMP U-creatinine (mg/dl) U-phosphorus (mg/dl) U-cAMP Urine volume (ml) Urine (U) samples were collected hourly in order from U1 to U5. Synthetic human parathyroid hormone (1-34) was injected just before starting to collect U4. and Chvostek signs were negative. The laboratory test results obtained on admission (day 8 of 1α-hydroxyvitamin D3 therapy withdrawal) are shown in Table 1. Mild hypocalcemia was still evident, with a corrected serum calcium level of 8.0 mg/dl. The serum intact PTH level was normal (41 pg/ml; normal range, pg/ml, as measured using an electrochemiluminescence immunoassay, Mitsubishi Chemicals), and the patient s liver and renal functions were preserved. Hand radiography did not reveal any shortened metacarpals; however, destruction of the distal end of the metacarpal bones and proximal phalanxes was observed. The bone mineral density was g/cm 2 in the lumbar region, g/cm 2 in the left hip and g/cm 2 in the left forearm. The T-score was -0.4 SD, -1.5 SD and -1.5 SD, respectively. Computed tomography of the head revealed bilateral basal ganglion calcification. In addition, thyroid function tests confirmed subclinical hypothyroidism, and a thyroid ultrasound examination indicated a residual right lobe and isthmus with findings suggestive of chronic thyroiditis. No renal calcification was evident on abdominal ultrasonography. The Schirmer tear test was positive in both eyes; however, the Saxon test was negative. In order to accurately evaluate the patient s hypocalcemic status, bazedoxifene acetate was discontinued after admission. Thereafter, her symptoms were gradually exacerbated, and the serum corrected calcium level decreased to 7.7 mg/ dl (Figure). Furthermore, the serum 1,25-dihydroxyvitamin D level was 41.3 pg/ml (normal range, pg/ml) and the 25-hydroxyvitamin D level was 29 ng/ml (normal range, 7-41 ng/ml). Based on the suspicion of the presence of PHP, the Ellsworth-Howard test was performed on day 9 as per the standard method with the intravenous injection of synthetic human PTH (1-34) (Asahi Kasei Co., Tokyo, Japan) at a dose of 100 U under a 24-hour dairy-free and phosphorus-restricted diet (10, 11). The urinary phosphorus level observed two hours before PTH injection was mg, which was over 10 mg, the difference in the urinary phosphorus levels between the two urine samples collected before PTH injection was mg per hour, which was under 17.5 mg per hour, and the ratio of the urinary creatinine level before PTH injection to that observed after 745

4 Table 3. The List of Reported Adult Cases of PHP Type II Reference Age Sex Corrected IP Mg Intact 25(OH)D 1,25(OH) 2D Complications serum Ca PTH [18] 27 F Sjögren's syndrome [19] 65 M Hashimoto s disease [19] 67 F Graves disease [20] 16 M [21] 21 M Ca: serum corrected calcium (mg/dl), IP: serum phosphorus (mg/dl), Mg: serum magnesium (mg/dl), Intact PTH: intact parathyroid hormone (pg/ml), 25(OH)D: 25-hydroxyvitamin D (ng/dl), 1,25(OH) 2 D: 1,25-dihydroxyvitamin D (pg/ml) PTH injection was 1.14, which was between 0.8 and 1.2. Therefore, no phosphate deficiency, excessive diurnal variation in urinary phosphate excretion or urine collection errors were reported. Although an incremental response was observed in the urinary camp levels, the increase in urinary phosphate excretion following PTH injection was blunted (< 35 mg/2 hours, Table 2). In accordance with these findings, a final diagnosis of PHP type II was established. Therefore, 1α-hydroxyvitamin D3 (1.5 μg/day) therapy was resumed on day 11, and the corrected serum calcium level subsequently improved to 8.4 mg/dl. The patient s muscle cramps and stiffness in her hands and lower legs resolved, although the numbness in her hands remained. Discussion Hypocalcemia is a relatively common clinical finding; however, making the differential diagnosis of the underlying cause of hypocalcemia can be complex and often confusing. Hypocalcemic disorders with a normal to elevated serum phosphate level are primarily caused by chronic renal failure; the remaining cases are divided into diseases caused by impaired PTH secretion and those caused by resistance to the actions of PTH (1, 2). Hypoparathyroidism caused by impaired PTH secretion includes secondary hypoparathyroidism due to neck surgery, radiation, infiltration of cancer and so on (2). When patients exhibit hypocalcemia following thyroidectomy, insufficient PTH secretion should be suspected; nevertheless, the occurrence of hypocalcemia in the late post-thyroidectomy period is not common, and the serum intact PTH level is likely to be extremely low in such cases. In the present case, the patient s serum calcium level before the onset of symptoms was within the normal range. Moreover, the repeated serum intact PTH level was over 30 pg/ml. It has been reported that the threshold level for sufficient PTH secretion is 30 pg/ml (8, 12). The patient s intact PTH level appeared to be mildly elevated relative to her low serum calcium level, although it was within the normal range. Therefore, we speculate that her hypocalcemia resulted not from impairment of PTH secretion, but rather from resistance to the actions of PTH. PHP, which is characterized by resistance to the actions of PTH, constitutes a very rare group of