Toksisitas Bahan Kimia atau

Obat Pada hati dan Penggunaan

Obat Pada Penggunaan Fungsi
Hati
Bambang Tri Laksono 20720014
Harlena Pratama Putri 20720312
Khairun Nisa
 TABLE OF CONTENTS

1 3

Latar Belakang Diagnosis

Definisi, Klasifikasi, Etiologi Pencegahan dan
dan Faktor Resiko Penanganan Terapi

2 4

Patofisiologi Studi Kasus

Mekanisme, Gejala, dan
Manifestasi Klinik
 Latar Belakang

Anatomi Hati
 Fungsi Hati

1 2 3

Metabolisme Glukosa Metabolisme Lemak Penyimpanan Vitamin dan

Zat Besi

4 5 6

Metabolisme Obat Pembentukan Empedu Ekskresi Bilirubin

Definisi

Kerusakan organ hati

yang disebabkan oleh
obat/bahan kimia
lainnya.
Drug Induced Liver Injury
Etiologi
Penyebab DILI
 EFEK TOKSIK DAN MEKANISMENYA

Penghambatan Deplesi Kofaktor

DIAWALI OLEH
Enzim atau metabolit
CEL INJURY

Peningkatan
Deplesi Jumlah ATP
Calcium Intracel Perubahan pada
Interaksi dengan membrane sel hati
Terbentuk Formasi
Reseptor
Metabolit Reaktif
TAHAP KERUSAKAN HATI
 EFEK TOKSIK TERHADAP
TUBUH
Zat Kimia yang Masuk ke
Tubuh Berubah Menjadi
Zat Toksik

Inisiasi Zat Beracun yang

merubah Molekul Sel hati

Sel Hati dapat Kembali

normal atau terjadi
Perubahan yang
irreversible
Perubahan sel yang
irreversible berujung
pada kematian sel
 Faktor Resiko

Faktor Genetik dan Non Genetik

Faktor Farmasetika

Faktor Lingkungan
 Faktor Genetika dan Non Genetika

Genetika Non Genetika

Mengacu pada hubungan 1. Umur
antara resiko DILI dan 2. Jenis Kelamin
polimorfisme genetik yang 3. Kehamilan
melibatkan enzim
4. Penyakit yang
metabolisme obat, transport
mendasari
protein obat dan Human
Leukocyte Antigen (HLA).
 1. Sifat Kimia Obat
Faktor Farmasetika 2. Dosis
3. Pengobatan
4. Interaksi Obat
Faktor Lingkungan 1. Konsumsi
Alkohol
2. Merokok
 Tipe Klinis DILI

Berdasarkan Patogenesis Berdasarkan Perjalanan

Penyakit
● InDILI (Intrinsic Drug ● Acute Drug Induced
Induced Liver Injury) liver Injury

● IDILI (Idionsinkrasi ● Chronic Drug Induced

Drug Induced Liver Liver Injury
Injury)
 Manifestasi Klinis Pada DILI

● Acute DILI – Tidak Spesifik ● Chronic DILI dapat bermanifestasi

● Periode singkat bisa beberapa hari sebagai hepatitis kronis, fibrosis hati,
atau beberapa bulan. sirosis, kompensasi dan
● Tidak memiliki gejala yang signifikan dekompensasi.
● Hanya muncul pada indeks biokimia ● Beberapa pasien mungkin dating
hati, termasuk : serum ALT, AST, ALT, dengan SOS/VOD. SOS/VOD dapat
dan GGT. muncul secara akut dengan ascites,
● Beberapa pasien mungkin mengeluh icterus, dan hepatomegaly.
seperti kelelahan, penurunan nafsu
makan.
● Dengan penyakit cholestasis
mungkin mengalami penyakit kuning,
feses warna terang, dan pruritus.
 ● Grade 0 ( Tidak ada cedera hati )
● Grade 1 ( Cedera hati ringan )
Tingkat ● Grade 2 ( Cedera hati sedang )

