Evidence-Base Medicine
Supervisor 施相宏 醫師
Intern 朱能生 李涵蓉 郭欣慧
99/12/23
Patient Profile
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Chart No. :00042534
Name: 黃o崴
Age: 13 y/o
Gender: male
Admission date:99.11.16
Chief Complaint
Fever up to 38。C this morning and skin
rashes over face, extremities and trunk
with itching sensation (since 11/16)
Present illness-1
This 12-year-6-month old boy has suffered
from folliculitis for almost a month.
Because of the folliculitis, he went to the
local clinics and has taken some medicine
for almost a month.
Present illness-2
Three weeks ago, he suffered from fever
without any other symptoms.
Last week, he suffered from fever again
accompanied by skin rashes over
extremities and abdomen.
11/15 - He vomited without other symptoms
Present illness-3
 11/16 - He suffered from fever at the third
time with skin rashes over face, extremities
and trunk, so he was brought to our
emergency department for help.
 There were no cough, no rhinorrhea, no
vomiting, no diarrhea and no tea color urine.
Past history
 Systemic disease: denied
 Heart/liver disease(-),asthma(-)
 Hospitalization hx:
88-05-21 to 88-05-25 for hand-foot-mouth disease
89-10-4 to 89-10-9 for herpangina
 Vaccination: as scheduled
 Operation history: denied
 Full-term, delivered by : C-section
Personal History
Occupation: nil
Travel history: nil
Contact history: nil
Allergy: denied drug or food allergy
Current Medication
 Doxycycline
 Clindamycin
 Cotrizine
 Diclofenac
Physical Examination
• Consiousness:
– alert
• Vital sign:
–
–
–
–
BP: 144/73 mmHg,
PR: 80 bpm,
RR: 16 cpm,
BT: 37.4 ℃
• Head:
•
–
–
–
–
• Chest:
– Breathing sound: coarse
– Heart sound: regular heart beat, no
murmur
• Abdomen: .
–
–
–
–
Soft and flat ,no tenderness
Bowel sounds: normoactive
Percussion: not tympanic
Muscle garding (-)
Conjuctiva: not pale
Sclera: not icteric.
Throat: no injected
• Extremities
Tonsil: no enlarged and congested
– Free movable, no pitting edema
Neck:
– Supple,
– No palpable lymphoadenopathy• Skin
– No jugular vein engorgement
– skin rash over face, chest, abdominal
and extremities
99/11/16 : Lab data-1
99/11/16 : Lab data-2
99/11/16 : Lab data-3
Tentative diagnosis
Acute liver injury
Urticaria
Proteinuria
Folliculitis
Management on 11/16
General survey (blood exam, urine
routine , mycoplasma titer).
IVF supply.
Monitor vital sign and clinical s/s.
Oral medications for symptoms relief.
Arrange abdominal echo.
Add cisbile use.
After admission
99.11.16 (D1)
Abdominal echo:
1.Increased liver echogenecity ,
susp. fatty liver or chronic liver, parnechymal disease.
99.11.19 (D3)
99.11.22 (D7)
MBD
99.11.26 (D11)
OPD
99.12.04 (D19)
OPD
GOT/GPT :178/1029
GOT/GPT : 63/ 391 ; r-GT:129 Bil (T/D):0.73/0.21
GOT/GPT : 33/ 139 ; r-GT:104 Bil (T/D):
GOT/GPT : 30/ 52 ; r-GT:71
/0.28
Bil (T/D):0.85/0.23
GOT
GPT
T-Bil
D-Bil
Background question
Question 1: How to approach the patient
with suspected drug induced liver
injury(DILI)?
Question 2: How to treat DILI?
Question 1~ How to approach the patient with suspected drug
induced liver injury(DILI)?
 key diagnostic elements
the time to onset
clinical features
the time and course of recovery
specific risk factors
the exclusion of other diagnoses
previous reports on the hepatotoxicity of the
implicated agent
rechallenge
 liver biopsy
Robert J. Fontana et al, Standardization of Nomenclature and Causality Assessment
in Drug-Induced Liver Injury: Summary of a Clinical Research Workshop.
