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< Presentation of Case
>
This 19-year-old female had been
well before until recently when abnormal liver function was
detected in a health examination on entry into the college.
She also began to experience swelling of bilateral lower legs
one month later. She denied associated symptoms, such as
orthopnea, excertional dyspnea, foamy urine and abdominal
fullness. She also denied jaundice, nausea, vomiting, general
malaise or poor appetite. She sought medical attention at a
local clinic where abdominal sonography revealed abnormal
findings suggestive of cirrhosis of the liver, for which she
was referred to our gastroenterology outpatient department for
further evaluation and admission was suggested. She did not
consume alcohol or tobacco, and had no recent history of
animal contact or travel.
On admission, her
temperature was 36.2oC, pulse rate 82 beats per minute,
respiratory rate 20 breaths per minute and blood pressure
104/64 mmHg. She had no distress. The conjunctiva was pink and
sclera was anicteric. Isocoric pupil with prompt light reflex
was recorded. No lymph nodes were palpable. Her breath sounds
were clear. There were no audible cardiac murmurs. The abdomen
was soft and flat without tenderness. The liver and spleen
were not palpable, and no shifting dullness was noted. Her
bowel sounds were mildly hyperactive. There was no flank
percussion tenderness. The extremities were warm without
cyanosis. But, grade II pitting edema over bilateral legs was
found. There was no rash or discoloration over her skin.
< Laboratory data
>
Table 1. CBC/DC
|
WBC |
RBC |
Hb |
Hct |
MCV |
MCH |
MCHC |
PLT |
|
/μL |
M/μL |
g/dL |
% |
fL |
Pg |
g/dL |
K/μL |
|
6490 |
4.28 |
14.4 |
41.9 |
97.9 |
33.6 |
33.4 |
179.0 |
Table 2. Biochemistry and electrolytes
|
Alb |
TP |
AST |
ALT |
T-BIL |
D-BIL |
ALP |
r-GT |
|
g/dL |
g/dL |
U/L |
U/L |
mg/dl |
mg/dl |
U/l |
U/l |
|
3.2 |
5.6 |
51 |
43 |
1.11 |
0.3 |
274 |
44 |
|
Na |
K |
Cl |
Ca |
TG |
T-CHO |
UN |
CRE |
UA |
|
mmol/L |
mmol/L |
mmol/L |
mmol/L |
mg/dL |
mg/dL |
mg/dL |
mg/dL |
mg/dL |
|
|
|
|
2.09 |
121 |
205 |
13.2 |
1.1 |
2.4 |
Table 3. Urine analysis
|
|
Bil.(C) |
Nitrite(C) |
RBC(S) |
WBC(S) |
EpithCell(S) |
Cast(S) |
Crystal(S) |
Bacteria |
|
2006/09/07 |
- |
- |
- |
- |
- |
- |
- |
- |
Table 4. Coagulation profile
|
PT |
INR |
PTT |
|
sec |
|
sec |
|
15.7 |
1.3 |
31.5 |
< Course and treatment
>
After admission, abnormal liver
function was noted; AST was 51 U/L, ALT 43 U/L and total
bilirubin 1.11 mg/dL (Table 2). Serum
albumin was 3.2 g/dL. Urinalysis did not show proteinurea.
Abdominal sonography showed cirrhosis of the liver and
splenomegaly (figure
1). Viral hepatitis markers showed negative for HBsAg and
anti-HCV antibody. ANA was weakly positive (1:40, speckle),
while anti-mitochondrial antibody was negative. Iron profile
showed serum 73.1μg/dL , TIBC 201 μg/dL and ferritin 150 ng/mL
( reference values: serum iron for males, 75-178; and for
females, 66-155 μg/dL; TIBC 275-332 μg/dL; ferritin for males,
26.6-377; and for females, 0-151 ng/mL). The level of iron of
hemochromatosis was elevated. So the diagnosis of
hemochromatosis was not favor. Ceruloplasmin was 11.1 mg/dL
(reference value, 16.4-65.4mg/dL). Tentative diagnosis of
Wilson's disease was made. Slit lamp examination by an
ophthalmologist revealed Kayser-Fleischer rings (fig2).
24-hour urinary excretion of copper was 450 μg per day
(reference value, < 100 μg/24h). A liver biopsy was
performed and pathology revealed chronic active hepatitis with
cirrhosis and positive stains for copper (figures 3
and 4 ),
which confirmed the diagnosis of Wilson's disease. Neurologic
examination revealed normal and magnetic resonance imaging
(MRI) of the brain did not disclose any lesions of the basal
ganglia. Dietician consultation suggested a low-copper diet.
She was then discharged and regularly followed up as an
outpatient.
