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A 71-year-old female patient
was brought to our outpatient clinic for generalized bone pain
with disability for two months. Six months prior to this
visit, she began to feel episodes of dizziness and she was
seen by another doctor and anemia was diagnosed after a blood
examination. Two months before this visit, intermittent
episodes of pain developed over the back, anterior chest,
bilateral knees, hips and lower legs. The pain was aggravated
by changes of position and relieved by keeping herself
immobilized. Therefore, she became nearly bed-ridden at home
for one month. In addition, she experienced progressive
numbness over her peri-oral region and tingling over her
fingers and toes. At our clinic, serum globulin, albumin,
calcium and immuno-electrophoresis were arranged initially for
exclusion of multiple myeloma. The results were within normal
limits except hypocalcemia with Ca of 7.5 mg/dl. For
evaluation of the nature of generalized bone pain and
hypocalcemia, she was admitted to our ward for further survey.
She had had a history
of old cerebral infarction with focal seizure and left
hemiparesis for 11 years. She was treated with phenytoin 100
mg three times daily for 8 years in the past. She had gastric
ulcer bleeding complicated with perforation for which she
underwent emergent subtotal gastrectomy 7 years earlier and
then took omeprazole later.
On admission, physical examination
revealed a woman of 56 kg in weight and 164 cm in height. Her
blood pressure was 142/78 mmHg, temperature 36.5 °c, pulse
rate 78 beats per minute and respirations 20 per minute. Her
conjunctivae were pale, sclerae were anicteric, and pupils
were isocoric with prompt light reflex. Her neck was supple
without a goiter, engorged jugular veins, or lymphadenopathy.
Chvostek's sign showed a positive result but Trousseau's sign
was negative. Tenderness was elicited by pressing her upper
sternum. Tightness sensation and tenderness were also noted
over her quadratus lumborums, hamstrings, and leg adductors.
There was no local heat, erythematous change, swelling, or
joint deformity of all involved sites. There was no malar
rash, oral ulcer, dry eye, dry mouth, photosensitivity,
passage of foamy urine, hematuria, or weight loss.
The results
of the laboratory investigations are shown in Tables. EKG
showed no remarkable QT prolongation (QTc. =
0.4 sec). Chest X-ray revealed no osteoblastic lesion
or soft tissue mass. On account of the history of
post-subtotal gastrectomy with anemia, vitamine B12, folic
acid and serum iron, saturation, and ferritin were checked. The
results showed normal levels of vitamine B12 and folic acid.
The iron concentration was 66 μg/dl (reference value, 60-160),
total iron binding capacity (TIBC) 341μg /dl (reference value,
250-350), iron saturation (Fe/TIBC) 19%, and the ferritin
was 13 ng/ml (reference value>20)Examination of the
isoenzymes of alkaline phosphatase showed 84.5 % were originated from
bone. Further investigations showed serum 25-(OH) D3
3.2 ng/ml (reference value, 10-42) and intact PTH 272 pg/ml
(reference value, 12-72). 24-hour urine levels of calcium and
phosphorus were 75 mg and 142 mg. Radiography of the
painful bone showed osteoporotic change without fracture.
Urinary analysis and immunological survey, such as ANA, showed
negative. The diagnosis of vitamine D deficiency complicated
with osteomalacia and secondary hyperparathyroidism was