heterogeneous disorders. Patients with PHP exhibit a reduced phosphaturic response to PTH, which leads to hyperphosphatemia. PHP is divided into types Ia, Ib, Ic and II. PHP type Ia is caused by mutations in the coding region of the GNAS1 gene, which encodes the guanine nucleotide binding protein alpha stimulating activity polypeptide 1 (Gsα) (13). PHP type Ib is caused by aberrant imprinting of the GNAS1 gene and, in some familial patients, by deletions in the upstream promoter region (14-16). PHP type Ia patients often present with additional hormonal resistance and manifest characteristic physical features that are collectively termed Albright s hereditary osteodystrophy (AHO). On the other hand, PHP type Ib patients predominantly present with renal PTH resistance and lack any features of AHO. In addition, PHP type I patients fail to show adequate increases in the urinary excretion of either camp or phosphate. Conversely, PHP type II patients exhibit normal urinary excretion of camp with an impaired phosphaturic response (1, 2, 4). PHP type II is a very rare disorder that was first reported by Drezner et al. in 1973 (5). To date, very few cases of PHP type II have been reported (Table 3) (11). Unlike PHP type I, the clinical mechanisms of abnormal PTH signaling in PHP type II remain unclear. Furthermore, it is questionable whether PHP type II should be listed as a disease entity because the results of the Ellsworth-Howard test in some patients with vitamin D deficiency and/or renal tubular damage have been reported to resemble the PHP type II pattern (4, 6-9). However, in the present case, the presence of vitamin D deficiency was excluded based on the patient s normal dietary habits and normal serum 25-hydroxyvitamin D level. Moreover, her urinary β2 microglobulin and N- Acetyl-β-D-Glucosamidase levels were normal. Some cases of idiopathic hypoparathyroidism also involve a blunted phosphaturic response to PTH due to phosphate deficiency, excessive diurnal variation in urinary phosphate excretion and urine collection errors (17). However, in the present case, the possibility of these conditions was denied according to previously reported criteria (10-12). Therefore, this case meets the diagnostic criteria for PHP type II. While previously reported diagnostic criteria may not have complete sensitivity and specificity, the fact that some patients presenting with hypocalcemia following thyroidectomy meet the diagnostic criteria for PHP type II is very interesting and should lead researchers to reconsider the disease entity and etiology of PHP type II. Most cases of PHP type II are preceded by or simultane- 746

5 ously present with autoimmune disorders, such as Sjögren s syndrome, Hashimoto s thyroiditis and/or Graves disease, as observed in the present case. Therefore, autoimmune mechanisms or antibodies may be the cause of hypocalcemia associated with a discrepancy between urinary camp excretion and the phosphaturic actions of PTH. Indeed, Yamada et al. evaluated the effects of serum immunoglobulin G obtained from a patient with PHP type II and Sjögren s syndrome on the renal function in rats (18). That study demonstrated that autoantibodies react with components of the renal tubular plasma membrane and can block the development of PTH-induced phosphaturia (19). It is possible that patients with PHP type II may be treated for associated hypocalcemia without obtaining a definitive diagnosis of the underlying condition. Furthermore, in spite of the presence of other etiologies for hypocalcemia that may exist simultaneously, normalization of the calcium levels with calcium and vitamin D supplementation may result in a missed diagnosis. For these reasons, physicians should be aware of and consider the possibility for the development of PHP type II in patients presenting with hypocalcemia. The accumulation of clinical cases, as well as further studies investigating the association between the incidence of PHP type II and that of autoimmune disorders, is needed to better understand the disease. In summary, we herein reported a case of PHP type II in a patient with a history of thyroid surgery. Conducting diagnostic studies, such as the Ellsworth-Howard test and measurements of the serum intact PTH level, is critical for making a definitive diagnosis. Although very few cases of PHP type II have been reported, this case demonstrates the importance of considering PHP type II in the differential diagnosis of patients presenting with hypocalcemia. The authors state that they have no Conflict of Interest(COI). References 1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 12th Ed. Saunders, Philadelphia, 2011: Fukumoto S, Namba N, Ozono K, et al. Causes and differential diagnosis of hypocalcemia-recommendation proposed by expert panel supported by Ministry of Health, Labour and Welfare, Japan. Endocr J 55: , Glinoer D, Andry G, Chantrain G, Samil N. Clinical aspects of early and late hypocalcaemia after thyroid surgery. Eur J Surg Oncol 26: , Seki T, Yamamoto M, Kimura H, et al. Vitamin D deficiency in two young adults with biochemical findings resembling pseudohypoparathyroidism type I and type II. Endocr J 57: , Drezner M, Neelon F, Lebovitz E. 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