Case |
Age/sex |
Ibuprofen daily dose mg (duration, d) |
Time to onset, d |
Clinical presentation |
Pre-existing conditions |
Concomitant medications |
Time to resolu-tion, w |
Liver biopsy (Time after recognition) |
Outcome |
Ref |
Idiosyncratic DILI cases |
1 |
48/F |
2400 (N/A) |
15 |
Fever, nausea, vomiting, |
Polyarthritis, Raynauds'sphenomeneon, potentially mixed connective tissue disease |
Ampicillin, aspirin |
- |
90% of hepatocytes replaced by fatty material with no areas of parenchymal collapse; minimal portal chronic inflammation (autopsy; 3 d) |
Exitus (3 days after hospital admission) |
16 |
2 |
12/F |
1200 (15) + 1500 (2) |
17 |
Fever, malaise, anorexia, vomiting, weakness |
Juvenile rheumatoid arthritis |
Aspirin |
2 |
- |
Complete recovery |
17 |
3 |
44/M |
1200 (8) + 400 [7 days later] |
8 |
Fever, rash, severe sore throat, eosinophilia, jaundice |
None |
Penicillin |
28 |
Cholestatic hepatitis (N/A) |
Required corticosteroid treatment. Complete recovery |
18 |
4 |
29/M |
600 (21) |
21 |
Jaundice, pruritus, nausea, vomiting, abdominal pain, choluria, acholia |
Childhood asthma, allergic rhinitis |
Hypoallergenic injections |
- |
1. Damaged bile ducts with neutrophil and eosinophil infiltrates; mononuclear infiltrate in portal zones; canalicular cholestasis (11 d) 2. Less portal inflammation, but more cholestasis and obliteration of bile ducts (42 d) 3. Bile duct paucity (6 mo) |
Required prednisone, antihistamines, choles-tyramine and ursodiol treatments. Deeply jaundiced 12 months after ibuprofen ingestion→referred for LTx evaluation (1 year after first presentation) |
19 |
5 |
9/F |
<30 mg/kg (6) |
6 |
Jaundice, pruritus, anorexia, fever, fatigue, choluria, rash, acholia |
None |
APAP occasionally |
- |
1. Moderately severe cholestasis; portal inflammation; interlobular bile duct damage and loss (45 d) 2. Absence of bile ducts and cirrhosis without active inflammation (5 mo) |
Required UDCA, prednisone and tacrolimus treatments. Referred for LTx (6 months after detection) |
20 |
6 |
33/M |
800 (3) |
3 |
Asymptomatic |
HCV |
N/A |
12 |
- |
Return to baseline values (Positive inadvertent re-exposure 6 months later→return to baseline values after 3 months) |
21 |
7 |
44/M |
4800/week (N/A) |
N/A |
Asymptomatic |
HCV |
N/A |
8 |
- |
Return to baseline values |
21 |
8 |
34/M |
1600 (N/A) |
N/A |
Asymptomatic |
HCV |
N/A |
8 |
- |
Return to baseline values |
21 |
9 |
59/F |
1800 (10) |
5 |
Jaundice, choluria, fatigue |
Insufficient peripheral venous blood flow |
Dobesilate |
- |
Submassive hepatic necrosis (explant; 70 d) |
Subacute liver failure →LTx(70 days after dection) |
22 |
10 |
35/M |
400 (single dose) |
7# |
Rash, pruritus, jaundice# |
None |
Tetanus toxoid injection |
28 |
Inflammation; marked cholestasis; spotty necrosis of hepatocytes with focal areas of ballooning and fatty changes (2 mo) |
Required antihistaminics and UDCA treatments. Complete recovery |
23 |
11 |
10/F |
<30 mg/kg (2+4 [8 days later]) |
14 |
Jaundice, choluria, acholia, cheilitis, arthralgia, pruriginousrash |
None |
None |
28 |
Centrolobular cholestasis; loss of interlobular bile ducts in 50% of portal tracts; bile duct injury in the remainder; portal polymorphous infiltrate with eosinophils (48 d) |
Required UDCA and rifampicin treatments. Complete recovery |
24 |
12 |
0*/F |
<30 mg/kg (2)** |
2 |
Rash |
None |
None |
16 |
Lymphocyte infiltration; marked degeneration of interlobular bile duct epithelium; destructive narrowing of ducts in portal tracts; no intralobular bile ducts in at least 10 portal areas (20 d) |
Required UDCA treatment. Complete recovery |