Keparahan DILI ●
●
Grade 3 ( Cedera hati parah )
Grade 4 ( Acute liver Failure )
● Grade 5 ( Kematian )
 SIMPTOM TOKSIK
SIMTOM YANG SERING MUNCUL PADA KONDISI DILI
Diagnose of
DILI
Clinical-pathological manifestations
● Clinical presentation
● Patterns of DILI
● Specific phenotypes
○ Drug-induced autoimmune hepatitis.
○ Liver injury associated with immunotherapy for cancer.
○ Secondary sclerosing cholangitis.
○ Granulomatous hepatitis
○ Acute fatty liver.
○ Drug-associated fatty liver disease.
○ Nodular regenerative hyperplasia and sinusoidal obstruction syndrome
○ Liver tumours.
Laboratory test
● Aminotransferases
● Laboratory workup for excluding alternative causes
Imaging
● As DILI is a diagnosis of exclusion, some form of liver imaging is usually undertaken in
the diagnostic workup of a patient with suspected DILI.
● Liver imaging in DILI is typically normal.
● All patients with suspected DILI should at least undergo an abdominal ultrasound to
exclude focal changes in the liver and biliary obstruction.
Liver Biopsy
● Liver biopsy is an integral part of the specific investigations performed by clinicians to establish the
diagnosis of parenchymal liver disease; it has a limited role when the condition presents with typical
manifestations and the non-invasive tests are considered diagnostic.
● However, shares clinical features with other parenchymal liver diseases and lacks definitive tests and
hence, liver histology can provide complementary information and assist in the process of securing an
accurate diagnosis.
Causality assessment methods and scales
● Council for International Organizations of medical Sciences (CIOMS) scale
○ This causality assessment method, also called RUCAM (after the host pharmaceutical Roussel-Uclaf) includes weighted scoring
of an event according to 7 distinct domains related to the temporal relationship between exposure to a particular drug and the
liver injury (both its onset and course), exclusion of alternative non-drug-related aetiologies, exposure to other medications that
could explain DILI, risk factors for the adverse hepatic reaction, evidence in the literature regarding DILI from the drug in question
and response to re-exposure to the medication. The total score derived (ranging from -9 to +10) from the domain specific
assessment classifies the event as highly probable (>8), probable (6–8), possible (3–5), unlikely (1–2) or excluded (≤0) according
to its likelihood to be DILI.
● Clinical diagnostic scale (CDS)
○ Causality is graded according to the final score as definite drug-induced hepatotoxicity (score >17), probable (score 14–17),
possible (score 10–13), unlikely (score 6–9) and excluded (score <6).
● Structured expert opinion process
○ Following the assessment, the likelihood of an event being DILI was described using both a percentage figure and a descriptive
legal terminology as definite (>95% likelihood), highly likely (75–95%), probable (50–74%), possible (25–49%), or unlikely (<25%).
 Roussel Uclaf causality assessment method (RUCAM).

