|
< Chief complaint
>
Intermittent abdominal
pain for two months.
< Brief history
>
This 29-year-old lady
was healthy before except that she was easily allergic to
drugs. Two months prior to admission, she began to suffer from
intermittent abdominal pain after a common cold. The pain or
cramping was most often situated in the epigastric area but
sometimes was poorly localized. Additionally, every episode of
which was accompanied by nausea, vomiting, tachycardia,
sweating and constipation. The discomfort got worsened during
menstruation and improved slightly after food intake. She had
visited the outpatient clinics for 3 times where panendoscopy
only revealed superficial gastritis, but all treatments given
for which were in vain. She even had visited the emergency
room for 4 times in one week where all examinations including
complete blood counts, biochemical studies, urinalysis,
abdominal X-ray and echogram were negative. The pain worsened
after metoclopramide injection and resolved during glucose
infusion. Under the impression of chronic abdominal pain, she
was admitted for further study.
Throughout her
disease course, there was no motor paralysis, sensory defect,
seizure, consciousness disturbance, hypertension,
photosensitivity, dark-purple-color urine, oral ulcer or
arthralgia. She denied smoking, alcohol consumption and a
family history of chronic abdominal discomfort.
Physical
examination revealed a 46 kg, 165 cm tall lady with an anxious
appearance. Her blood pressure was 120/80 mmHg, respiratory
rate was 18/min, pulse rate was 82/min and her temperature was
36.1℃. Her consciousness was clear, conjunctivae were pink,
and her sclerae were anicteric. The pupils were isocoric with
prompt light reflex. The neck, chest, abdominal, extremity and
skin examinations were unremarkable.
< Laboratory data
>
1. CBC/DC
|
WBC |
RBC |
HB |
HCT |
MCV |
MCHC |
PLT |
|
K/μL |
M/μL |
g/dL |
％ |
fL |
g/dL |
K/μL |
|
3.40 |
4.15 |
13 |
37.2 |
89.6 |
34.9 |
138
| 2. BCS+e-
|
ALB |
TP |
T-Bil |
AST |
ALT |
ALP |
γ-GT |
Glucose |
|
g/dL |
g/dL |
mg/dL |
U/L |
U/L |
U/L |
U/L |
mg/dL |
|
3.5 |
6.5 |
0.4 |
27 |
39 |
226 |
25 |
89 |
|
UN |
CRE |
Na |
K |
Ca |
Mg |
P |
Cl |
|
mg/dL |
mg/dL |
mmol/L |
mmol/L |
mmol/L |
mmol/L |
mg/dL |
mmol/L |
|
2.0 |
0.4 |
135 |
3.5 |
2.0 |
0.82 |
3.0 |
96 |
3. Urine analysis and porphyrin
|
Appearance |
Sp. Gr |
pH |
Protein |
Glucose |
Ketone |
Porphyrin |
|
|
|
|
g/dL |
mg/dL |
|
|
|
Y;C |
1.028 |
6.0 |
- |
- |
- |
+ |
|
Urobilirubin |
Bilirubin |
Nitrate |
WBC |
RBC |
Epi |
Cast |
|
|
|
|
|
|
HPF |
|
|
1.0 |
- |
- |
- |
- |
3-5 |
- |
4.Watson-Schwartz test and urine levels of porphyrin
precursors
|
Porphobilinogen (PBG) |
PBG |
δ-aminolevulinic acid |
|
|
mg/day
(0-4) |
mg/day
(1-7) |
|
positive |
7.38 |
2.21 |
< Course and treatment
>
During hospitalization,
complete blood counts, biochemical and immunological studies
were all within normal limits. Neuropathic pain was highly
suspected. Further check-up for urine porphyrin was positive
by using fluorescence microscopic exam. Watson-Schwartz test
for urine porphobilinogen (PBG) which was a porphyrin
precursor was also positive. Her abdominal pain improved
during glucose infusion. However, severe discomfort including
nausea, vomiting and epigastralgia flared up again 3 days
later and gradually resolved after a hematin arginate infusion
for 4 consecutive days that was complicated with phlebitis.
Intermittent
complex partial seizure (abnormal inward gaze and
unresponsiveness for about 1 to 5 minutes each time) happened
suddenly. Biochemical exams reported hyponatremia ([Na+]=
122 mmol/L). Both computer tomography of
the brain and electroencephalogram (EEG) were negative.
