CASE 1

• Case description: – Ethnicity, gender, age: Caucasian, female, 37 years – Comorbid conditions: none, history of gestational

diabetes and cholestasis of pregnancy – Alcohol consumption: occasionally – Suspected medication(s)/start and stop dates:

azithromycin 500 mg/day (25/11/2013-28/11/2013) and amoxicillin-clavulanate 875-125 mg/8 hrs (27/11/2013-03/12/2013)

– Concomitant medications (start and stop dates): none

Case 1

• When did symptoms suggestive of DILI appear? pruritus (29/11/2013)

• Liver parameters at DILI recognition: ALT 8.8x ULN, TBL 2x ULN (01/12/2013)

• Baseline values prior to DILI episode: not available

• Time to onset: 4 days (azithromycin), 2 days (amoxicillin-clavulanate

• Did the patient experience hypotension, bradycardia, sepsis, etc suggestive of ischemic hepatitis? No

Case 1

Anti-HAV IgM Anti-HCV RNA-HCV AgHBs Anti-HBc DNA-HBV EBV IgM CMV IgM HSV1 IgM HSV2 IgM

Case 1

Negative

Ultrasound: Normal (30/12/2013)

Autoantibodies: ANA, ASMA, AMA, anti-LKM were negative (10/12/2013) Biopsy: No information (not likely to have been performed)

1840

175

88 90 72 69

149 150 133

27 0100200300400500

AST (ULN: 40)

Liver parameter progression

602

270

142 134 83 59

142 159 198

35 0100200300400500600700800

ALT (ULN: 42)

216

256

218 220 240

190 208 215 211

128

0

100

200

300ALP (ULN: 117)

3,2

7,7

10,7 12,1

8,5

10,4

7,5

2,3 0,7 0

2468

101214

TBL (ULN: 1.1)

• Outcome: Patient was treated with dexchlorpheniramine and cholestyramine for pruritus. Complete recovery.

• Time to recovery: 124 days

Outcome

CASE 2

• Case description: – Ethnicity, gender, age: Caucasian, female, 85 years – Comorbid conditions: Hypertension, dyslipidaemia – Alcohol consumption: Denied – Suspected medication(s)/start and stop dates: Amoxixillin-clavulanate: 1g/8h for 8 days (8-16 March 2008) – Concomitant medications (start and stop dates) – Amiloride (longterm, specific dates unknown) – Lovastatin (longterm, specific dates unknown)

Case 2

• When did symptoms suggestive of DILI appear? Pruritus, dark urine and scleral icterus (07/04/2008)

• Liver parameters at DILI recognition: AST: 238 IU/L ALT: 495 IU/L ALP: 396 IU/L TBL: 6.4 mg/dL

• Baseline values prior to DILI episode: unknown

• Time to onset: 1 month

• Did the patient experience hypotension, bradycardia, sepsis, etc. suggestive of ischemic hepatitis? No, but complete information on pneumonia outcome unavailable.

Case 2

anti-HAV IgM HBsAg Anti-HBc Anti-HCV CMV IgM EBV IgM Anti-HBc

Case 2

Negative

Ultrasound: Normal (15/04/2008)

Autoantibodies: ANA, ASMA, AMA, anti-LKM were negative (16/04/2008) Biopsy: No information (most likely not performed)

238

35 30 29

050

100150200250

1º 16/04/2008 2º 25/04/2008 3º 15/05/2008 4º 22/06/2008

AST (ULN: 40)

Liver parameter progression

495

111

44 34 0

100

200

300

400

500

1º 16/04/2008 2º 25/04/2008 3º 15/04/2008 4º 22/06/2008

ALT (ULN: 40)

396

211

135 89

0

100

200

300

400

500

1º 16/04/2008 2º 25/04/2008 3º 15/04/2008 4º 22/06/2008

ALP (ULN: 104)

6,4

2,8

1,7 0,9

01234567

1º 16/04/2008 2º 25/04/2008 3º 15/05/2008 4º 22/06/2008

TBL (ULN: 1.1)

• Outcome: Complete recovery

• Time to recovery: 77 days

Outcome

CASE 3

• Case description: – Ethnicity, gender, age: Caucasian, male, 35 years – Comorbid conditions: none – Alcohol consumption: no – Suspected medication(s)/start and stop dates:

terbinafine: 500 g/12 hrs (17/03/2018-14/04/2018)

Case 3

• Case description: – Concomitant medications (start and stop dates):

Amoxicillin-clavulanate (12/02/2018 - 22/02/2018) – Fusidic acid (topic) 12/02/2018 - 26/02/2018 and

17/03/2018 - 27/03/2018) – Betamethasone clotrimazol (topic) 17/03/2018 –

17/04/2018 – Clobetasol propionate (topic) 17/03/2018 – ongoing

during hospitalization

Case 3

• When did symptoms suggestive of DILI appear? Jaundice, choluria, acholic stools, discomfort in upper right quadrant and pruritus (23/04/2018) • Liver parameters at DILI recognition: AST 4.6x ULN and TBL 4.3x ULN

• Baseline values prior to DILI episode: Not available

• Time to onset: 37 days

• Did the patient experience hypotension, bradycardia, sepsis, etc suggestive of ischemic hepatitis? No

Case 3

Anti-HAV IgM HBsAg Anti-HBc Anti-HCV HCV-RNA Anti-HEV IgM Anti-EBV IgM Anti-CMV IgM Anti-HSV1 IgM Anti-HSV2 IgM

