|
< Chief complaint
>
A
62-year-old housewife with frequent attacks of confused
consciousness for 5 years
< Brief
history >
This 62-year-old woman
had been in good state of health until 5 years ago, when she
began to have frequent attacks of general weakness, cold
sweating and confused consciousness which mostly happened in
the late afternoon and evening and sometimes in the early
morning. Those episodes could be relieved by eating and
deteriorated with starvation and exercise. Most of the attacks
last for several minutes and could recover spontaneously.
Because of confused consciousness and syncope, she was brought
to a local hospital where hypoglycemia was noted. She regained
her consciousness after intravenous dextrose infusion. She was
suggested to admission for further study but she refused. In
recent months, both the frequency and severity of hypoglycemic
attacks increased. It took longer time to regain her muscle
power and consciousness (several minutes in past 5 years
compared to one hour recently). Besides, she was noted to have
involuntary movement of limbs during the hypoglycemic
episodes. She had a weight gain of 25 kg in recent four years.
Under the impression of recurrent symptomatic hypoglycemia,
she was admitted for further evaluation.
She denied any
use of alcohol, tobacco or other medication. There was no
family history of pituitary or pancreatic tumor, bone disease,
thyroid disease, parathyroid disease, nephrolithiasis or
diabetes mellitus.
< Physical examination
>
On physical
examinations, she had clear consciousness but was in anxious
state. She was obese in general appearance. Her body height
was 153 cm and body weight was 86.5 kg. The body temperature
was 37°C, the pulse rate 88 per minute and the respiratory
rate 20 per minute. Her blood pressure in supine position was
120/84 mmHg. Her conjunctivae were pink and the sclerae were
anicteric. The pupils were isocoric with prompt light
reflexes. There was no moon face, acne nor buffalo hump. The
neck was supple without lymphadenopathy, engorged jugular
veins, palpable thyroid gland or carotid bruit. The chest was
symmetric expansion and breath sounds were bilaterally clear.
The heart beats were regular without audible murmur. The
abdomen was distended but soft without purple striae.
Normoactive bowel sounds and impalpable liver and spleen were
noticed. Her extremities were freely movable without edema.
There was no cyanosis, petechiae, purpura or
pigmentation.
<
Laboratory data
>
1. CBC/DC
|
WBC |
RBC |
HB |
HCT |
MCV |
MCHC |
PLT |
|
K/μL |
M/μL |
g/dL |
％ |
fL |
g/dL |
K/μL |
|
5.17 |
4.6 |
13.4 |
42.8 |
29.1 |
31.3 |
271 | 2.
BCS+e- (Overnight fasting)
|
ALB |
TP |
T-Bil |
AST |
ALT |
ALP |
ACTH |
Cortisol |
|
g/dL |
g/dL |
mg/dL |
U/L |
U/L |
U/L |
pg/mL |
μg/dL |
|
3.7 |
6.9 |
0.4 |
27 |
39 |
226 |
60
(10-65) |
25
(5-25) |
|
UN |
CRE |
Na |
K |
Ca |
Glucose |
Insulin |
C-peptide |
|
mg/dL |
mg/dL |
mmol/L |
mmol/L |
mmol/L |
mg/dL |
μU/mL |
μg/mL |
|
16.1 |
0.7 |
146 |
4.2 |
2.22 |
39 |
31.6 |
10.8 |
3. Urine analysis
|
Appearance |
Sp. Gr |
pH |
Protein |
Glucose |
Ketone |
OB |
|
|
|
|
g/dL |
mg/dL |
|
|
|
Y;C |
1.028 |
6.0 |
- |
- |
- |
- |
|
Urobilirubin |
Bilirubin |
Nitrate |
WBC |
RBC |
Epi |
Cast |
|
|
|
|
|
|
HPF |
|
|
1.0 |
- |
- |
- |
- |
3-5 |
- |
4. Prolonged fasting test
|
Glucose |
Insulin |
C-peptide |
Cortisol |
|
mg/dL |
μU/mL |
ng/mL |
μg/dL |
|
33 |
31 (5-20) |
7.9 (0.5-3) |
25
(5-25) |
< Course and treatment
>
Overnight fasting plasma glucose was 39 mg/dL. Prolonged
fasting tests showed hypoglycemia (glucose 33 mg/dL) with
inappropriate high serum insulin and C-peptide levels (insulin
31 μU/mL, C-peptide 7.9 ng/mL ). Elevation of amended
insulin-glucose ratio (AIGR＝1030)* proved hyperinsulinemic
hypoglycemia. Insulinoma was highly suspected. Endoscopic
ultrasound study showed a tumor about 0.5 cm at the pancreatic
neck（Fig
1）. Both abdominal computer tomography scan （Fig 2）and
magnetic resonance cholangiopancreatography（Fig
3）reported negative finding. She received exploratory
laparotomy with intraoperative ultrasonography but the excised
nodule turned out to be only a lymph node. Medical therapy
with diazoxide was suggested. Diazoxide 3 ml bid was adjusted
with 90 mg/dL of serum fasting glucose level. Loop diuretics
were administered for fluid retention. Antacids were
prescribed for GI upset. She was discharged in a stable
condition and followed up at our OPD.
*AIGR＝serum insulin (μU/mL) × 100 ÷ (plasma
glucose (mg/dL)－30)＝31×100÷(33-30)＝1030
When AIGR is more than
30, insulinoma is
suggested.