HEPATOLOGY 2010;52:730-742.
Clinical guidelines for DILI
1
Apply to our patient
Careful history taking / rule out other
etiologies
Doxycycline, Clindamycin, Diclofenac,
Ketoconazole for 2-3 wk
herbal remedies(-), 鈣片(+)
Drinking(-), smoking(-)
underlying liver disease(-), other systemic
disease (-)
10月中學校體檢肝指數正常
Rule out autoimmune
hepatitis
Rule out virus hepatitis
Rule out bile duct disorders
N ENGL J MED 354;7
Evaluation the type of liver injury
11/16 data
AST = 1456 IU/L, ALT = 1586 IU/L , ALP = 775 IU/L
R= (1586/45)/(775/495)= 22.51
heptocellular type
UpToDate®
Situations in which DILI should be particularly
suspected:
1) start of a new drug in the past 3 months
2) presence of rash or eosinophilia
3) mixed type
4) cholestasis with normal hepatobiliary
imaging and
5) acute or chronic hepatits without
autoantibodies or
hypergammaglobulinemia
2
Apply diagnostic scale
CIOMS/RUCAM has
been widely used as
a standardized scale
with high reliability,
reproducibiliy and
specificity
RUCAM: 8
M&V: 16
3
Question 2 ~ How to treat DILI?
Data source: Robert J. Fontana et al, Standardization of Nomenclature and Causality
Assessment in Drug-Induced Liver Injury: Summary of a Clinical Research Workshop.
HEPATOLOGY 2010;52:730-742.
Discontinue the implicated drug as soon
as diagnosis is suspected
Corticosteroids, ursodiol and antioxidant
therapy used in severe or progressive liver
injury
data supporting safety and efficacy are lacking
N-acetylcysteine should be offered to
patients with ALF due to DILI
Apply to our patient
Discontinue Doxycycline, Clindamycin,
Diclofenac
Supportive care
Lab:
ALT: 1586(11/16) -> 391(11/22)
ALP: 775 (11/16) -> 648(11/22)
提出Foreground questions
What are the prognostic factors of
long-term outcome of patients with
idiosyncratic drug-induced liver injury
(DILI)?
PICOT
P Patients with a diagnosis of idiosyncratic druginduced liver injury with jaundice
I Any factor that affects the long term outcome
C Patient with DILI developed liver-related
mortality and morbidity
O Liver-related morbidity and mortality during
the follow-up
T Not defined
The "5S" levels of organisation of evidence from healthcare research
Brian Haynes, R Evid Based Med 2006;11:162-164
UpToDate
DynaMed
ACP PIER
BMJ Clinical Evidence
ACP journal club
Evidencebasedmedic
ine.com
Cochrane Library
BMJ Evidence Updates
Other Systemic reviews eg.
PubMed systemic reivew
PubMed
SUMsearch
TRIP
Google
Copyright ©2006 BMJ Publishing Group Ltd.
Search for useful information
Data base :
UpToDate, DynaMed, PubMed
Key words:
idiosyncratic, drug-induced liver injury,
jaundice
 … should be followed by serial biochemical
measurements. ... Recovery should be expected
in the majority of patients after discontinuing the
drug.
 … acute liver failure caused by an idiosyncratic
drug reaction has a mortality rate of over 80
percent without liver transplantation.
 … recover from acute DILI with jaundice
generally have a favorable prognosis, although
some patients appear to develop progressive
chronic liver disease.
Drugs and the liver: Patterns of drug-induced liver injury
Last literature review version 18.3: 九月 2010
This topic last updated: 七月 16, 2010
No meaningful finding!
Search Studies, PubMed
Title:
The long-term follow-up after
idiosyncratic drug-induced liver injury
with jaundice
Einar Björnsson, Loa Davidsdottir
Journal of Hepatology 50 (2009) 511–517
Introduction
 In general, the outcome of severe DILI has been
considered an all-or-nothing phenomenon.
 Only a very few studies have analyzed the longterm outcome of patients with DILI.
 Although recent two studies have reported that
chronicity following DILI is common, it has not been
convincingly demonstrated that the perceived
chronic liver injury does indeed lead to any liverrelated morbidity or mortality in the long run.