Hyponatremia-related seizure was impressed. She received 3% NaCl solution
drip and gabapentin for porphyria-related seizure. The
frequency of seizures gradually decreased and subsided completely later.
However, she developed persistent left
chest pain that was accompanied by cold
sweating. Twelve-lead electrocardiogram showed T-inversion over II, III,
aVF, and V2 to V5, but
serum levels of cardiac enzymes were within normal limits. Aspirin,
isosorbide mononitrate and propranolol were prescribed for the
angina.
Acute
intermittent porphyria was confirmed by urine level of PBG,
which was significantly elevated (PBG 7.38 mg/day). Sudden
onset hypotension and loss of consciousness occurred
unexpectedly. Hemodynamic studies revealed good cardiac output
and lower peripheral vascular resistance. Septic shock was
impressed and empirical antibiotics infusion was given. Brain
MRI showed irreversible ischemic changes at bilateral medial
thalamus, posterior brainstem, and several areas of cortex and
only ischemia in the medulla area was reversible. EEG
manifested a severe and diffuse cortical dysfunction. Hematin
arginate infusion was given immediately. Spiking fever up to
39.5℃ occurred and laboratory exams reported pancytopenia.
Bone marrow aspiration and biopsy revealed a hypocellular
marrow, and a drug-related bone marrow suppression was highly
suspected. Granulocyte-colony stimulating factor and strong
antibiotics were administered. Three days later, blood
cultures yielded Enterococcus faecium. However,
massive hemoptysis, pulmonary hemorrhage and hypoxemia
developed. She expired on the 37th day of admission due to
profound shock, refractory hypoxemia and multi-organ failure.
< Discussion
>
紫質(porphyrin)是人類血色素(hemoglobin)組成物－血基質(heme)的前驅物。紫質症(porphyrias)是因為血基質合成過程中酵素活性異常，使得患者身體內的紫質或其前驅物過量累積所致。分為遺傳性或後天性，若為酵素缺陷則為遺傳性，大多是體染色體顯性遺傳；後天影響為環境因子造成，如飲食、藥物、化學物質、及紫外線過度照射暴露。目前已知此疾病至少可以分成八種類型，分別是因合成血基質過程中不同的酵素缺陷所致。這八種疾病被歸類為肝性(hepatic)或紅血球生成性(erythropoietic)紫質症，雖然症狀可能有所重疊，但是前者主要是神經性(neurologic)症狀，包括神經性腹痛、神經病變、精神紊亂等；而後者會引起皮膚光敏感(cutaneous
photosensitivity)。對於為何會有神經病變的症狀目前原因不明。長波紫外線活化皮膚中過多的紫質，會導致細胞傷害、疤痕及變形。
紫質症中的急性間歇性紫質症(Acute intermittent
porphyria，AIP)是體染色體顯性遺傳疾病，主要是因為hydroxymethylbilane (HMB)
synthases活性只有正常人一半。這種肝性紫質症全世界都有，但是好發於北歐及英國。雖然異型合子個體(heterozygous