Keuntungan : Kekurangan :
● Tidak dipengaruhi oleh usia, jenis ● Standar penilaian tidak jelas
kelamin, atau ras ● Parameter perlu ditingkatkan
● Parameter yang dipilih bersifat ● Instruksi untuk melengkapi di dalam
komprehensif, relatif rasional, dan table harus lebih rinci dan jelas.
objektif
● Sistem semi kuantitatif berdasarkan
pertanyaan spesifik dapat dipahami
dan diterapkan bahkan oleh klinisi
non-hepatologi
Rechallenge and recurrent DILI
● Once DILI subsides the individual can be exposed again to the same drug usually in an
inadvertent way. This is called rechallenge and if followed by a recrudescence of the hepatic
damage is a strong argument to incriminate the agent. In fact, a ‘‘positive” rechallenge is
currently the strongest proof of causality in the adjudication process of suspected DILI cases
● The definition of positive rechallenge relies on the threshold reached by aminotransferases
upon drug resumption. By common convention it is currently defined as ALT >3x ULN
● Importantly, rechallenge of a patient who showed initial liver injury caused by a drug has
traditionally been regarded as a dangerous practice with potentially serious consequences, as
it sometimes leads to rapid, worse liver injury or even fulminant liver failure.
Genetic Testing
● The rarity of an occurrence of DILI in relation to a given drug means that many of these
HLA alleles have a negative predictive value of >95%. Consequently, genetic tests can
be used to exclude the diagnosis of DILI or to exclude a specific drug as an aetiological
agent when more than one potential medication could have caused DILI. Published
case reports demonstrate such examples of effective use of genetic tests in clinical
practice.
● While exclusion of alternative causes is an important component of causality
assessment in a suspected DILI, HLA genotyping in combination could strengthen the
diagnosis of DILI.
New Biomarkers
● In human acetaminophen-induced liver injury, miR-122, miR-192-5p and other miRNAs
are elevated, but further studies are needed to assess whether drug-induced
pathognomonic ‘‘signatures” of circulating miRNAs could serve as diagnostic ‘‘liquid
biopsies”.
● Glutathione S-transferases (GSTs) are phase II detoxifying enzymes, which metabolise
reactive metabolites. Data from the Spanish DILI registry suggest that GST gene
polymorphisms confer susceptibility to hepatotoxicity induced by multiple drugs.
Therapy of DILI
General measures
● The most important initial step in terms of management of suspected DILI is to
discontinue the implicated agent. In the large majority of DILI, spontaneous recovery
occurs, without the need for any treatment or specific measure. In fact, spontaneous
recovery after discontinuation of the offending drug is an important criterion in the
causality assessment.
Spesific Therapies
● Cholestyramine
A short administration of cholestyramine may be used to decrease the course of hepatotoxicity induced by very selected
drugs, such as leflunomide and terbinafine.
● Carnitine administration
Carnitine may be used to improve the course of valproate hepatotoxicity. The typically recommended dose is 100 mg/kg
intravenously over 30 minutes (but less than 6 g), followed by 15 mg/kg every 4 hours until clinical improvement
● N-acetylcysteine
These patients received 10 g of NAC given intravenously over 24 hours for 7 days and an oral dose of 1 mg/kg
prednisolone per day, with the dose tapered according to biochemical response. The combined NAC/prednisolone
treatment led to significant liver profile improvements within 2 weeks and the cases resolved more rapidly than in
untreated sFILI patients.
● Ursodeoxycholic acid
Chronic cholestasis following DILI is often treated with ursodeoxycholic acid (UDCA).
Management of drug-induced ALF
● Treatments non-specific to DILI
○ Current approaches to treat ALF are aimed at providing temporary replacement of hepatic function and detoxification
(extracorporeal devices) while awaiting spontaneous recovery or recovery with therapies that enhance liver regeneration (stem
cell and growth factors).
○ Liver transplantation is still the primary rescue treatment for ALF, with a 1-year survival rate of around 80% in liver transplant
recipients with ALF.
● Treatments specific to DILI
There are 2 main treatment approaches for drug-induced ALF:
a) rapid depuration of the body from the toxic drug to stop further aggression before the agent may reach the
liver;
b) administration of an antidote to prevent and/or stop the aggression once the drug has reached the liver.
○ Charcoal depuration is mainly used as a treatment for paracetamol toxicity. It is an efficient treatment that prevents further
absorption of the drug if administered within 3–4 hours following an acute ingestion.
○ N-acetylcysteine used early in the course of ALF may prevent progression to more severe encephalopathy and may also exert
renal protective effects.
○ Liver injury caused by antiepileptic drugs are commonly associated with features of hypersensitivity and may respond to steroids
Preventing DILI
The value of liver test monitoring
● As with other liver diseases, clinical symptoms associated with DILI may occur only
when serious injury has already happened. In most cases, the first sign of injury is
elevation in liver enzymes.
● One exception is prevention of anti-TBC treatment associated hepatotoxicity. These
drugs, in particular isoniazid, are a leading cause of liver injury and early treatment
cessation is important for a better outcome. According to the ATS guidelines patients
should stop isoniazid treatments if ALT >3 x ULN in the presence of symptoms, such as
nausea, abdominal pain, jaundice and/or unexpected fatigue, or when ALT >5x ULN in
the absence of symptoms
Class effect and cross reactivity
● Although almost any drug can in theory elicit idiosyncratic DILI given an individual
patient’s susceptibility, incidence across different drug classes seems to vary
significantly.
● Certain groups of medical drugs such as antibiotics, NSAIDs, statins, anticonvulsants,
antivirals, kinase inhibitors, TNF a antagonists, and checkpoint inhibitors apparently
confer a higher risk for hepatotoxicity than others.
 Case Study