Aithal PG, Day CP. Gut 1999;44:731–735.
Pachkoria K, et al. Hepatology 2006;44:1581–1588
Patients and methods
 A cohort of patients with a diagnosis of DILI
reported to the SADRAC 1970-2004
 Only idiosyncratic DILI with jaundice (Bil≧ 2* ULN)
were included (exclude acetaminophen induced
DILI)
 The Fisher exact test for differences between
groups regarding dichotomous variables; the
Mann–Whitney test for continuous variables.
 All tests were two-tailed and were conducted at 5%
significance level.
SADRAC: Swedish Adverse Drug Reactions Committee
＊Cryptogenic cirrhosis: no known
cause for the liver cirrhosis
(include the metabolic syndrome)
median follow-up of 11 yrs
(range: 3–23 yrs)
Results (1)
Results (2)
 None of these patients were followed to complete
normalization of liver tests during the original
evaluation for the DILI.
Results (3)
 6/7(86%) pts with protracted DILI were CS type.
 5/685(0.73%) pts were diagnosed with AIH during f/u, and all
were female gender.
Results (4)
 In three out of five cases who developed AIH, the immunosuppressive treatment could be discontinued at follow-up.
Results (5)
 Pts with a liver-related morbidity and mortality during the
follow-up had been treated with the drug associated with
DILI for a longer period of time (135 ± 31 days vs. 53 ± 3
days, p < 0.0001)
Discussion (1)
 Development of clinically important liver disease
is rare (23/685, 3.4%) when a patient has
survived a severe DILI.
 Protracted DILI was mostly seen in patients with
cholestatic/mixed type (6/7, 86%) of DILI in
whom liver tests in the vast majority of cases
normalized during follow-up.
 Autoimmune hepatitis (5/23, 22%) developed in
a substantial number of patients with a
seemingly good prognosis.
Ortiz N, et al. J Hepatol 2008;48:A896.
Yamamoto S. J Gastroenterol 2002;37:1345–1346
Discussion (2)
 Duration of drug therapy before diagnosis of
DILI was found to be significantly longer in
those who experienced liver-related
morbidity/mortality during follow-up.
 Decompensated ‘‘cryptogenic” cirrhosis
developed in some patients in which DILI might
have played a role in this development.
Appraisal
AAMPICOT
Answer: Does this paper answer your
question?
Yes.
Author:
Is the author an expert of the field?
yes
Is there any conflict of interest?
Not mentioned
Method
Level of evidence
Level
Prognosis
1a
SR (with homogeneity) of inception cohort studies; CDR validated in
different populations
1b
Validating cohort study with good reference standards; or CDR tested
within one clinical centre
1c
All or none case-series
2a
SR (with homogeneity) of either retrospective cohort studies or untreated
control groups in RCTs
2b
Retrospective cohort study or follow-up of untreated control patients in
an RCT; Derivation of CDR or validated on split-sample only
2c
"Outcomes" Research
3a
3b
4
Case-series (and poor quality prognostic cohort studies)
5
Expert opinion without explicit critical appraisal, or based on physiology,
bench research or "first principles"
Grades of Recommendation
A
consistent level 1 studies
B
consistent level 2 or 3 studies or extrapolations from
level 1 studies
C
level 4 studies or extrapolations from level 2 or 3
studies
D
level 5 evidence or troublingly inconsistent or
inconclusive studies of any level
PICOT
P Patients with a diagnosis of idiosyncratic druginduced liver injury with jaundice
I Any factor that affects the long term outcome
C Patient with DILI developed liver-related
mortality and morbidity
O Liver-related morbidity and mortality during
the follow-up
T Not defined
PROGNOSIS WORKSHEET
(VIP rule)
Are the results of this prognosis study valid?
Was a defined, representative
sample of patients assembled at a
common (usually early) point in
the course of their disease?
Yes.(662/685 pts diagnosed
with DILI within a mean of 53
± 3 days)
2.Was patient follow-up
sufficiently long and complete?
Yes. (median follow-up: 11 yrs,
range: 3–23 yrs).
