|
< Chief
Complaint >
Intermittent palpitation and headache for two
months.
< Brief
History
>
This 54 year-old man, a boss of a factory, is a
patient with diabetes mellitus diagnosed for 1 year. He took
oral hypoglycemic agents (glimeperide 4 mg Q.D, metformin 500
mg T.I.D) and his average fasting plasma glucose level was
around 110 mg/dL. Two months prior to admission, he developed
intermittent palpitation and headache. Each episode of which
lasted several minutes and resolved spontaneously without
overt precipitating or aggravating factors. Occasionally the
episode happened at bedtime and was accompanied by pallor,
dizziness and perspiration. There was no chest tightness,
vomiting or abdominal pain. He had ever visited a local
medical clinic where hypertension was noted. Because these
episodes were paroxysmal, he refused to take any medication.
He denied a family history of hypertension.
Because the
frequency of headache increased recently, he underwent a
health examination. Whole body magnetic resonance imaging
revealed a left adrenal tumor measuring 3.2 cm in diameter
which presented with hyperintense signal on T2-weighted image
(fig
1& 2
). Whole body positron emission tomography (PET)
showed negative findings. Secondary hypertension which was
related to a pheochromocytoma was highly suspected and he was
admitted for further study.
<
Physical examination >
Physical examination
revealed a 76 kg, 169 cm tall man without round face, acne or
truncal obesity. His blood pressure was 120/80 mmHg,
respiratory rate was 18/min, pulse rate was 88/min and his
temperature was 36.2℃. His consciousness was clear,
conjunctivae were pink, and his sclerae were anicteric. The
pupils were isocoric with prompt light reflex. The neck was
supple without goiter, lymphadenopathy, engorged jugular veins
or carotid bruit. Chest, abdominal and extremity examinations
were normal. There was no gynecomastia, galactorrhea, buffalo
hump or purple striae.
<
Laboratory Examination >
Table1. Endocrine test
|
Renin |
Aldosterone |
Cortisol (8AM) |
Cortisol (4PM) |
DHEA-SO4* |
|
ng/mL/hr |
ng/dL |
μg/dL |
μg/dL |
μmol/L |
|
3.48
(1-5) |
19.5
(5-30) |
10
(5-25) |
6
(2.5-12.5) |
4.2
(4.6-13.4) |
Table 2. 24 HR urine catecholamines
|
Dopamine |
Epinephrine |
Norepinephrine |
VMA** |
|
μg/24h |
μg/24h |
μg/24h |
mg/24h |
|
286.72
(50-450) |
213.37
(< 22.4) |
175.93
(12.1-85.5) |
8.25
(1-7)
|
*DHEA-SO4: dehydroepiandrosterone sulfate;
**VMA: vanillylmandelic acid ��
< Course and Treatment
>��
During
hospitalization, he experienced another two episodes of