25 |
13 |
38/F |
600 (7) + 800 (2) when needed |
7 |
Generalized body aches, vomiting, fever |
None |
None |
2 |
Mild lobular hepatitis with eosinophilic infiltrate (N/A) |
Complete recovery |
26 |
14 |
16/M |
1200 (14) + 200–400 (28) when needed |
42 |
Jaundice, choluria |
Chronic shoulder pain |
None |
12 |
Centrilobular intrahepatic + canalicular cholestasis; cytoplasmic changes in bile duct epithelium compatible with mild duct damage (18 d) |
Required UDCA, diphenhydramine, rifampin and vitamin K supplement treatments. Complete recovery |
27 |
15 |
36/F |
300 (20) |
25 |
Fever, choluria, rash (erythema) |
None |
Famotidine, azulene sodium sulfonate, dompreidone |
4 |
Collapse of hepatocytes primarily around centrilobular areas with infiltration of inflammatory cells (9 d) |
Required intravenous methylprednisolone and and oral corticosteroid treatment treatment. Complete recovery |
28 |
16 |
40+/F |
600, 2–3 days/month (over a time period of 365 days) |
N/A |
Jaundice, fatigue, choluria |
Diabetes type II, adenomyosis |
Acarbose, metformin |
>45§ |
1. Biliary injury and absence of small terminal bile ducts around hepatic arteries affecting >50% of sampled portal tracts (28 d) 2. Absence of small terminal bile ducts, interstitial fibrous tissue hyperplasia, bile salt deposition in peripheral liver cells, lymphocytes with small amount of plasma cell infiltration (7 mo) |
Required polyene phosphatidylcholine, silibinin, GSH and UDCA therapies. Loss of followúp prior to complete recovery |
29 |
17 |
54/F |
1200 (10) + 400 (< 3) a few days later |
10 |
Fever, rash, vomit, abdominal pain |
SLE |
N/A |
2 |
Minimal fatty changes (10 d)§§ |
Positive inadvertent re-exposure 8 days later. Required chloroquine therapy. Complete recovery |
30 |
18 |
15/F |
1200 (6) |
6 |
Abdominal pain, fever, vomiting, rash |
SLE |
Aurothio-glucose |
N/A |
- |
N/A |
30 |
19 |
57/M |
1200 (30) |
30 |
Asymptomatic |
HCV |
None |
12 |
- |
Return to baseline values |
31 |
20 |
7/M |
<30 mg/kg (3) |
2 |
Jaundice, rash |
None |
None |
32 |
Lymphocyte infiltration; marked degeneration of interlobular bile duct epithelium; absence of intralobular bile ducts in at least 10 portal areas (21 d) |
Required treatment with methylprednisolone and UCDA. Complete recovery |
32 |
21 |
36/F |
2000 (10) |
7 |
Epigastric pain, fever, nausea, vomiting |
SLE |
Aspirin |
N/A |
- |
Complete recovery (Positive controlled re-exposure3 weeks later → new episode → prednisone therapy → complete recovery) |
33 |
22 |
22/M |
1200 (N/A) |
1 |
Fever, rash, eosinophilia |
Kawasaki disease at age 14 |
Metamizole, codeine, APAP |
- |
Submassive confluent necrosis with inflammatory polymorphous reaction, hypereosinophilia and phlebitis (explant, 3 d) |
Liver failure and encephalopathy → LTx (3 days after initial symptoms) |
34 |
Intrinsic DILI cases |
23 |
29/F |
60000 (single dose) |
1 |
Altered mental status, lethargy, jaundice |
Depression, asthma, prior alcohol and drug abuse |
- |
>2 |
- |
Liver profile normalizing, but loss of followúp prior to complete recovery |
35 |
24 |
55/F |
9600 (single dose) |
8 |
Jaundice, asthenia |
Arterial hyper-tension, alcohol abuse |
Amlodipine |
- |
Large areas of confluent necrosis and zones of confluent collapses of zone 3, both infiltrated with mononuclear cells, leucocytes and macrophages (6 d) |
Liver failure and stage III encephalopathy → LTx (22 days after detection) |
36 |
25 |
48/M |
20000 (single dose) |
1 |
Depressed conciuosness, severe metabolic acidosis |
Alcohol abuse |
- |
>3 |
- |
Complete recovery |
37 |
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