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Corso di SMC1- IV anno

12 Ottobre 2018

Prof. Mirko Tarocchi

Dipartimento di Scienze Biomediche Sperimentali e Cliniche


Gastrostroenterologia Clinica
Email: mirko.tarocchi@unifi.it
Danno epatico da farmaci (DEF)
Drug Induced Liver Injury (DILI)
Ampio spettro di sindromi clinico-patologiche associate
a ridotta funzione epatica secondarie all’assunzione di farmaci
Epatite acuta
fulminante
Epatite
acuta Fosfolipidosi

Epatite Epatite
cronica Danno epatico colestatica
da farmaci

Steatosi/ Fibrosi
steatoepatite epatica

Sindrome di
Epatite Budd-Chiari
granulomatosa Alterazioni
biochimiche
Danno epatico da farmaci (DILI)

• Rappresenta circa il 6% di tutti gli eventi avversi da


farmaci
• È la causa più frequente di sospensione di farmaci
dal commercio
• Rappresenta circa il 5% dei casi di ittero o di epatite
acuta extraospedalieri
• Rappresenta circa il 10-40% dei casi di ittero o di
epatite acuta ospedalizzati: l’incidenza è più elevata
tra i soggetti anziani
• È una causa importante di insufficienza epatica acuta
(16% dei casi; incidenza più elevata nei soggetti
anziani).
Pagliaro L. Medicina Pratica, 2003
Drug Induced Liver Injury
Incidence

Estimated 1: 5000 - 1: 100.000


Patients taking medications

Population-based 2.4 cases /100.000/year


case control studies

2.0 cases /100.000/year

Population-based 13.9 cases /100.000/year


prospective study

0.8 fatal cases /100 000/year


DILI: incidenza

14 casi /1.000.000 abitanti/anno


Una quota 16 volte più elevata delle
denunce all’Agenzia di farmacovigilanza francese

Ospedalizzazione: 12%

Mortalità: 6%
Incidenza: 0,8/100.000/anno

Sgro C., Hepatology 2002;36:451


Drug Induced Liver Injury
DILI as cause of Acute Liver Disease

1.2 – 4.0 % of acute liver injury

DILI as cause of Acute Liver Failure

Acetaminophen overdose 120/308 patients (39%)

Idiosyncrasic drug reactions 40/308 patients (13%)

Other 148/308 patients (48%)


 Drug-induced liver injury (DILI) is increasingly
being recognized as a significant cause of
both acute and chronic liver disease.

 The most commonly implicated agents are


paracetamol, antimicrobials, CNS drugs,
NSAIDs, statins, isoniazid, captopril and
herbal remedies.
Epatiti acute fulminanti negli USA

PARACETAMOL0: 40%
Ingestione massiva intenzionale
Farmaci: 52% Sovradosaggio da autoprescrizione

Altri farmaci: 12%

Altre cause: 48%

Lee WM, Sem Liver Dis, 2003;23:217


Leise MD, Mayo Clin Proc, 2014;89: 95-106
DILI: quadri clinico-patologici
Paracetamolo, alotano, isoniazide, metildopa, fluconazolo
Epatite acuta nitrofurantoina, ketoconazolo, ac. calproico, idroclorochina
Clorpropamide, metimazolo, naprossene, fenilbutazone,
Epatite colestatica ciprofloxacina, trazodone

Estrogeni, acido clavulanico, clorpromazina, amitriptilina,


Colestasi ticlopidina, triciclici, trimetoprin-sulfamettasozolo, carbamazepina,
tolbutamide
Epatite cronica Alfametildopa, isoniazide, nitrofurantoina, ossifenisatina
Epatite granulomatosa Fenilbutazone, chinidina, alpurinolo, dapsone, diltiazem