● Valproate Induced Liver Injury

● Acetaminophen Induced Liver Injury
Case 1
● A 27-year-old African American male presented to the emergency department with a 3-day history of hypersomnolence, fatigue, and
anorexia. The patient denied fever, chills, sweating, headaches, abdominal pain, nausea, or vomiting. He had a past medical history of
asthma, chronic marijuana and tobacco use, bipolar disorder, schizoaffective disorder, and multiple suicidal attempts. His medications
included haloperidol, benztropine, aripiprazole, and was recently started on valproic acid (VPA). On admission, he had a temperature
of 98.2°F, blood pressure of 117/82 mm Hg, heart rate of 70 beats per minute, and a respiratory rate of 20 beats per minute. Physical
examination revealed a somnolent patient with an ataxic gait, scleral icterus, and prominent asterixis. There was no appreciable
lymphadenopathy or organomegaly, and no signs of palmar erythema, gynecomastia, shifting dullness, or spider angioma. Initial
laboratory results were remarkable for an AST level of 12 000 IU/L (reference 8-46 IU/L), ALT of 7000 IU/L (reference 7-55 IU/L), an ALP
of 96 IU/L (reference 45-115 IU/L), total bilirubin of 1.5 mg/dL (reference 0.1-1.2 mg/dL), and serum ammonia of 184 µmol/L
(reference 15-45 µmol/L). The patient also had thrombocytopenia and coagulopathy. Abdominal ultrasound and computed
tomography of the head were both unremarkable. Viral hepatitis serology and acetaminophen toxicity were both negative. Urine
toxicology was positive for ethyl alcohol at 9 mg/dL. An ADR to VPA was suspected, and VPA was discontinued with the initiation of
lactulose for hyperammonemia. On the second day after discontinuing VPA, his LFTs started to trend downward and his clinical
symptomology of hyperammonemia improved. By the eighth day, his ALT and AST levels had dropped to 634 IU/L and 61 IU/L,
respectively, and his total bilirubin was within reference range at 0.8 mg/dL. A final diagnosis of VPA-induced DILI resulting in hepatic
encephalopathy was made.
Subjective Data
● Pasien : A 27-year-old African American male
● Keluhan : 3-day history of hypersomnolence, fatigue, and anorexia. The
patient denied fever, chills, sweating, headaches, abdominal pain,
nausea, or vomiting.
● Riwayat Penyakit : asthma, chronic marijuana and tobacco use, bipolar
disorder, schizoaffective disorder, and multiple suicidal attempts.
● Riwayat Penggunaan Obat : haloperidol, benztropine, aripiprazole, and was
recently started on valproic acid (VPA).
Objective Data
● Tanda Vital
○ Suhu 98.2°F (36.7 oC),
○ TD 117/82 mm Hg,
○ HR 70 beats per minute,
○ RR 20 beats per minute.
● Pemeriksaan fisik
○ somnolent
○ ataxic gait,
○ scleral icterus,
○ prominent asterixis.
○ no appreciable lymphadenopathy or organomegaly, and no signs of palmar erythema, gynecomastia,
shifting dullness, or spider angioma.
Objective Data (2)
● Hasil Lab
○ AST 12 000 IU/L (reference 8-46 IU/L),
○ ALT 7000 IU/L (reference 7-55 IU/L),
○ ALP 96 IU/L (reference 45-115 IU/L),