individual)都有酵素缺損，但是臨床表現卻大不相同，因為環境和荷爾蒙因素，如藥物、食物、或類固醇都和疾病的活化有關。因此，病人或有此種基因的家人都應該盡量避免這些已知的催化因子。大部分異型合子個體都沒有症狀(latent)，除非遇到會造成紫質過度累積的狀況。內生性及外源性性腺荷爾蒙、喝酒、低卡飲食、體重減輕、藥物、感染、手術、甚至月經週期，都會誘發紫質症。通常青春期之前很少發作，而且神經內臟(neurovisceral)症狀不具特異性，所以診斷常會延遲。
急性間歇性紫質症會造成病人傷殘，但是卻很少因此而死亡。腹痛是最常見的症狀，通常很難定位；也可以出現絞痛、腸阻塞、腹脹、腸音減少或增加、腹瀉。臨床上沒有腹部壓痛、發燒、白血球增加，主要是因為是神經性(neurologic)病變而非發炎性(inflammatory)疾病。出現噁心、嘔吐、便秘、心跳加快、高血壓、意識症狀、肌肉無力、感覺喪失、排尿疼痛、尿液滯留、流汗，及肢體、頭部、頸部或胸口疼痛都是典型的症狀。心跳加快、高血壓、煩躁不安、手抖和大量流汗是因為交感神經過度活化。週邊神經病變是因為軸突退化(degeneration)而非去髓鞘(demyelination)，且並非每一次發作時都會出現明顯的神經病變。運動神經的影響先從近端肌肉開始，最常影響肩膀和上臂；深部肌腱反射可以是正常或增加，但是通常是減少或消失；漸進性的肌肉無力會造成呼吸和延腦麻痺，如果沒有及早插管會導致死亡；然而，也可能因為交感神經過度活化及心律不整而猝死。意識的症狀包括焦慮、失眠、憂鬱、失去方向感、幻覺及妄想，也會出現癲癇，可能是因為低血鈉或神經病變。癲癇的治療很困難，因為除了bromides，大部分的藥物都會惡化病情，使用低劑量clonazepam比pheytoin或barbiturates安全。低血鈉的原因包括嘔吐、腹瀉、少吃、腎臟流失、或疾病影響下視丘造成血管加壓素(vasopressin)不正常分泌(SIADH)。除此之外，也會出現持續性高血壓和腎功能不良。當病情改善後，腹痛會在數小時內消失，麻痺症狀可在幾天內改善，且往後數年後仍可持續改善。
急性發作時，血漿和尿液中的δ-aminolevulinic acid (ALA)和porphobilinogen
(PBG)濃度會上升。尿液中的PBG可達50至200 mg/d (正常是0到4 mg/d)，ALA可至20至100 mg/d
(正常是1至7
mg/d)。急性發作時如果尿液中的PBG濃度正常就可以排除急性間歇性紫質症。給予葡萄糖後，這些紫質前趨物濃度會減少，臨床症狀就會改善，尤其是給予血色素(hematin)後。大部分沒有症狀異型合子個體的尿液ALA和PBG濃度是正常的，測紅血球中的HMB
synthases濃度，可以確定診斷及篩檢沒有症狀的親屬。
病人應該避免會活化或惡化疾病的藥物，包括巴比妥鹽、磺胺類抗生素、治皮膚表面黴菌病抗生素(glutethimide)、抗癲癇藥(如phenytoin)、避孕丸、麥角(ergots)、metoclopramide、rifampin、解熱鎮痛劑(如diclofenac)、酒精、荷爾蒙製劑(如danazol)等。有些藥物是安全的，如narcotic
analgesics、aspirin、acetaminophen、phenothiazines、penicilline及其衍生物、chloral
hydrate(鎮靜安眠抗痙劑)、streptomycin、glucocorticoids、bromides、insulin、atropine、cimetidine。
急性發作時，需要narcotic
analgesics治療腹痛；phenothiazines對於噁心、嘔吐、焦慮、不安是有效的。失眠可以用chloral
hydrate，而低劑量的benzodiazepines是安全的。雖然靜脈給予葡萄糖(每天至少300克)對於急性發作的腹痛有效，但是更建議給予全靜脈營養，因為這些病人通常食慾差已經有一段時間了。然而對於降低紫質前趨物濃度，靜脈給予血基質(heme)比葡萄糖更有效，改善也更快；但是如果治療延遲，則對血基質的反應也會下降，因此應該在急性發作時盡快每天給予3至4克血基質且持續4天，要小心靜脈炎(phlebitis)及抗凝集反應(anticoagulant)。
紫質症少見且症狀不具特異性，很容易診斷延遲，因此臨床上如果遇到長期腹痛病患，應該將此病列入鑑別診斷。
< References
>
- De Siervi A et al: Identification
and characterization of hydroxymethylbilane synthase
mutations causing acute intermittent porphyria: evidence for
an ancestral founder of common G111r mutation. Am J Med
Genet 86:366, 1999.
- Lindberg RL et al: Motor neuropathy
in porphobilinogen deaminase-deficient mice imitates the
peripheral neuropathy of human acute porphyria. J Clin
Invest 103:1127, 1999.
- Bonkowsky et al: Seizure management in acute hepatic
porphyria: risks of valproate and clonazepam. Neurology
30:588, 1980.
| 
Case Discussion
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