M.veno-occlusiva Azatioprna, 6-mercaptopurina

S. Budd-Chiari Estrogeni

Steatosi, NASH Aspirina, amiodarone, ac. valproico

Fibrosi epatica/cirrosi Metotrexate, isoniazide, cloruro di vinile

Iperplasia nodulare focale Estrogeni

Colangiocarcinoma Thorotrast

Epatocarcinoma Steroidi anabolizzanti, cloruro di vinile

Angiosarcoma Cloruro di vinile, arsenico, thorotrast


DILI: quadri clinico-patologici
Prevalentemente Prevalentemente
epatocellulare Misto
colestatico
Paracetamolo Amitriptilina Amoxicillina-acido clavulanico
Allopurinolo Azatioprina Anabolizzanti
Amiodarone Captopril Ciclosporina
Baclofene Carbamazepina Clorpromazina
Fluoxetina Clindamicina Clopidogrel
HAART ( terapia HIV) Ciproeptadina Contraccettivi orali
Isoniazide Enalapril Eritromicina
Ketoconazolo Flutamide Estrogeni
Metotrexate Nitrofurantoina Irbesartan
Omeprazolo Fenobarbital Mirtazapina
FANS Sulfonamidi Fenotiazine
Paroxetina Trazodone Terbinafina
Rifampina Trimetoprim-sulfometossazolo Triciclici
Risperidone Verapamile
Statine
Tetracicline
Troglitazone
Acido valproico
Metabolismo epatico dei farmaci

Fase 1
Ossidazione
Idrolisi
Cit-P450 Idrossilazione

Metaboliti idrofili

Farmaco lipofilo
Acido glicuronico
Acido sulfonico
Fase 2 Glicina
Metilazione Escrezione
Acetilazione
Biotrasformazione dei farmaci

Cit-P450
Inattivo

Farmaco Cit-P450
Attivo

Cit-P450
Tossico
Fisiopatologia del danno da farmaci

Difetto Legame
genetico covalente

Metabolita Proteine
FARMACO tossico
+
cellulari NECROSI *

Antigene

T linfociti
riesposizione sensibilizzati **
*DANNO DIRETTO **DANNO IMMUNO-MEDIATO
Fisiopatologia del danno da farmaci
farmaco
Timo Tessuto linfoide periferico

Inibizione della
tolleranza metabolita
Inibizione della tolleranza periferica
centrale Difetto in
apoptosi
Ipometilazione del DNA

espressione di LFA-1
Autoimmunità
T cellule autoreattive
Cellule B
farmaco

plasmacellule Macromolecole APC


tissutali
farmaco
Aptenizzazione del farmaco
DILI: meccanismi patogenetici
Farmaco
CYP 450

Metabolita attivo

Legame covalente
 GSH
Proteine

Reazione immuno-allergica Tossicità diretta

1. Non è dose dipendente 1. Compare a breve distanza


2. Può comparire dopo un periodo di latenza dall’assunzione del farmaco
oscillante da una settimana ad un mese 2. Dose dipendente
3. Può associarsi a febbre, porpora cutanea,
ipereosinofilia
 Hepatotoxicity can be classified as

 predictable

 unpredictable (idiosyncratic).
 This form is dose related.
 has a high incidence.
 and occurs with a short latency (within a few
days).

The classical example of predictable drug


toxicity is paracetamol.
 occur with variable latency (1 week to 1 year
or more)
 with low incidence,
 may or may not be dose related.

The majority of hepatotoxic drugs cause


idiosyncratic reactions.
 DILI can also be classified as:

1)immune mediated (allergic)

2) non-immune mediated (non- allergic)


 fever,
 rash,
 eosinophilia and
 autoantibodies (such as antinuclear and smooth
muscle antibodies).

Severe cases may be accompanied by


 toxic epidermal necrolysis, and
 haematological features such as
granulocytopenia, thrombocytopenia or
haemolytic anaemia.
 The key to causality is to assess :
1) the temporal relationship between drug
initiation and development of an abnormal
liver panel,
2) the individual susceptibility to DILI
3) and to diligently exclude other causes of
liver diseases.
Drug Induced Liver Injury
Causality assessment
CIOS-RUCAM Scale
Causality assessment
Drug Induced Liver Injury

Tujios, S. & Fontana, R. J. (2011)Nat. Rev. Gastroenterol. Hepatol.


 In a cohort study of patients with suspected
DILI:

(21%) had a Positive HEV serology.

(23.1%) were subsequently diagnosed


with AIH.
 Laboratory tests that might aid diagnosis of
immune-mediated reactions include :
the lymphocyte-stimulation test.