3.Were objective outcome criteria
applied in a “blind” fashion?
No. (Lab data and hx all need
to be measured or asked.)
4.If subgroups with different
prognoses are identified, was
there adjustment for important
prognostic factors?
Yes. (But it should be very
careful)
5.Was there validation in an
independent group (“test-set”) of
patients?
No. (There was no such independent group set up for
this study.)
1.
Are the valid results of this prognosis study important?
How likely are the outcomes
over time?
Not sure. (But it may play a
role while physicians meet
the pts with DILI)
2.How precise are the
prognostic estimates?
Not sure. (It needs to be
used in different races to
confirm these results.)
1.
Can you apply this valid, important evidence about
prognosis in caring for your patient?
Were the study patients
similar to your own?
Not exactly, due to our pt is
a teenager not an adult.
2.Will this evidence make a
clinically important impact on
your conclusions about what
to offer or tell your patient?
Yes.
1.
Apply
醫療現況
病人已順利出院，改由門診追
蹤。
病人意願
未知，但其與家屬在臨床醫療
的配合度佳。
生活品質
社會脈絡
由於患者於診斷DILI前用藥天數
約一個月，單純就文獻結果而言，
應屬預後較差的一群，故有賴良
好習慣的維持與長期追蹤，以確
保終身生活品質。
只要患者的狀況能有效改善，且
無complication或危害生活品質，
適當地衛教加上長期追蹤，仍是
最值得推展的醫療方針。
Audit
在「提出臨床問題」方面的自我評估
 我提出的問題是否具有臨床重要性？是，可作為預後參考
 我是否明確的陳述了我的問題？
我的foreground question 是否可以清楚的寫成PICO？可
我的background question是否包括what, when, how,
who等字根？未能全部涵蓋
 我是否清楚的知道自己問題的定位？（亦即可以定位自己
的問題是屬於診斷上的、治療上的、預後上的或流行病學
上的），並據以提出問題？知道，屬於預後範疇。
 對於無法立刻回答的問題，我是否有任何方式將問題紀錄
起來以備將來有空時再找答案？ 有，將其另列問題清單
在「搜尋最佳證據」方面的自我評估
 我是否已盡全力搜尋？是
 我是否知道我的問題的最佳證據來源？是
 我是否從大量的資料庫來搜尋答案？是
 我工作環境的軟硬體設備是否能支援我在遇到問
題時進行立即的搜尋？尚可，學校的電子資源仍
有不足之處
 我是否在搜尋上愈來愈熟練了？是
 我會使用「斷字」、布林邏輯、同義詞、MeSH
term，限制（limiters)等方法來搜尋？是
 我的搜尋比起圖書館人員或其他對於提供病人最
新最好醫療有熱情的同事如何？應屬「刻苦耐勞型」
關於「嚴格評讀文獻」方面的自我評估
 我是否盡全力做評讀了？是，已盡力而為
 我是否了解Number need to treat 的意義？了解
 我是否了解Likelihood Ratios的意義？了解
 我是否了解worksheet每一項的意義？了解
 評讀後，我是否做出了結論？是
關於「應用到病人身上」的自我評估
 我是否將搜尋到的最佳證據應用到我的臨床工作
中？目前尚無機會，但未來可運用
 我是否能將搜尋到的結論如NNT,LR用病人聽得懂
的方式解釋給病人聽？能
 當搜尋到的最佳證據與實際臨床作為不同時，我
如何解釋？臨床工作不一定能面面俱到，且人種
與國情差異也需考量
改變「醫療行為」的自我評估
當最佳證據顯示目前臨床策略需改變時，
我是否遭遇任何阻止改變的阻力？沒有
我是否因此搜尋結果而改變了原來的治療
策略？做了那些改變？未改變，因搜尋結果為
預後相關，不影響原來治療策略，但可能影響後
續追蹤時的臨床決策。
效率評估
這篇報告，我總共花了多少時間？ 2天
我是否覺得這個進行實證醫學的過程是值
得的？值得，因為對臨床工作有極高的參考價值
我還有那些問題或建議？目前暫無
Thanks for your attention!