< Discussion
>
威爾森氏症(Wilson's
disease)為一種較少見體染色體隱性遺傳疾病，發生率大約是1/500,000新生兒。西元1985年Fryman首先報告此病的基因異常是位在第十三對染色體之esterase
D
locus上；西元1990年Houwen等學者則更清楚指出此病的異常基因位於第十三對染色體的長臂上q14-21上，是一負責產生copper-transporting
ATPase酵素的基因(ATP7B)上發生突變，導致人體內銅代謝時經由膽汁分泌的途徑發生故障，使得過多的銅堆積在肝臟，並逐漸波及全身器官，對人體組織產生毒性與破壞。
威爾森氏症(Wilson's disease)
患者臨床症狀出現在5歲前並不多見，一般症狀多發生於青少年晚期，大多會以肝臟或中樞神經系統的問題表現出來。其中以肝的表現為先，也可能兩者同時出現，事實上超過一半的患者，肝臟是其唯一影響的器官。
威爾森氏症(Wilson's
disease)在肝臟方面的臨床症狀很像肝炎或肝硬化，不易區分；常常被誤認為病毒性肝炎(infectious
hepatitis)，但兩者形成病因、治療相差很大。威爾森氏症是因過多的銅在肝臟堆積，導致肝臟組織發炎、壞死及纖維化。患者可能出現肝酵素指數上升、黃疸、白蛋白降低、腹水、凝血機能異常、血氨增高等病症。唯一不尋常的是威爾森氏症好發年齡多在10~15歲，故對於不明原因的慢性肝炎患者，尤其當發生於孩童期或青年期之時，應將威爾森氏症(Wilson's
disease)列為鑑別診斷。
威爾森氏症(Wilson's
disease)在神經系統方面的臨床表現，通常在成人階段，一般會出現顫抖、不自主運動、步伐不穩、肢體張力異常、口齒不清、流口水、吞嚥困難等情形；也有患者會出現類似巴金森氏症的行動遲緩、寫字縮小症、面具臉、休息性顫抖或肢體僵硬。
威爾森氏症患者約三分之一患者會出現多樣化精神症狀，像是情緒不穩、憂鬱症、躁症、精神錯亂人格改變、甚至自殺行為等。角膜異常之Kayser-Fleischer
rings，亦不少見，約可在50%-62%的患者的角膜上發現，發生的原因是銅沉積在角膜的Descemet's
membrane。此外，女性患者可能會有月經不規則，甚至停經、不孕或流產等現象。其他臨床症狀：如腎小管病變 (renal
tubular acidosis)或腎功能異常；白血球與血小板過低、溶血性貧血則較少見。
威爾森氏症(Wilson's
disease)診斷初步懷疑仍藉由醫療會談與理學檢查，40歲以下患者有無法解釋的慢性活動性肝炎、無法解釋的肝硬化之症狀和病徵、無法解釋的中樞神經系統疾病，都應該考慮到此疾病。大多數患者會從父母親各遺傳到一條有缺陷的基因，不分性別，每一胎皆有1/4的機率會罹患此症。故患者的兄弟姊妹應有1/4罹病機率，不管有無症狀，建議皆需接受篩檢。
威爾森氏症(Wilson's
disease)的診斷，可藉由以下證實：
- 角膜存在Kayser-Fleischer氏環
- 血清中藍胞漿素（cerulopasmin）含量低於20 mg %
- 每克乾燥肝臟活體切片標本的含銅量超過250 μg
- 24小時尿液銅排出超過100 μg
威爾森氏症的治療目標是降低組織中銅的含量至正常狀態；治療應愈早開始，預後愈好。如果沒有適當的治療，時間愈久，身體的器官損傷也愈大。在飲食方面，含高量銅的食品，如巧克力、核果、脫水的果類、動物肝臟、有殼類海鮮等等，都要盡量避免食用。
威爾森氏症的治療，需終身服藥，以加速將銅從體內排除，患者接受治療也需持之以恆，不可隨意減藥或停藥，避免造成病情惡化而有生命危險。
目前可用的藥物有：
- 銅的螫合劑 (chelating
agent)：D青黴胺(D-penicillamine)和trientrine HCl
(Syprine)，藉由與銅進行螯合或鍵結，再經由尿液排泄掉體內過多的銅。在治療的最初一個月內，每週要接受幾次白血球檢查和血小板計數、尿分析及體溫測量，之後也需不時的檢驗，可及早發現是否發生藥物過敏現象和副作用；一旦發生過敏，則應考慮更換藥物或停止治療。治療期中任何時間，甚至治療好幾年後，都還是有可能出現顆粒性白血球減少、血小板減少、腎病症候群、Goodpasture's症候群、全身性紅斑性狼瘡、嚴重關節痛、或重症肌無力等。
- 其他常用藥物還有醋酸鋅鹽(zinc
salts)，可阻止小腸對銅的吸收，藉此減少體內聚積的銅，也可避免銅的再吸收，其副作用較小。
威爾森氏症的患者如果肝臟的損害已經到了不可逆的階段，就必須考慮實行肝臟移植。
< References
>
- Roberts EA, Schilsky ML. Diagnosis
and treatment of Wilson disease: an update. Hepatology 2008
;47(6):2089-111.
- Roberts, EA, Schilsky, ML. A
practice guideline on Wilson disease. Hepatology 2003;
37:1475-92.
- Gitlin JD. Wilson disease. Gastroenterology.
2003;125:1868-77.
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Case Discussion
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