palpitation and headache which were accompanied by concomitant
elevation of blood pressure (systolic/diastolic 170/100 mmHg).
Complete blood counts and biochemical studies, including serum
electrolytes, were within normal ranges except for an
overnight fasting glucose of 130 mg/dL. Twenty-four-hour urine
exam revealed elevated VMA (8.25 mg) and catecholamine levels
(epinephrine 213.37μg, norepinephrine 175.93μg). Plasma renin
activity, aldosterone and cortisol levels were all within
normal limits. The laboratory test confirmed the diagnosis of
pheochromocytoma. Doxazosin 2 mg daily initially was
prescribed and the dose was gradually increased to 16 mg daily
for better blood pressure control. He received laparoscopic
adrenalectomy smoothly. The pathology proved the diagnosis of
pheochromocytoma (fig 3
&
4
). Both his blood pressure and
fasting blood glucose levels gradually returned to normal
ranges without necessitating any medications. He was
discharged and regularly followed up at out-patient
department. ��
< Discussion
>
嗜鉻細胞瘤(pheochromocytoma)是一種少見的腫瘤，每年每一百萬人約有兩位，是造成續發性高血壓(secondary
hypertension)的原因之一，佔所有高血壓少於0.1％。沒有性別上的差異，可以發生在任何年紀，尤其常見於30至40歲。90％的成人及70％的小孩位於腎上腺，右側又比左側常見，右側的嗜鉻細胞瘤較常出現陣發性(paroxysmal)高血壓，約10％的成人及35％的小孩兩側腎上腺皆有腫瘤。大部分偶發性嗜鉻細胞瘤是有包膜的(encapsulated)，很少會侵犯周邊組織，但是有時腫瘤會進入腎上腺靜脈、下腔靜脈，造成肺栓塞。嗜鉻細胞瘤的大小變異很大，可以很微小(microscopic)也可以大至3600克，平均直徑約4.5公分，重約100克。Paragangliomas是腎上腺外的嗜鉻細胞瘤(extra-adrenal
pheochromocytomas)，從神經節長出，佔成人嗜鉻細胞瘤約10％，其中85％可以在腹部發現。
大部分的嗜鉻細胞瘤是偶發的(sporadic)，但是超過10％可以是遺傳的，這些病人需要作基因篩檢，如multiple
endocrine neoplasia type 2 (MEN 2)是因為ret
proto-oncogene突變，造成嗜鉻細胞瘤、甲狀腺髓質癌(medullary thyroid
carcinoma)及副甲狀腺機能亢進(hyperparathyroidism)或黏膜神經瘤(mucosal
neuroma)；又如Von Hipple-Lindau disease是因為VHL tumor suppressor
gene突變等。大部分偶發性腫瘤是良性的，而有15％的嗜鉻細胞瘤是惡性的，可以轉移到頭骨、肋骨、脊椎、肺、胸管、腸繫膜和肺臟。MEN
2的惡性機會較高，paragangliomas有30-50％是惡性的。腎上腺外嗜鉻細胞瘤、大腫瘤(直徑6公分以上)、腫瘤有融合性壞死、血管侵犯或廣泛性局部侵犯則惡性機會較大。
雖然有些嗜鉻細胞瘤不會分泌catecholamine，但是大部分都可以製造catecholamine
，甚至高於正常的27倍。然而因為無法回饋抑制，所以造成持續且過度分泌，而增加心臟輸出量(cardiac
output)、週邊血管阻抗(peripheral
resistance)及腎素(renin)分泌，繼而造成高血壓。但是，血中catecholamine的濃度和腫瘤大小不一定相關，因為大腫瘤可能會有內部出血性壞死。腫瘤內自發性出血、生理性刺激如排尿(micturation)、身體疼痛、心煩意亂、插管、麻醉都可能引起高血壓危象(hypertensive
crisis)。除此之外，嗜鉻細胞瘤還會分泌neuropeptide Y
(NPY，非常強的血管收縮劑，引起高血壓)、neuron-specific enolase
(NSE，良性腫瘤血中濃度會正常，一半的惡性嗜鉻細胞瘤濃度會上升)、ACTH(造成庫欣症候群)、erythropoietin(紅血球生成素，造成紅血球過多)、parathyroid
hormone- related peptide (PTHrP，造成高血鈣)、IL-6 (發燒)。
超過三分之一的病人於診斷出嗜鉻細胞瘤前就已經因為心律不整或中風死亡。90%的成人有高血壓，然而腎上腺素也可能引起偶發性低血壓及昏厥。80％的病人有頭痛，70％會冒汗，60％有心悸，50％會焦慮不安，40％會手抖，甚至出現感覺異常、心絞痛、腹痛或視覺改變。但是，MEN
