Evidence-Base Medicine

Supervisor 施相宏 醫師 Intern 朱能生 李涵蓉 郭欣慧

99/12/23

Patient Profile

• 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-1This 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: deniedHeart/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 herpanginaVaccination: as scheduled Operation history: deniedFull-term, delivered by : C-section

Personal History

Occupation: nilTravel history: nilContact history: nilAllergy: denied drug or food allergy

Current Medication

DoxycyclineClindamycin CotrizineDiclofenac

Physical Examination

• Consiousness:– alert

• Vital sign:– BP: 144/73 mmHg,– PR: 80 bpm, – RR: 16 cpm,– BT: 37.4 ℃

• Head: – Conjuctiva: not pale– Sclera: not icteric.– Throat: no injected– Tonsil: no enlarged and congested

• Neck: – Supple,– No palpable lymphoadenopathy– No jugular vein engorgement

• 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 (-)

• Extremities– Free movable, no pitting edema

• Skin– 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 injuryUrticariaProteinuriaFolliculitis

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)

99.11.19 (D3)

Abdominal echo:1.Increased liver echogenecity , susp. fatty liver or chronic liver, parnechymal disease.

99.11.26 (D11)OPD

GOT/GPT :178/1029 99.11.22 (D7)MBD GOT/GPT : 63/ 391 ; r-GT:129 Bil (T/D):0.73/0.21

GOT/GPT : 33/ 139 ; r-GT:104 Bil (T/D): /0.28

GOT/GPT : 30/ 52 ; r-GT:71 Bil (T/D):0.85/0.23 99.12.04 (D19)OPD

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 elementsthe time to onsetclinical featuresthe time and course of recoveryspecific risk factorsthe exclusion of other diagnosesprevious reports on the hepatotoxicity of the

implicated agentrechallenge 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 patientCareful history taking / rule out other

etiologiesDoxycycline, Clindamycin, Diclofenac,

Ketoconazole for 2-3 wkherbal 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

CIOMS/RUCAM has been widely used as a standardized scale with high reliability, reproducibiliy and specificity

Apply diagnostic scale

RUCAM: 8 M&V: 16

3

Question 2 ~ How to treat DILI?

Discontinue the implicated drug as soon as diagnosis is suspected

Corticosteroids, ursodiol and antioxidant therapy used in severe or progressive liver injurydata supporting safety and efficacy are lacking

N-acetylcysteine should be offered to patients with ALF due to 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.

Apply to our patient

Discontinue Doxycycline, Clindamycin, Diclofenac

Supportive careLab:

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 drug-induced 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

Copyright ©2006 BMJ Publishing Group Ltd.

Brian Haynes, R Evid Based Med 2006;11:162-164

The "5S" levels of organisation of evidence from healthcare research

UpToDate

DynaMed

ACP PIER

BMJ Clinical Evidence

ACP journal club

Evidencebasedmedicine.com

Cochrane Library

BMJ Evidence Updates

Other Systemic reviews eg. PubMed systemic reivew

PubMed

SUMsearch

TRIP

Google

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 injuryLast literature review version 18.3: 九月 2010This 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 long-term 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 liver-related 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 immuno-suppressive 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 drug-induced 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?

1.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 in-dependent group set up for this study.)

Are the valid results of this prognosis study important?

1.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.)

Can you apply this valid, important evidence about prognosis in caring for your patient?

1.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.

Apply

醫療現況 病人意願病人已順利出院，改由門診追蹤。

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!