○ TBL 1.5 mg/dL (reference 0.1-1.2 mg/dL),
○ serum ammonia of 184 µmol/L (reference 15-45 µmol/L).
○ thrombocytopenia
○ coagulopathy.
● Abdominal ultrasound and computed tomography of the head were both unremarkable.
● Viral hepatitis serology and acetaminophen toxicity were both negative.
● Urine toxicology was positive for ethyl alcohol at 9 mg/dL.
Causality Assessment.
● The causality of drug-induced hepatotoxicity in this case was established by Roussel
Uclaf Causality Assessment Method/Council for International Organizations of Medical
Sciences score as follows:
○ Hepatocellular, second exposure, onset of <5 days(+1),
○ time from withdrawal of drug until reaction onset <15 days (+1),
○ risk factors being alcohol (+1),
○ age <55 (0),
○ >50% improvement in 8 days (+3),
○ no concomitant therapy (0),
○ excluded non–drug-related causes: rule out (+2),
○ response to read administration positive (+3)
○ with total score of 11 indicating “Highly Probable” (>8)
ADR Assessment
● This drug-related adverse event was confirmed by Naranjo Algorithm as follows:
○ Previous reports positive (+1),
○ Adverse events appeared after the suspected drug was given (+2),
○ With the transaminases improving after the discontinuation of the drug (+1),
○ And the adverse reaction appearing after the readministration of the drug (+2),
○ With no alternative causes to explain this adverse reaction (+2),
○ Placebo not been given (0),
○ Drug levels not done (0),
○ Without changing the administered dose of the drug (0),
○ Similar reaction in the past with the same drug (+1),
○ And the adverse event confirmed by objective evidence (+1)
● With a total score of 10 which is >9, thus “definite ADR.”
The temporal association also strongly proves drug-induced hepatotoxicity in this case.
Planning
● An ADR to VPA was suspected, and VPA was discontinued with the initiation of
lactulose for hyperammonemia.
● A final diagnosis of VPA-induced DILI resulting in hepatic encephalopathy was made.
● Carnitine may be used to improve the course of valproate hepatotoxicity. The typically
recommended dose is 100 mg/kg intravenously over 30 minutes (but less than 6 g),
followed by 15 mg/kg every 4 hours until clinical improvement
Monitoring and Evaluation
● On the second day after discontinuing VPA, his LFTs started to trend downward and
his clinical symptomology of hyperammonemia improved.
● By the eighth day, his ALT and AST levels had dropped to 634 IU/L and 61 IU/L,
respectively, and his total bilirubin was within reference range at 0.8 mg/dL.
● A final diagnosis of VPA-induced DILI resulting in hepatic encephalopathy was made.
Case 2
● A woman aged 23 years was bought to the ED having taken a large mixed overdose of
predominantly paracetamol. The exact quantity and timing of the overdose were
unknown, but possibly as much as 47.5 g paracetamol (864 mg/kg bodyweight) as well
as codeine, ibuprofen and alcohol had been consumed in the preceding 24 hours.
Subjective Data
● Pasien : A woman aged 23 years
● Keluhan :