established. 1, 25- dihydroxyvitamin D 0. 5 μg daily and
calcium carbonate 1000 mg (elemental calcium, 400 mg) three
times daily were begun and the bone pain improved apparently
about 2 weeks later and the serum calcium, phosphorus,
alkaline phosphatase returned to normal 3 months later.
< Laboratory data
>
1. Results of baseline
data
|
WBC |
HB |
HCT |
MCV |
PLT |
ESR |
RBC count |
|
4.5-1.1 |
12.0-16.0 |
36.1-44.3 |
80.8-100 |
140-440 |
0-30 |
3.9-5.0x106 |
|
K/μL |
g/dL |
％ |
fL |
K/μL |
mm/hour |
/μL |
|
5.41 |
9.6 |
31.7 |
92 |
118 |
22 |
3.4 |
|
LDH |
ALB |
ALT |
CK |
Alk-p |
uric acid |
plasma
glucose |
r-GT |
|
100-250
mg/dL |
3.5-5.0
g/dL |
4-44
U/L |
10-160
U/L |
50-190
U/l |
2.4-7.2
mg/dL |
70-100
mg/dL |
0-30
U/l |
|
184 |
3.4 |
7 |
39 |
792 |
4.8 |
101 |
6 |
|
CRE |
Na |
K |
Ca |
Pi |
Free Ca |
LDH |
|
0.7-1.4
mg/dL |
137-153
mmol/L |
3.5-5.3
mmol/L |
9.0-10.6
mg/dl |
2.5-4.5
mg/dl |
4.5-5.9
mg/dL |
120-240
U/L |
|
1.3 |
138 |
3.4 |
7.4 |
1.7 |
4.18 |
184 |
2. Results of the baseline endocrine tests
|
iPTH |
25-(OH)D3 |
Ca (24-hr urine) |
|
12-72
pg/ml |
10-42
ng/ml |
< 250 mg |
|
272 |
3.2 |
75 | ***intact parathyroid hormone＝iPTH
< 病例解析 >
鈣離子在人體內，對於神經及肌肉組織有很大的影響。當低血鈣時，口角附近及四肢末端的感覺會麻木或異常。另外，神經肌肉亢奮性也會增加，而出現反射過度，肌肉痙攣、強直(tetany)，甚至呼吸肌會痙攣衰竭，或癲癇發作。在心臟血管方面則可能出現QT延長、心律不整、心跳過慢甚至心衰竭•理學檢查方面，有時可出現Chvostek's
sign及Trousseau's
sign。以手指敲耳前方顴骨正下方的面神經時，若同側之面部肌肉會收縮，則為陽性的Chvostek's
sign。而以血壓計之纏臂充氣壓迫手臂至其收縮壓20 mmHg以上，維持3分鐘，若腕肌肉痙孿( carpal
spasm)出現則為陽性的Trousseau's
sign。但值得注意的是正常人亦可能出現以上的陽性表現，而已有低血鈣症的患者亦不一定會表現，因此只能作為參考。鈣離子在體內主要受副甲狀腺素(PTH)，活性維生素D
(1,25 (OH)2 D)及抑鈣素(calcitonin)三者所調節，
特別是前二者。低血鈣的原因有可能有[1]副甲狀腺功能低下(腺體先天缺乏或手術切除，放射線治療、免疫或浸潤性破壞或分泌PTH被低血鎂抑制)或阻抗；[2]維生素D缺乏或代謝障礙(營養吸收不良，肝腎衰竭)或阻抗；[3]
鈣離子結合態增加而減少游離鈣，如急性胰臟炎時與脂肪酸結合;
橫紋肌溶解(rhabdomyolysis)、癌細胞溶解(tumor
lysis)、溶血(hemolysis)時與磷；或大量輸血時與檸檬酸(citrate)
結合；鹼血症時與血中白蛋白結合；另外，也需細究病患的藥物史，因很多藥會造成低血鈣。一般在探究低血鈣的原因時，除了先排除病人是否有相關的藥物、相關的疾病背景可能造成低血鈣外，在實驗檢查方面，最重要的是血磷的濃度。由血磷的高低可以分兩個方向。若是低鈣、低磷，則可能是維生素D缺乏(或影響維生素D合成吸收代謝的藥物)及阻抗；若是低鈣、高磷，則可能是副甲狀腺素缺乏或阻抗及血磷高等情形(如橫紋肌溶解、癌細胞溶解、溶血等)。我們的病人的血磷低，進一步驗25-(OH)
D3濃度亦低，加上臨床的症狀及相關的實驗數據而診斷為維生素D不足造成的軟骨病(osteomalacia)。
維生素D的生理作用，
在小腸可幫助鈣、磷的吸收，在骨頭可協同副甲狀腺素，增加骨質吸收溶解而釋出鈣、磷，在腎臟可促進遠曲小管重吸收鈣、在近曲小管重吸收磷酸根。維生素D缺乏會造成低血鈣，進而間接刺激副甲狀腺荷爾蒙分泌(即所謂次發性副甲狀腺機能亢進)，而促使鈣自骨頭中釋出，並減少腎臟排出鈣。因此病人的血鈣通常是正常或略微低下。但血磷在副甲狀腺代償下，腎臟的再吸收又更減少，故常明顯低下。而在血鈣及血磷不足的情況下，骨質會礦物質化不完全。軟骨病初始大多沒有明顯症狀，但隨著時間上的演進，可能會演變成廣泛性的骨頭痛及壓痛，且伴隨近端肢體無力，嚴重的話，病人甚至會因骨頭痛及無力而長期臥床。軟骨病主要的診斷依據在於低下的25-(OH)
D3濃度。至於可以反映骨生成母細胞(osteoblast)之活性的alkaline
phosphatase，可以是正常也可以增加；因在低血磷及高副甲狀腺荷爾蒙的刺激下，1α-hydroxylase仍可正常作用，所以血中1,
25-(OH)2D3，濃度可以是正常， 但在25-(OH)D3極度缺乏時或1α-hydroxylase 有缺陷時，血中1,
25-(OH)2D3 濃度則會下降。至於診斷的黃金標準則是作骨骼切片(藉助tetracycline
labeling)。另外，在影像上，X光有些會表現出一些垂直延伸自骨表面的低密度線條，即偽性骨折線(pseudo-fracture
line)。其發生處多在供應營養的動脈穿出處，並經常分布在骨頭兩側。我們的病人維生素D缺乏的原因可能有二,
一為胃切除術後(因伴隨脂肪瀉的機率高而使脂溶性維生素吸收不良)；另一為長期吃抗癲癇的藥(phenytoin會加速25(OH)D3的代謝流失)。在治療方面，由於活性維生素D[1,
25(OH)2D3]較25(OH)D3有水溶性，不會大量存於脂肪組織內，而且不受肝腎功能影響，因此臨床上常使用，其劑量為每日0.25
μg--1.0μg，視血鈣濃度而調整•我們的病人在開始補充治療後約二週，骨頭酸痛症狀即獲得改善，而血中鈣、磷、副甲狀腺荷爾蒙及alkaline
phosphatase的濃度在稍後亦回到正常。
< 參考文獻
>
- Lyman D. Undiagnosed vitamin D
deficiency in the hospitalized patient. Am Fam Physician
2005;71:299-304.
- Holick MF. Vitamin D deficiency. N
Engl J Med 2007;357:266-81
- Shoback D. Update in osteoporosis and
metabolic bone disorders. J Clin Endocrinol Metab
2007;92:747-53.
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Case Discussion
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