2和VHL的病人血壓常常是正常而沒有症狀。因為血管運動腎上腺接收器去敏感(vasomotor adrenergic
receptor
desensitization)造成血管內容積減少會導致姿勢性低血壓；有些病人因為去敏感、耐受(tolerance)、或tachyphylasix，即使血中catecholamine過高血壓也正常。此外，血中catecholamine濃度過高也會導致左心室肥大、心肌炎、擴張型心肌病(dilated
cardiomyopathy)，如果沒有造成心肌纖維化，於腫瘤切除後可以完全恢復。
生化檢查通常是測血漿和尿液中的catecholamine及metanephrine(catecholamine的代謝物)。目前以測尿液metanephrine的敏感性最高，為97％，但是因為實驗室的限制，我們的病人只有測尿液norepinephrine、epinephrine、VMA及dopamine，卻也已經足夠診斷了。MEN
2的病人血漿metanephrine會上升，VHL disease的病人血漿norepinephrine會上升。測serum
chromogranin A
(CgA)對診斷也有幫助；正常情況下，CgA有晝夜節律，早上八點時血中濃度最低，下午及晚上11點時濃度最高，CgA的濃度和腫瘤大小有關，所以是一個有用的腫瘤標誌，正常人的CgA是48
ng/mL，良性嗜鉻細胞瘤為188 ng/mL，惡性嗜鉻細胞瘤是2932
ng/mL。CgA的敏感性為83-90％，而特異性為96％。除此之外，有些病人會出現白血球(主要是中性球)、紅血球、或紅血球沉降速度(ESR)增加、高血鈣，35％的病人有高血糖，如同我們的病人。有些藥物、食物(咖啡因或香蕉)、或疾病都會影響血漿或尿液catecholamine的濃度，因此會干擾我們對嗜鉻細胞瘤的診斷，所以應該仔細問診。
臨床上主要使用metaiodobenzylguanidine (MIBG)
scans來定位嗜鉻細胞瘤，benzylquanidine是quanethidine的衍生物，是一種假性神經傳導物質，會累積在分泌catecholamine的細胞中，因此可以定位嗜鉻細胞瘤。為了阻斷甲狀腺攝取放射碘，必須事先給予potassium
iodide。如要做電腦斷層檢查，一定要先控制血壓，因為顯影劑會造成高血壓危象。懷孕病人首選的檢查是核磁共振，因為不需要打顯影劑，也沒有輻射線，75％的病人於T2-weighted
image會呈現hyperintense signal，比肝臟亮，但是特異性差。正子攝影(positron emission
tomography，PET)對定位惡性嗜鉻細胞瘤的轉移敏感性不錯，但是特異性較MIBG差，好處是可以立即作不需事前準備，但是很貴。如果強烈懷疑有paragagliomas或轉移，尤其是MIBG
scans無異常時，應該考慮somatostatin receptor imaging。
治療以手術切除為主，目前外科醫師傾向內視鏡腎上腺切除(laparoscopic
adrenalectomy)，但是術前要先做好準備，以防發生高血壓危象或休克。血壓的控制比較建議使用鈣離子阻斷劑，因為術前水份不需要補充太多，而且病人的耐受性較好。但是α-blockers仍舊是最廣泛被使用的降壓藥，一般常用phenoxybenzamine，但是其會增加catecholamines和metanephrine的合成，使得心跳加快；也可以使用doxazosin或prazosin。由於catecholamine會刺激腎素分泌且嗜鉻細胞瘤上有angiotensin-coverting
enzyme (ACE)的結合位置，所以可以同時使用ACE inhibitors或angiotensin receptor
blockers (ARBs)，但是孕婦禁用，因為會致畸胎。一般不建議使用β-
blockers，除非是為了治療潮紅、心跳過速，但是要在α-blockers使用後。Metyrosine
(α-methylparatyrosine)少用，因為副作用多，通常用於已經轉移了。可以使用NSAIDs來治療嗜鉻細胞瘤引起的發燒。
腫瘤切除後仍有25％的病人會有高血壓。良性嗜鉻細胞瘤5年存活率為96％，惡性腫瘤只有44％。即使切除腫瘤10天或更久後，仍舊可以在血液及尿液中測得高濃度的catecholamine，因此術後2星期再追蹤24小時尿液catecholamine及metanephrine，之後第一年每三個月追蹤一次，之後每6個月，然後每年，至少持續五年。腎功能正常的病人可以追蹤CgA；惡性腫瘤或有轉移的病人要在手術後數個月追蹤第一次MIBG
scan。
嗜鉻細胞瘤雖然罕見，但是卻很危險，所以臨床醫師應該有高度的警覺，那麼何時需要篩檢呢？年輕高血壓病人、嚴重高血壓、頭痛、心悸、冒汗、無法解釋的腹部或胸口疼痛、有家族史、無法使用降壓藥控制血壓等。
< References
>
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Pheochromocytoma. J Clin Hypertens 2002;4:62.
- Higashi Y et al: Excess
norepinephrine impairs both endothelium-dependent and
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deletion and point mutation in MEN 2A-associated
pheochromocytoma. Oncogene 2002;21:479.
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pheochromocytoma. Clin Lab 2002;48:5.
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Case Discussion
繼續教育考題