○ Ingested a large mixed overdose of predominantly paracetamol as much as 47.5 g paracetamol (864
mg/kg bodyweight) as well as codeine, ibuprofen and alcohol had been consumed in the preceding 24
hours.
● Riwayat Penyakit : depression, bulimia, alcohol abuse, self-harm and suicide attempts
● Riwayat Pengobatan : no other medical history of note, took no regular medications and
had no known allergies
Objective Data
● Tanda Vital : unremarkable
● Kesadaran : fluctuating consciousness with confusion and was unable to provide a full
history
● no clinical signs of opiate toxicity.
● Hematologi
○ lactic acidosis (pH 7.22, pCO2 3.9 kPa, base excess (BE) −11 mmol/L and lactate 7.9 mmol/L).
○ Renal function was normal (creatinine 52 µmol/L),
○ liver function was deranged (alanine aminotransferase (ALT) 562 U/L, alkaline phosphatase 122 U/L and
bilirubin 12 µmol/L),
○ synthetic function was not yet affected (International Normalised Ratio (INR) 0.99).
○ Plasma ammonia level was 72 µmol/L (normal 11-32 µmol/L).
○ paracetamol level was 536 mg/L (normal : <30 mg/L).
Causality Assessment.
● The causality of drug-induced hepatotoxicity in this case was established by Roussel
Uclaf Causality Assessment Method/Council for International Organizations of Medical
Sciences score as follows:
○ Hepatocellular, second exposure, onset of <5 days(+1),
○ time from withdrawal of drug until reaction onset <15 days (+1),
○ risk factors being alcohol (+1),
○ age <55 (0),
○ >50% improvement in 8 days (+3),
○ no concomitant therapy (0),
○ excluded non–drug-related causes: rule out (+2),
○ response to read administration positive (+3)
○ with total score of 11 indicating “Highly Probable” (>8)
ADR Assessment
● This drug-related adverse event was confirmed by Naranjo Algorithm as follows:
○ Previous reports positive (+1),
○ Adverse events appeared after the suspected drug was given (+2),
○ With the transaminases improving after the discontinuation of the drug (+1),
○ And the adverse reaction appearing after the readministration of the drug (+2),
○ With no alternative causes to explain this adverse reaction (+2),
○ Placebo not been given (0),
○ Drug levels not done (0),
○ Without changing the administered dose of the drug (0),
○ Similar reaction in the past with the same drug (+1),
○ And the adverse event confirmed by objective evidence (+1)
● With a total score of 10 which is >9, thus “definite ADR.”
The temporal association also strongly proves drug-induced hepatotoxicity in this case.
Planning
● Aggressive fluid resuscitation and instigating N-acetylcysteine (NAC)
● These patients received 10 g of NAC given intravenously over 24 hours for 7 days
● Two hours later, despite aggressive fluid resuscitation and instigating N-acetylcysteine
(NAC), the acidosis persisted (pH 7.21, pCO2 4.1 kPa, BE (BE) −10.5 mmol/L and
bicarbonate 17.1 mmol/L), the lactate remained elevated at 5.6 mmol/L and the patient
remained confused. In light of the above, the patient underwent haemodialysis and
following this, all markers of acid–base homeostasis improved, as did cognition.
Monitoring and Evaluation
● Checking a paracetamol level 2hrs before the end of bag 2 is NEW for this protocol.
● U&E, HCO3, glu, LFTs, FBC and INR should be done 2hrs before the end of each infusion
2. Ensure results are READY for the end of the infusion.
● If unable to achieve blood sampling at the correct time and a delay of >90 minutes is
predicted then proceed to the next infusion to avoid prolonged omission of NAC. Bloods
should be checked at the earliest opportunity and discontinuation criteria referred to.
● Capillary Blood Glucose (CBG) 6 hourly while on NAC.
● If rapid or progressive biochemical deterioration then discuss with senior and consider
referral to regional transplant centre.
● IV NAC can be associated with minor rise in INR without an acute liver injury.
 Daftar Pustaka

1. Yu YC, Mao YM, Chen CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver
injury. Hepatol Int. 2017;11(3):221-241. doi:10.1007/s12072-017-9793-2
2. Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clin Mol Hepatol. 2012;18(3):249-257.
doi:10.3350/cmh.2012.18.3.249
3. Vijay Gayam, MD, et al. 2018. Drug-Induced Liver Injury: An Institutional Case Series and Review of
Literature. Journal of Investigative Medicine High Impact Case Reports 2018; (6) :1-7.
https://doi.org/10.1177/232470961876175
4. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, Clinical
Practice Guideline Panel: Chair:, Panel members, & EASL Governing Board representative: (2019).
EASL Clinical Practice Guidelines: Drug-induced liver injury. Journal of hepatology, 70(6), 1222–1261.
https://doi.org/10.1016/j.jhep.2019.02.014