 In atypical cases of paracetamol overdose:


detection of serum paracetamol adducts.
individual drugs exhibit a characteristic clinical
signature, which may assist in the diagnosis of DILI:

(1)the pattern of the abnormal liver panel


(hepatitis, cholestasis or mixed);
(2) duration of latency to symptomatic
presentation;
(3) presence or absence of immune-mediated
hypersensitivity (ie, immune or non-immune
reaction)
(4) response to drug withdrawal.
Drug Inducedpresentations
Clinicopathological Liver Injury
of DILI
Clinical presentation of DILI

Tujios, S. & Fontana, R. J. (2011)Nat. Rev. Gastroenterol. Hepatol.


 hepatitis form most likely to be associated
with acute liver failure.
 There is usually poor correlation between
degree of ALT elevation and the severity of
the liver disease.

 histology being a more accurate indicator.

 However, jaundice is a good predictor of


mortality in drug-induced hepatitis.
A consistent serum bilirubin ≥3 ×ULN, ( in
the absence of biliary obstruction or
Gilbert’s syndrome,) is associated with a
mortality of approximately 10%. (range, 5–
50%)
 This pattern of liver injury probably has the
lowest mortality.
 prompt discontinuation of the offending drug,

 supportive and symptomatic therapy,

 monitoring for the development of ALF.


 Use of glucocorticoids for immune-
mediated reactions and ursodeoxycholic
acid (UDCA) for cholestatic liver injury
remain controversial therapies
 in the subset with DILI, there was a trend
towards a worse prognosis in those on
steroid therapy
 it may be reasonable to treat prolonged
cholestasis due to DILI with UDCA in a dose
of 13–15 mg/kg.
 in drug-induced hepatitis with allergic
features, with no improvement after drug
withdrawal, a short course of steroids may be
justifiable.
 Antioxidants have also been proposed as a
treatment modality for severe DILI
 N-acetylcysteine (NAC) is the treatment of
choice for paracetamol overdose.
 At the earliest signs of liver failure (INR.1.5,
development of ascites, or any grade of
hepatic encephalopathy), prompt referral to a
liver transplant unit is indicated.
 vigilance,
 identification of risk factors,
 ALT monitoring with certain drugs, and
 safer marketing strategies.
 the most useful way to prevent DILI would be
to educate our patients about the warning
signs of severe drug injury such as abdominal
pain, nausea, vomiting and jaundice.
 Drugs that result in predictable injury would
not qualify for monthly monitoring, since
such reactions occur early. (within a few days)

 The apparent non-immune cases associated


with delayed toxicity may be suitable for such
a risk management strategy
 though there may still be a number of
concerns:
 1)compliance with monthly monitoring is
poor.
 2 ) such a strategy may lead to premature
termination of drugs in patients who would
otherwise benefit from their use.
 3) Finally, serious DILI can occur despite
monitoring of the liver panel
 where a benefit–risk analysis would favour
continued therapy, monthly monitoring may
be beneficial compared with no monitoring at
all
 DILI is most often a diagnosis of exclusion. All the known
causes of liver disease have to be excluded (viral hepatitis,
autoimmune disorders, Alcohol intake, Metabolic and genetic
disorders, hemodynamic dysfunction and billiary
abnormalities.

 drug-induced liver injury must be included as a differential


diagnosis in all patients with an abnormal liver panel.

 Management of patients with drug induced liver injury needs


increased vigilance, as once liver failure develops
spontaneous survival (in the absence of liver transplantation)
is rare, except in those with paracetamol-induced
hepatotoxicity
CONCLUSION
DILI: Difficult to avoid, predict and diagnose

TWO GOLDEN RULES


1. Always consider
the possibility of DILI

2. Immediately withdraw
all suspected drugs
in severe cases
Clinicopathological presentations of DILI

Tujios, S. & Fontana, R. J. (2011)Nat. Rev. Gastroenterol. Hepatol.


Clinicopathological presentations of DILI

Tujios, S. & Fontana, R. J. (2011)Nat. Rev. Gastroenterol. Hepatol.