< Discussion
>
低血糖除了會出現腎上腺症狀（adrenergic
symptoms），包括心悸、緊張、手抖、冒汗及心跳加快外，也會出現神經性低血糖症狀（neuroglycopenic
symptoms），如無力、倦怠、頭痛、語言不清、行為改變、意識改變、甚至癲癇發作，因此容易被當成是精神方面的問題。發生低血糖時須先區分是空腹低血糖（fasting）或飯後低血糖（postprandial）。完全符合Whipple's
triad時就可以診斷為空腹低血糖，包括出現低血糖的症狀及徵兆，血糖值45
mg/dL以下，及給予葡萄糖後症狀立刻緩解。因此我們的病人符合空腹低血糖的診斷。
造成空腹低血糖的原因很多，包括肝臟疾病、腎臟疾病、藥物作用、升糖荷爾蒙缺乏或血中胰島素量增加。外源性胰島素的使用、降血糖藥物、胰島素抗體或胰島素接受體抗體以及內生性胰島素量增加，均會造成空腹低血糖。然而健康成人出現自發性空腹低血糖最常見的原因是胰島素瘤（insulinoma）。
80％的胰島素瘤是單一且良性的；10％是惡性的；剩下的是多發且散在性腺瘤（multiple
with scattered micro- or
macroadenomas），需嚴密監控是否為惡性。超過99％的胰島素瘤位於胰臟內，尤其是胰臟頭。雖然最常發生在30到40歲，但是可以在任何年紀出現，沒有性別上的差異，然而有些研究顯示女性較多。
臨床表現主要以亞急性神經性低血糖（subacute
neuroglycopenia）為主，而非腎上腺症狀，因此容易以為是精神疾病而延遲診斷。常常在運動或空腹時出現反覆性的中樞神經系統功能失常。吃含糖食物可以減輕症狀，因此約30％的病人有肥胖的問題。
當血糖值小於45 mg/dL且血中胰島素量大於5
μU/mL時就要高度懷疑是胰島素瘤。臨床上最常使用抑制性試驗（prolonged fasting
test）來作診斷。正常人在禁食72小時後血糖也不會低於55 mg/dL，而此時的胰島素濃度會低於10
μU/mL。有些正常女性甚至血糖可以低至30 mg/dL，胰島素下降到小於5
μU/mL而仍然沒有症狀，因為酮體形成（ketogenesis）可以提供足夠的燃料給中樞神經。以前會使用胰島素與血糖的比值（正常非肥胖的人小於0.25
μU/mL），但是目前少用。大部分胰島素瘤的病人在禁食24至36小時後會出現進行性低血糖症狀併血中胰島素上升，但是沒有酮尿。
也可以使用刺激試驗（stimulation
tests）來作診斷。靜脈注射1
mg的升糖素（glucagon）或鈣離子，之後每五分鐘抽一次血，共15分鐘，當血中胰島素濃度大於130
μU/mL時，50％是胰島素瘤，但是如缺乏過多的胰島素分泌並不能完全排除胰島素瘤的可能性。也可以測前胰島素（Proinsulin），正常人前胰島素與胰島素的比值小於20％，但是胰島素瘤的病人比值為30-90％，因此對於胰島素瘤而言，測前胰島素有較高的特異性。
臨床上仍需測C胜(月太)（C-peptide）、磺醯尿素（sulfonylurea）及胰島素抗體來排除外源性胰島素、降血糖藥物及自體免疫疾病的可能性。
然而，臨床上最重要的仍是腫瘤的定位，包括腹部超音波、電腦斷層、核磁共振、血管攝影、內視鏡超音波（endoscopic
ultrasound）及手術中超音波使用，後者常用於小腫瘤，被認為是目前最有效的方法。手術中外科醫師仔細的觸摸配合手術中超音波使用，成功率可以高達97%。但是因為這些腫瘤通常太小而找不到(平均直徑為1.5
cm)，因此常需要重新開刀。
治療胰島素瘤主要以手術切除腫瘤為主，然而2-5％的病人即使有術中超音波的輔助也無法找到腫瘤。這些腫瘤大部分位於胰臟的頭，因此不建議盲目的切除胰臟遠端三分之二，也不建議將胰臟完全切除。這時可以先以內科治療。手術後會有數天出現高血糖，原因為術後胰臟水腫及發炎無法分泌胰島素、手術使得一些反調節荷爾蒙升高（counterregulatory
hormone）、胰島素受體因為長期高胰島素而降低調節（chronic down regulation of insulin
receptors）、長期的低血糖抑制正常胰臟B細胞的功能；給予外源性胰島素治療，大部分胰島素的分泌會在48至72小時之後恢復。內科治療胰島素瘤首用diazoxide（每天300-400
mg），副作用為腸胃不適、多毛、水腫、體重增加及高血鉀，腎臟及心臟功能不良的病人應小心使用。通常建議並用利尿劑（hydrochlorothiazide，每天25-50
mg）。如果無法忍受副作用，可以選擇鈣離子阻斷劑（如verapamil 80
mg，每天三次），長效體制素（octreotide）的效果有限，streptozocin用於胰島細胞癌。
< References >
Localization of
insulinomas. Arch Surg 1999;28:467.
Symptoms of hypoglycemia, thresholds
for their occurrence, and hypoglycemic unawareness.
Endocrinol metab Clin North Am 1999;28:495.
Plasma proinsulin-like component in
insulinoma: a 25-year experience. J Clin Endocrinol Metab
1995;80:2884.
Insulinoma. Surg Oncol Clin N Am
1998;7:819.
Intraoperative ultrasound and
preoperative localization detects all occult insulinomas.
Arch Surg 2001;136:1020.
A practical approach to fasting
hypoglycemia. N Engl J Med 1992;326:1020.
Hypoglycemic disorders. N Engl J Med
1995;332:1144.
Diagnostic approach to adults with
hypoglycemic disorders. Endocrinol Metab Clin North Am
1999;28:519.
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Case Discussion
繼續教育考題