Case 3

Negative

Ultrasound: Normal (28/04/2018) MRCP: Normal (28/04/2018)

Autoantibodies: ASMA: 1/320, actine-F positive, while ASMA, AMA and anti-LKM were negative (30/04/2018)

Biopsy (11/05/2018): Eosinophils, signs of cholestasis signs. Histological data not concordant with AIH, suggestive of mild stage drug-induced hepatitis

585

291 242

202

97 105 51

0100200300400500600

ALT (ULN: 40)

183

254

82 112 100

56 54 32

050

100150200250300

AST (ULN: 40)

Liver parameter progression

178

220

187 175 173 167

99

0

50

100

150

200

250ALP (ULN: 117)

4,3

6

7,8 6,8 7,6

4,3

1,4 0,8

0

2

4

6

8

10TBL (ULN: 1)

• Outcome: Complete recovery

• Time to recovery: >180 days

Outcome

CASE 4

• Case description: – Ethnicity, gender, age: Caucasian, female, 49 years – Comorbid conditions: hypertension, history of knee

surgery and miscarriages (4) – Alcohol consumption: no – Suspected medication(s)/start and stop dates:

paracetamol: ~ 7 g (12 February 2015) – Concomitant medications (start and stop dates):

unknown

Case 4

• When did symptoms suggestive of DILI appear? abdominal pain, nausea, anorexia, dark urine (13/02/2015)

• Liver parameters at DILI recognition: AST 26 xULN, ALT 40xULN, ALP 3xULN and TBL 3xULN

• Baseline values prior to DILI episode: ALT and TBL: normal (21/05/2013)

• Time to onset: 1 day

• Did the patient experience hypotension, bradycardia, sepsis, etc suggestive of ischemic hepatitis? No, but received hyaluronic acid injections, which may have resulted in infection

Case 4

Anti-HAV IgM Anti-HCV RNA-HCV AgHBs DNA-HBV EBV IgM CMV IgM HSV1 IgM HSV2 IgM

Case 4

Negative

Ultrasound: Normal (14/02/2014, no ultrasound made more recently)

Autoantibodies: ANA, ASMA, AMA, anti-LKM were negative (18/02/2015) Biopsy: Not performed

1840

1063

65 23 0400800

120016002000

1º15/02/2015

2º18/02/2015

3º25/02/2015

4º18/03/2015

AST (ULN: 40)

Liver parameter progression

1657

347

31 0

400

800

1200

1600

2000

1º15/02/2015

2º18/02/2015

3º25/02/2015

4º18/03/2015

ALT (ULN: 42)

378

250

88

0

100

200

300

400

1º15/02/2015

2º18/02/2015

3º25/02/2015

4º18/03/2015

ALP (ULN: 117)

2,2

3,13

1,1

0,53

00,5

11,5

22,5

33,5

1º 15/02/2015 2º 18/02/2015 3º 25/02/2015 4º 18/03/2015

TBL (ULN: 1.1)

• Outcome: Complete recovery

• Time to recovery: 35 days

Outcome

CASE 5

• Case description: – Ethnicity, gender, age: Caucasian, male, 20 years – Comorbid conditions: Thalassemia minor – Alcohol consumption: Occasionally – Suspected medication(s)/start and stop dates: Anabolic steroids (epithiostanol) : (26/09/2016-31/10/2016) – Concomitant medications (start and stop dates): None

Case 5

• When did symptoms suggestive of DILI appear? Pruritus, jaundice, asthenia (31/10/2016)

• Liver parameters at DILI recognition: ALT: 344 IU/L ALP: 190 IU/L TBL: 13 mg/dL (creatinine: 1.4 mg/dL)

• Baseline values prior to DILI episode: unknown

• Time to onset: 1 month

• Did the patient experience hypotension, bradycardia, sepsis, etc. suggestive of ischemic hepatitis? No.

Case 5

anti-HAV IgM HBsAg Anti-HBc Anti-HCV CMV IgM EBV IgM Anti-HBc

Case 5

Negative

Ultrasound: Normal (07/11/2016) MRI: Normal (08/11/2016)

Autoantibodies: ANA, ASMA, AMA, anti-LKM were negative (10/11/2016)

Biopsy (27/11/2016): Accumulation of biliary pigment inside hepatocytes together with necrosis and a small number of neutrophil and eosinophil aggregates mostly in central areas.

Renal biopsy (25/11/2016): Acute tubular necrosis with tubular deposits of biliary pigment

190 202

292

156 109

0

100

200

300

400

1º07/11/2016

2º 24/11/16 3º05/12/2016

4º05/01/2017

5º09/02/2017

ALP (ULN: 117 IU/L)

344

125

63 45 33 0

100

200

300

400

07/11/2016 24/11/2016 05/12/2016 05/01/2017 09/02/2017

ALT (ULN: 40 IU/L)

Liver parameter progression

13

46,2

56,5

24,8

0,8 0

20

40

60

1º 07/11/2016 2º 24/11/16 3º 05/12/2016 4º 05/01/2017 5º 09/02/2017

TBL (ULN: 1.1 mg/dL)

1,4

1,9

2,3

1,6

0,9

0

0,5

1

1,5

2

2,5

1º07/11/2016

2º 24/11/16 3º05/12/2016

4º05/01/2017

5º09/02/2017

Cr (ULN: 1.1 mg/dL)

• Outcome: Required extracorporeal albumin dialysis (MARS). Complete recovery

• Time to recovery: 101 days

Outcome